research articles on management of diabetes

Advances in the management of type 2 diabetes in adults

Author affiliations

Rodolfo J Galindo 1 2

Jennifer M Trujillo 3

Cecilia C Low Wang 4

Type 2 diabetes is a chronic and progressive cardiometabolic disorder that affects more than 10% of adults worldwide and is a major cause of morbidity, mortality, disability, and high costs. Over the past decade, the pattern of management of diabetes has shifted from a predominantly glucose centric approach, focused on lowering levels of haemoglobin A 1c (HbA 1c ), to a directed complications centric approach, aimed at preventing short term and long term complications of diabetes, and a pathogenesis centric approach, which looks at the underlying metabolic dysfunction of excess adiposity that both causes and complicates the management of diabetes. In this review, we discuss the latest advances in patient centred care for type 2 diabetes, focusing on drug and non-drug approaches to reducing the risks of complications of diabetes in adults. We also discuss the effects of social determinants of health on the management of diabetes, particularly as they affect the treatment of hyperglycaemia in type 2 diabetes.

• Introduction

Diabetes, a chronic and progressive cardiometabolic disorder, is a major cause of morbidity, disability, and mortality worldwide. Comprehensive person centred management of diabetes requires attention to glycaemic control and risk factors for cardiovascular disease (hyperlipidaemia, hypertension, and tobacco use), weight management, early detection and treatment of microvascular, macrovascular, and metabolic complications of diabetes and mental health concerns, mitigation of burden of treatment, addressing social determinants of health, and improving quality of life. 1 The past decade has seen multiple developments in each aspect of the management of diabetes. This review focuses specifically on recent advances in the management of hyperglycaemia in diabetes, including drug and non-drug treatments. People with diabetes, caregivers, clinicians, health systems, payers, and policy makers need to appreciate the complexity and cost associated with optimal care of diabetes to meaningfully improve the health and well being of people living with diabetes.

• Epidemiology

The current prevalence of diabetes among adults is 10.5% worldwide (536.6 million adults), with marked variation across regions and countries, and is estimated to reach 12.2% (783.2 million adults) by 2045. 2 Diabetes is more prevalent in high income (11.1%) and middle income (10.8%) countries than in low income countries (5.5%). The prevalence of diabetes is rising everywhere, most rapidly in middle income countries where the prevalence is expected to reach 13.1% by 2045, 2 probably because of changing diet and lifestyle factors, rising rates of obesity, inadequate resources for early diagnosis and prevention, and potentially greater genetic or epigenetic susceptibility arising from inadequate fetal and childhood nutrition. Data for low and middle income countries are likely to be underestimated because of barriers to screening and timely diagnosis.

More than 90% of people with diabetes have type 2 diabetes, 3 characterised by insulin resistance and progressive beta cell failure, and commonly associated with other cardiometabolic disorders, including obesity, hypertension, cardiovascular disease, and hepatic steatosis. Diabetes contributed to 6.7 million deaths in 2021 alone, 4 highlighting the urgency of preventing diabetes and optimising its management to improve health outcomes and quality of life for all people at risk of or with the disease. 1

• Sources and selection criteria

We searched PubMed for articles published in English. We prioritised randomised controlled trials, clinical guidelines, consensus statements, and systematic reviews. Search terms were: ((type 2 diabetes mellitus AND management (medical subject headings (MeSH) terms)) AND (type 2 diabetes mellitus (MeSH terms))) AND (care management, patient (MeSH terms)). Filters applied were: clinical trial, guideline, meta-analysis, practice guideline, randomised controlled trial, and systematic review, from 1 January 2013 to 1 January 2023. The reference lists of these articles were screened for relevant publications.

• Goals and targets of management of type 2 diabetes

The primary objectives of the management of diabetes are to reduce the incidence and burden of complications and to improve quality of life ( figure 1 ). Historically, these objectives were pursued through control of hyperglycaemia. In this glucose centric approach, clinical practice guidelines recommend targeting haemoglobin A 1c (HbA 1c ) concentrations at <7% (53 mmol/mol) or <6.5% (47.5 mmol/mol) and, more recently, continuous glucose monitoring time in range >70% for most non-pregnant adults with type 2 diabetes, with lower or higher glycaemic thresholds individualised for each person. 5–7 These recommendations for levels of HbA 1c come from data from randomised controlled trials showing a reduction in microvascular complications with more intensive glycaemic control, 8–12 although data for the association between time in range and risk of complications of chronic diabetes are limited but emerging. 13 Implementation of glycaemic targets based on continuous glucose monitoring has also been limited by gaps in insurance coverage and accessibility, although continuous glucose monitoring is increasingly recommended for and used by people with type 2 diabetes. 14 15

Randomised controlled trials of older antihyperglycaemic treatments, such as sulfonylureas and insulins, however, have not shown a consistent association between intensive glycaemic control and reduction in macrovascular complications or mortality. 16 Nevertheless, longer term follow-up of intensively treated adults provides some evidence of a lower risk of macrovascular events and cardiovascular death. 8 17 Conversely, intensive glycaemic control in individuals with frailty, advanced age, and multimorbidity was associated with an increased risk of severe hypoglycaemia and death. 18–20 Therefore, future research is needed to examine the effect of intensive glycaemic control when achieved with newer glucose lowering drugs, which have a lower risk of hypoglycaemia and additional cardio-reno-metabolic benefits. Taken together, these data highlight the importance of individualised glycaemic management and the need to shift the emphasis away from the imperfect surrogate of levels of HbA 1c towards reducing hard outcomes of the adverse health effects of diabetes, while lessening the burden of treatment. 21 22

Shifting pattern of management of type 2 diabetes. HbA 1c =haemoglobin A 1c ; ASCVD=atherosclerotic cardiovascular disease; CKD=chronic kidney disease; HF=heart failure; GIP=glucose dependent insulinotropic polypeptide; GLP1RA=glucagon-like peptide 1 receptor agonist; SGLT2i=sodium glucose cotransporter 2 inhibitor; SU=sulfonylurea; DPP4i=dipeptidyl peptidase 4 inhibitor. *Insulin is preferred for acute management of severe hyperglycaemia; †Thiazolidinediones improve insulin resistance

Over the past decade, multiple randomised controlled trials have shown a reduction in cardiovascular disease, kidney disease, heart failure, and mortality with the use of glucagon-like peptide 1 receptor agonists (GLP1RAs) and sodium glucose cotransporter 2 inhibitors (SGLT2is), independent of a reduction in levels of HbA 1c . 23 These findings signalled a new complications centric era of the management of diabetes, focused directly on preventing or reducing macrovascular, microvascular, and other emerging complications of diabetes, such as heart failure. Many, 6 24 25 although not all, 26 clinical practice guidelines recommend treatment with GLP1RAs or SGLT2is, or both, for patients with cardiovascular or kidney disease, or both, or with risk factors for atherosclerotic cardiovascular disease, independent of glycaemic control, although all continue to stress the concurrent importance of achieving HbA 1c targets.

More recently, the pattern of management of diabetes has begun to shift further, with a renewed focus on looking at the causes of type 2 diabetes and its metabolic comorbidities and long term complications. This pathogenesis centric approach places the management of obesity at the centre of the prevention and treatment of the disease. 27 Even a relatively small amount (5-7%) of weight loss reduced the risk of incident diabetes and improved glycaemic control in people with type 2 diabetes. 28–31 Greater amounts of weight loss have been reported to have greater beneficial effects on glycaemic control (including remission of diabetes), metabolic dysfunction, and quality of life. 29 30 32–37 Weight loss achieved with metabolic surgery reduced the risks of microvascular and macrovascular complications of diabetes and reduced mortality. 38–41

By contrast, intensive lifestyle treatments in the Look AHEAD (Action for Health in Diabetes) randomised controlled trial of 5145 adults with type 2 diabetes and overweight/obesity did not reduce the risk of cardiovascular events compared to usual care. 30 The likelihood of detecting differences between the intensive lifestyle and conventional treatment groups might have been reduced because the cardiovascular event rate in the Look AHEAD population was much lower than anticipated (0.7% per year v estimated 3.1% per year). 42 A post hoc analysis suggested that those who lost at least 10% of their body weight in the first year had a significantly lower risk of the primary outcome, which was a composite of the first occurrence of death from cardiovascular causes, non-fatal acute myocardial infarction, stroke, and hospital admission for angina (adjusted hazard ratio 0.79, 95% confidence interval 0.64 to 0.98, P=0.034). 35 How weight loss achieved with drug treatment, particularly agents such as semaglutide and tirzepatide, compares with metabolic surgery for glycaemic control, microvascular and macrovascular complications, and mortality, should be examined.

• Lifestyle treatments: medical nutrition treatment, physical activity, and sleep

Successful management of type 2 diabetes must include consistent attention to behaviours that sustain a healthy lifestyle and are foundational for achieving glycaemic control, preventing complications, supporting quality of life, and preserving optimal health. Medical nutrition treatment for diabetes emphasises a balanced selection of nutrient dense foods while minimising or eliminating added sugar, refined grains, and highly processed foods. 6 7 43 Recommendations for optimal carbohydrate intake and composition vary, with the strongest evidence supporting an overall reduction in intake of carbohydrates. This principle can be applied to multiple dietary patterns, including a Mediterranean diet high in monounsaturated and polyunsaturated fats, low carbohydrate, vegetarian, or a plant based diets, and the Dietary Approaches to Stop Hypertension diet, with a focus on non-starchy vegetables, fruits, and legumes, and some dairy in those who are lactose tolerant. 6 43 Only the Mediterranean diet has been shown to reduce cardiovascular disease and mortality. 44 Also, evidence indicates the beneficial effects of involvement of community health workers to support education in self-management of diabetes and overall care, especially in rural or underserved communities, or both. 45 Because hypertension and cardiovascular disease are major causes of mortality in individuals with diabetes, more attention needs to be paid to overall sodium intake and limiting the content of saturated fat and trans fat in the diet. 6

Stopping smoking and abstinence from tobacco products is also imperative for cardiovascular health in adults with diabetes, and robust evidence supports the benefit of stopping smoking despite the potential for weight gain. 6 46 Although nicotine replacement products and electronic cigarettes might facilitate stopping smoking, nicotine itself can impair glucose tolerance and adversely affect the cardiovascular system through increased sympathetic activation. 47

Baseline levels of physical activity should be assessed to set reasonable and realistic behaviour oriented goals. Increasing the duration of physical activity and reducing sedentary time have been reported to improve cardiorespiratory fitness and HbA 1c levels. 48 Recommendations can be made to increase leisure time physical activity (walking, taking the stairs, and household chores), decrease sedentary time, and introduce physical activity on most days. 6 49 Physical activities include both aerobic and resistance training, as well as flexibility and balance training. 50

The length and quality of sleep are increasingly recognised as essential components of the management of diabetes and individuals should be screened for sleep related disorders. 6 43 Referral for diagnosis and treatment of obstructive sleep apnoea and other sleep disorders should be considered if indicated. Screening for psychosocial factors and social determinants of health that might affect an individual's diabetes care and quality of life should also be performed, with engagement of or referral to relevant clinical team members for further evaluation and care, as appropriate. 43

Lifestyle interventions in individuals with obesity or who are overweight are most successful when efforts are intensive and frequent follow-up is available, either in person or virtually. 6 49 Weight loss can be achieved in various ways, and is most effective when strategies are combined: caloric restriction, increased caloric expenditure, elimination or substitution of drugs that promote weight gain, use of weight reducing drugs and, in select individuals, metabolic or bariatric surgery. One dietary strategy that has received considerable attention in recent years is time restricted eating, 51 although data in adults with type 2 diabetes are limited to one randomised controlled trial 52 53 and a larger trial is ongoing (n=344; Using Early Time Restricted Feeding and Timed Light Therapy to Improve Glycemic Control in Adults With Type 2 Diabetes, NCT04155619 ). Weight management is discussed in more detail below.

• Drug treatment of type 2 diabetes

Initial management of type 2 diabetes has traditionally included metformin in most adults because of its glucose lowering effect, neutral effects on weight, minimal risk of hypoglycaemia, safety profile, low cost, and ease of administration. Now, in the light of evidence from trials of cardiovascular and kidney outcomes, decisions on treatment of diabetes with drugs should be made based on cardiac comorbidities (established atherosclerotic cardiovascular disease and heart failure), risk factors for atherosclerotic cardiovascular disease and kidney disease, engaging adults in shared decision making, and prioritising the use of drugs shown to reduce the risk of cardiovascular or kidney adverse outcomes, or both, in adults with specific comorbidities. 7 24–26

Adults with atherosclerotic cardiovascular disease or indicators of high risk

In people with established atherosclerotic cardiovascular disease or risk factors for atherosclerotic cardiovascular disease, a GLP1RA or SGLT2i with known cardiovascular benefit should be started, regardless of levels of HbA 1c or background glucose lowering treatments. 24 Drugs that have been shown to cause significant reductions in major adverse cardiovascular events in cardiovascular outcomes trials compared with placebo include the GLP1RAs dulaglutide (hazard ratio 0.88, 95% confidence interval 0.79 to 0.99), liraglutide (0.87, 0.78 to 0.97), and subcutaneous semaglutide (0.74, 0.58 to 0.95), and the SGLT2is canagliflozin (0.86, 0.75 to 0.97) and empagliflozin (0.85, 0.75 to 0.97). 54–58 None of the trials of cardiovascular outcomes involved head-to-head comparisons of GLP1RAs versus SGLT2is. 59

Individual components of the composite major adverse cardiovascular events outcome as well as secondary outcomes in the cardiovascular outcomes trials vary between GLP1RAs and SGLT2is. A reduction in stroke was seen in meta-analyses of randomised controlled trials of GLP1RAs compared with placebo (hazard ratio 0.83, 95% confidence interval 0.76 to 0.92) but not with SGLT2is compared with placebo (0.95, 0.85 to 1.05). 59 The mechanisms and benefits of GLP1RAs and SGLT2is seem to be complementary, and evidence is emerging to support combination treatment, which might provide more benefit than each used alone. 60–62 Currently, guidelines from the American Diabetes Association/European Association for the Study of Diabetes recommend the addition of the alternative class when more glucose lowering is needed. 24 25

Adults with heart failure

GLP1RAs have not shown benefit for heart failure outcomes in individual randomised controlled trials of cardiovascular outcomes, 55 56 58 although meta-analyses of these studies suggested a potential benefit. 59 63 64 SGLT2is, by contrast, have consistently shown significant benefit for heart failure outcomes. 54 57 65 Also, dapagliflozin and empagliflozin were beneficial in people with reduced or preserved ejection fraction without type 2 diabetes, and have an indication for improving heart failure outcomes. 66–69 Accordingly, in people with heart failure, an SGLT2i with known benefit should be started to reduce the risk of major adverse cardiovascular events and worsening heart failure. 24 26

Adults with chronic kidney disease

GLP1RAs have shown benefit for secondary kidney related outcomes in large individual randomised controlled trials 55 56 70 and meta-analyses 59 63 64 of cardiovascular outcomes, but dedicated kidney outcome trials are ongoing. 71 Several SGLT2is, including canagliflozin, dapagliflozin, and empagliflozin, have shown benefit in adults with chronic kidney disease with or without type 2 diabetes and in dedicated kidney outcome trials, and have an indication for improving chronic kidney disease outcomes. 24 72 Therefore, SGLT2is with primary evidence are preferred for individuals with an estimated glomerular filtration rate <60 mL/min/1.73 m 2 or albuminuria, or both, to reduce the progression of chronic kidney disease. If SGLT2is are not tolerated or cannot be used, GLP1RAs with demonstrated renal benefit are a reasonable alternative. 24 26 73 Current prescribing information allows SGLT2is to be started in adults with an estimated glomerular filtration rate of ≥20 mL/min/1.73 m 2 for kidney benefit, although the glucose lowering effects are substantially reduced at an estimated glomerular filtration rate <45 mL/min/1.73 m 2 . 74 A small reduction in the estimated glomerular filtration rate can be seen after starting treatment with SGLT2is because of reversal or correction of the previous hyperfiltration state in adults with diabetes, but it does not predict further reductions in estimated glomerular filtration rate or require discontinuation of treatment.

Role of metformin

Although metformin was a commonly used background drug in most large trials of cardiovascular and kidney outcomes, 75 several post hoc analyses have demonstrated benefit with GLP1RAs or SGLT2is regardless of background use of metformin. 76–82 Current guidelines from the American Diabetes Association/European Association for the Study of Diabetes and the American Association of Clinical Endocrinology no longer recommend metformin as the preferred first line agent for all individuals with type 2 diabetes, and instead suggest consideration of cardiac and kidney comorbidities when selecting first line treatment. 6 24 25 Cost is a major consideration in selecting the most appropriate treatment, however, probably contributing to differences in these recommendations from guidelines used in other countries. In the US, insurers have not caught up with the guidelines, and require that metformin is used before other agents. Guidance from the National Institute for Health and Care Excellence (NICE) still recommends metformin as the first line treatment for people with cardiac or kidney comorbidities, or both, with introduction of an SGLT2i in people who cannot tolerate metformin or need intensification of treatment. 26 Despite robust outcome data, GLP1RAs are not recommended ny NICE until failure of triple oral drug treatment and only in people with a high body mass index or in whom insulin treatment cannot be used. 26 Insurance formulary restrictions on prescribing GLP1RAs and SGLT2is, including the requirement of step treatment starting with metformin, still persist but should be reconsidered to better align with scientific evidence.

Other situations when a drug other than metformin can be considered as first line treatment include severe or symptomatic hyperglycaemia (HbA 1c >10%, ketosis, or weight loss), creatinine clearance or estimated glomerular filtration rate <30 mL/min/1.73 m 2 , or when the person cannot tolerate metformin despite slow up titration of the dose or a trial of the extended release formulation, or both. Sulfonylureas and thiazolidinediones are now less commonly recommended because of their adverse effect profiles. Sulfonylureas can lead to weight gain and are associated with a high risk of hypoglycaemia, and thiazolidinediones can also cause weight gain, as well as fluid retention and osteoporosis. People treated with thiazolidinediones must be monitored for the development of heart failure; thiazolidinediones are not recommended for those with symptoms of heart failure and are contraindicated in class 3 or 4 heart failure. Because generic forms of sulfonylureas and thiazolidinediones are available, however, these drug classes are options when cost is a barrier to accessing other agents or the individual's clinical situation requires these drugs. Pioglitazone, a thiazolidinedione, has beneficial effects in hepatic steatosis and stroke, and can be considered in these contexts. 6 83

Effect on weight and weight related comorbidities

Clinicians should also consider the effect of the glucose lowering regimen on weight and weight related comorbidities, including overweight or obesity and non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. Weight loss is greatest with the dual glucose dependent insulinotropic polypeptide (GIP)-GLP1RA, tirzepatide, and subcutaneous semaglutide, followed by dulaglutide and liraglutide. 27 Moderate weight loss is seen with the other GLP1RAs and SGLT2is. Drugs with neutral effects on weight include the dipeptidyl peptidase 4 inhibitors (DPP4is) and metformin, whereas the sulfonylureas, thiazolidinediones, and insulin all increase the risk of weight gain ( table 1 ). 24 27 84 Recent single centre and population based cross sectional studies in the US estimated that >70% of people with type 2 diabetes have non-alcoholic fatty liver disease and more than half of those with type 2 diabetes and non-alcoholic fatty liver disease have steatohepatitis. 85–88 Insulin resistance, impaired lipid and glucose metabolism, and altered insulin secretion play a part in non-alcoholic fatty liver disease and progression of type 2 diabetes, and might indicate why the two diseases are so closely linked. 89 Although limited evidence exists so far, current guidelines recommend the use of a GLP1RA or pioglitazone for the treatment of diabetes in people with non-alcoholic steatohepatitis. 90 91 Weight management, which is essential for the treatment of hepatic steatosis, is discussed below.

Glucose lowering efficacy

In addition to choosing a drug that targets cardiovascular, kidney, and metabolic outcomes, clinicians should also develop a treatment approach that has sufficient efficacy to achieve glycaemic targets. 24 Although some guidelines (most notably, the Australian Diabetes Society) cite a lack of evidence to support substantial differences in glucose lowering between antihyperglycaemic drug classes when used as monotherapy, 92 prior meta-analyses, including a meta-analysis of 453 trials assessing nine drug classes, and the recently completed Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness (GRADE) pragmatic randomised clinical trial comparing insulin glargine U-100, the sulfonylurea glimepiride, the GLP1RA liraglutide, and the DPP4i sitagliptin in 5047 individuals with moderately uncontrolled type 2 diabetes found insulin and GLP1RA to be significantly more effective at lowering HbA1c than the other examined drugs. 93 , 94 The American Diabetes Association Standards of Care there categorise drug classes as having very high, high, or intermediate glucose lowering efficacy ( table 1 ). 24 The greatest reductions in levels of HbA 1c are seen with the dual GIP-GLP1RAs, GLP1RAs, and insulin. In the GLP1RA class, subcutaneous semaglutide and dulaglutide had the highest efficacy for glucose lowering. The recently approved dual GIP-GLP1RA, tirzepatide, seems to have the greatest efficacy for reducing levels of glucose. SGLT2is and DPP4is have less robust HbA 1c lowering effects and are classified as intermediate to high (SGLT2is) and intermediate (DPP4is). 24 25 93

GRADE, a large scale, comparative effectiveness study of four drugs in combination with metformin, found that insulin glargine and liraglutide achieved and maintained HbA 1c targets more effectively than glimepiride and sitagliptin. The study did not, however, include newer agents, such as the SGLT2is, or once weekly GLP1RAs. 95 The GRADE study also highlighted the challenges of maintaining glucose targets over time, with 71% of study participants progressing to HbA 1c ≥7% within four years, regardless of the treatment option. 94 A meta-analysis of 229 randomised controlled trials comprising 121 914 participants suggested that glucose lowering efficacy was highest with GLP1RA and weakest with DPP4i, with other agents in between. 96 By contrast, a meta-analysis of 140 randomised trials and 26 observational studies showed that each new class of non-insulin drugs added to metformin monotherapy lowers levels of HbA 1c by about 0.7-1%. 95 A shift towards earlier use of combination treatment, in contrast with a stepwise approach, to reach glucose targets and provide better glycaemic durability has been reported. 24 97 For people with marked hyperglycaemia (eg, HbA 1c >10% or with symptoms), clinicians should start insulin, or a combination of insulin with GLP1RAs. 98 When improved glycaemic control is achieved, many people with type 2 diabetes can be safely transitioned to non-insulin treatments with close monitoring to prevent hypoglycemia and hyperglycemia.

• Safety considerations

Other considerations in the selection of treatment for diabetes are the risks of hypoglycaemia, other adverse effects and safety considerations, as well as cost and administration requirements that often result in barriers to adherence. Therefore, individuals with diabetes, care partners, and clinicians need to engage in shared decision making to identify treatment strategies that are aligned with the individual's goals of care, treatment preferences, the clinical and psychosocial context, and risks and benefits associated with each treatment option. Tables 1 and 2 summarise this information. Some key and controversial safety considerations are discussed below.

Acute pancreatitis

Acute pancreatitis has been reported in individuals who received GLP1RAs, DPP4is, and the GIP-GLP1RA, tirzepatide. After early post-marketing reports, the US Food and Drug Administration warned of a potential link between acute pancreatitis and GLP1RAs and DPP4is. 99 Multiple preclinical, observational, and randomised controlled studies were inconsistent, with some showing positive associations and others showing no association. 100 Ultimately, the FDA concluded that a causal relation could not be established and insufficient evidence existed to modify treatment. Systematic reviews and meta-analyses of randomised controlled trials (eg, long term cardiovascular outcomes trials) concluded that treatment with GLP1RAs or DPP4is was not associated with an increased risk of pancreatitis or pancreatic cancer. 101–103

Nonetheless, current prescribing information, FDA guidance, and treatment guidelines recommend cautious use of these drug classes in people with a history of pancreatitis, in part because these people were excluded from most trials. 24 If these drug classes are used, individuals should be monitored for signs and symptoms of pancreatitis and, if pancreatitis develops, treatment should be discontinued and not restarted. 24 99 We also suggest caution in starting these drugs in people with a previous history of pancreatitis, particularly when the cause of pancreatitis is unknown or persists. Monitoring of lipase levels in randomised controlled trials showed asymptomatic fluctuations in both groups (intervention and placebo). Hence no evidence exists to suggest ongoing monitoring during treatment.

Gallbladder or biliary disease

GLP1RAs, DPP4is, and GIP-GLP1RAs are also associated with an increased risk of gallbladder and biliary disease, including cholelithiasis and cholecystitis. 104–107 Although the absolute risk of biliary or gllbladder disease with GLP1RA therapy seems to be small, with a recent meta-analysis of 76 randomised controlled trials involving 103 371 103 371 participants reporting an additional 27 incidences per 10 000 patients per year, 104 this finding might under-represent the true risk, because many studies did not report biliary related events. The risk seems to be higher with higher doses of drugs, longer duration of use, and when used for weight loss rather than glycaemic control. We therefore advise caution with the use of GLP1RAs, DPP4is, and GIP-GLP1RAs in people at high risk of biliary complications.

Diabetic retinopathy

A significant increase in retinopathy complications (3% v 1.8%, P=0.02), including vitreous haemorrhage, blindness, or need for photocoagulation treatment or an intravitreal agent, was seen in people receiving semaglutide during the SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) randomised controlled trial with 3297 participants with type 2 diabetes. 56 Of those with retinopathy complications, 83.5% had a history of retinopathy at baseline. In a meta-analysis of four cardiovascular outcomes trials of dulaglutide, liraglutide, oral semaglutide, and subcutaneous semaglutide, use of GLP1RAs was associated with an increased risk of rapidly worsening retinopathy (odds ratio 1.23, 95% confidence interval 1.05 to 1.44). 108 In another meta-analysis, GLP1RAs were not independently associated with an increased risk of retinopathy, but an association between retinopathy and the magnitude of the reduction in levels of HbA 1c was found. 109 Rapid glucose lowering has previously been associated with worsening diabetic retinopathy, 110 and the GLP1RA cardiovascular outcomes trials were not powered to detect differences in retinopathy complications. Thus whether worsening retinopathy is caused by the drug itself, a change or rate of change in glucose levels, or a combination of both is unclear. We advise caution when GLP1RAs are used, particularly semaglutide, in people with diabetic retinopathy, and individuals should be monitored closely for progression of retinopathy. 111

Whether other GLP1RAs similarly increase the risk of progressive diabetic retinopathy is not known. Consultation with an ophthalmologist should be considered before starting GLP1RAs in people with pre-existing retinopathy. 111 A large randomised controlled trial (A Research Study to Look at How Semaglutide Compared to Placebo Affects Diabetic Eye Disease in People With Type 2 Diabetes (FOCUS), NCT03811561 ) evaluating the long term effects of subcutaneous semaglutide on eye disease in 1500 people with type 2 diabetes is ongoing and should provide more evidence.

Amputations

An increased risk of lower limb amputations was first reported in the cardiovascular outcomes trial for canagliflozin that included 10 142 participants with type 2 diabetes and high cardiovascular risk (6.3 v 3.4 participants per 1000 patient years; hazard ratio 1.97, 95% confidence interval 1.41 to 2.75) 57 and led to a warning added to the prescribing information for canagliflozin in 2017. 112 The FDA removed the warning in 2020 based on more clinical trial data that found that the risk was less than previously described. 113 Subsequent real world cohort studies, randomised controlled studies, and meta-analyses have reported conflicting results, with some suggesting an increased risk with all SGLT2is and others finding no increased risk. 114–121 Therefore, reasonable steps to take are to consider factors that increase the risk of amputations before starting an SGLT2i, closely monitor people for lower limb ulcers or infections, and discontinue the SGLT2i if these occur. Subgroup and exploratory analyses of the SGLT2i cardiovascular outcomes trials, however, suggest cardiovascular benefit in patients with peripheral arterial disease, 122–124 so clinicians should use shared decision making when assessing the benefits and risks of SGLT2is in those at high risk.

Diabetic ketoacidosis

SGLT2is are associated with an increased risk of diabetic ketoacidosis, particularly in people with type 1 diabetes and in the perioperative population. 125 126 Rates in adults with type 2 diabetes are low and range from 0.16 to 0.76 events per 1000 patient years. 127 In type 2 diabetes, the risk is increased in people who are insulin deficient, in older people, with prolonged use of SGLT2is, or in those with a combination of these factors. 128 Guidance on risk management of diabetic ketoacidosis is mainly from individuals with type 1 diabetes, with little guidance specific to type 2 diabetes, and recommendations are mostly extrapolated from the type 1 diabetes context. 126 129 People with diabetes should be informed of the importance of adherence to insulin treatment, avoiding very low carbohydrate diets (such as ketotic diets), and excessive intake of alcohol. Education on management of sick days should also be given, and insulin doses should be monitored carefully; basal insulin should not be discontinued completely during illness or planned activity, particularly in those receiving intensive insulin treatment.

Clinicians and people with diabetes should be aware of predisposing factors and the clinical presentation of diabetic ketoacidosis, which often occurs with lower serum glucose levels (so-called euglycaemic diabetic ketoacidosis), sometimes at glucose concentrations of ≤200 mg/dL (11.1 mmol/L). The SGLT2i should be discontinued and treatment started promptly if diabetic ketoacidosis is suspected. SGLT2is should also be discontinued 3-4 days before scheduled surgery, during prolonged fasting or low carbohydrate intake, or during critical illness to lessen the risk of diabetic ketoacidosis. 24 Some have suggested that absence of ketosis (<0.6 mmol/L blood ketones, negative urine ketones) should be confirmed in people with type 1 diabetes before the start of treatment if SGLT2is are being used off label in this population, 126 but no evidence exists in support of this practice for people with type 2 diabetes.

• Starting and titrating insulin treatment

Many people with type 2 diabetes will eventually require insulin because of the progressive nature of the disease. For most people, a GLP1RA should be considered as the first injectable agent before basal insulin, based on the strong evidence of similar efficacy, beneficial effect on weight, and less hypoglycaemia. 130 131 If more treatment is needed after a GLP1RA, basal insulin should be started first and titrated to a maximum effective dose in a safe and timely way. 7 98 Several steps are necessary to support optimisation of insulin treatment, including clear communication of expectations, adequacy of glucose monitoring (including continuous glucose monitoring for people with basal insulin or intensive insulin treatment, and remote telemonitoring), a feasible dose titration plan, clearly defined glycaemic targets, and education on proper administration of insulin and storage. 131–134 Whether the individual can self-titrate the dose or if more support is needed should be assessed. People who can self-titrate can be instructed to continue uptitrating the dose until fasting glucose levels are consistently between 80 and 130 mg/dL (4.4 to 7.2 mmol/L; or an individualised glycaemic target), an anticipated maximum basal dose is reached (eg, 0.5 units/kg/day), or have unexplained hypoglycaemia. Providing these endpoints is key to reducing the risk of being treated with an inappropriately high dose of basal insulin in an attempt to compensate for inadequate post-prandial glycaemic control (ie, overbasalisation) while facilitating continued titration to an effective dose. 135 If the individual cannot self-titrate, consider providing weekly follow-up healthcare remotely (ie, telehealth) for timely dose titrations.

If the basal insulin dose has been sufficiently titrated but levels of HbA 1c remain above the person's individualised target or concern for overbasalisation exists, targeting postprandial glucose excursions is warranted. Initially, consider adding a GLP1RA or GIP-GLPRA if not already being used. The next step is to add prandial insulin as a separate injection or by switching to a fixed ratio combination. Basal bolus insulin treatment requires more injections, more glucose testing, more education, and carries a higher risk of hypoglycaemia and weight gain. 98 Metformin or complication centric drugs (GLP1RAs and SGLT2is), or both, should be continued. Sulfonylureas should be discontinued because of the risk of hypoglycaemia with concurrent insulin treatment.

• Weight management in type 2 diabetes

Among adults with diabetes in the US, almost 28% are overweight (body mass index 25.0-29.9), 46% have obesity (body mass index 30.0-39.9), and 16% have severe obesity (body mass index ≥40.0). 136 Increasingly recognised as a chronic disease, obesity (termed adiposity based chronic disease) 137 138 is characterised by excessive, maldistributed, and dysfunctional adipose tissue, and is associated with increased risks of hyperglycaemia (ie, prediabetes and type 2 diabetes), cardiovascular disease, hyperlipidaemia, hypertension, chronic kidney disease, cancer, urinary incontinence, non-alcoholic fatty liver disease, osteoarthritis, infertility, obstructive sleep apnoea, and gastro-oesophageal reflux disease. 137

Obesity is closely related to the pathogenesis and pathophysiology of type 2 diabetes and it also affects the management and outcomes of diabetes. 137 139 Strong evidence indicates that weight loss, particularly if >10% of body weight, can prevent, improve, and even reverse type 2 diabetes. 140 The Diabetes Prevention Programme showed that people with prediabetes who were randomised to receive an intensive lifestyle intervention had a 16% reduction in the risk of progressing from prediabetes to diabetes for every kilogram of weight loss. 37 In the Look AHEAD study of people with type 2 diabetes and overweight or obesity, improvement in fasting glucose and HbA 1c levels was found with weight loss as little as ≥2 kg, and improvements were directly proportional to the amount of weight lost. 31 After initial weight loss from lifestyle interventions or pharmacotherapy, compensatory physiological responses often make efforts at further weight loss more difficult, less successful, or difficult to maintain, a biological phenomenon referred to as obesity protecting obesity. 141 Hence clinicians should provide a supportive approach, recognising personal biases, and avoiding stigma and judgment to facilitate weight management efforts. 141

Despite years of commercial availability, obesity drugs are rarely used, with fewer than 5-10% of people with diabetes and obesity receiving obesity drugs in the US. 142 This finding could be driven by the relatively low efficacy of historically available drugs for weight loss, with most drugs causing <7% body weight loss. 141 Recent developments with incretin treatments have closed this gap, however, with up to 20% weight loss reported with tirzepatide. 107 Several studies in people with obesity, with or without type 2 diabetes, treated with semaglutide or tirzepatide have reported reductions in body weight of at least 5-10% in up to 80-90% of people, and reductions of 15-20% in up to 40-50% of people. 106 107 143 144 Efforts to lose weight in people with type 2 diabetes and obesity should be supported through preferential use of glucose lowering drugs that are associated with weight loss, avoiding glucose lowering and non-diabetes drugs associated with weight gain, and aiming for weight loss of 12-15% as appropriate, to achieve maximum benefits. 7 140

• Equity and affordability of diabetes care

Affordability, accessibility, and feasibility of implementing the diabetes care plan are major considerations in shared decision making. In the US, the high and rising costs of insulin and non-insulin drugs 145 have contributed to diabetes distress, 146 cost related non-adherence 147 148 with a detrimental effect on diabetes health outcomes 149 and rationing of other vital expenses. 150 Therefore, healthcare providers must discuss concerns about affordability with all people with diabetes, ensure that prescribed drugs are available and accessible, and leverage care team and community support systems to reduce the financial burden of the management of diabetes. 151 152

To deal with the growing concerns about affordability of insulin in the US, out-of-pocket costs have been capped in 2023 by the Centers for Medicare and Medicaid Services (which oversee publicly funded insurance for seniors, low income individuals, and people with disabilities or end-stage kidney disease), several private insurance plans, and insulin manufacturers, and the effect of these changes on cost related non-adherence and rationing will need to be assessed. The cost of drugs is generally much lower outside of the US because of highly regulated policies on drug pricing and cost effectiveness in other high income countries, 153 154 but 80% of people with diabetes live in low and middle income countries 155 and half do not have access to recommended diabetes treatments. 156 These findings call for multifaceted policy solutions to lower costs, increase supply, and improve accessibility of evidence based diabetes treatments and technologies in all settings and populations. 157

Socioeconomic barriers to optimal management of diabetes are multifaceted and include not only the high costs of diabetes drugs, technology, and equipment, but also foundational social determinants of health, such as the home environment with access to healthy food choices and space for physical activity, environmental pollution and endocrine disrupting chemicals, stable housing with access to electricity and refrigeration, employment type and stability, and educational attainment. 152 Geographical differences in the quality of care and prevalence of type 2 diabetes and its complications exist across levels of rurality, 158 159 neighbourhood disadvantage, 158 160 and geopolitical environment. 161–163 Several interventions have been shown to be successful in improving the management of diabetes, including community health worker programmes, diabetes prevention and self-management programmes adapted specifically to the needs of underserved and disadvantaged populations, expansion of health insurance as part of the Affordable Care Act, food and housing support programmes, and others. 152

We must also be cognisant of pervasive racial and ethnic inequalities in the quality of diabetes care and health outcomes. In the US, racial and ethnic minority populations are disproportionately affected by diabetes 164 and its complications. 152 165 166 Multiple studies have shown worse glycaemic control 165 167 168 and higher rates of acute complications (hypoglycaemia, 160 165 169–172 diabetic ketoacidosis, and hyperglycaemic hyperosmolar state), 160 165 170 173 chronic complications (kidney disease, 165 174–178 amputation, 165 175 cardiovascular disease, 165 175 and retinopathy), 176 179 and mortality 180 181 among black people with type 2 diabetes relative to other racial and ethnic groups. People with type 2 diabetes from racial and ethnic minority groups are also substantially less likely to be treated with GLP1RAs and SGLT2is than non-Hispanic white people. 182 183 Similar inequalities in the prevalence, management, and health outcomes of diabetes have been described in Europe 184 185 and around the world. 186 187 These inequalities highlight the need for structural solutions and multisector collaborations that deal with the barriers to optimal diabetes management and health at all levels to ensure that all people, regardless of race, ethnic group, socioeconomic status, or place of residence, receive high quality care.

• Conclusions

The paradigm of diabetes management has shifted over the past decade from a predominantly glucose-centric approach to approaches that prioritise prevention of diabetes complications and addressing the underlying causes of diabetes and metabolic dysfunction, such as obesity ( figure 2 ). High quality, evidence based management of diabetes therefore requires reducing glucose levels to a safe, patient centred range; using glucose lowering drugs with a strong evidence base for reduction of diabetes complications and excess adiposity, not just lowering levels of HbA 1c ; minimising burden of treatment and improving quality of life; and implementing care delivery models that support high quality (effective, efficient, safe, equitable, timely, and person centred) care. 188 Access and affordability remain major barriers, as is the sustainable implementation of effective lifestyle interventions.

Person centred goals of treatment of type 2 diabetes

Questions for further research

What are the short term and long term health outcomes associated with combined GLP1RA and SGLT2i treatment?

What is the optimal weight loss target (>10% or 15%) in the management of type 2 diabetes?

What is the comparative effectiveness and safety of drug treatments for obesity compared with metabolic surgery for long term metabolic, microvascular, and macrovascular complications?

How can effective lifestyle treatments for long term weight loss be implemented effectively, sustainably, and equitably?

What are effective and sustainable ways to engage people with diabetes, care partners, and communities in the prevention and management of diabetes to ensure equitable access to care?

How can structural barriers to optimal metabolic health be removed?

Patient involvement

Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

• Publication history
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Management of type 2 diabetes in the new era

• Review Article
• Open access
• Published: 13 September 2023
• Volume 22 , pages 677–684, ( 2023 )

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• Aris Liakos   ORCID: orcid.org/0000-0003-3261-2979 1 , 2 ,
• Thomas Karagiannis 1 , 2 ,
• Ioannis Avgerinos 1 , 2 ,
• Konstantinos Malandris 1 , 2 ,
• Apostolos Tsapas 1 , 2 , 3 &
• Eleni Bekiari 1 , 2  

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Management of type 2 diabetes is advancing beyond glycemic control and is increasingly based on cardiovascular risk stratification. This review summarizes recent advances in the field and identifies existing knowledge gaps and areas of ongoing research.

A bibliographic search was carried out in PubMed for recently published cardiorenal outcome trials, relevant guidelines, and studies on antidiabetic agents in the pipeline.

Findings from cardiovascular outcome trials support the use of glucagon-like peptide 1 (GLP-1) receptor agonists or sodium-glucose cotransporter 2 (SGLT-2) inhibitors for patients with established cardiovascular disease or multiple risk factors, although it as yet remains uncertain whether the benefits are transferable to patients at lower absolute cardiovascular risk. Additionally, robust evidence suggests that SGLT-2 inhibitors improve clinical outcomes for people with concomitant heart failure or chronic kidney disease. Gut hormone multiagonists will likely represent another major addition to the therapeutic armamentarium for morbidly obese individuals with diabetes. Moreover, nonalcoholic fatty liver disease is a common comorbidity and several liver outcome trials are awaited with great interest. Use of insulin as first-line injectable therapy has been displaced by GLP-1 receptor agonists. Once-weekly formulations of basal insulins along with combinations with GLP-1 receptor agonists are also under development and could increase patient convenience. Technologies of glucose sensors are rapidly evolving and have the potential to reduce the burden of frequent blood glucose measurements, mainly for patients treated with intensified insulin regimens.

Management of type 2 diabetes requires a holistic approach and recent breakthroughs are expected to improve the quality of care.

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Introduction

Maintaining normoglycemia has been the primary focus in the pharmacological management of type 2 diabetes for a very long time. Accordingly, practicing clinicians largely relied on hemoglobin A 1c (HbA 1c ) to initiate or modify antidiabetic treatment. In this context, hypoglycemia was the main limiting factor of first-generation antidiabetic agents, such as sulfonylureas and insulin. In the following years, new antihyperglycemic agents were gradually introduced in clinical practice, including the dipeptidyl-peptidase 4 (DPP-4) inhibitors, which have a safe profile in terms of hypoglycemia. Newer insulin regimens that closely mimic physiologic response, such as basal insulin degludec and glargine U-300 as well as the fast-acting insulin aspart (FIAsp) and ultra-rapid lispro (URLi) along with advances in insulin injection devices, also simplified insulin therapy while reducing the risk of hypoglycemia [ 1 , 2 ]. However, the landscape as regards management of type 2 diabetes was virtually transformed following publication of the results of a series of cardiovascular outcome trials (CVOTs), which were imposed by the drug regulators back in 2008 in response to safety concerns about rosiglitazone [ 3 ]. In 2015, EMPA-REG OUTCOME [ 4 ] was the first large randomized controlled trial of this kind that provided robust evidence of the cardiovascular benefits of empagliflozin, and soon thereafter, more CVOTs supported the cardioprotective effects of other sodium-glucose cotransporter 2 (SGLT-2) inhibitors and certain glucagon-like peptide 1 (GLP-1) receptor agonists. The salutary effects of the aforementioned drug classes on hard cardiovascular endpoints were more pronounced for patients with established cardiovascular disease (CVD) or multiple risk factors and likely extend beyond glycemic control. Hence, current management of patients with type 2 diabetes is increasingly based on stratification of cardiovascular risk and, in this regard, SGLT-2 inhibitors and GLP-1 receptor agonists are prioritized for patients at high cardiovascular risk [ 5 ]. Moreover, high-quality evidence now suggests that SGLT-2 inhibitors reduce rates of hospitalization for heart failure and ameliorate progression of diabetic kidney disease, and this is also taken into account when making treatment choices for patients with these comorbidities. Finally, rates of obesity are constantly increasing among people with diabetes and contemporary recommendations for the management of the disease has put increased emphasis on use of certain GLP-1 receptors agonists for body weight control, such as liraglutide and semaglutide as well as the recently approved dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide which is highly effective in reducing body weight [ 6 ].

In the foreseeable future, new agents that are currently under clinical development will possibly be added to the therapeutic armamentarium for type 2 diabetes. Regarding glycemic management, insulin icodec is a basal insulin analog under clinical development with prolonged duration of action that allows for once-weekly administration, thereby further reducing the complexity of insulin therapy while increasing its acceptance [ 7 ]. Uptake of technological innovations initially designed for type 1 diabetes is also increasing. Soon, traditional measures of blood glucose control such as HbA 1c may become outdated and more widespread use of the ambulatory glucose profile derived from continuous glucose monitoring will help to develop a more personalized treatment plan. Finally, nonalcoholic fatty liver disease (NAFLD) represents a significant comorbidity amongst individuals with diabetes for whom effective interventions beyond lifestyle modifications are lacking. Several randomized trials assessing the effect of antidiabetic agents such as SGLT-2 inhibitors, GLP-1, and dual GIP/GLP-1 receptor agonists on liver outcomes are underway. If the encouraging preliminary findings from these liver outcome trials (LOTs) are corroborated, targeting NAFLD will probably be upgraded as a therapeutic priority in upcoming treatment algorithms for type 2 diabetes.

This review highlights recent changes in the management of type 2 diabetes to date and outlines existing challenges and future advances that will likely address unmet needs for a chronic condition that represents a substantial burden not only for individuals but also for healthcare systems and society as a whole (Table 1 ). We conducted a PubMed search up to July 2023 for recently published cardiorenal outcome trials and evidence syntheses thereof as well as pertinent guidelines for the management of diabetes and its associated comorbidities. Moreover, we scanned pharmaceutical companies’ websites to identify candidate molecules under development that might be introduced in clinical practice in the years to come.

Mitigation of cardiovascular risk

The American Diabetes Association and the European Association for the Study of Diabetes recommend that GLP-1 receptor agonists or SGLT-2 inhibitors should be used for patients with established CVD as well as patients without established CVD but with high-risk indicators, including age ≥ 55 years plus two or more additional risk factors, such as obesity, hypertension, smoking, dyslipidemia, or albuminuria [ 5 ]. The European Society of Cardiology questions the primacy of metformin and advocates upfront treatment with a GLP-1 receptor agonist or a SGLT-2 inhibitor for patients at high or very high cardiovascular risk, such as those with established CVD, end organ damage (i.e., proteinuria, estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m 2 , left ventricular hypertrophy or retinopathy), and presence of three or more major risk factors as well as patients with diabetes duration ≥ 10 years plus any additional risk factor [ 8 ]. For these individuals, the decision to initiate a GLP-1 receptor agonist or a SGLT-2 inhibitor should be independent of background use of metformin or baseline HbA 1c [ 9 ]. Of note, GLP-1 receptor agonists appear more effective in preventing stroke and should be prioritized for patients with atherosclerotic CVD, whereas SGLT-2 inhibitors are superior in reducing heart failure hospitalizations [ 10 ].

Nevertheless, it still remains unclear whether the favorable cardiovascular effects of the aforementioned drug classes are applicable to people with type 2 diabetes at low absolute cardiovascular risk given that this population was excluded from the respective CVOTs [ 3 ]. Randomized controlled trials are needed to address the paucity of evidence about the cardioprotective effects of glucose-lowering medications for this low-risk subgroup, although fewer cardiovascular events are expected and, hence, large sample sizes will be required to effectively capture differences among antidiabetic agents. The remaining knowledge gap concerns a significant number of patients with type 2 diabetes; thus, the conduct of such complex and resource-intensive megatrials is probably less appealing to the ongoing diabetes research enterprise. Registry-based randomized trials, which rely on routinely collected healthcare data for the ascertainment of the outcome, can be proposed to rectify this issue since they allow enrollment of a large sample, which is also representative of a real-world population, at minimal cost. As opposed to observational studies, the randomization protects against the effects of unmeasured confounders and selection bias by indication [ 11 ].

To reduce incidence of vascular complications and mortality among patients with type 2 diabetes, a multifactorial approach, apart from glucose regulation, is required taking into consideration the management of hypertension and dyslipidemia [ 12 ]. Guidelines for the management of hypertension have not changed substantially in recent years; clinicians should target a systolic blood pressure (SBP) of < 130 mmHg if it can be safely attained, although not < 120 mmHg, as well as a diastolic blood pressure of < 80 mmHg, but not < 70 mmHg, and these blood pressure targets should be individualized. For older people aged > 65 years, a more moderate SBP goal of < 140 mmHg might be appropriate, whereas for patients at increased risk of a cerebrovascular event, such as those with a history of stroke, a SBP of < 130 could be considered. Renin angiotensin aldosterone system (RAAS) blockers are considered first-line antihypertensive therapy for patients with type 2 diabetes, especially in the presence of albuminuria or coronary artery disease, while treatment can be advanced with the addition of a calcium channel blocker or a thiazide like diuretic [ 8 , 12 ].

Regarding the management of dyslipidemia, low-density lipoprotein cholesterol (LDL-C) targets are constantly on the decrease. Based on the underlying cardiovascular risk, a LDL-C target of < 100 mg/dl is recommended for moderate-risk patients, whereas for patients with multiple atherosclerotic CVD factors or for secondary prevention, LDL-C levels below 70 and 55 mg/dl, respectively, should be aimed for, along with a reduction of at least 50% in LDL-C. In this regard, the majority of patients with type 2 diabetes will eventually qualify for high-intensity statin therapy, such as atorvastatin 40–80 mg or rosuvastatin 20–40 mg: if the target LDL-C level is not achieved stepwise, addition of ezetimibe followed by a proprotein convertase subtilisin/kexin type 9 inhibitor should be considered [ 13 ]. Nevertheless, real-world data consistently suggest that control of LDL-C remains decidedly suboptimal in high-risk individuals [ 14 ]. Because practicing clinicians are often reluctant to pursue very low LDL-C targets, more efforts are needed to bridge this gap between guideline recommendations and clinical care.

Management of concomitant heart failure

Heart failure is predicted to be the new epidemic of the twenty-first century. People with type 2 diabetes are at increased risk for developing heart failure, which further increases their risk of adverse outcomes, mainly severe exacerbations that require hospitalization, as well as of mortality. Several trials have documented the effectiveness of SGLT-2 inhibitors for reducing rates of worsening heart failure in individuals across the full range of ejection fraction [ 15 , 16 , 17 ]. The beneficial effects of SGLT-2 inhibitors on heart failure outcomes are mediated by osmotic diuresis and occur irrespective of the presence of diabetes, thereby expanding the indication of these agents for patients with isolated heart failure without diabetes. Guidelines for the management of heart failure from the American College of Cardiology/American Heart Association have been modified accordingly and now include strong recommendations in favor of SGLT-2 inhibitors for patients with reduced ejection fraction as well as for individuals with preserved ejection fraction, for whom effective medical therapies are, admittedly, more limited [ 18 ].

Recent findings derived from network meta-analysis suggest that GLP-1 receptor agonists probably also reduce hospital admissions for worsening heart failure [ 19 ], although, in contrast to SGLT-2 inhibitors, dedicated trials for heart failure outcomes with these agents are lacking. GLP-1 receptor agonists are increasingly being used as a component of obesity treatment, which is clearly a pressing need for patients with comorbid heart failure. However, at the same time these agonists increase heart rate and, hence, any modest clinical benefits might diminish, especially among individuals with severe left ventricular dysfunction. Patients with preserved ejection fraction who have less well-established treatment options could benefit more from weight reduction. In this regard, it might be prudent for future research on GLP-1 receptor agonists to focus primarily on this subpopulation. Indeed, results from the SUMMIT trial (NCT04847557), a study of the newly approved GIP/GLP-1 receptor agonist tirzepatide in people with heart failure with preserved ejection fraction and obesity, could offer new insights.

Prevention of diabetic kidney disease

Diabetic nephropathy affects as many as 40% of patients with type 2 diabetes and is the leading cause of end-stage kidney disease requiring renal replacement therapy. Interventions to stabilize renal function in patients with diabetic kidney disease include optimal glycemic control, more stringent blood pressure targets, and use of RAAS inhibitors as well as management of excess cardiovascular risk with an appropriate lipid-lowering regimen. Beyond RAAS blockade, based on findings from cardiorenal outcome trials patients with type 2 diabetes and an eGFR < 60 ml/min/1.73 m 2 or albuminuria defined as an albumin to creatinine ratio ≥ 30 mg/g should preferably be treated with a SGLT-2 inhibitor to reduce the risk of kidney failure [ 20 , 21 , 22 ]. Because their effect on blood glucose is modest with worsening renal function owing to the decrease in the filtered glucose load, favorable kidney outcomes with SGLT-2 inhibitors are likely related to a reduction in intraglomerular pressure and are independent of the presence of type 2 diabetes.

GLP-1 receptor agonists are considered second-line therapy for cardiovascular risk reduction in patients with type 2 diabetes and chronic kidney disease (CKD) who do not meet glycemic targets with a SGLT-2 inhibitor or for whom a SGLT-2 inhibitor is contraindicated [ 5 , 23 ]. Nevertheless, this recommendation is mainly driven by the positive effect of these agents on reducing the risk for persistent macroalbuminuria and evidence for hard renal endpoints is still lacking. In this regard, the FLOW trial (NCT03819153) is a dedicated kidney outcomes trial with semaglutide that is expected to clarify whether this once-weekly GLP-1 receptor agonist delays the progression of kidney disease [ 24 ].

Apart from glucose-lowering medications, the nonsteroidal mineralocorticoid receptor antagonist finerenone has recently received regulatory approval for people with type 2 diabetes and concomitant nephropathy with albuminuria. The FIDELIO-DKD trial showed that finerenone ameliorates progression of CKD and reduces rates of cardiovascular events [ 25 ]. All participants in this trial received background therapy with RAAS blockers, but only a small minority were treated with a SGLT-2 inhibitor. Hence, the added value of finerenone for kidney protection on top of standard of care therapy with SGLT-2 inhibitors warrants further investigation. Finally, initial promising evidence of renoprotection with endothelin receptor antagonists such as atrasentan should prompt further research to investigate the potential role of this drug class for the treatment of patients with type 2 diabetes at high renal risk [ 26 ].

Development of new GLP-1 receptor agonists

Tirzepatide is the first-in-class dual GIP/GLP-1 receptor agonist with marketing authorization for the treatment of diabetes in Europe and the USA administered once weekly by subcutaneous injection. Compared to GLP-1 receptor monoagonism, combined activation of GLP-1 and GIP appears to have a synergistic effect. In tirzepatide’s clinical development program, SURPASS, the drug was highly effective in reducing HbA 1c up to approximately 2% for the maximal approved dose of 15 mg and even outperformed other potent GLP-1 receptor agonists without increasing the risk of hypoglycemia. Moreover, tirzepatide 15 mg was associated with weight loss of up to approximately 9 kg relative to placebo and was also superior in head-to-head comparisons with dulaglutide and semaglutide. The incidence of gastrointestinal side effects was similar to that of GLP-1 receptor agonists [ 6 ]. Given the well-documented cardiovascular benefits of certain GLP-1 receptor agonists, evidence of the effect of tirzepatide on long-term, hard clinical endpoints is much anticipated. Initial meta-analytic findings from the SURPASS clinical development program are encouraging [ 27 ]. The ongoing SURPASS-CVOT trial (NCT04255433) with more than 13,000 participants, to be completed by the end of 2024, is expected to clarify the cardiovascular effects of tirzepatide compared to dulaglutide.

The continuous refinement of GLP-1 receptor agonists has led to the development of multiagonist peptides that have the potential to reshape the management of obesity and hyperglycemia. In a phase 2 trial involving adults with obesity, the GIP, GLP-1, and glucagon receptor triple agonist retatrutide induced substantial body weight reduction of 24.2% after 48 weeks of intervention [ 28 ]. Hopefully, triple peptide hormone receptor agonists could more closely mimic the effects of metabolic surgery, which, though not scalable, offers substantial weight loss benefits and could even lead to remission of diabetes.

An oral formulation of the GLP-1 receptor agonist semaglutide taken once daily has also received marketing authorization. Although less effective for weight reduction, it could offer a more attractive option for earlier initiation of GLP-1 receptor agonist therapy in patients reluctant to use injectable agents [ 29 ]. Propitiously, results from the dedicated CVOT for oral semaglutide PIONEER 6 trial suggest a positive impact on all-cause and cardiovascular mortality [ 30 ]. Finally. orforglipron is another nonpeptide GLP-1 receptor agonist for daily oral administration for which weight loss up to 14.7% among patients with obesity has been observed in a phase 2 clinical trial [ 31 ].

The “diabesity” epidemic and NAFLD

Liver steatosis, which can progress to nonalcoholic steatohepatitis (NASH) and cirrhosis, is the most common hepatic disorder in Western countries that affects as many as 70% of people with type 2 diabetes, especially those who are overweight or obese. NAFLD represents a major public health problem of growing prevalence for which licensed treatments are lacking. Several antidiabetic agents have been evaluated as candidate molecules for the management of NAFLD [ 32 ]. Pioglitazone is associated with reductions in hepatic steatosis and lobular inflammation, while the GLP-1 receptor agonists liraglutide and semaglutide, which have also received marketing authorization at higher doses for chronic weight management, might promote histologic resolution of NASH and halt the progression of fibrosis. Finally, studies using mainly magnetic resonance imaging (MRI)-based techniques for evaluation of liver fat content and fibrosis have also pointed to potential benefits with the use of several SGLT-2 inhibitors. Interestingly, reduction in liver fat content has been noted in a MRI substudy with the dual GIP/GLP-1 receptor agonist tirzepatide [ 33 ]; however, SYNERGY-NASH, a dedicated trial with liver histological endpoints (NCT04166773), will provide more specific data on hepatoprotection for this agent.

Progress in insulin therapy

Many patients with type 2 diabetes will at some point during the course of the disease need insulin. Although insulin therapy has made considerable progress over the last few years, insulin is no longer regarded as first-line injectable therapy for people with type 2 diabetes. Before initiation of insulin, use of GLP-1 receptor agonists should be considered unless contraindicated because of their comparable glycemic efficacy and their favorable profile with respect to hypoglycemia [ 34 ]. Moreover, for patients already receiving basal insulin, a GLP-1 receptor agonist should be preferred over prandial insulin. Fixed ratio combinations of basal insulin with GLP-1 receptor agonists are also commercially available that minimize the injection burden while balancing out the risk of hypoglycemia and weight gain [ 35 ]. Nevertheless, it is still imperative not to postpone insulin therapy if it is deemed appropriate for certain individuals. Clinician and patient inertia regarding initiation of insulin has long been recognized and the extent to which this phenomenon will be affected by modern perceptions as to the role of insulin in type 2 diabetes pharmacotherapy remains to be elucidated.

The added value of newer basal insulin analogs such as degludec and glargine U-300 for glycemic control has so far been negligible, their main advantages being related to the lower risk of nocturnal hypoglycemia [ 2 ]. Regarding prandial insulin, ultra-rapid acting insulin analogs including FIAsp and URLi have recently been introduced in everyday clinical practice. Theoretically, their faster onset of action could better control mealtime glucose excursions and allows for greater dosing flexibility. However, these pharmacokinetic properties have not been shown to translate into clinically relevant benefits regarding the effect on HbA 1c or incidence of hypoglycemia compared to their rapid-acting counterparts [ 1 ]. All these advancements should be put in context with the steeply rising cost of insulin in the USA and elsewhere which deters compliance and hampers optimal glycemic control. Biosimilars did not have a sizeable impact on cost savings; thus, professional diabetes associations and patient advocacy groups are calling for further reductions in insulin prices and especially out-of-pocket expenses.

Icodec and basal insulin Fc (efsitora alfa) represent novel basal insulin formulations with a pharmacokinetic profile suitable for once-weekly administration. Insulin icodec is currently being evaluated in a series of clinical trials (ONWARDS). Specifically, in a 26-week, phase 2 trial, icodec showed comparable glycemic efficacy to insulin glargine and similar rates of hypoglycemia among patients treated with metformin with or without a DPP-4 inhibitor [ 7 ]. In another 26-week, phase 3 study enrolling patients treated with basal insulin, switching to icodec was superior to insulin degludec for reducing HbA 1c , though with modest weight gain and numerically more episodes of hypoglycemia [ 36 ]. Preliminary results also suggest that basal insulin Fc is non-inferior to degludec in terms of HbA 1c lowering [ 37 ]. Although more research is needed on the optimal titration scheme, the potential introduction in clinical practice of a once-weekly basal insulin regimen could encourage insulin acceptance and improve adherence. Finally, a combination of insulin icodec with the GLP-1 receptor agonist semaglutide (icosema) intended for once-weekly administration is in the pipeline.

Continuous glucose monitoring and insulin pumps

Self-monitoring of blood glucose in type 2 diabetes has consistently failed to provide clinically meaningful benefits. Use of continuous glucose monitoring (CGM) is widespread among patients with type 1 diabetes but its place in the management of type 2 diabetes and predominantly people treated with intensified insulin regimens remains controversial. HbA 1c reductions in the order of 0.3–0.4% have been observed with CGM compared to fingerprick measurements in randomized trials enrolling patients with type 2 diabetes receiving basal insulin alone or multiple daily injections [ 38 , 39 ], but evidence of the ability to decrease risk of severe hypoglycemia is lacking. In contrast to use of HbA 1c to evaluate glycemic control, CGM additionally captures glycemic variability and hypoglycemic episodes and, in this sense, time spent in target range as well as time spent in hypoglycemic range are gradually replacing traditional measures of glycemic efficacy initially in the context of clinical research and potentially in clinical practice as well. Similarly, the effectiveness of continuous subcutaneous insulin infusion has not been convincingly demonstrated in type 2 diabetes. In a large, randomized trial (OpT2mise), patients with type 2 diabetes and inadequate glycemic control achieved a greater reduction by 0.7% in HbA 1c with insulin pump therapy compared to multiple daily injections. The daily insulin dose was also lower, but the two groups did not differ in rates of hypoglycemia [ 40 ]. Interestingly, extensive research is currently being conducted on sweat-based and other noninvasive, wearable glucose sensors. Although all the aforementioned technologies are attractive tools for the management of insulin-treated patients with type 2 diabetes, their high cost and concerns about the associated user information overload are still barriers to their wider adoption. The promise that such exciting technologies will lead to improvements in patient-oriented outcomes has not yet been realized.

Conclusions

Recent innovations, including the introduction of antidiabetic drugs with proven cardiorenal benefits, highly effective agents for inducing weight loss, and more convenient insulin regimens and glucose sensors are having a profound impact on the everyday lives of patients with type 2 diabetes. Beyond these exciting interventions, lifestyle modification and diabetes self-management education and support, which are the mainstay of a holistic diabetes care plan, should continue to be energetically promoted.

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Liakos, A., Karagiannis, T., Avgerinos, I. et al. Management of type 2 diabetes in the new era. Hormones 22 , 677–684 (2023). https://doi.org/10.1007/s42000-023-00488-w

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Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Melanie j davies, vanita r aroda, billy s collins, robert a gabbay, jennifer green, nisa m maruthur, sylvia e rosas, stefano del prato, chantal mathieu, geltrude mingrone, peter rossing, tsvetalina tankova, apostolos tsapas, john b buse.

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Received 2022 Aug 2; Accepted 2022 Aug 18; Issue date 2022.

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycaemia in type 2 diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional healthcare team providing diabetes care in the USA and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the healthcare system and physical activity behaviours including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. After a summary listing of consensus recommendations, practical tips for implementation are provided.

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Supplementary Information

The online version of this article (10.1007/s00125-022-05787-2) contains peer-reviewed but unedited supplementary material.

Keywords: Cardiovascular disease, Chronic kidney disease, Glucose-lowering therapy, Guidelines, Heart failure, Holistic care, Person-centred care, Social determinants of health, Type 2 diabetes mellitus, Weight management

Introduction

Type 2 diabetes is a chronic complex disease and management requires multifactorial behavioural and pharmacological treatments to prevent or delay complications and maintain quality of life (Fig. 1 ). This includes management of blood glucose levels, weight, cardiovascular risk factors, comorbidities and complications. This necessitates that care be delivered in an organised and structured way, such as described in the chronic care model, and includes a person-centred approach to enhance engagement in self-care activities [ 1 ]. Careful consideration of social determinants of health and the preferences of people living with diabetes must inform individualisation of treatment goals and strategies [ 2 ].

Decision cycle for person-centred glycaemic management in type 2 diabetes. Adapted from [5] with permission from Springer Nature, © European Association for the Study of Diabetes and American Diabetes Association, 2018

This consensus report addresses the approaches to management of blood glucose levels in non-pregnant adults with type 2 diabetes. The principles and approach for achieving this are summarised in Fig. 1 . These recommendations are not generally applicable to individuals with diabetes due to other causes, for example monogenic diabetes, secondary diabetes and type 1 diabetes, or to children.

Data sources, searches and study selection

The writing group members were appointed by the ADA and EASD. The group largely worked virtually with regular teleconferences from September 2021, a 3 day workshop in January 2022 and a face-to-face 2 day meeting in April 2022. The writing group accepted the 2012 [ 3 ], 2015 [ 4 ], 2018 [ 5 ] and 2019 [ 6 ] editions of this consensus report as a starting point. To identify newer evidence, a search was conducted on PubMed for RCTs, systematic reviews and meta-analyses published in English between 28 January 2018 and 13 June 2022; eligible publications examined the effectiveness or safety of pharmacological or non-pharmacological interventions in adults with type 2 diabetes. Reference lists in eligible reports were scanned to identify additional relevant articles. Details of the keywords and the search strategy are available at https://data.mendeley.com/datasets/h5rcnxpk8w/2 . Papers were grouped according to subject and the authors reviewed this new evidence. Up-to-date meta-analyses evaluating the effects of therapeutic interventions across clinically important subgroup populations were assessed in terms of their credibility using relevant guidance [ 7 , 8 ]. Evidence appraisal was informed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines on the formulation of clinical practice recommendations [ 9 , 10 ]. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgements). Nevertheless, although evidence based with stakeholder input, the recommendations presented herein reflect the values and preferences of the consensus group.

The rationale, importance and context of glucose-lowering treatment

Fundamental aspects of diabetes care include promoting healthy behaviours, through medical nutrition therapy (MNT), physical activity and psychological support, as well as weight management and tobacco/substance abuse counselling as needed. This is often delivered in the context of diabetes self-management education and support (DSMES). The expanding number of glucose-lowering interventions—from behavioural interventions to pharmacological interventions, devices and surgery—and growing information about their benefits and risks provide more options for people with diabetes and providers but complicate decision making. The demonstrated benefits for high-risk individuals with atherosclerotic CVD, heart failure (HF) or chronic kidney disease (CKD) afforded by the glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium–glucose cotransporter-2 inhibitors (SGLT2i) provide important progress in treatment aimed at reducing the progression and burden of diabetes and its complications. These benefits are largely independent of their glucose-lowering effects. These treatments were initially introduced as glucose-lowering agents but are now also prescribed for organ protection. In this consensus report, we summarise a large body of recent evidence for practitioners in the USA and Europe with the aim of simplifying clinical decision making and focusing our efforts on providing holistic person-centred care.

Attaining recommended glycaemic targets yields substantial and enduring reductions in the onset and progression of microvascular complications [ 11 , 12 ] and early intervention is essential [ 13 ]. The greatest absolute risk reduction comes from improving very elevated glycaemic levels, and a more modest reduction results from near normalisation of plasma glucose levels [ 2 , 14 ]. The impact of glucose control on macrovascular complications is less certain but is supported by multiple meta-analyses and epidemiological studies. Because the benefits of intensive glucose control emerge slowly while the harms can be immediate, people with longer life expectancy have more to gain from early intensive glycaemic management. A reasonable HbA 1c target for most non-pregnant adults with sufficient life expectancy to see microvascular benefits (generally ∼10 years) is around 53 mmol/mol (7%) or less [ 2 ]. Aiming for a lower HbA 1c level than this may have value if it can be achieved safely without significant hypoglycaemia or other adverse treatment effects. A lower target may be reasonable, particularly when using pharmacological agents that are not associated with hypoglycaemic risk. Higher targets can be appropriate in cases of limited life expectancy, advanced complications or poor tolerability or if other factors such as frailty are present. Thus, glycaemic treatment targets should be tailored based on an individual’s preferences and characteristics, including younger age (i.e. age <40 years), risk of complications, frailty and comorbid conditions [ 2 , 15 – 17 ], and the impact of these features on the risk of adverse effects of therapy (e.g. hypoglycaemia and weight gain).

Principles of care

Language matters.

Communication between people living with type 2 diabetes and healthcare team members is at the core of integrated care, and clinicians must recognise how language matters. Language in diabetes care should be neutral, free of stigma and based on facts; be strengths-based (focus on what is working), respectful and inclusive; encourage collaboration; and be person-centred [ 18 ]. People living with diabetes should not be referred to as ‘diabetics’ or described as ‘non-compliant’ or blamed for their health condition.

Diabetes self-management education and support

DSMES is a key intervention, as important to the treatment plan as the selection of pharmacotherapy [ 19 – 21 ]. DSMES is central to establishing and implementing the principles of care (Fig. 1 ). DSMES programmes usually involve face-to-face contact in group or individual sessions with trained educators, and key components of DSMES are shown in Supplementary Table 1 [ 19 – 24 ]. Given the ever-changing nature of type 2 diabetes, DSMES should be offered on an ongoing basis. Critical junctures when DSMES should be provided include at diagnosis, annually, when complications arise, and during transitions in life and care (Supplementary Table 1 ) [ 22 ].

High-quality evidence has consistently shown that DSMES significantly improves knowledge, glycaemic levels and clinical and psychological outcomes, reduces hospital admissions and all-cause mortality and is cost-effective [ 22 , 25 – 30 ]. DSMES is delivered through structured educational programmes provided by trained diabetes care and education specialists (termed DCES in the USA; hereafter referred to as ‘diabetes educators’) that focus particularly on the following: lifestyle behaviours (healthy eating, physical activity and weight management), medication-taking behaviour, self-monitoring when needed, self-efficacy, coping and problem solving.

Importantly, DSMES is tailored to the individual’s context, which includes their beliefs and preferences. DSMES can be provided using multiple approaches and in a variety of settings [ 20 , 31 ] and it is important for the care team to know how to access local DSMES resources. DSMES supports the psychosocial care of people with diabetes but is not a replacement for referral for mental health services when they are warranted, for example when diabetes distress remains after DSMES. Psychiatric disorders, including disordered eating behaviours, are common, often unrecognised and contribute to poor outcomes in diabetes [ 32 ].

The best outcomes from DSMES are achieved through programmes with a theory-based and structured curriculum and with contact time of over 10 h [ 26 ]. While online programmes may reinforce learning, a comprehensive approach to education using multiple methods may be more effective [ 26 ]. Emerging evidence demonstrates the benefits of telehealth or web-based DSMES programmes [ 33 ] and these were used with success during the COVID-19 pandemic [ 34 – 36 ]. Technologies such as mobile apps, simulation tools, digital coaching and digital self-management interventions can be used to deliver DSMES and extend its reach to a broader segment of the population with diabetes and provide comparable or even better outcomes [ 37 ]. Greater HbA 1c reductions are demonstrated with increased engagement of people with diabetes [ 35 , 38 ]. However, data from trials of digital strategies to support behaviour change are still preliminary in nature and quite heterogeneous [ 22 , 37 ].

Individualised and personalised approach

Type 2 diabetes is a very heterogeneous disease with variable age at onset, related degree of obesity, insulin resistance and tendency to develop complications [ 39 , 40 ]. Providing person-centred care that addresses multimorbidity and is respectful of and responsive to individual preferences and barriers, including the differential costs of therapies, is essential for effective diabetes management [ 41 ]. Shared decision making, facilitated by decision aids that show the absolute benefit and risk of alternative treatment options, is a useful strategy to determine the best treatment course for an individual [ 42 – 45 ]. With compelling indications for therapies such as SGLT2i and GLP-1 RA for high-risk individuals with CVD, HF or CKD, shared decision making is essential to contextualise the evidence on benefits, safety and risks. Providers should evaluate the impact of any suggested intervention in the context of cognitive impairment, limited literacy, distinct cultural beliefs and individual fears or health concerns. The healthcare system is an important factor in the implementation, evaluation and development of the personalised approach. Furthermore, social determinants of health—often out of direct control of the individual and potentially representing lifelong risk—contribute to medical and psychosocial outcomes and must be addressed to improve health outcomes. Five social determinants of health areas have been identified: socioeconomic status (education, income and occupation), living and working conditions, multisector domains (e.g. housing, education and criminal justice system), sociocultural context (e.g. shared cultural values, practices and experiences) and sociopolitical context (e.g. societal and political norms that are root cause ideologies and policies underlying health disparities) [ 46 ]. More granularity on social determinants of health as they pertain to diabetes is provided in a recent ADA review [ 47 ], with a particular focus on the issues faced in the African American population provided in a subsequent report [ 48 ]. Environmental, social, behavioural and emotional factors, known as psychosocial factors, also influence living with diabetes and achieving satisfactory medical outcomes and psychological well-being. Thus, these multifaceted domains (heterogeneity across individual characteristics, social determinants of health and psychosocial factors) challenge individuals with diabetes, their families and their providers when attempting to integrate diabetes care into daily life [ 49 ].

Current principles of, and approaches to, person-centred care in diabetes (Fig. 1 ) include assessing key characteristics and preferences to determine individualised treatment goals and strategies. Such characteristics include comorbidities, clinical characteristics and compelling indications for GLP-1 RA or SGLT2i for organ protection [ 6 ].

Weight reduction as a targeted intervention

Weight reduction has mostly been seen as a strategy to improve HbA 1c and reduce the risk for weight-related complications. However, it was recently suggested that weight loss of 5–15% should be a primary target of management for many people living with type 2 diabetes [ 50 ]. A higher magnitude of weight loss confers better outcomes. Weight loss of 5–10% confers metabolic improvement; weight loss of 10–15% or more can have a disease-modifying effect and lead to remission of diabetes [ 50 ], defined as normal blood glucose levels for 3 months or more in the absence of pharmacological therapy in a 2021 consensus report [ 51 ]. Weight loss may exert benefits that extend beyond glycaemic management to improve risk factors for cardiometabolic disease and quality of life [ 50 ].

Glucose management: monitoring

Glycaemic management is primarily assessed with the HbA 1c test, which was the measure used in trials demonstrating the benefits of glucose lowering [ 2 , 52 ]. As with any laboratory test, HbA 1c measurement has limitations [ 2 , 52 ]. There may be discrepancies between HbA 1c results and an individual’s true mean blood glucose levels, particularly in certain racial and ethnic groups and in conditions that alter erythrocyte turnover, such as anaemia, end-stage kidney disease (especially with erythropoietin therapy) and pregnancy, or if an HbA 1c assay insensitive to haemoglobin variants is used in someone with a haemoglobinopathy. Discrepancies between measured HbA 1c levels and measured or reported glucose levels should prompt consideration that one of these may not be reliable [ 52 , 53 ].

Regular blood glucose monitoring (BGM) may help with self-management and medication adjustment, particularly in individuals taking insulin. BGM plans should be individualised. People with type 2 diabetes and the healthcare team should use the monitoring data in an effective and timely manner. In people with type 2 diabetes not using insulin, routine glucose monitoring is of limited additional clinical benefit while adding burden and cost [ 54 , 55 ]. However, for some individuals, glucose monitoring can provide insight into the impact of lifestyle and medication management on blood glucose and symptoms, particularly when combined with education and support [ 53 ]. Technologies such as intermittently scanned or real-time continuous glucose monitoring (CGM) provide more information and may be useful for people with type 2 diabetes, particularly in those treated with insulin [ 53 , 56 ].

When using CGM, standardised, single-page glucose reports, such as the ambulatory glucose profile, can be uploaded from CGM devices. They should be considered as standard metrics for all CGM devices and provide visual cues for management opportunities. Time in range is defined as the percentage of time that CGM readings are in the range 3.9–10.0 mmol/l (70–180 mg/dl). Time in range is associated with the risk of microvascular complications and can be used for assessment of glycaemic management [ 57 ]. Additionally, time above and below range are useful variables for the evaluation of treatment regimens. Particular attention to minimising the time below range in those with hypoglycaemia unawareness may convey benefit. If using the ambulatory glucose profile to assess glycaemic management, a goal parallel to an HbA 1c level of <53 mmol/mol (<7%) for many is time in range of >70%, with additional recommendations to aim for time below range of <4% and time at <3.0 mmol/l (<54 mg/dl) of <1% [ 2 ].

Treatment behaviours, persistence and adherence

Suboptimal medication-taking behaviour and low rates of continued medication use, or what is termed ‘persistence to therapy plans’ affects almost half of people with type 2 diabetes, leading to suboptimal glycaemic and CVD risk factor control as well as increased risks of diabetes complications, mortality and hospital admissions and increased healthcare costs [ 58 – 62 ]. Although this consensus report focuses on medication-taking behaviour, the principles are pertinent to all aspects of diabetes care. Multiple factors contribute to inconsistent medication use and treatment discontinuation among people with diabetes, including perceived lack of medication efficacy, fear of hypoglycaemia, lack of access to medication and adverse effects of medication [ 63 ]. Focusing on facilitators of adherence, such as social/family/provider support, motivation, education and access to medications/foods, can provide benefits [ 64 ]. Observed rates of medication adherence and persistence vary across medication classes and between agents; careful consideration of these differences may help improve outcomes [ 61 ]. Ultimately, individual preferences are major factors driving the choice of medications. Even when clinical characteristics suggest the use of a particular medication based on the available evidence from clinical trials, preferences regarding route of administration, injection devices, side effects or cost may prevent use by some individuals [ 65 ].

Therapeutic inertia

Therapeutic (or clinical) inertia describes a lack of treatment intensification when targets or goals are not met. It also includes failure to de-intensify management when people are overtreated. The causes of therapeutic inertia are multifactorial, occurring at the levels of the practitioner, person with diabetes and/or healthcare system [ 66 ]. Interventions targeting therapeutic inertia have facilitated improvements in glycaemic management and timely insulin intensification [ 67 , 68 ]. For example, the involvement of multidisciplinary teams that include non-physician providers with authorisation to prescribe (e.g. pharmacists, specialist nurses and advanced practice providers) may reduce therapeutic inertia [ 69 , 70 ].

Therapeutic options: lifestyle and healthy behaviour, weight management and pharmacotherapy for the treatment of type 2 diabetes

This section summarises the lifestyle and behavioural therapy, weight management interventions and pharmacotherapy that support glycaemic management in people with type 2 diabetes. Specific pharmacological treatment options are summarised in Table 1 . Additional details are available in the previous ADA/EASD consensus report and update [ 5 , 6 ] and the ADA’s 2022 Standards of medical care in diabetes [ 71 ].

Medications for lowering glucose, summary of characteristics

Nutrition therapy

Nutrition therapy is integral to diabetes management, with goals of promoting and supporting healthy eating patterns, addressing individual nutrition needs, maintaining the pleasure of eating and providing the person with diabetes with the tools for developing healthy eating [ 22 ]. MNT provided by a registered dietitian/registered dietitian nutritionist complements DSMES, can significantly reduce HbA 1c and can help prevent, delay and treat comorbidities related to diabetes [ 19 ]. Two core dimensions of MNT that can improve glycaemic management include dietary quality and energy restriction.

Dietary quality and eating patterns

There is no single ratio of carbohydrate, proteins and fat intake that is optimal for every person with type 2 diabetes. Instead, individually selected eating patterns that emphasise foods with demonstrated health benefits, minimise foods shown to be harmful and accommodate individual preferences with the goal of identifying healthy dietary habits that are feasible and sustainable are recommended. A net energy deficit that can be maintained is important for weight loss [ 5 , 6 , 22 , 72 – 74 ].

A network analysis comparing trials of nine dietary approaches of >12 weeks’ duration demonstrated reductions in HbA 1c from −9 to −5.1 mmol/mol (−0.82% to −0.47%), with all approaches compared with a control diet. Greater glycaemic benefits were seen with the Mediterranean diet and low carbohydrate diet [ 75 ]. The greater glycaemic benefits of low carbohydrate diets (<26% of energy) at 3 and 6 months are not evident with longer follow-up [ 72 ]. In a systematic review of trials of >6 months’ duration, compared with a low-fat diet, the Mediterranean diet demonstrated greater reductions in body weight and HbA 1c levels, delayed the requirement for diabetes medication and provided benefits for cardiovascular health [ 76 , 77 ]. Similar benefits have been ascribed to vegan and vegetarian diets [ 78 ].

There has been increased interest in time-restricted eating and intermittent fasting to improve metabolic variables, although with mixed, and modest, results. In a meta-analysis there were no differences in the effect of intermittent fasting and continuous energy restriction on HbA 1c , with intermittent fasting having a modest effect on weight (−1.70 kg) [ 79 ]. In a 12 month RCT in adults with type 2 diabetes comparing intermittent energy restriction (2092–2510 kJ [500–600 kcal] diet for 2 non-consecutive days/week followed by the usual diet for 5 days/week) with continuous energy restriction (5021–6276 kJ [1200–1500 kcal] diet for 7 days/week), glycaemic improvements were comparable between the two groups. At 24 months’ follow-up, HbA 1c increased in both groups to above baseline [ 80 ], while weight loss (−3.9 kg) was maintained in both groups [ 81 ]. Fasting may increase the rates of hypoglycaemia in those treated with insulin and sulfonylureas, highlighting the need for individualised education and proactive medication management during significant dietary changes [ 82 ].

Non-surgical energy restriction for weight loss

An overall healthy eating plan that results in an energy deficit, in conjunction with medications and/or metabolic surgery as individually appropriate, should be considered to support glycaemic and weight management goals in adults with type 2 diabetes [ 5 , 22 ]. Structured nutrition and lifestyle programmes may be considered for glycaemic benefit and can be adapted for specific cultural indications [ 83 – 87 ].

The Diabetes Remission Clinical Trial (DiRECT) demonstrated greater remission of diabetes with a weight management programme than with usual best practice care in adults with type 2 diabetes within 6 years of diagnosis. The structured, primary care-led intensive weight management programme involved total diet replacement (3452–3569 kJ/day [825–853 kcal/day] for 3–5 months) followed by stepped food reintroduction and structured support for long-term weight loss maintenance. In the whole study population, remission directly varied with degree of weight loss [ 88 ]. At the 2 year follow-up, sustained remission correlated with extent of sustained weight loss. In the whole study population, of those maintaining at least 10 kg weight loss, 64% achieved diabetes remission. However, only 24% of the participants in the intervention group maintained at least 10 kg weight loss, highlighting both the potential and the challenges of long-term durability of weight loss [ 89 ].

The Look AHEAD: Action for Health in Diabetes (Look AHEAD) trial on the longer-term effects of an intensive lifestyle intervention in adults who were overweight/obese with type 2 diabetes showed improvements in diabetes control and complications, depression, physical function and health-related quality of life, sleep apnoea, incontinence, brain structure and healthcare use and costs, with positive impacts on composite indices of multimorbidity, geriatric syndromes and disability-free life-years. This should be balanced against potential negative effects on body composition, bone density and frailty fractures [ 90 , 91 ]. Although there was no difference in the primary cardiovascular outcome or mortality rate between the intervention and the control groups, post hoc exploratory analyses suggested potential benefits in certain groups (e.g. in those who achieved at least 10% weight loss in the first year of the study). Progressive metabolic benefits were seen with greater degrees of weight loss from >5% to ≥15%, with an overall suggestion that ≥10% weight loss may be required to see benefits for CVD events and mortality rate and other complications such as non-alcoholic steatohepatitis [ 50 , 90 , 92 – 95 ].

Physical activity behaviours including sleep

Physical activity behaviours significantly impact cardiometabolic health in type 2 diabetes (Fig. 2 ) [ 96 – 117 ]. Regular aerobic exercise (i.e. involving large muscle groups and rhythmic in nature) improves glycaemic management in adults with type 2 diabetes, resulting in less daily time in hyperglycaemia and reductions of ~7 mmol/mol (~0.6%) in HbA 1c [ 118 ], and induces clinically significant benefits in cardiorespiratory fitness [ 101 , 110 , 119 ]. These glycaemic effects can be maximised by undertaking activity during the postprandial period and engaging in activities for ≥45 min [ 101 , 120 ]. Resistance exercise (i.e. using your own body weight or working against a resistance) also improves blood glucose levels, flexibility and balance [ 101 , 110 ]. This is important given the increased risk of impaired physical function at an earlier age in type 2 diabetes [ 112 ].

Importance of 24-hour physical behaviours for type 2 diabetes

A wide range of physical activities, including leisure time activities, can significantly reduce HbA 1c levels [ 5 , 22 , 121 , 122 ]. Even small, regular changes can make a difference to long-term health, with an increase of only 500 steps/day associated with 2–9% decreased risk of cardiovascular morbidity and all-cause mortality rates [ 105 – 107 ]. Beneficial effects are evident across the continuum of human movement, from breaking prolonged sitting with light activity [ 103 ] to high-intensity interval training [ 123 ].

Healthy sleep is considered a key lifestyle component in the management of type 2 diabetes [ 124 ], with clinical practice guidelines promoting the importance of sleep hygiene [ 113 ]. Sleep disorders are common in type 2 diabetes and cause disturbances in the quantity, quality and timing of sleep and are associated with an increased risk of obesity and impairments in daytime functioning and glucose metabolism [ 114 , 115 ]. Additionally, obstructive sleep apnoea affects over half of people with type 2 diabetes and its severity is associated with blood glucose levels [ 115 , 116 ].

The quantity of sleep is known to be associated (in a ‘U’ shaped manner) with health outcomes (e.g. obesity and HbA 1c ), with both long (>8 h) and short (<6 h) sleep durations having negative impacts [ 97 ]. By extending the sleep duration of short sleepers, it is possible to improve insulin sensitivity and reduce energy intake [ 117 , 125 ]. However, ’catch-up’ weekend sleep alone is not enough to reverse the impact of insufficient sleep [ 126 ].

Weight management beyond lifestyle interventions

Medications for weight loss in type 2 diabetes.

Weight loss medications are effective adjuncts to lifestyle interventions and healthy behaviours for management of weight and have also been found to improve glucose control in people with diabetes [ 127 ].

Newer therapies have demonstrated very high efficacy for weight management in people with type 2 diabetes. In the Semaglutide Treatment Effect in People with Obesity (STEP) 2 trial, subcutaneous semaglutide 2.4 mg once a week as an adjunct to a lifestyle intervention performed better than either semaglutide 1.0 mg or placebo, with weight loss of 9.6% (6.2% more than with placebo and 2.7% more than with semaglutide 1.0 mg). More than two thirds of participants in the semaglutide 2.4 mg arm achieved an HbA 1c level of ≤48 mmol/mol (≤6.5%) [ 128 ]. However, the weight loss was less pronounced than the 14.9% weight loss (vs 2.4% with placebo) seen in the STEP 1 trial in adults with overweight or obesity without diabetes [ 129 ]. Tirzepatide, a novel glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA, at weekly doses of 5 mg, 10 mg and 15 mg reduced body weight by 15%, 19.5% and 20.9%, respectively, compared with 3.1% with placebo at 72 weeks in people with obesity but without diabetes; however, tirzepatide has not yet been approved for weight management by regulatory authorities [ 130 ]. Studies in adults with overweight or obesity suggest that withdrawing treatment with semaglutide leads to increases in body weight [ 131 ], highlighting the chronic nature of, and need for, obesity/weight management.

Metabolic surgery

Metabolic surgery should be considered as a treatment option in adults with type 2 diabetes who are appropriate surgical candidates [ 127 , 132 ]. Metabolic surgery also appears to be effective for diabetes remission in people with type 2 diabetes and a BMI ≥25 kg/m 2 , although efficacy for both weight loss and diabetes remission appears to vary by surgical type [ 133 – 135 ]. One mixed-effects meta-analysis model has estimated a 43% diabetes remission rate (95% CI 34%, 53%) following metabolic surgery in people with type 2 diabetes and a BMI <30 kg/m 2 [ 136 ], significantly higher than that achieved with traditional medical management [ 137 ]. However, there is a strong association between duration of diabetes and the likelihood of postoperative diabetes remission. People with more recently diagnosed diabetes are more likely to experience remission after metabolic surgery, and the likelihood of remission decreases significantly with duration of diabetes longer than about 5–8 years [ 138 ]. Even in people with diabetes who do not achieve postoperative diabetes remission, or relapse after initial remission, metabolic surgery is associated with better metabolic control than medical management [ 137 , 139 ]. In the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial, metabolic surgery was also associated with improvements in patient-reported outcomes related to physical health; however, measures of social and psychological quality of life did not improve [ 140 ]. It is important to note that many of these estimates of benefit included data from non-randomised studies and compared outcomes with medical treatments for obesity that were less effective than those available today.

Medications for lowering glucose

Cardiorenal-protective glucose-lowering medications, sodium–glucose cotransporter-2 inhibitors.

The SGLT2i are oral medications that reduce plasma glucose by enhancing urinary excretion of glucose. They have intermediate-to-high glycaemic efficacy, with lower glycaemic efficacy at lower eGFR. However, their scope of use has significantly expanded based on cardiovascular and renal outcomes studies [ 5 , 141 ]. Cardiorenal outcomes trials have demonstrated their efficacy in reducing the risk of composite major adverse cardiovascular events (MACE), cardiovascular death, myocardial infarction, hospitalisation for heart failure (HHF) and all-cause mortality and improving renal outcomes in individuals with type 2 diabetes with an established/high risk of CVD. This is discussed in the section on ‘Personalised approach to treatment based on individual characteristics and comorbidities: recommended process for glucose-lowering medication selection’. Evidence supporting their use is summarised in Table 1 [ 141 , 142 ].

Recent data have increased confidence in the safety of the SGLT2i drug class [ 141 , 142 ]. Their use is associated with increased risk for mycotic genital infections, which are reported to be typically mild and treatable. While SGLT2i use can increase the risk of diabetic ketoacidosis (DKA), the incidence is low, with a modest incremental absolute risk [ 142 ]. The SGLT2i cardiovascular outcomes trials (CVOTs) have reported DKA rates of 0.1–0.6% compared with rates of <0.1–0.3% with placebo [ 143 – 147 ], with very low rates in the HF [ 148 – 151 ] and CKD [ 152 , 153 ] outcomes studies. Risk can be mitigated with education and guidance, including education on signs and symptoms of DKA that should prompt medical attention, and temporary discontinuation of the medication in clinical situations that predispose to ketoacidosis (e.g. during prolonged fasting and acute illness, and perioperatively, i.e. 3 days prior to surgery) [ 154 – 158 ]. The Dapagliflozin in Respiratory Failure in Patients With COVID-19 (DARE-19) RCT demonstrated a low risk of DKA (0.3% vs 0% in dapagliflozin-treated vs placebo-treated participants) with structured monitoring of acid–base balance and kidney function during inpatient use in adults admitted with COVID-19 and at least one cardiometabolic risk factor without evidence of critical illness [ 159 ].

While early studies brought attention to several safety areas of interest (acute kidney injury, dehydration, orthostatic hypotension, amputation and fractures) [ 5 , 6 ], longer-term studies that have prospectively assessed and monitored these events [ 160 , 161 ] have not seen a significant imbalance in risks. Analyses of SGLT2i outcomes trial data also suggest that people with type 2 diabetes and peripheral arterial disease derive greater absolute outcomes benefits from SGLT2i therapy than those without peripheral arterial disease, and without an increase in risk of major adverse limb events [ 162 ]. In post hoc analyses, SGLT2i use has been associated with reduced incidence of serious and non-serious kidney-related adverse events in people with type 2 diabetes and CKD, and greater full recovery from acute kidney injury [ 163 ].

Glucagon-like peptide-1 receptor agonists

GLP-1 RA augment glucose-dependent insulin secretion and glucagon suppression, decelerate gastric emptying, curb post-meal glycaemic increments and reduce appetite, energy intake and body weight [ 5 , 6 , 164 ]. Beyond improving HbA 1c in adults with type 2 diabetes, specific GLP-1 RA have also been approved for reducing risk of MACE in adults with type 2 diabetes with established CVD (dulaglutide, liraglutide and subcutaneous semaglutide) or multiple cardiovascular risk factors (dulaglutide) (Table 1 ) and for chronic weight management (subcutaneous liraglutide titrated to 3.0 mg once daily; subcutaneous semaglutide titrated to 2.4 mg once weekly). This is discussed in the sections on ‘Medications for weight loss in type 2 diabetes’ and ‘Personalised approach to treatment based on individual characteristics and comorbidities: recommended process for glucose-lowering medication selection’. GLP-1 RA are primarily available as injectable therapies (subcutaneous administration), with one oral GLP-1 RA now available (oral semaglutide) [ 165 ].

The recent higher dose GLP-1 RA studies have indicated incremental benefits for glucose and weight at higher doses of GLP-1 RA, with greater proportions of people achieving glycaemic targets and the ability of stepwise dose escalation to improve gastrointestinal tolerability. The Assessment of Weekly AdministRation of LY2189265 (dulaglutide) in Diabetes (AWARD)-11 trial evaluated higher doses of dulaglutide (3.0 mg and 4.5 mg weekly) compared with 1.5 mg weekly, demonstrating superior HbA 1c reductions (−19.4 vs −16.8 mmol/mol [−1.77 vs −1.54%], estimated treatment difference [ETD] −2.6 mmol/mol [−0.24%]) and weight loss (−4.6 vs −3.0 kg, ETD −1.6 kg) with dulaglutide 4.5 mg compared with 1.5 mg at 36 weeks in people with type 2 diabetes inadequately controlled with metformin [ 166 ]. Likewise, the SUSTAIN FORTE trial studied higher doses of once-weekly subcutaneous semaglutide (2.0 mg) compared with the previously approved 1.0 mg dose, reporting a mean change in HbA 1c from baseline to week 40 of −23 vs −21 mmol/mol (−2.1 vs −1.9%; ETD −2 mmol/mol [−0.18%]) and weight change of −6.4 kg with semaglutide 2.0 mg and −5.6 kg with semaglutide 1.0 mg (ETD −0.77 kg [95% CI −1.55, 0.01]) [ 167 ].

The most common side effects of GLP-1 RA are gastrointestinal in nature (nausea, vomiting and diarrhoea) and tend to occur during initiation and dose escalation and diminish over time. Gradual up-titration is recommended to mitigate gastrointestinal effects [ 164 , 168 , 169 ]. Education should be provided when initiating GLP-1 RA therapy. GLP-1 RA promote a sense of satiety, facilitating reduction in food intake. It is important to help people distinguish between nausea, a negative sensation, and satiety, a positive sensation that supports weight loss. Mindful eating should be encouraged: eating slowly, stopping eating when full and not eating when not hungry. Smaller meals or snacks, decreasing intake of high-fat and spicy foods, moderating alcohol intake and increasing water intake are also recommended. Slower or flexible dose escalations can be considered in the setting of gastrointestinal intolerance [ 168 , 169 ].

Data from CVOTs on other safety areas of interest (pancreatitis, pancreatic cancer and medullary thyroid cancer) indicate that there is no increase in these risks with GLP-1 RA. GLP-1 RA are contraindicated in people at risk of the rare medullary thyroid cancer [ 164 ], that is, those with a history or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2, due to thyroid C-cell tumours seen in rodents treated with GLP-1 RA in preclinical studies. Increased retinopathy complications seen in the SUSTAIN 6 CVOT appear attributable to the magnitude and rapidity of HbA 1c reductions in individuals with pre-existing diabetic retinopathy and high glycaemic levels, as has been seen in previous studies with insulin [ 170 , 171 ]. GLP-1 RA are also associated with higher risks of gallbladder and biliary diseases [ 172 ].

Other glucose-lowering medications

Because of its high efficacy in lowering HbA 1c , minimal hypoglycaemia risk when used as monotherapy, weight neutrality with the potential for modest weight loss, good safety profile and low cost, metformin has traditionally been recommended as first-line glucose-lowering therapy for the management of type 2 diabetes. However, there is ongoing acceptance that other approaches may be appropriate. Notably, the benefits of GLP-1 RA and SGLT2i for cardiovascular and renal outcomes have been found to be independent of metformin use and thus these agents should be considered in people with established or high risk of CVD, HF or CKD, independent of metformin use [ 173 – 175 ]. Early combination therapy based on the perceived need for additional glycaemic efficacy or cardiorenal protection can be considered at treatment initiation to extend the time to treatment failure [ 176 ]. Metformin should not be used in people with an eGFR <30 ml/min per 1.73 m 2 and dose reduction should be considered when the eGFR is <45 ml/min per 1.73 m 2 [ 177 ]. Metformin use may result in lower serum vitamin B 12 concentrations and worsening of symptoms of neuropathy; therefore, periodic monitoring and supplementation are generally recommended if levels are deficient, particularly in those with anaemia or neuropathy [ 178 , 179 ].

Dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are oral medications that inhibit the enzymatic inactivation of endogenous incretin hormones, resulting in glucose-dependent insulin release and a decrease in glucagon secretion. They have a more modest glucose-lowering efficacy and a neutral effect on weight and are well tolerated with minimal risk of hypoglycaemia. CVOTs have demonstrated the cardiovascular safety without cardiovascular risk reduction of four DPP-4i (saxagliptin, alogliptin, sitagliptin and linagliptin) [ 141 ]. Reductions in risk of albuminuria progression were noted with linagliptin in the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA) trial [ 180 ]. While generally well tolerated, an increased risk of HHF was found with saxagliptin, which is reflected in its label, and there have been rare reports of arthralgia and hypersensitivity reactions with the DPP-4i class [ 16 ].

The high tolerability and modest efficacy of DPP-4i may mean that they are suitable for specific populations and considerations. For example, in a 6 month open-label RCT comparing a DPP-4i (linagliptin) with basal insulin (glargine) in long-term care and skilled nursing facilities, mean daily blood glucose was similar, with fewer hypoglycaemic events with linagliptin compared with insulin [ 181 ]. Treatment of inpatient hyperglycaemia with basal insulin plus DPP-4i has been demonstrated to be effective and safe in older adults with type 2 diabetes, with similar mean daily blood glucose but lower glycaemic variability and fewer hypoglycaemic episodes compared with the basal–bolus insulin regimen [ 182 ].

Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist

In May 2022, the FDA approved tirzepatide, a GIP and GLP-1 RA, for once-weekly subcutaneous administration to improve glucose control in adults with type 2 diabetes as an addition to healthy eating and exercise. In the Phase III clinical trial programme, tirzepatide demonstrated superior glycaemic efficacy to placebo [ 183 , 184 ], subcutaneous semaglutide 1.0 mg weekly [ 185 ], insulin degludec [ 186 ] and insulin glargine [ 187 ]. For HbA 1c , placebo-adjusted reductions of 21 mmol/mol (1.91%), 21 mmol/mol (1.93%) and 23 mmol/mol (2.11%) were demonstrated with tirzepatide 5, 10 and 15 mg weekly, respectively, and mean weight reductions of 7–9.5 kg were seen [ 183 ]. Additional metabolic benefits included improvements in liver fat content and reduced visceral and subcutaneous abdominal adipose tissue volume [ 188 ]. Based on meta-analysis findings, tirzepatide was superior to its comparators, including other long-acting GLP-1 RA, in reducing glucose and body weight, but was associated with increased odds for gastrointestinal adverse events, in particular nausea [ 189 ]. Similar warnings and precautions are included in the prescribing information for tirzepatide as for agents in the GLP-1 RA class. Additionally, current short-term data from RCTs suggest that tirzepatide does not increase the risk of MACE vs comparators; however, robust data on its long-term cardiovascular profile will be available after completion of the SURPASS-CVOT trial [ 190 ]. Tirzepatide has received a positive opinion in the EU.

Sulfonylureas

As per the previous consensus report and update, sulfonylureas are assessed as having high glucose-lowering efficacy, but with a lack of durable effect, and the advantages of being inexpensive and accessible [ 5 , 6 ]. However, due to their glucose-independent stimulation of insulin secretion, they are associated with an increased risk for hypoglycaemia. Sulfonylureas are also associated with weight gain, which is relatively modest in large cohort studies [ 191 ]. Use of sulfonylureas or insulin for early intensive blood glucose control in the UK Prospective Diabetes Study (UKPDS) significantly decreased the risk of microvascular complications, underscoring the importance of early and continued glycaemic management [ 192 ]. Adverse cardiovascular outcomes with sulfonylureas in some observational studies have raised concerns, although findings from systematic reviews have found no increase in all-cause mortality rates compared with other active treatments [ 191 ]. The incidence of cardiovascular events was comparable in those treated with a sulfonylurea or pioglitazone in the Thiazolidinediones Or Sulfonylureas and Cardiovascular Accidents Intervention Trial (TOSCA.IT) [ 193 ], and no difference in the incidence of MACE was found in people at high cardiovascular risk treated with glimepiride or linagliptin [ 194 ], a medication whose cardiovascular safety was demonstrated in a population at high cardiovascular and renal risk [ 195 ].

Thiazolidinediones

Thiazolidinediones (TZDs) are oral medications that increase insulin sensitivity and are of high glucose-lowering efficacy [ 5 , 6 ]. TZDs have a high durability of glycaemic response, most likely through a potent effect on preserving beta cell function [ 196 ]. In the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) in adults with type 2 diabetes and macrovascular disease, a reduction in secondary cardiovascular endpoints was seen, although significance was not achieved for the primary outcome [ 197 ]. In the Insulin Resistance Intervention After Stroke (IRIS) study in adults without diabetes but with insulin resistance (HOMA-IR >3.0) and recent history of stroke or transient ischaemic attack, there was a lower risk of stroke or myocardial infarction with pioglitazone vs placebo [ 198 , 199 ]. Beneficial effects on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have been seen with pioglitazone [ 200 , 201 ]. However, these benefits must be balanced against possible side effects of fluid retention and congestive HF [ 196 , 197 , 202 ], weight gain [ 196 – 198 , 202 , 203 ] and bone fracture [ 204 , 205 ]. Side effects can be mitigated by using lower doses and combining TZD therapy with other medications (SGLT2i and GLP-1 RA) that promote weight loss and sodium excretion [ 199 , 206 ].

The previous consensus report and update provide detailed descriptions of the different insulins [ 5 , 6 ]. The primary advantage of insulin therapy is that it lowers glucose in a dose-dependent manner and thus can address almost any level of blood glucose. However, its efficacy and safety are largely dependent on the education and support provided to facilitate self-management [ 5 , 6 ]. Careful consideration should be given to the pharmacokinetic and pharmacodynamic profiles of the available insulins, and the matching of the dose and timing to an individual’s physiological requirements. Numerous formulations of insulin are available, with advances in therapy geared toward better mimicking physiological insulin release patterns. Challenges of insulin therapy include weight gain, the need for education and titration for optimal efficacy, risk of hypoglycaemia, the need for regular glucose monitoring, and cost. The approval of biosimilar insulins may improve accessibility at lower treatment costs. Both insulin glargine U100 and insulin degludec have demonstrated cardiovascular safety in dedicated CVOTs [ 207 , 208 ]. Comprehensive education on self-monitoring of blood glucose, diet, injection technique, self-titration of insulin and prevention and adequate treatment of hypoglycaemia are of utmost importance when initiating and intensifying insulin therapy [ 5 , 6 ]. Novel formulations and devices including prefilled syringes, auto-injectors and intranasal insufflators are now available to administer glucagon in the setting of severe hypoglycaemia and should be considered for those at risk [ 209 ].

Starting doses of basal insulin (NPH or analogue) are estimated based on body weight (0.1–0.2 U/kg per day) and the degree of hyperglycaemia, with individualised titration as needed. A modest but significant reduction in HbA 1c and the risk of total and nocturnal hypoglycaemia has been observed for basal insulin analogues vs NPH insulin [ 210 ]. Longer-acting basal insulin analogues have a lower risk of hypoglycaemia than earlier generations of basal insulin, although may cost more. Concentrated insulins allow injection of a reduced volume [ 5 ]. Cost and access are important considerations and can contribute to treatment discontinuation. Short- and rapid-acting insulin can be added to basal insulin to intensify therapy to address prandial blood glucose levels. Premixed insulins combine basal insulin with mealtime insulin (short- or rapid-acting) in the same vial or pen, retaining the pharmacokinetic properties of the individual components. Premixed insulin may offer convenience for some but reduces treatment flexibility. Rapid-acting insulin analogues are also formulated as premixes, combining mixtures of the insulin with protamine suspension and the rapid-acting insulin. Analogue-based mixtures may be timed in closer proximity to meals. Education on the impact of dietary nutrients on glucose levels to reduce the risk of hypoglycaemia while using mixed insulin is important. Insulins with different routes of administration (inhaled, bolus-only insulin delivery patch pump) are also available [ 211 – 213 ].

Combination glucagon-like peptide-1/insulin therapy

Two fixed-ratio combinations of GLP-1 RA with basal insulin analogues are available: insulin degludec plus liraglutide (IDegLira) and insulin glargine plus lixisenatide (iGlarLixi). The combination of basal insulin with GLP-1 RA results in greater glycaemic lowering efficacy than the mono-components, with less weight gain and lower rates of hypoglycaemia than with intensified insulin regimens, and better gastrointestinal tolerability than with GLP-1 RA alone [ 214 , 215 ]. In studies of people with type 2 diabetes inadequately controlled on basal insulin or GLP-1 RA, switching to a fixed-ratio combination of basal insulin and GLP-1 RA demonstrated significant improvements in blood glucose levels and achievement of glycaemic goals with fewer hypoglycaemic events than with basal insulin alone [ 216 – 220 ].

Less commonly used glucose-lowering medications

Alpha-glucosidase inhibitors improve glycaemic control by reducing postprandial glycaemic excursions and glycaemic variability and may provide specific benefits in cultures and settings with high carbohydrate consumption or reactive hypoglycaemia [ 221 , 222 ]. Other glucose-lowering medications (i.e. meglitinides, colesevelam, quick-release bromocriptine and pramlintide) are not commonly used in the USA and most are not licensed in Europe. There was no new evidence that impacts clinical practice.

Comparative efficacy of glucose-lowering agents

In a network meta-analysis of 453 trials assessing glucose-lowering medications from nine drug classes, the greatest reductions in HbA 1c were seen with insulin regimens and GLP-1 RA [ 223 ]. A network meta-analysis comparing the effects of glucose-lowering therapy on body weight and blood pressure indicates that the greatest efficacy for reducing body weight is seen with subcutaneous semaglutide followed by the other GLP-1 RA and SGLT2i, and the greatest reduction in blood pressure is seen with the SGLT2i and GLP-1 RA classes [ 224 ]. As discussed above, the novel GIP and GLP-1 RA tirzepatide was associated with greater glycaemic and weight loss efficacy than semaglutide 1 mg weekly [ 185 ].

Combination therapy

The underlying pathophysiology of type 2 diabetes is complex, with multiple contributing abnormalities resulting in a naturally progressive disease and increasing HbA 1c over time in many. While traditional recommendations have focused on the stepwise addition of therapy, allowing for clear delineation of positive and negative effects of new drugs, there are data to suggest benefits of combination approaches in diabetes care. Combination therapy has several potential advantages, including (1) increased durability of the glycaemic effect [ 225 – 227 ], addressing therapeutic inertia, (2) simultaneous targeting of the multiple pathophysiological processes characterised by type 2 diabetes, (3) impacts on medication burden, medication-taking behaviour and treatment persistence and (4) complementary clinical benefits (e.g. on glycaemic control, weight and cardiovascular risk profiles) [ 215 , 228 – 244 ].

The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) was a multicentre open-label RCT designed to test four different diabetes medication classes in people with type 2 diabetes and compare their ability to achieve and maintain HbA 1c levels <53 mmol/mol (<7%). Eligible participants had their metformin therapy optimised and were randomly assigned to receive a sulfonylurea (glimepiride), a DPP-4 inhibitor (sitagliptin), a GLP-1 RA (liraglutide) or basal insulin (insulin glargine), with the primary outcome being the time to metabolic failure, defined as the time to an initial HbA 1c level ≥53 mmol/mol (≥7%), if it was confirmed at the next visit to remain above that threshold. Starting with a mean baseline HbA 1c level of 58 mmol/mol (7.5%) before the addition of one of the four medications, over 5 years of follow-up, 71% of the cohort reached the primary metabolic outcome. Insulin glargine and liraglutide were significantly, albeit modestly, more effective at achieving and maintaining HbA 1c targets. Liraglutide exhibited a lower risk than the pooled effect of the other three medications on a composite cardiovascular outcome comprising MACE, revascularisation, or HF or unstable angina requiring hospitalisation [ 245 , 246 ].

Personalised approach to treatment based on individual characteristics and comorbidities: recommended process for glucose-lowering medication selection

People with cardiorenal comorbidities.

The 2018 ADA/EASD consensus report and 2019 update focused on the consideration of clinically important factors when choosing glucose-lowering therapy. In people with established CVD or with a high risk for CVD, GLP-1 RA were prioritised over SGLT2i. Given their favourable drug class effect in reducing HHF and progression of CKD, SGLT2i were prioritised in people with HF, particularly those with a reduced ejection fraction, or CKD. Since 2019, additional cardiovascular, kidney and HF outcomes trials have been completed, particularly with SGLT2i. In addition, updated meta-analyses have been published that compare subgroup populations based on clinically relevant characteristics, such as presence of CVD, use of background therapy with metformin, stage of CKD, history of HF and age. Collectively, this new evidence was systematically retrieved and appraised to be incorporated into these clinical practice recommendations (Fig. 3 ).

Use of glucose-lowering medications in the management of type 2 diabetes

New evidence from cardiorenal outcomes studies since the last consensus report

In the Evaluation of Ertugliflozin Efficacy and Safety CVOT (VERTIS CV), which recruited exclusively people with established CVD and type 2 diabetes, ertugliflozin was similar to placebo with respect to the primary MACE outcome and all key secondary outcomes (including a composite kidney outcome) except for HHF [ 146 ]. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study included adults with type 2 diabetes with an eGFR from 30 to <90 ml/min per 1.73 m 2 and albuminuria (30–500 mg/mmol [300–5000 mg/g] creatinine) [ 152 ]. In CREDENCE, canagliflozin treatment significantly reduced the risk of a composite primary outcome of progression to renal replacement therapy, eGFR of <15 ml/min per 1.73 m 2 , a doubling of serum creatinine level or death from cardiovascular or kidney causes. The Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) trial recruited participants with and without type 2 diabetes with an eGFR of 25–75 ml/min per 1.73 m 2 and a urinary albumin/creatinine ratio (UACR) of 20–500 mg/mmol [200–5000 mg/g] [ 153 ]. Results of the trial demonstrated a clear benefit of dapagliflozin on a composite kidney outcome, on individual kidney-specific outcomes and on cardiovascular death or HHF, both in the overall population and in the subgroup of people with diabetes (68% of participants). In CREDENCE, the SGTL2i was continued until initiation of dialysis or transplantation.

The Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial assessed sotagliflozin (a dual SGLT1i/SGLT2i, currently not approved for type 2 diabetes in the USA or the EU) in people with type 2 diabetes who had CKD and additional cardiovascular risk factors [ 147 ]. Sotagliflozin reduced the composite endpoint of cardiovascular mortality, HHF or urgent visits for HF compared with placebo, but had no effect on the composite kidney endpoint.

SGLT2i have been recently assessed in people with HF in dedicated HF outcome trials. In the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced), empagliflozin reduced the primary composite endpoint of cardiovascular mortality or HHF in people with HF and a reduced ejection fraction, irrespective of the presence of type 2 diabetes (50% of participants) [ 149 ]. Notably, this beneficial effect of empagliflozin regardless of diabetes status was consistently evident in those with a preserved ejection fraction (>40%), as demonstrated in the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Preserved Ejection Fraction (EMPEROR-Preserved) [ 151 ]. Additionally, the Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trial showed that, in people with type 2 diabetes and worsening HF, sotagliflozin reduced the total number of cardiovascular deaths or hospitalisations or urgent visits for HF compared with placebo regardless of ejection fraction [ 150 ]. All these data corroborate the salutary drug class effects of SGLT2i on HF-related outcomes in the setting of HF, irrespective of ejection fraction or diabetes status.

Finally, among GLP-1 RA, the Effect of Efpeglenatide on Cardiovascular Outcomes (AMPLITUDE-O) trial demonstrated a beneficial effect of weekly efpeglenatide on MACE and on a composite kidney outcome (decrease in kidney function or severe albuminuria) [ 247 ]. Of note, an exploratory analysis suggested a possible dose–response effect of efpeglenatide on MACE. In a CVOT of an osmotic mini-pump delivering exenatide subcutaneously (ITCA 650) over 3–6 months, ITCA 650 had a neutral effect on MACE compared with placebo over 16 months [ 248 ]. Both trials recruited individuals with type 2 diabetes with an established, or high, risk for CVD. Neither efpeglenatide nor ITCA 650 have received marketing authorisation by the FDA or EMA. As mentioned previously, the cardiovascular effects of tirzepatide are being assessed in the ongoing SURPASS-CVOT trial, with dulaglutide as an active comparator.

Evidence is emerging regarding the potential benefits of combined treatment with both an SGLT2i and a GLP-1 RA on outcomes. A post hoc analysis of data from the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) has suggested that the combination of exenatide once-weekly (EQW) plus open-label SGLT2i reduces all-cause mortality rates and attenuates the decline in eGFR compared with treatment with EQW alone [ 244 ]. Importantly, a prespecified exploratory analysis of the AMPLITUDE-O trial found comparable benefits of GLP-1 RA treatment in participants who were receiving an SGLT2i as background therapy (15% of the total trial population) and those who were not [ 241 ].

Results from evidence syntheses

Recent cardiovascular, kidney and HF outcomes trials have been incorporated in updated meta-analyses assessing SGLT2i or GLP-1 RA, both in the overall trial populations and in clinically relevant subgroups. Pairwise meta-analyses of SGLT2i CVOTs verified that SGLT2i reduced MACE, HHF and a composite kidney outcome in the overall population vs placebo [ 142 , 249 ]. Regarding GLP-1 RA, a meta-analysis of relevant CVOTs demonstrated the favourable effect of GLP-1 RA vs placebo on MACE and its individual components including stroke, HHF and a composite kidney outcome including severe albuminuria [ 250 , 251 ]. It should be noted, however, that the overall effect estimate for HHF seems to have been driven by CVOTs of albiglutide and efpeglenatide, which are not available for clinical use. Similarly, the overall effect estimate for the composite kidney outcome was most likely driven by the effect of GLP-1 RA on severe albuminuria only and not on hard kidney endpoints. Of note, the beneficial kidney effects of canagliflozin, dapagliflozin and empagliflozin were also evident for hard kidney outcomes including chronic dialysis and kidney transplantation [ 252 ]. When individual components of MACE were analysed separately, GLP-1 RA reduced all three outcomes, with a more pronounced effect on stroke followed by cardiovascular death and myocardial infarction [ 253 , 254 ]. Conversely, SGLT2i, albeit reducing cardiovascular death, had a neutral effect on stroke [ 142 , 255 ].

The applicability of data to support selection of subgroups has been questioned because of a lack of RCTs focusing on specific populations, such as those using vs those not using metformin. This has been examined in subgroup analyses of recent meta-analyses [ 6 ]. It should be noted that findings of subgroup analyses should not be regarded as conclusive, their credibility should always be formally assessed and, ideally, they should be complemented by findings from relevant RCTs [ 7 , 8 ]. Recently published subgroup analyses have explored the role of background use of metformin as a potential effect modifier of cardiovascular benefit. For SGLT2i, no differences were observed in MACE, cardiovascular death or HHF, major kidney outcomes and mortality rates in those using vs those not using metformin [ 174 ]. Further, for GLP-1 RA, no differences were shown in MACE and mortality outcomes [ 256 – 258 ] in metformin users compared with non-users. The similarity of the direction and magnitude of the effect estimates between individual trials, the number of trials that contributed data, mostly to within-trial comparisons, and the statistical analyses implemented support the credibility of the conclusions favouring use of SGLT2i or GLP-1 RA in individuals with compelling indications independent of the use of metformin.

Similarly, other subgroup analyses have explored the role of baseline cardiovascular risk as a potential effect modifier regarding the effect of treatment on MACE, HHF or kidney outcomes. Consistency of findings from between-trial and within-trial comparisons, formal statistical testing verifying the absence of a subgroup effect and the similarity of baseline cardiovascular risk across different cardiovascular risk categories between individual CVOTs despite the use of seemingly different enrolment criteria suggest the benefits of the use of SGLT2i or GLP-1 RA in people with type 2 diabetes and established CVD and in those at high cardiovascular and/or kidney risk [ 142 , 253 ]. Of note, the level of certainty in this recommendation is higher for the former subgroup, because some CVOTs recruited exclusively people with established CVD, while fewer events were recorded for participants with cardiovascular risk factors only in CVOTs that recruited both subgroup populations. In addition, the definition used for risk factors was not identical among CVOTs. However, in general it comprised age ≥55 years plus two or more additional risk factors (including obesity, hypertension, smoking, dyslipidaemia or albuminuria). Furthermore, in terms of absolute effects, the cardiovascular benefits of GLP-1 RA and SGLT2i were less pronounced in people with three or more cardiovascular risk factors than in those with established CVD. This was shown in a network meta-analysis that estimated the absolute effects of treatment with GLP-1 RA or SGLT2i on cardiovascular and kidney outcomes for different categories of baseline cardiovascular risk by combining relative effect estimates with baseline risk estimates [ 259 ].

Subgroup meta-analyses based on participants’ kidney function indicated that the salutary effects of SGLT2i on MACE, cardiovascular death or HHF, and a composite kidney outcome (substantial loss of kidney function, end-stage kidney disease or death due to kidney disease) do not significantly differ among subgroups based on eGFR [ 142 , 252 ]. Moreover, the overall effect on MACE and the kidney outcome seemed to be consistent across the three subgroups (normal urine albumin excretion rate [UACR <3.0 mg/mmol (<30 mg/g)], moderate albuminuria [UACR 3.0–30 mg/mmol (30–300 mg/g)] and severe albuminuria [UACR ≥30 mg/mmol (≥300 mg/g)]) [ 252 ]. In addition, no modification of the effect estimates for MACE, cardiovascular death or HHF, and the composite kidney outcome was observed for SGLT2i in subgroup meta-analyses based on history of HF [ 142 ]. Regarding GLP-1 RA, a subgroup meta-analysis found that their effect on MACE did not significantly differ between people with an eGFR <60 ml/min per 1.73m 2 and those with an eGFR ≥60 ml/min per 1.73 m 2 [ 253 ]. Moreover, the effect on MACE did not appear to differ between people with lower and higher HbA 1c at baseline, both for SGLT2i and for GLP-1 RA [ 142 , 253 ]. Nevertheless, the conclusions of all subgroup analyses should be regarded with increased caution because of the small number of trials contributing data to within-trial comparisons, heterogeneity between individual trials or lack of formal statistical testing.

Comparative effectiveness data

While CVOTs and pairwise meta-analyses allow inferences about the overall efficacy and safety of novel glucose-lowering therapies, none of them directly compared SGLT2i with GLP-1 RA. However, the comparative effectiveness of the two drug classes has been assessed in three recent network meta-analyses, which found that, in people with type 2 diabetes, SGLT2i were superior to GLP-1 RA in reducing HHF and a composite kidney outcome, while GLP-1 RA seemed more efficacious in reducing the risk of stroke [ 223 , 259 , 260 ]. No important differences between the two drug classes were evident in terms of mortality rates and other cardiovascular outcomes. These conclusions are further supported by observational data from a large population-based cohort study in the USA, which showed that SGLT2i reduced HHF compared with GLP-1 RA in people both with CVD (HR 0.71; 95% CI 0.64, 0.79) and without CVD (HR 0.69; 95% CI 0.56, 0.81). Differences between the two drug classes with regard to mortality rates and other cardiovascular outcomes were not clinically important [ 261 ].

In terms of differences among individual SGLT2i and GLP-1 RA, choice should be based on country-specific label indications and data on efficacy, safety and outcome benefits considering within-class heterogeneity. No CVOT is available focusing on people with type 2 diabetes who are at low cardiovascular risk. Some inferences about the effect of glucose-lowering medications as primary cardiovascular prevention in populations with low cardiovascular risk can be made from network meta-analyses, suggesting that no agent or drug class has a notable beneficial effect on cardiovascular events in low-risk individuals with diabetes [ 223 , 259 ].

Additional clinical considerations

Age: older people with diabetes.

Type 2 diabetes represents a model of accelerated biological ageing. As such, type 2 diabetes is associated with declines in physical capacity, underpinned by dysfunction within skeletal muscle. The ability of people with type 2 diabetes to undertake simple functional exercises in middle-age has been shown to be like those at least a decade older within the general population. Importantly, this places people living with type 2 diabetes at a high risk of impaired physical function and frailty, which in turn reduces quality of life and increases healthcare use. As such, frailty is increasingly recognised as a major complication of type 2 diabetes and an important target for treatment [ 112 , 262 ].

Informed decisions regarding treatment of older (>65 years) adults with diabetes are limited by the under-representation of such participants in clinical trials. When older individuals have been studied, analyses from trials such as Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) suggested that more frail individuals have worse outcomes and benefit less from intensive control of blood glucose levels and blood pressure [ 263 ]. However, our confidence in selecting medications to improve outcomes has improved, in part because of regulatory requirements to include older people in trials to determine the efficacy and safety of new drugs for diabetes [ 264 , 265 ]. For example, a recent meta-analysis of 11 large outcomes trials found that, in those aged 65 years or older, the cardiovascular and/or kidney outcomes benefits of GLP-1 RA or SGLT2i therapy were consistent with the effects seen in the overall trial population [ 266 ]. Therefore, recommendations for the selection of medications to improve cardiovascular and kidney outcomes do not differ for older people. Older age should not be an obstacle to treatment of individuals with established or high risk for CVD. However, medication choices for people who are frail or who have multiple comorbidities may require modification for safety and tolerability. People with diabetes should also understand and be able to appropriately modify use of their prescribed medications during times of illness. Frailty is associated with poorer prognosis, and some attenuation of benefit from intensive glucose-lowering and blood pressure-lowering treatments has been demonstrated in frail individuals [ 263 ]. Consideration of de-prescribing medication to avoid unnecessary medication or medication associated with harm, such as hypoglycaemia and hypotension, is important in such populations.

Age: younger people with diabetes

Rates of impaired glucose tolerance and/or impaired fasting glucose and type 2 diabetes have increased significantly in the adolescent and young adult population, in concert with increases in obesity [ 267 ]. It is estimated that one in five adolescents and one in four young adults now have impaired glucose tolerance and/or impaired fasting glucose in the USA, which in turn increases the risks of progression to type 2 diabetes, CKD and cardiovascular complications [ 267 ]. Minority populations are particularly affected, with half or more of newly diagnosed cases of type 2 diabetes in childhood and adolescence occurring in Hispanic, non-Hispanic Black, Asian/Pacific Islander and American Indian populations [ 268 ]. Affected young people have a more rapid deterioration in blood glucose levels, an attenuated response to diabetes medication and more rapid development of diabetes complications [ 269 – 273 ]. Early disease onset, higher levels of hyperglycaemia, and the multiple cardiometabolic risk factors found in adolescents and young adults with impaired glucose tolerance and/or impaired fasting glucose and diabetes all contribute to an increase in risk of adverse outcomes [ 267 ]. Most children and adolescents who develop type 2 diabetes will have microvascular complications by young adulthood [ 274 ]; in addition, a recently identified 25% increase in the risks of hyperglycaemic crises, acute myocardial infarction, stroke and lower extremity amputation over a 5 year period was most notable in people with diabetes aged 18–44 years [ 275 ]. Younger people with type 2 diabetes should be considered at very high risk for complications and treated correspondingly. Early use of combination therapy may be considered, as the Vildagliptin Efficacy in combination with metfoRmIn for earlY treatment of type 2 diabetes (VERIFY) trial findings suggest that this approach provides superior and more durable effects on blood glucose levels than metformin monotherapy in people with both early-onset (age <40 years) and later-onset diabetes [ 276 ]. Most of the evidence for health behaviour interventions, glucose-lowering approaches and the effectiveness of medications to improve cardiovascular and kidney outcomes in younger people with diabetes is poorly understood because of the very limited enrolment of this group in completed trials [ 15 ]. Beyond the scope of this statement, there are data emerging on the use of GLP-1 RA and SGLT2i in children that suggest glycaemic benefit; however, the durability of this effect and any impact on cardiorenal outcomes in children and young adults remain unknown.

Race and ethnicity

Although specific populations are disproportionately affected by diabetes, they are consistently under-represented in outcomes and other trials. A meta-analysis of six large cardiovascular and kidney outcomes trials found that non-White participants had higher rates of cardiovascular and other comorbidities than the White cohort but comprised only about 21% of the overall enrolled trial populations. Importantly, both non-White and White subgroups had significant reductions in the risk of cardiovascular death or HHF with SGLT2i therapy compared with placebo (OR 0.66 and 0.82, respectively) [ 277 ]. The increased burden of complications in under-represented populations with diabetes should be factored into personalised treatment plans, and beneficial medications should be used irrespective of race or ethnicity. Ongoing and future trials should recruit to be representative of the overall population of people with diabetes, so that the effects of interventions in understudied subgroups may be better ascertained [ 278 , 279 ].

Sex differences

In women with reproductive potential, the use of highly effective contraception should be ensured, such as long-acting reversible contraception (intrauterine device or progesterone implant), prior to prescribing medications that may adversely affect a fetus. Diabetes significantly increases the risk of cardiovascular complications in both sexes, and CVD causes most hospitalisations and deaths in women and men with diabetes [ 280 , 281 ]. In the general population, women are at lower risk for cardiovascular events than men of the same age; however, this vascular protection or advantage is reduced in women who develop type 2 diabetes [ 282 , 283 ]. In fact, the increase in relative risk of CVD due to type 2 diabetes is greater in women than in men [ 284 – 286 ]. Despite this, women have been under-represented in recent CVOTs in diabetes, comprising between 28.5% and 35.8% of participants [ 287 ]. This analysis also described differing patterns of cardiovascular complications in women compared with men, and poorer management of cardiovascular risk factors in women [ 287 ]. Within-trial analyses and meta-analyses suggest that there are likely no between-sex differences in outcomes achieved with SGLT2i and GLP-1 RA therapy [ 288 , 289 ]. Continued efforts should be made to enrol women in outcomes trials and to identify and address modifiable cardiovascular risk factors in women with diabetes.

Obesity and weight-related comorbidities, particularly NAFLD and NASH

The care of people with diabetes who have weight-related comorbidities such as NAFLD, HF with preserved ejection fraction or obstructive sleep apnoea should include strategies intended to result in weight loss. People with type 2 diabetes frequently have NAFLD and are at increased risk for progression to more severe stages of liver disease, including NASH, hepatic fibrosis and cirrhosis [ 290 ]. The management of type 2 diabetes in people with NASH should include lifestyle modification with a goal of weight loss, including strong consideration of medical and/or surgical approaches to weight loss in those at higher risk of hepatic fibrosis [ 291 ]. Pioglitazone, GLP-1 RA therapy and metabolic surgery have all been shown to reduce NASH activity; pioglitazone therapy and metabolic surgery may also improve hepatic fibrosis [ 188 , 292 – 298 ].

Although not licensed for this purpose, it has therefore been suggested that people with type 2 diabetes at intermediate to high risk of fibrosis should be considered for treatment with pioglitazone and/or a GLP-1 RA with evidence of benefit [ 291 , 299 ]. Although SGLT2i therapy has also been shown to reduce elevated levels of liver enzymes and hepatic fat content in people with NAFLD, at this time there is less evidence to support use of this class of drug as treatment for NASH [ 300 – 302 ]. NAFLD, and in particular NASH, is also associated with an increased risk of cardiovascular complications; therefore, people with NAFLD should have their cardiovascular risk factors assessed and managed to minimise this risk [ 303 ].

SGLT2i have been shown to reduce incident obstructive sleep apnoea in two SGLT2i CVOTs based on adverse event reporting [ 304 , 305 ]. However, it is not clear that the data collected on incident obstructive sleep apnoea in these trials were complete, or that the benefit is mediated through changes in weight.

Consensus recommendations

All people with type 2 diabetes should be offered access to ongoing DSMES programmes.

Providers and healthcare systems should prioritise the delivery of person-centred care.

Optimising medication adherence should be specifically considered when selecting glucose-lowering medications.

MNT focused on identifying healthy dietary habits that are feasible and sustainable is recommended in support of reaching metabolic and weight goals.

• Adults with type 2 diabetes should engage in physical activity regularly (>150 min/week of moderate- to vigorous-intensity aerobic activity) and be encouraged to reduce sedentary time and break up sitting time with frequent activity breaks.
• Aerobic activity should be supplemented with two to three resistance, flexibility and/or balance training sessions/week. Balance training sessions are particularly encouraged for older individuals or those with limited mobility/poor physical function.

Metabolic surgery should be considered as a treatment option in adults with type 2 diabetes who are appropriate surgical candidates with a BMI ≥40.0 kg/m 2 (BMI ≥37.5 kg/m 2 in people of Asian ancestry) or a BMI of 35.0–39.9 kg/m 2 (32.5–37.4 kg/m 2 in people of Asian ancestry) who do not achieve durable weight loss and improvement in comorbidities (including hyperglycaemia) with non-surgical methods.

In people with established CVD, a GLP-1 RA with proven benefit should be used to reduce MACE, or an SGLT2i with proven benefit should be used to reduce MACE and HF and improve kidney outcomes.

In people with CKD and an eGFR ≥20 ml/min per 1.73 m 2 and a UACR >3.0 mg/mmol (>30 mg/g), an SGLT2i with proven benefit should be initiated to reduce MACE and HF and improve kidney outcomes. Indications and eGFR thresholds may vary by region. If such treatment is not tolerated or is contraindicated, a GLP-1 RA with proven cardiovascular outcomes benefit could be considered to reduce MACE and should be continued until kidney replacement therapy is indicated.

In people with HF, SGLT2i should be used because they improve HF and kidney outcomes.

In individuals without established CVD but with multiple cardiovascular risk factors (such as age ≥55 years, obesity, hypertension, smoking, dyslipidaemia or albuminuria), a GLP-1 RA with proven benefit could be used to reduce MACE, or an SGLT2i with proven benefit could be used to reduce MACE and HF and improve kidney outcomes.

In people with HF, CKD, established CVD or multiple risk factors for CVD, the decision to use a GLP-1 RA or SGLT2i with proven benefit should be independent of background use of metformin.

SGLT2i and GLP-1 RA reduce MACE, which is likely to be independent of baseline HbA 1c . In people with HF, CKD, established CVD or multiple risk factors for CVD, the decision to use a GLP-1 RA or an SGLT2i with proven benefit should be independent of baseline HbA 1c .

In general, selection of medications to improve cardiovascular and kidney outcomes should not differ for older people.

In younger people with diabetes (<40 years), consider early combination therapy.

In women with reproductive potential, counselling regarding contraception and taking care to avoid exposure to medications that may adversely affect a fetus are important.

Putting it all together: strategies for implementation

Importance of integrated care.

The overall goal of the management of type 2 diabetes is to maintain quality of life and avoid complications. The management approach must be holistic and multifactorial and account for the lifelong nature of type 2 diabetes (Figs 1 , 3 , 4 ). The person living with type 2 diabetes should be at the centre of care. The structure and organisation of the healthcare team will vary across systems but generally involves multiple disciplines, including the primary care provider, diabetologist, diabetes care and education specialist, registered dietitian/nutritionist, pharmacists, nurses and other specialists as needed (e.g. dentist, eye care professional, podiatrist, mental health provider, cardiologist, nephrologist, neurologist, hepatologist, sleep medicine specialist and pain management specialist) [ 306 ]. Technology is now an important tool to enhance communication, support and monitoring. Communication between people living with type 2 diabetes and healthcare team members is at the core of integrated care, and clinicians must recognise the importance of language in this communication.

Holistic person-centred approach to T2DM management

Practical tips for clinicians (Supplementary Fig. 1 )

Acknowledge the lifelong and evolving nature of type 2 diabetes.

Identify and coordinate with the team.

Know your local resources.

Language matters in diabetes care.

Individualisation of care

The integrated care of type 2 diabetes must consider the person with diabetes as an individual (Figs 1 , 3 , 4 ) with respect to specific preferences and values, social determinants of health, barriers to care, comorbid conditions, degree of hyperglycaemia, risks of complications and susceptibility to medication side effects. Attention should be given to how the balance of risks and benefits of each intervention is communicated to each person living with diabetes. ‘Risk estimator’ tools, especially for CVD risk, may also be helpful, but when using these tools one must be aware that they work best when they are derived from and/or are validated in a population similar to the population in which they are applied [ 307 ]. These risk estimator tools are often developed in populations that exclude younger and older people and under-represent women and various minority populations. Finally, shared decision making is essential to incorporating an individual’s preferences and values when formulating a management plan.

Social determinants of health must be assessed and addressed [ 47 ] to achieve health equity in diabetes. Health systems must ensure equity in the delivery of all diabetes care, including access to the more expensive, organ-protecting pharmacotherapies (SGLT2i and GLP-1 RAs) and technologies (e.g. CGM).

Many people living with type 2 diabetes have multiple comorbidities, some related to diabetes, such as obesity, hypertension, dyslipidaemia, cardiorenal disease, NASH/NAFLD and mental health problems. Other important conditions whose relationship to diabetes is not as well established, such as chronic obstructive pulmonary disease and cancer, are prevalent. Attention to these comorbidities should be paid throughout the lifespan of the person living with diabetes, as such comorbidities may impact the tailoring and implementation of the holistic plan for diabetes management, including choice of glucose-lowering medication.

Importantly, diabetes is associated with cognitive decrements, which can substantially impact management [ 308 , 309 ]. Further, long-term hyperglycaemia is associated with worsening cognitive decline. Screening for cognitive impairment should be performed when risk factors are identified such as frequent hypoglycaemia, difficulty with diabetes self-management or unexplained falls. People with cognitive impairment should be referred for additional support. Other conditions such as serious mental illness and substance use disorders must also be identified and managed appropriately in the holistic approach to diabetes. Mental illness, including depression, is associated with an increased risk of diabetes and with poorer prognosis but may also complicate diabetes management and be a barrier to self-management.

Consider each person living with diabetes as an individual with specific context, risks and preferences.

Healthcare systems should monitor and address inequity in the delivery of evidence-based interventions for type 2 diabetes.

Assess and address social determinants of health for each individual living with diabetes, particularly in those not achieving goals.

Incorporate comorbidities when developing and implementing the management plan.

DSMES is critical to integrated, holistic, person-centred care in type 2 diabetes [ 19 – 21 , 23 ] and is as important to the management plan as the selection of medication. DSMES should be offered on an ongoing basis, should be provided by trained diabetes care and education specialists and can be delivered using multiple approaches and in a variety of settings (Supplementary Table 1 ) [ 20 , 31 ]. The care team must be aware of the available local DSMES resources and how to access them. Importantly, DSMES is complementary to but does not replace MNT (see below) [ 310 ] or referral for mental health services when they are warranted [ 49 ].

Embrace DSMES as being as important as other aspects of diabetes care such as pharmacotherapy.

Identify and know how to access your local DSMES resources.

Impress on the person and the healthcare team the importance of DSMES in the ongoing holistic approach to the management of type 2 diabetes.

Initiate or refer for DSMES at diagnosis, annually, with changes in social or health status and with transitions of care or life situation.

Facilitating healthy behaviours and weight management

Promotion of healthy behaviours is central to the holistic management of type 2 diabetes and should be addressed at the time of diagnosis and throughout the course of diabetes. Healthy behaviours include healthy nutrition, regular physical activity, adequate sleep and smoking cessation. Health behaviours should always be assessed and addressed when glycaemic targets are not met and when new pharmacotherapy or interventions (e.g. metabolic surgery) are initiated.

All individuals with type 2 diabetes should be offered MNT to develop a personal food plan in the context of diabetes. The need for additional dietary advice should be re-evaluated over time [ 310 ]. There is no single dietary pattern recommended for all individuals with type 2 diabetes; many dietary patterns can be effective for achieving treatment goals and a structured food plan should be based on an individual person’s preferences and context.

Explicit physical activity and minimisation of sedentary time should be the focus of the physical activity regimen for people living with type 2 diabetes (Fig. 2 ). Individual preferences and circumstances should inform the specific activity regimen. A reasonable target for physical activity is at least 150 min/week. In addition to these activity minutes, breaking up sedentary time with activity breaks (e.g. 5 min activity break every hour) can be beneficial [ 101 ]. A gradual increase in overall volume and intensity of activity does not require medical clearance [ 101 ]. Additional clinical assessment may be warranted in those with moderate-to-severe diabetic retinopathy, diabetic kidney disease, peripheral neuropathy and unstable HF and for those prescribed insulin or with a history of hypoglycaemia [ 101 ]. Individual preferences, motivations and circumstances should inform choice.

Weight management should be a central focus for individuals with type 2 diabetes with overweight or obesity, with individualised weight loss goals. For most people, a target of at least 5% weight loss is reasonable and can be expected to have clinical benefits. Substantial (>10%) weight loss and weight loss early in the course of type 2 diabetes increase the chance of remission of disease [ 50 ]. The use of glucose-lowering agents that provide significant weight loss, particularly GLP-1 RA with high weight loss efficacy, should be considered as they can often provide 10–15% weight loss or more. Metabolic surgery, which is most effective when performed early during diabetes, can be considered in those without a sufficient response to non-surgical weight loss interventions based on the specific context and preferences and should be accompanied by health behaviour interventions. The benefits of metabolic surgery need to be balanced against its potential adverse effects, which vary by procedure and include surgical complications, late metabolic or nutritional complications and impact on psychological health [ 5 , 6 , 127 ]. People being considered for metabolic surgery should be evaluated for comorbid psychological conditions and social and situational circumstances that may interfere with surgery outcomes. People who undergo metabolic surgery should receive long-term medical and behavioural support. Metabolic surgery should be performed in high-volume centres with experienced multidisciplinary teams [ 127 ].

SMART (specific, measurable, attainable, relevant, time-based) goals are more effective for achieving behaviour change than non-specific recommendations [ 311 ]. An ‘all or none’ approach related to behavioural goals should be avoided as any improvement in healthy behaviours can have a positive impact in diabetes [ 93 , 312 ]. Self-monitoring of achievements (e.g. physical activity monitoring and weight measurement) is crucial to the achievement of health behaviour goals (Fig. 1 ). Behavioural health specialists or psychologists with specific training in behaviour change interventions can be of particular value as members of the team to help the person with type 2 diabetes achieve goals.

Practical tips for clinicians (Supplementary Fig. 2 )

Specific health behaviour and weight management goals should be agreed on between the person with type 2 diabetes and the care team; shared decision making is an important component of this discussion.

Emphasise self-monitoring behaviours and review data collected (e.g. glucose monitoring, weight, tracking physical activity) in clinical visits to convey their importance in achieving the desired health behaviour goals.

People taking insulin or a sulfonylurea should be educated about the risk, symptoms and treatment of hypoglycaemia when undertaking physical activity or adopting a specific nutritional plan; prescribe glucagon in people at risk for severe hypoglycaemia.

DSMES and MNT can help the person living with diabetes to identify and address barriers to implementing healthier behaviours.

Choice of glucose-lowering medication

The choice of glucose-lowering agents should be directed by the individual profile of the person with type 2 diabetes, in particular the presence of comorbidities, risk of side effects, preferences and context (Figs 3 , 4 ). Pharmacological treatment of hyperglycaemia must be integrated in DSMES and accompanied by a focus on healthy behaviours from diagnosis onwards. This should be integrated as part of a holistic, multifactorial approach to type 2 diabetes that includes weight, blood pressure and lipid management (Fig. 4 ).

Whereas the pursuit of glycaemic control and the pursuit of organ-specific (e.g. heart and kidney) protection are complementary and not mutually exclusive, clinicians should not confuse the discussion of choice of agents for their glucose-lowering effect with the discussion of choice of specific agents for their direct organ-protecting effect. Some agents, in particular SGLT2i, have been shown to protect organs (heart, kidney) partly independently of their glucose-lowering effect, as this organ protection also occurs in those not affected by type 2 diabetes.

Based on these principles, regardless of HbA 1c level or the presence of other glucose-lowering agents, all individuals with diabetes and established or subclinical CVD should be prescribed an agent with proven cardiovascular benefit from the GLP-1 RA class or SGLT2i class [ 5 , 6 ]. The evidence for cardiovascular benefits of GLP-1 RA and SGLT2i in those with only risk factors for CVD, based on MACE (myocardial infarction, stroke or cardiovascular death), is less robust, as fewer people with lower event rates are included in studies [ 313 – 315 ]. Furthermore, it is important to recognise that the predicted absolute benefit of an intervention is dependent on the absolute risk and thus those with prior CVD events are more likely to experience a benefit over intermediate time frames than those with cardiovascular risk factors only. Through shared decision making, considering an individual’s lifelong CVD risk, introduction of a GLP-1 RA or SGLT2i with proven cardiovascular benefit into the regimen for a person with CVD risk factors can be considered in the context of increased treatment burden and potential side effects with lower absolute risk reduction.

All individuals with diabetes and CKD (eGFR <60 ml/min per 1.73 m 2 or UACR >3.0 mg/mmol [>30 mg/g]) should receive an agent with proven kidney benefit from the SGLT2i class (or GLP-1 RA class if SGLT2i are contraindicated or not preferred or their use is not permitted under license). Likewise, those with HF (HF with reduced ejection fraction or HF with preserved ejection fraction) should receive an agent from the SGLT2i class with proven benefit for HF. In both instances, the goal of organ protection with SGLT2i or GLP-1 RA should be independent of background glucose-lowering therapies, current HbA 1c level or target HbA 1c level (Figs 3 , 4 ).

While there is compelling evidence to support a place for SGLT2i and the GLP-1 RA class in the treatment of many people with type 2 diabetes based on their direct organ-protecting effects, it is acknowledged that to date these agents are expensive. In the setting of resource constraints, prioritisation of the highest risk groups for access to these agents may be needed, with consideration of absolute risk reduction in addition to relative risk reductions.

Evidence on specific agents and their effects on other comorbidities, such as NAFLD, is emerging. For those with NAFLD/NASH at high risk of fibrosis, pioglitazone could be considered. There is emerging evidence for benefits of metabolic surgery and three classes of glucose-lowering therapy (GLP-1 RA, SGLT2i, and GIP and GLP-1 RA) [ 188 , 292 – 298 , 316 ].

Overall, for treatment of hyperglycaemia, metformin remains the agent of choice in most people with diabetes, based on its glucose-lowering efficacy, minimal risk of hypoglycaemia, lack of weight increase and affordability. Often, monotherapy with metformin will not suffice to maintain glucose levels at target. As proposed in the previous consensus report and update [ 5 , 6 ], other classes of agents are useful in combination with metformin or when metformin is contraindicated or not tolerated. Selection of other glucose-lowering agents will be determined by the balance between the glucose-lowering efficacy and the side effect profile of the individual agents (see Table 1 ).

Special attention needs to be given to populations in which hypoglycaemia is most dangerous, for example people with frailty, in whom agents without risk of hypoglycaemia need to be prioritised. If sulfonylureas or insulin are used, consideration of less stringent targets in such settings is prudent and de-prescribing if asymptomatic or severe hypoglycaemia ensues.

Finally, it needs to be stated that the evidence on organ-protecting or glucose-lowering effects of specific pharmacotherapies in specific subpopulations (e.g. younger and older people, women and various racial/ethnic groups) continues to be limited. This lack of evidence is, however, not a reason to withhold these medications in these subpopulations, given their proven benefits in large general populations.

Providers should continually update their knowledge on the efficacy and side effects of diabetes pharmacotherapy (see Table 1 ).

Identify relevant comorbidities (e.g. obesity, CVD, HF, CKD, NAFLD).

Assess the profile of the person with diabetes (e.g. younger age, frailty, limited life expectancy, cognitive impairment, social determinants of health).

Consider risk factors for medication adverse events (e.g. hypoglycaemia, volume depletion, genital infections, history of pancreatitis).

Prioritise the use of organ-protective medications (GLP-1 RA, SGLT2i, TZD) in those with cardiorenal disease or NASH or at high risk.

Proactive care: avoiding inertia

Reassessment of individual glycaemic targets and their achievement at regular intervals is key (Figs 1 , 3 , 4 ). When targets are not met, in addition to addressing health behaviours and referral to DSMES, the intensification of glucose-lowering medication by combining agents with complementary mechanisms of action should be pursued. Traditionally, a stepwise approach was advocated, in which a new agent is added to the existing regimen, but evidence is growing to support a more proactive approach in many, by combining glucose-lowering agents from initial diagnosis [ 6 ].

Early use of combinations of agents allows tighter glucose control than monotherapy with the individual agents, and thus combinations of agents are indicated in those who have HbA 1c levels >16.3 mmol/mol (>1.5%) above their target at diagnosis (e.g. ≥70 mmol/mol [8.5%] in most) [ 6 ]. In particular, among young adults with type 2 diabetes, immediate and sustained glycaemic management should be pursued, aiming for HbA 1c <53 mmol/mol (7%) (or even lower). This presents the best opportunity to avoid complications of diabetes across the lifespan. Moreover, the pathophysiology of micro- and macrovascular damage shares more commonality than usually thought, suggesting that the prevention of microvascular disease may, in the long term, contribute to a reduction in macrovascular complications as well [ 317 ].

The knowledge base guiding clinicians beyond dual therapy in type 2 diabetes is still limited. In general, intensification of treatment beyond two medications follows the same general principles as the addition of a second medication, with the assumption that the effectiveness of third and fourth medications will be generally less than when they are used alone. Whereas solid evidence exists for combining SGLT2i and GLP-1 RA for weight and glucose lowering, emerging data suggest promise for combined effects on cardiorenal outcomes [ 228 ].

As more medications are added, there is an increased treatment burden and risk of adverse effects. It is important to consider medication interactions and whether regimen complexity may become an obstacle to adherence. Fixed-dose combination preparations can improve medication-taking behaviours. Finally, with each additional medication comes increased costs, which can affect medication-taking behaviour and medication effectiveness [ 318 – 326 ].

Response to all therapies should be reviewed at regular intervals, including the impact on efficacy (HbA 1c , weight), safety and organ protection. While most people with diabetes require intensification of glucose-lowering medications, some require medication reduction or discontinuation, particularly if the therapy is ineffective or associated with side effects such as hypoglycaemia or when glycaemic goals have changed because of a change in clinical circumstances (e.g. development of comorbidities or even healthy ageing). Medication should be stopped, or the dose reduced, if there are minimal benefits or if harm outweighs any benefit. Ceasing or reducing the dose of medications that have an increased risk of hypoglycaemia is suggested when any new glucose-lowering treatment (behavioural or medication) is started and the individual’s glycaemic levels are close to target [ 66 ]. HbA 1c levels below 48 mmol/mol (6.5%) or substantially below the individualised glycaemic target as well as any increased risk of hypoglycaemia should prompt stopping or reducing the dose of medications associated with an increased risk of hypoglycaemia.

Consider initial combination therapy with glucose-lowering agents, especially in those with high HbA 1c at diagnosis (i.e. >70 mmol/mol [>8.5%]), in younger people with type 2 diabetes (regardless of HbA 1c ) and in those in whom a stepwise approach would delay access to agents that provide cardiorenal protection beyond their glucose-lowering effects.

Avoid therapeutic inertia and re-evaluate health behaviours, individuals’ medication-taking behaviours and side effects of agents at every clinic visit.

When additional glycaemic control is needed, incorporate, rather than substitute, glucose-lowering therapies with complementary mechanisms of action.

Consider fixed-dose combinations to reduce prescription burden.

Consider de-intensification of therapy, e.g. in frail older adults and in the setting of hypoglycaemia-causing medications, in those with glycaemic metrics substantially better than target.

Place of insulin in type 2 diabetes

Insulin is a useful and effective glucose-lowering agent (Fig. 5 ). When glycaemic measurements do not reach targets, and insulin is the best choice for the individual, its introduction should not be delayed. When clinicians are not familiar with insulin use, referral to specialist care is indicated. However, with the growing evidence supporting use of particular agents in people with type 2 diabetes with specific profiles (comorbidities, overweight/obesity) and with the availability of multiple glucose-lowering agents with good efficacy and acceptable side effect profiles, the initiation of insulin can be postponed in many to later stages of the disease. GLP-1 RA should be considered in all when no contraindications are present before initiation of insulin therapy, as they allow lower glycaemic targets to be reached with a lower injection burden and lower risk of hypoglycaemia and weight gain than with insulin alone.

Place of insulin 1

The preferred way of initiating insulin in people with type 2 diabetes is to add basal insulin to the existing pharmacological therapy, in conjunction with revisiting health behaviours and re-referral to DSMES. However, agents that cause hypoglycaemia in themselves, such as sulfonylureas, should be discontinued once insulin is started. Technologies allowing continuous monitoring of glucose levels without finger sticking have clear advantages in those on insulin. Other support tools and systems such as apps guiding insulin dose adaptation or phone-based guidance can also be helpful.

In specific circumstances, insulin may be the preferred agent for glucose lowering, specifically in the setting of severe hyperglycaemia (HbA 1c >86 mmol/mol [>10%]), particularly when associated with weight loss or ketonuria/ketosis and with acute glycaemic dysregulation (e.g. during hospitalisation, surgery or acute illness), in underweight people or when the diagnosis of type 1 diabetes is suspected.

If affordable, basal insulin analogue formulations are preferred to NPH insulin because of their reduced risk of hypoglycaemia, particularly nocturnal hypoglycaemia, when titrated to the same fasting glucose target [ 327 ]. Basal insulins are typically administered before bedtime but, with newer analogues, more flexibility in the timing of insulin injection is possible (i.e. any time of the day).

In some, as the disease progresses, despite titration of the basal insulin to correct fasting hyperglycaemia (typically more than 0.5 U/kg), mealtime insulin may have to be added to meet glycaemic targets, particularly postprandial glucose [ 328 ]. Mealtime insulin may be required to enhance postprandial blood glucose levels and achieve HbA 1c targets. Therapeutic inertia in intensification of insulin therapy should be avoided and, when clinicians are not familiar with multiple daily injection therapy, referral to specialist care and/or DSMES is warranted. A straightforward way to introduce mealtime insulin is to start with a short- or rapid-acting insulin injection before the meal associated with the largest glucose excursion. Adding mealtime rapid-acting insulin requires increased DSMES and self-monitoring of glucose levels and adds complexity and cost to the therapy. In contrast to basal insulin analogues, the evidence supporting the choice of mealtime rapid-acting insulin analogues is less clear [ 329 ]. Another simpler and still popular way of combining mealtime and basal insulin components is using premixed insulins. Insulin analogue-based combinations have the advantage of resulting in fewer hypoglycaemic events and weight gain than are typically observed with human premixed insulin [ 330 ].

Finally, it needs to be re-emphasised that, in all insulin-treated people with type 2 diabetes, agents associated with cardiorenal protection or weight reduction should be kept in the treatment regimen whenever possible [ 331 ]. The combination of a basal insulin analogue and GLP-1 RA in one injection may be a simple way to reduce the burden and complexity of treatment [ 332 ].

Practical tips for clinicians (Supplementary Fig. 3 )

The use of a GLP-1 RA should be considered prior to initiation of insulin.

When initiating insulin, start with a basal insulin and intensify the dose in a timely fashion, titrating to achieve an individualised fasting glycaemic target set for every person.

When insulin is initiated, continue organ-protective glucose-lowering medications and metformin.

Refer for DSMES when initiating insulin or advancing to basal–bolus therapy.

Place of technology

The use of technology in the therapy of people with type 2 diabetes is increasing through a broad range of approaches, for example telehealth, remote monitoring systems, CGM and behavioural aids to support physical activity, meal planning and monitoring, medication-taking behaviour, mindfulness and stress management. Evidence on the impact of these systems is variable and highly dependent on the embedding of the technology in a more comprehensive approach. Evidence for a beneficial impact of telehealth on achieving treatment goals in those living with type 2 diabetes is growing [ 333 , 334 ]. During the COVID-19 pandemic, telehealth has proven to be an efficient way of overseeing the treatment of people with type 2 diabetes. In particular, interventions using apps as tools to support DSMES have been shown to have an impact on outcomes [ 34 ].

For those needing insulin as part of their treatment, smart insulin pens and insulin pumps (continuous subcutaneous insulin infusion [CSII]) are available. Specific evidence on the benefit of smart pens in people with type 2 diabetes is still scarce. CSII use is associated with small improvements in HbA 1c and fewer hypoglycaemic events, suggesting that CSII can be considered in people living with type 2 diabetes treated with multiple daily insulin injections and able to manage the device [ 71 ]. Again, for optimal effect, this technology should be embedded in an integrated approach to type 2 diabetes therapy, specifically to avoid weight gain [ 335 ].

In individuals with type 2 diabetes treated with insulin, CGM, both intermittently scanned CGM and real-time CGM, has gained traction, with evidence that CGM results in better overall glucose control as defined by HbA 1c and time in range (3.9–10.0 mmol/l [70–180 mg/dl]), fewer hyperglycaemic and hypoglycaemic episodes and improvements in diabetes distress [ 336 , 337 ].

As with other wearables, for example those collecting steps walked or monitoring dietary intake, medication dose administered or sleep quality, use of CGM has also been proposed as a motivational tool for those with type 2 diabetes not on insulin therapy, but the evidence on this is modest [ 337 ].

Finally, to date, no convincing evidence is available on the use of hybrid closed loop systems specifically in people with type 2 diabetes.

Technology can be useful in people with type 2 diabetes but needs to be part of an holistic plan of care and supported by DSMES.

Consider CGM in people with type 2 diabetes on insulin.

Adapt the clinic/system to optimise effective use of technology among people with type 2 diabetes, particularly to support behaviour change through self-monitoring.

Working within the system to deliver improved care

We are fortunate to have evidence on numerous effective interventions in type 2 diabetes, but translating this evidence into practice cannot rest only with front-line clinicians during individual clinic visits. The systems of care that support front-line clinicians have a significant role in improving diabetes clinical management, outcomes and experience for people living with diabetes. Front-line clinicians must inform and drive the design of care, but the systems of care should be held accountable for implementation. Supplementary Table 2 , informed by the Effective Practice and Organisation of Care (EPOC) taxonomy [ 338 ], outlines key domains and questions that must be answered to achieve the goal of better care and outcomes for people living with type 2 diabetes. All levels of the care delivery system have a role and responsibility in improving diabetes management. Clinic leaders have a responsibility to improve workflows to make it easy to provide evidence-based care and provide data to inform quality improvement efforts. Continuing education is necessary to ensure evolving evidence reaches people living with type 2 diabetes. Policy makers have a responsibility to ensure that evidence-based interventions are available and affordable to all. Interventions to improve diabetes must also include the health system (including the microsystems within a system) and governmental agencies. Policy makers, together with all stakeholders, should reflect on care delivery: How, where and by whom is care delivered? Who coordinates care and the management of care processes? Practices and systems must establish enhanced communication technology to improve engagement. Governance arrangements must be implemented specifically around accountability for health professionals, with a focus on training and evaluation of quality of practice. Finally, reflection is needed around implementation strategies at the level of the system, facility and individual healthcare workers. These principles are aligned with recommendations outlined in the recent Lancet Commission on diabetes [ 339 ].

Identify and incorporate continuing education activities on the management of type 2 diabetes for all members of the healthcare team.

Team-based care is required for integrated care of diabetes; this includes coordination between multiple disciplines (diabetes care and education specialist, dietitians, psychologists, etc.) and often other medical specialties (primary care, endocrinology, ophthalmology, nephrology, etc.).

Management of type 2 diabetes requires continuous quality improvement interventions tailored to the local setting.

Key knowledge gaps and a call to action

In this 100th year since the discovery and partial purification of insulin, we should remember the remarkable speed at which this first glucose-lowering medication was developed and distributed as life-saving therapy for people with diabetes. Through our experience in the last few years with the COVID-19 pandemic, we have demonstrated how quickly many governments, industry, healthcare systems and academic institutions can respond to global healthcare crises. Within a year of identification of the SARS-CoV-2 virus, preventive and therapeutic products were not only developed and tested but also administered on a massive scale. The annual global mortality rate directly attributable to diabetes is approximately 1.5 million people, with 540 million people affected [ 340 , 341 ]. Although not as spectacular as the impact of COVID-19 on the health of society, diabetes is sure and steady in its burden, increasing in prevalence and with an increase in mortality and morbidity over time.

Two centuries of investigation into the pathophysiology of diabetes have led to the extraordinary advances in treatment of the last two decades. As reviewed in this consensus report, encouraging healthy behaviours, DSMES, medications, devices, technologies and organisation of care all represent effective tools for the management of diabetes to reduce its morbidity and mortality. However, despite the generous approach of Banting and Best in licensing the patent for insulin for one Canadian dollar, it is not yet readily available to all people with diabetes [ 342 , 343 ]. Recent events have focused attention on the contribution of social determinants of health and a lack of equity in the delivery of care to disparate and unfavourable outcomes. Today, the major opportunities to improve diabetes outcomes in the near term come from more effective implementation of best evidence through organisation of care at all levels (national to individual practices) and from addressing social determinants of health. Every reader of this consensus report has a role to play in better implementation with a focus on equity. For providers, that could involve a focus on shared decision making to improve adherence to behavioural and medication interventions as well as organising practice to minimise therapeutic inertia and enhance engagement and support for all people with diabetes. For policy makers, healthcare systems, payors and companies with marketed products or services, ensuring equitable access to minimise health disparities should be a priority.

Broad support for basic science is necessary to bring about the next generation of interventions. Implementation science is an essential area for future work, particularly in the context of ‘learning healthcare systems’, in which internal data are systematically integrated with published evidence to drive quality improvement [ 344 – 346 ]. Precision medicine initiatives, whether ‘omics’-based or focused on social determinants of health, aim to optimally target interventions based on the wide heterogeneity of the population affected by diabetes. Precision medicine has tremendous but largely unrealised promise. When these efforts are driven by real-world data, causal inference study design and analysis create greater confidence in the implementation and evaluation of insights. Studies should be conducted to support the better understanding of precision medicine approaches to the full spectrum of diabetes interventions, from medications to behavioural treatments and diabetes support.

Several key areas where further research could better inform future consensus reports were of particular interest to the writing group. For each area, one could add the need for more precision medicine insights and a better understanding of the full spectrum of investigations that are supporting efforts to advance the field from basic to implementation science. With upwards of 10% of the population affected by diabetes and the enormous attendant costs, a focus on individualising care to make sure that the right person is getting the right therapy at the right time while working to overcome barriers dependent on social determinants of health is essential. Regulatory reform, more efficient study conduct and analysis, coordinated global efforts in defining outcomes and data collection instruments, data sharing, exploration of new forms of healthcare delivery (e.g. telehealth) and increased efforts to reach underserved populations, as were made to address COVID-19, would accelerate progress in defining and implementing optimal approaches for diabetes care.

Study conduct. Across the spectrum from highly controlled trials to observational studies, paying greater attention to subgroups, in particular vulnerable populations, is essential. Dedicated studies in young adults with type 2 diabetes, or including much larger numbers of younger adults in broader studies, are essential to better understand how to mitigate their high risk of early disability. As more younger adults are being treated with therapies that have been inadequately studied in pregnancy, it is essential to describe the reproductive safety of recommended approaches. Similarly, there have been inadequate studies of frail older people and those aged >75 years with regard to understanding both appropriate targets and interventions, to minimise harms and maximise quality of life. Sex balance is another dimension where our present studies fail to be representative. Better recruitment, retention and analysis to ensure safety and effectiveness in populations historically under-represented in studies and generally suffering from health inequities is a minimal first step to enhance health justice by sex, race/ethnicity and nationality, etc.

Weight management. With the emergence of more effective behavioural and medical therapies and novel surgical approaches for the treatment of people who are overweight with diabetes, more direct comparisons are required to better target interventions based on impact and cost-effectiveness.

Targets. Studies designed to explicitly examine glucose-centric vs weight-centric approaches to diabetes management are needed. The impact of prioritising early aggressive therapy to induce remission is unclear.

Cardiorenal protection. Data are required to better inform when to select a GLP-1 RA and/or an SGLT2i in the setting of CVD but without HF or CKD, and to fully validate the recommendation for combination therapy in those at high risk who do not meet glycaemic targets. As discussed, there is considerable uncertainty about the absolute benefits of GLP-1 RA and SGLT2i for CVD outcomes in those with risk factors only. As a result, there is variability in the recommendations on how to define high-risk people with diabetes, to whom these disease-modifying agents should be prescribed to have the greatest benefit/impact. As all people with diabetes are at high risk of CVD, HF and CKD over time, real-world evidence and cost-effectiveness studies of GLP-1 RA and SGLT2i in broad populations would help to better target interventions to have the greatest impact on outcomes.

Glucose monitoring. Further studies to understand the role and optimal implementation of CGM and/or episodic CGM in type 2 diabetes are needed.

Comorbidities. There are numerous studies under way to understand the role of interventions in the setting of NAFLD and cognitive impairment. NAFLD is highly prevalent and thus understanding the impact of interventions on person-centred outcomes and costs is essential. Cognitive impairment is a major burden to people with diabetes, their families and society; better understanding of the pathophysiology and the impact of interventions is a challenging but high reward area for investigation. There are virtually no data to inform best practice in the care of people with diabetes and advanced CKD, particularly in dialysis-dependent kidney disease. Additional studies, particularly of GLP-1 RA, GIP and GLP-1 RA, and SGLT2i, will hopefully provide new avenues to reduce mortality in this population, in which there are enormous health disparities.

Screening and prevention. Screening for diabetes and its complications and comorbidities remains inadequate. Early intervention to prevent progression is also generally suboptimal. National healthcare systems should comprehensively assess the implementation of recommendations and create incentives for effective programmes. To optimally target resources, additional studies may be required on natural history and subpopulations, as much of the rationale for screening is based on studies conducted decades ago.

Technology. Remote care, wearables, apps and decision support aids have exploded in availability and clear rationale exists as to why they may be of benefit. However, their optimal application is poorly understood.

Sleep and chronotype. Poor sleep is common and clearly associated with poor outcomes. Further studies are needed to understand behavioural sleep therapy and its benefits more fully, as well as the benefits of medication and device aids. As chronotype is potentially modifiable, future research should focus on social and lifestyle factors to optimise interventional responses.

Until science and medicine bring us further insights, we recommend empathic, person-centred decision making and support informed by an understanding of local resources and individual social determinants of health. Combined with consistent efforts to improve health behaviours (nutrition, activity, sleep and self-monitoring) and to provide DSMES, these form the foundation of diabetes management. In this context, acceptance of, adherence to and persistence with medical and behavioural interventions to support cardiorenal health, cardiovascular risk reduction and attainment of glycaemic and weight goals will prevent complications and optimise quality of life. We must establish and refine quality improvement efforts in diabetes care at the local level to equitably implement evidence-based interventions for the benefit of all people with type 2 diabetes.

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Acknowledgements

F. Zaccardi performed the literature searches and M. Bonar, C. Franklin and S. Jamal assisted with the conception and execution of figures and tables. T. Yates and J. Henson supported the production and content of Fig. 2 (all from Leicester Diabetes Centre, University of Leicester and the University Hospitals of Leicester NHS Trust). T. Karagiannis (Clinical Research and Evidence-Based Medicine Unit, Aristotle University of Thessaloniki, Greece) assisted in the credibility assessment and interpretation of meta-analyses evaluating the effects of glucose-lowering medications across subgroup populations and contributed in applying GRADE guidance in the formulation of respective practice recommendations. D. Bradley (Ohio State University College of Medicine, Columbus, OH), P. Home (Newcastle University, Newcastle, UK), M. S. Kirkman (University of North Carolina, Chapel Hill, NC), S. Dinneen (Galway University Hospitals, Galway, Ireland), H. W. Rodbard (Adventis HealthCare Shady Grove Medical Center, Rockville, MD), G. Sesti (Sapienza University of Rome, Rome, Italy), P. Newland-Jones (University of Southampton, Southampton, UK), E. Montanya (University of Barcelona, Barcelona, Spain) and M. Nauck (Medical Department I, St. Josef-Hospital [Ruhr-University Bochum], Bochum, Germany) all served as invited reviewers. We acknowledge the support of N.A. El Sayed, R. R. Bannuru, M. Saraco and M. I. Hill (all ADA, Arlington, VA, USA), P. Niemann and N. Buckley-Mühge (all EASD, Dusseldorf, Germany), the Committee for Clinical Affairs of the EASD and the Professional Practice Committee of the ADA.

Authors’ relationships and activities

MJD has acted as a consultant, advisory board member and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Sanofi; an advisory board member and speaker for AstraZeneca; an advisory board member for Janssen, Lexicon, Pfizer and ShouTi Pharma; and as a speaker for Napp Pharmaceuticals, Novartis and Takeda Pharmaceuticals International. Her institution has received grants from Novo Nordisk, Sanofi-Aventis, Eli Lilly, Boehringer Ingelheim, AstraZeneca and Janssen. VRA has served as a consultant for Applied Therapeutics, Duke, Fractyl, Novo Nordisk, Pfizer and Sanofi. VRA’s spouse is an employee of Janssen and a former employee of Merck. VRA’s employer institution has received research funding for her role as investigator on clinical trials from Applied Therapeutics, Medpace, Eli Lilly, Fractyl, Premier, Novo Nordisk and Sanofi. BSC is a nominating work group member of the American Academy of Physician Assistants. RAG is an advisor to Vida and Lark. JG is a consultant for AstraZeneca, Pfizer, Boehringer Ingelheim/Lilly, Bayer, Sanofi, Anji, Vertex/ICON and Valo. She conducts research at her institution for Boehringer Ingelheim/Lilly, Merck and Roche. NMM is under a licence agreement between Johns Hopkins HealthCare Solutions and Johns Hopkins University. She and the university are entitled to royalty distributions related to an online diabetes prevention programme. SER participated in at least one advisory board for Bayer, Traverse and AstraZeneca. Her employer receives industry research support from Bayer and Astra Zeneca. SDP is a member of the advisory board for Abbott, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Hengrui Pharmaceuticals, Menarini International, Novo Nordisk, Sanofi and Vertex. He is a participant in a speaker’s bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novo Nordisk, Sanofi and Takeda. His employer receives research funding from AstraZeneca and Boheringer Ingelheim. CM serves or has served on the advisory panel for Novo Nordisk, Sanofi, MSD, Eli Lilly, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet and Zealand Pharma. Financial compensation for these activities has been received by KU Leuven. KU Leuven has received research support for CM from Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics. CM serves or has served on the speaker’s bureau for Novo Nordisk, Sanofi, Eli Lilly, Boehringer Ingelheim, AstraZeneca and Novartis. Financial compensation for these activities has been received by KU Leuven. GM is a consultant to Novo Nordisk, Fractyl, Recor, Keyron and Metadeq and is on the scientific board of Fractyl. PR’s institution has received industry research funding from AstraZeneca and Novo Nordisk. Her institution has also received consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, Gilead and MSD, and lecture fees from Sanofi, Astellas, Novo Nordisk, Bayer and AstraZeneca. TT is on the advisory board for Boehringer Ingelheim, AstraZeneca, Sanofi, Novo Nordisk and Eli Lilly, and in the speaker’s bureau for Boehringer Ingelheim, AstraZeneca, Sanofi, Novo Nordisk, Eli Lilly, MSD, Servier and Merck. AT has served on the advisory board for Novo Nordisk and Boehringer Ingelheim and his university has received research funding. His university also receives funding for educational and research support from Eli Lilly. JBB is a paid consultant to Anji Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Fortress Biotech, Janssen, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, ReachMD, Stability Health and Zealand Pharma. He is a member of the advisory board for Boehringer Ingelheim, Eli Lilly, Mellitus Health, Moderna, Novo Nordisk, Pendulum Therapeutics, Praetego, Stability Health, vTv Therapeutics and Zealand Pharma. His employer receives research funding from Dexcom, Eli Lilly, NovaTarg, Novo Nordisk, Sanofi, Tolerion and vTv Therapeutics. He is an investor in Mellitus Health, Pendulum Therapeutics and PhaseBio.

Contribution statement

All authors were responsible for drafting the article and revising it critically for important intellectual content. All authors approved the version to be published.

Abbreviations

Blood glucose monitoring

Continuous glucose monitoring

Continuous subcutaneous insulin infusion

Cardiovascular outcomes trial

Diabetic ketoacidosis

Estimated treatment difference

Glucose-dependent insulinotropic polypeptide

Glucagon-like peptide-1 receptor agonist(s)

Heart failure

Hospitalisation for heart failure

Major adverse cardiovascular events

Medical nutrition therapy

Non-alcoholic fatty liver disease

Non-alcoholic steatohepatitis

Sodium–glucose cotransporter-1 inhibitor

Sodium–glucose cotransporter-2 inhibitor(s)

Thiazolidinedione

Urinary albumin/creatinine ratio

This activity was funded by the American Diabetes Association and the European Association for the Study of Diabetes.

Data availability

Details of the search strategy and list of identified articles can be found at https://data.mendeley.com/datasets/h5rcnxpk8w/2

This article is being simultaneously published in Diabetologia (10.1007/s00125-022-05787-2) and Diabetes Care (10.2337/dci22-0034) by the European Association for the Study of Diabetes and American Diabetes Association.

A consensus report of a particular topic contains a comprehensive examination and is authored by an expert panel and represents the panel’s collective analysis, evaluation and opinion. MJD and JBB were co-chairs for the Consensus Report Writing Group. VRA, BSC, RAG, JG, NMM and SER were the writing group members for ADA. SDP, CM, GM, PR, TT and AT were the writing group members for EASD. The article was reviewed for EASD by its Committee on Clinical Affairs and approved by its Executive Board. The article was reviewed for ADA by its Professional Practice Committee.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Melanie J. Davies, Email: [email protected]

John B. Buse, Email: [email protected]

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Dietary and nutritional approaches for prevention and management of type 2 diabetes

Food for thought, click here to read other articles in this collection.

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• Peer review
• Nita G Forouhi , professor 1 ,
• Anoop Misra , professor 2 ,
• Viswanathan Mohan , professor 3 ,
• Roy Taylor , professor 4 ,
• William Yancy , director 5 6 7
• 1 MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK
• 2 Fortis-C-DOC Centre of Excellence for Diabetes, Metabolic Diseases and Endocrinology, and National Diabetes, Obesity and Cholesterol Foundation, New Delhi, India
• 3 Dr Mohan’s Diabetes Specialities Centre and Madras Diabetes Research Foundation, Chennai, India
• 4 Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle, UK
• 5 Duke University Diet and Fitness Center, Durham, North Carolina, USA
• 6 Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
• 7 Center for Health Services Research in Primary Care, Department of Veterans Affairs, Durham, North Carolina, USA
• Correspondence to: N G Forouhi nita.forouhi{at}mrc-epid.cam.ac.uk

Common ground on dietary approaches for the prevention, management, and potential remission of type 2 diabetes can be found, argue Nita G Forouhi and colleagues

Dietary factors are of paramount importance in the management and prevention of type 2 diabetes. Despite progress in formulating evidence based dietary guidance, controversy and confusion remain. In this article, we examine the evidence for areas of consensus as well as ongoing uncertainty or controversy about dietary guidelines for type 2 diabetes. What is the best dietary approach? Is it possible to achieve remission of type 2 diabetes with lifestyle behaviour changes or is it inevitably a condition causing progressive health decline? We also examine the influence of nutrition transition and population specific factors in the global context and discuss future directions for effective dietary and nutritional approaches to manage type 2 diabetes and their implementation.

Why dietary management matters but is difficult to implement

Diabetes is one of the biggest global public health problems: the prevalence is estimated to increase from 425 million people in 2017 to 629 million by 2045, with linked health, social, and economic costs. 1 Urgent solutions for slowing, or even reversing, this trend are needed, especially from investment in modifiable factors including diet, physical activity, and weight. Diet is a leading contributor to morbidity and mortality worldwide according to the Global Burden of Disease Study carried out in 188 countries. 2 The importance of nutrition in the management and prevention of type 2 diabetes through its effect on weight and metabolic control is clear. However, nutrition is also one of the most controversial and difficult aspects of the management of type 2 diabetes.

The idea of being on a “diet” for a chronic lifelong condition like diabetes is enough to put many people off as knowing what to eat and maintaining an optimal eating pattern are challenging. Medical nutrition therapy was introduced to guide a systematic and evidence based approach to the management of diabetes through diet, and its effectiveness has been demonstrated, 3 but difficulties remain. Although most diabetes guidelines recommend starting pharmacotherapy only after first making nutritional and physical activity lifestyle changes, this is not always followed in practice globally. Most physicians are not trained in nutrition interventions and this is a barrier to counselling patients. 4 5 Moreover, talking to patients about nutrition is time consuming. In many settings, outside of specialised diabetes centres where trained nutritionists/educators are available, advice on nutrition for diabetes is, at best, a printed menu given to the patient. In resource poor settings, when type 2 diabetes is diagnosed, often the patient leaves the clinic with a list of new medications and little else. There is wide variation in the use of dietary modification alone to manage type 2 diabetes: for instance, estimates of fewer than 5-10% of patients with type 2 diabetes in India 6 and 31% in the UK are reported, although patients treated by lifestyle measures may be less closely managed than patients on medication for type 2 diabetes. 7 Although systems are usually in place to record and monitor process measures for diabetes care in medical records, dietary information is often neglected, even though at least modest attention to diet is needed to achieve adequate glycaemic control. Family doctors and hospital clinics should collect this information routinely but how to do this is a challenge. 5 8

Progress has been made in understanding the best dietary advice for diabetes but broader problems exist. For instance, increasing vegetable and fruit intake is recommended by most dietary guidelines but their cost is prohibitively high in many settings: the cost of two servings of fruits and three servings of vegetables a day per individual (to fulfil the “5-a-day” guidance) accounted for 52%, 18%, 16%, and 2% of household income in low, low to middle, upper to middle, and high income countries, respectively. 9 An expensive market of foods labelled for use by people with diabetes also exists, with products often being no healthier, and sometimes less healthy, than regular foods. After new European Union legislation, food regulations in some countries, including the UK, were updated as recently as July 2016 to ban such misleading labels. This is not the case elsewhere, however, and what will happen to such regulation after the UK leaves the European Union is unclear, which highlights the importance of the political environment.

Evidence for current dietary guidelines

In some, mostly developed, countries, dietary guidelines for the management of diabetes have evolved from a focus on a low fat diet to the recognition that more important considerations are macronutrient quality (that is, the type versus the quantity of macronutrient), avoidance of processed foods (particularly processed starches and sugars), and overall dietary patterns. Many systematic reviews and national dietary guidelines have evaluated the evidence for optimal dietary advice, and we will not repeat the evidence review. 10 11 12 13 14 15 16 17 18 We focus instead in the following sections on some important principles where broad consensus exists in the scientific and clinical community and highlight areas of uncertainty, but we begin by outlining three underpinning features.

Firstly, an understanding of healthy eating for the prevention and management of type 2 diabetes has largely been derived from long term prospective studies and limited evidence from randomised controlled trials in general populations, supplemented by evidence from people with type 2 diabetes. Many published guidelines and reviews have applied grading criteria and this evidence is often of moderate quality in the hierarchy of evidence that places randomised controlled trials at the top. Elsewhere, it is argued that different forms of evidence evaluating consistency across multiple study designs including large population based prospective studies of clinical endpoints, controlled trials of intermediate pathways, and where feasible randomised trials of clinical endpoints should be used collectively for evidence based nutritional guidance. 19

Secondly, it is now recognised that dietary advice for both the prevention and management of type 2 diabetes should converge, and they should not be treated as different entities ( fig 1 ). However, in those with type 2 diabetes, the degree of glycaemic control and type and dose of diabetes medication should be coordinated with dietary intake. 12 With some dietary interventions, such as very low calorie or low carbohydrate diets, people with diabetes would usually stop or reduce their diabetes medication and be monitored closely, as reviewed in a later section.

Dietary advice for different populations for the prevention and management of type 2 diabetes

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Thirdly, while recognising the importance of diet for weight management, there is now greater understanding 10 of the multiple pathways through which dietary factors exert health effects through both obesity dependent and obesity independent mechanisms. The influence of diet on weight, glycaemia, and glucose-insulin homeostasis is directly relevant to glycaemic control in diabetes, while other outcomes such as cardiovascular complications are further influenced by the effect of diet on blood lipids, apolipoproteins, blood pressure, endothelial function, thrombosis, coagulation, systemic inflammation, and vascular adhesion. The effect of food and nutrients on the gut microbiome may also be relevant to the pathogenesis of diabetes but further research is needed. Therefore, diet quality and quantity over the longer term are relevant to the prevention and management of diabetes and its complications through a wide range of metabolic and physiological processes.

Areas of consensus in guidelines

Weight management.

Type 2 diabetes is most commonly associated with overweight or obesity and insulin resistance. Therefore, reducing weight and maintaining a healthy weight is a core part of clinical management. Weight loss is also linked to improvements in glycaemia, blood pressure, and lipids and hence can delay or prevent complications, particularly cardiovascular events.

Energy balance

Most guidelines recommend promoting weight loss among overweight or obese individuals by reducing energy intake. Portion control is one strategy to limit energy intake together with a healthy eating pattern that focuses on a diet composed of whole or unprocessed foods combined with physical activity and ongoing support.

Dietary patterns

The evidence points to promoting patterns of food intake that are high in vegetables, fruit, whole grains, legumes, nuts, and dairy products such as yoghurt but with some cautions. Firstly, some dietary approaches (eg, low carbohydrate diets) recommend restricting the intake of fruits, whole grains, and legumes because of their sugar or starch content. For fruit intake, particularly among those with diabetes, opinion is divided among scientists and clinicians (see appendix on bmj.com). Many guidelines continue to recommend fruit, however, on the basis that fructose intake from fruits is preferable to isocaloric intake of sucrose or starch because of the additional micronutrient, phytochemical, and fibre content of fruit. Secondly, despite evidence from randomised controlled trials and prospective studies 10 that nuts may help prevent type 2 diabetes, some (potentially misplaced) concern exists about their high energy content. Further research in people with type 2 diabetes should help to clarify this.

There is also consensus on the benefits of certain named dietary patterns such as the Mediterranean diet for prevention and management of type 2 diabetes. Expert guidelines also support other healthy eating patterns that take account of local sociocultural factors and personal preferences.

Foods to avoid

Consensus exists on reducing or avoiding the intake of processed red meats, refined grains and sugars (especially sugar sweetened drinks) both for prevention and management of type 2 diabetes, again with some cautions. Firstly, for unprocessed red meat, the evidence of possible harm because of the development of type 2 diabetes is less consistent and of a smaller magnitude. More research is needed on specific benefits or harms in people with type 2 diabetes. Secondly, evidence is increasing on the relevance of carbohydrate quality: that is that whole grains and fibre are better choices than refined grains and that fibre intake should be at least as high in people with type 2 diabetes as recommended for the general population, that diets that have a higher glycaemic index and load are associated with an increased risk of type 2 diabetes, and that there is a modest glycaemic benefit in replacing foods with higher glycaemic load with foods with low glycaemic load. However, debate continues about the independence of these effects from the intake of dietary fibre. Some evidence exists that consumption of potato and white rice may increase the risk of type 2 diabetes but this is limited and further research is needed.

Moreover, many guidelines also highlight the importance of reducing the intake of in foods high in sodium and trans fat because of the relevance of these specifically for cardiovascular health.

Areas of uncertainty in guidelines

Optimal macronutrient composition.

One of the most contentious issues about the management of type 2 diabetes has been on the best macronutrient composition of the diet. Some guidelines continue to advise macronutrient quantity goals, such as the European or Canadian recommendation of 45–60% of total energy as carbohydrate, 10–20% as protein, and less than 35% as fat, 13 20 or the Indian guidelines that recommend 50-60% energy from carbohydrates, 10-15% from protein, and less than 30% from fat. 21 In contrast, the most recent nutritional guideline from the American Diabetes Association concluded that there is no ideal mix of macronutrients for all people with diabetes and recommended individually tailored goals. 12 Alternatively, a low carbohydrate diet for weight and glycaemic control has gained popularity among some experts, clinicians, and the public (reviewed in a later section). Others conclude that a low carbohydrate diet combined with low saturated fat intake is best. 22

For weight loss, three points are noteworthy when comparing dietary macronutrient composition. Firstly, evidence from trials points to potentially greater benefits from a low carbohydrate than a low fat diet but the difference in weight loss between diets is modest. 23 Secondly, a comparison of named diet programmes with different macronutrient composition highlighted that the critical factor in effectiveness for weight loss was the level of adherence to the diet over time. 24 Thirdly, the quality of the diet in low carbohydrate or low fat diets is important. 25 26

Research to date on weight or metabolic outcomes in diabetes is complicated by the use of different definitions for the different macronutrient approaches. For instance, the definition of a low carbohydrate diet has ranged from 4% of daily energy intake from carbohydrates (promoting nutritional ketosis) to 40%. 15 Similarly, low fat diets have been defined as fat intake less than 30% of daily energy intake or substantially lower. Given these limitations, the best current approach may be an emphasis on the use of individual assessment for dietary advice and a focus on the pattern of eating that most readily allows the individual to limit calorie intake and improve macronutrient quality (such as avoiding refined carbohydrates).

Regular fish intake of at least two servings a week, including one serving of oily fish (eg, salmon, mackerel, and trout) is recommended for cardiovascular risk prevention but fish intake has different associations with the risk of developing type 2 diabetes across the world—an inverse association, no association, and a positive association. 27 It is thought that the type of fish consumed, preparation or cooking practices, and possible contaminants (eg, methyl mercury and polychlorinated biphenyls) vary by geographical location and contributed to this heterogeneity. More research is needed to resolve whether fish intake should be recommended for the prevention of diabetes. However, the current evidence supports an increase in consumption of oily fish for individuals with diabetes because of its beneficial effects on lipoproteins and prevention of coronary heart disease. Most guidelines agree that omega 3 polyunsaturated fatty acid (fish oil) supplementation for cardiovascular prevention in people with diabetes should not be recommended but more research is needed and the results of the ASCEND (A Study of Cardiovascular Events in Diabetes) trial should help to clarify this. 28

Dairy foods are encouraged for the prevention of type 2 diabetes, with more consistent evidence of the benefits of fermented dairy products, such as yoghurt. Similar to population level recommendations about limiting the intake of foods high in saturated fats and replacing them with foods rich in polyunsaturated fat, the current advice for diabetes also favours low fat dairy products but this is debated. More research is needed to resolve this question.

Uncertainty continues about certain plant oils and tropical oils such as coconut or palm oil as evidence from prospective studies or randomised controlled trials on clinical events is sparse or non-existent. However, olive oil, particularly extra virgin olive oil, has been studied in greater detail with evidence of potential benefits for the prevention and management of type 2 diabetes 29 and the prevention of cardiovascular disease within the context of a Mediterranean diet 30 (see article in this series on dietary fats). 31

Difficulties in setting guidelines

Where dietary guidelines exist (in many settings there are none, or they are adapted from those in developed countries and therefore may not be applicable to the local situation), they vary substantially in whether they are evidence based or opinion pieces, and updated in line with scientific progress or outdated. Their accessibility—both physical availability (eg, through a website or clinic) and comprehensibility— for patients and healthcare professionals varies. They vary also in scope, content, detail, and emphasis on the importance of individualised dietary advice, areas of controversy, and further research needs. The quality of research that informs dietary guidelines also needs greater investment from the scientific community and funders. Moreover, lack of transparency in the development of guidelines and bias in the primary nutritional studies can undermine the development of reliable dietary guidelines; recommendations for their improvement must be heeded. 32

Reversing type 2 diabetes through diet

Type 2 diabetes was once thought to be irreversible and progressive after diagnosis, but much interest has arisen about the potential for remission. Consensus on the definition of remission is a sign of progress: glucose levels lower than the diagnostic level for diabetes in the absence of medications for hyperglycaemia for a period of time (often proposed to be at least one year). 33 34 However, the predominant role of energy deficit versus macronutrient composition of the diet in achieving remission is still controversial.

Remission through a low calorie energy deficit diet

Although the clinical observation of the lifelong, steadily progressive nature of type 2 diabetes was confirmed by the UK Prospective Diabetes Study, 35 rapid normalisation of fasting plasma glucose after bariatric surgery suggested that deterioration was not inevitable. 36 As the main change was one of sudden calorie restriction, a low calorie diet was used as a tool to study the mechanisms involved. In one study of patients with type 2 diabetes, fasting plasma glucose normalised within seven days of following a low calorie diet. 37 This normalisation through diet occurred despite simultaneous withdrawal of metformin therapy. Gradually over eight weeks, glucose stimulated insulin secretion returned to normal. 37 Was this a consequence of calorie restriction or composition of the diet? To achieve the degree of weight loss obtained (15 kg), about 610 kcal a day was provided—510 kcal as a liquid formula diet and about 100 kcal as non-starchy vegetables. The formula diet consisted of 59 g of carbohydrate (30 g as sugars), 11.4 g of fat, and 41 g of protein, including required vitamins and minerals. This high “sugar” approach to controlling blood glucose may be surprising but the critical aspect is not what is eaten but the gap between energy required and taken in. Because of this deficit, the body must use previously stored energy. Intrahepatic fat is used first, and the 30% decrease in hepatic fat in the first seven days appears sufficient to normalise the insulin sensitivity of the liver. 37 In addition, pancreatic fat content fell over eight weeks and beta cell function improved. This is because insulin secretory function was regained by re-differentiation after fat removal. 38

The permanence of these changes was tested by a nutritional and behavioural approach to achieve long term isocaloric eating after the acute weight loss phase. 39 It was successful in keeping weight steady over the next six months of the study. Calorie restriction was associated with both hepatic and pancreatic fat content remaining at the low levels achieved. The initial remission of type 2 diabetes was closely associated with duration of diabetes, and the individuals with type 2 diabetes of shorter duration who achieved normal levels of blood glucose maintained normal physiology during the six month follow-up period. Recently, 46% of a UK primary care cohort remained free of diabetes at one year during a structured low calorie weight loss programme (the DiRECT trial). 40 These results are convincing, and four years of follow-up are planned.

A common criticism of the energy deficit research has been that very low calorie diets may not be achievable or sustainable. Indeed, adherence to most diets in the longer term is an important challenge. 24 However, Look-AHEAD, the largest randomised study of lifestyle interventions in type 2 diabetes (n=5145), randomised individuals to intensive lifestyle management, including the goal to reduce total calorie intake to 1200-1800 kcal/d through a low fat diet assisted by liquid meal replacements, and this approach achieved greater weight loss and non-diabetic blood glucose levels at year 1 and year 4 in the intervention than the control group. 41

Considerable interest has arisen about whether low calorie diets associated with diabetes remission can also help to prevent diabetic complications. Evidence is sparse because of the lack of long term follow-up studies but the existing research is promising. A return to the non-diabetic state brings an improvement in cardiovascular risk (Q risk decreasing from 19.8% to 5.4%) 39 ; case reports of individuals facing foot amputation record a return to a low risk state over 2-4 years with resolution of painful neuropathy 42 43 ; and retinal complications are unlikely to occur or progress. 44 However, other evidence highlights that worsening of treatable maculopathy or proliferative retinopathy may occur following a sudden fall in plasma glucose levels, 45 46 so retinal imaging in 4-6 months is recommended for individuals with more than minimal retinopathy if following a low calorie remission diet. Annual review is recommended for all those in the post-diabetic state, and a “diabetes in remission” code (C10P) is now available in the UK. 34

Management or remission through a low carbohydrate diet

Before insulin was developed as a therapy, reducing carbohydrate intake was the main treatment for diabetes. 47 48 Carbohydrate restriction for the treatment of type 2 diabetes has been an area of intense interest because, of all the macronutrients, carbohydrates have the greatest effect on blood glucose and insulin levels. 49

In a review by the American Diabetes Association, interventions of low carbohydrate (less than 40% of calories) diets published from 2001 to 2010 were identified. 15 Of 11 trials, eight were randomised and about half reported greater improvement in HbA1c on the low carbohydrate diet than the comparison diet (usually a low fat diet), and a greater reduction in the use of medicines to lower glucose. Notably, calorie reduction coincided with carbohydrate restriction in many of the studies, even though it was not often specified in the dietary counselling. One of the more highly controlled studies was an inpatient feeding study, 50 which reported a decline in mean HbA1c from 7.3% to 6.8% (P=0.006) over just 14 days on a low carbohydrate diet.

For glycaemia, other reviews of evidence from randomised trials on people with type 2 diabetes have varying conclusions. 51 52 53 54 55 56 Some concluded that low carbohydrate diets were superior to other diets for glycaemic control, or that a dose response relationship existed, with stricter low carbohydrate restriction resulting in greater reductions in glycaemia. Others cautioned about short term beneficial effects not being sustained in the longer term, or found no overall advantage over the comparison diet. Narrative reviews have generally been more emphatic on the benefits of low carbohydrate diets, including increased satiety, and highlight the advantages for weight loss and metabolic parameters. 57 58 More recently, a one year clinic based study of the low carbohydrate diet designed to induce nutritional ketosis (usually with carbohydrate intake less than 30 g/d) was effective for weight loss, and for glycaemic control and medication reduction. 59 However, the study was not randomised, treatment intensity differed substantially in the intervention versus usual care groups, and participants were able to select their group.

Concerns about potential detrimental effects on cardiovascular health have been raised as low carbohydrate diets are usually high in dietary fat, including saturated fat. For lipid markers as predictors of future cardiovascular events, several studies found greater improvements in high density lipoprotein cholesterol and triglycerides with no relative worsening of low density lipoprotein cholesterol in patients with type 2 diabetes following carbohydrate restriction, 15 with similar conclusions in non-diabetic populations. 57 60 61 62 Low density lipoprotein cholesterol tends to decline more, however, in a low fat comparison diet 61 63 and although low density lipoprotein cholesterol may not worsen with a low carbohydrate diet 63 in the short term, the longer term effects are unclear. Evidence shows that low carbohydrate intake can lower the more atherogenic small, dense low density lipoprotein particles. 57 64 Because some individuals may experience an increase in serum low density lipoprotein cholesterol when following a low carbohydrate diet high in saturated fat, monitoring is important.

Another concern is the effect of the potentially higher protein content of low carbohydrate diets on renal function. Evidence from patients with type 2 diabetes with normal baseline renal function and from individuals without diabetes and with normal or mildly impaired renal function has not shown worsening renal function at one or up to two years of follow-up, respectively. 22 65 66 67 Research in patients with more severely impaired renal function, with or without diabetes, has not been reported to our knowledge. Other potential side effects of a very low carbohydrate diet include headache, fatigue, and muscle cramping but these side effects can be avoided by adequate fluid and sodium intake, particularly in the first week or two after starting the diet when diuresis is greatest. Concern about urinary calcium loss and a possible contribution to increased future risk of kidney stones or osteoporosis 68 have not been verified 69 but evidence is sparse and warrants further investigation. The long term effects on cardiovascular disease and chronic kidney disease in patients with diabetes need further evaluation.

Given the hypoglycaemic effect of carbohydrate restriction, patients with diabetes who adopt low carbohydrate diets and their clinicians must understand how to avoid hypoglycaemia by appropriately reducing glucose lowering medications. Finally, low carbohydrate diets can restrict whole grain intake and although some low carbohydrate foods can provide the fibre and micronutrients contained in grains, it may require greater effort to incorporate such foods. This has led some experts to emphasise restricting refined starches and sugars but retaining whole grains.

Nutrition transition and population specific factors

Several countries in sub-Saharan Africa, South America, and Asia (eg, India and China) have undergone rapid nutrition transition in the past two decades. These changes have paralleled economic growth, foreign investment in the fast food industry, urbanisation, direct-to-consumer marketing of foods high in calories, sale of ultraprocessed foods, and as a result, lower consumption of traditional diets. The effect of these factors on nutrition have led to obesity and type 2 diabetes on the one hand, and co-existing undernutrition and micronutrient deficiencies on the other.

Dietary shifts in low and middle income countries have been stark: in India, these include a substantial increase in fat intake in the setting of an already high carbohydrate intake, with a slight increase in total energy and protein, 70 and a decreasing intake of coarse cereals, pulses, fruits, and vegetables 71 ; in China, animal protein and fat as a percentage of energy has also increased, while cereal intake has decreased. 72 An almost universal increase in the intake of caloric beverages has also occurred, with sugar sweetened soda drinks being the main beverage contributing to energy intake, for example among adults and children in Mexico, 73 or the substantial rise in China in sales of sugar sweetened drinks from 10.2 L per capita in 1998 to 55.0 L per capita in 2012. 74 The movement of populations from rural to urban areas within a country may also be linked with shifts in diets to more unhealthy patterns, 75 while acculturation of immigrant populations into their host countries also results in dietary shifts. 76

In some populations, such as South Asians, rice and wheat flour bread are staple foods, with a related high carbohydrate intake (60-70% of calories). 77 Although time trends show that intake of carbohydrate has decreased among South Asian Indians, the quality of carbohydrates has shifted towards use of refined carbohydrates. 71 The use of oils and traditional cooking practices also have specific patterns in different populations. For instance, in India, the import and consumption of palm oil, often incorporated in the popular oil vanaspati (partially hydrogenated vegetable oil, high in trans fats), is high. 78 Moreover, the traditional Indian cooking practice of frying at high temperatures and re-heating increases trans fatty acids in oils. 79 Such oils are low cost, readily available, and have a long shelf life, and thus are more attractive to people from the middle and low socioeconomic strata but their long term effects on type 2 diabetes are unknown.

Despite the nutrition transition being linked to an increasing prevalence of type 2 diabetes, obesity and other non-communicable diseases, strong measures to limit harmful foods are not in place in many countries. Regulatory frameworks including fiscal policies such as taxation for sugar sweetened beverages need to be strengthened to be effective and other preventive interventions need to be properly implemented. Efforts to control trans fatty acids in foods have gained momentum but are largely confined to developed countries. To reduce consumption in low and middle income countries will require both stringent regulations and the availability and development of alternative choices of healthy and low cost oils, ready made food products, and consumer education. 80 The need for nutritional labelling is important but understanding nutrition labels is a problem in populations with low literacy or nutrition awareness, which highlights the need for educational activities and simpler forms of labelling. The role of dietary/nutritional factors in the predisposition of some ethnic groups to developing type 2 diabetes at substantially lower levels of obesity than European populations 81 is poorly researched and needs investigation.

Despite the challenges of nutritional research, considerable progress has been made in formulating evidence based dietary guidance and some common principles can be agreed that should be helpful to clinicians, patients, and the public. Several areas of uncertainty and controversy remain and further research is needed to resolve these. While adherence to dietary advice is an important challenge, weight management is still a cornerstone in diabetes management, supplemented with new developments, including the potential for the remission of type 2 diabetes through diet.

Future directions

Nutritional research is difficult. Although much progress has been made to improve evidence based dietary guidelines, more investment is needed in good quality research with a greater focus on overcoming the limitations of existing research. Experts should also strive to build consensus using research evidence based on a combination of different study designs, including randomised experiments and prospective observational studies

High quality research is needed that compares calorie restriction and carbohydrate restriction to assess effectiveness and feasibility in the long term. Consensus is needed on definitions of low carbohydrate nutrition. Use of the findings must take account of individual preferences, whole diets, and eating patterns

Further research is needed to resolve areas of uncertainty about dietary advice in diabetes, including the role of nuts, fruits, legumes, fish, plant oils, low fat versus high fat dairy, and diet quantity and quality

Given recent widespread recommendations (such as from the World Health Organization 82 and the UK Scientific Advisory Committee on Nutrition 83 ) to reduce free sugars to under 10% or even 5% of total energy intake in the general population and to avoid sugar sweetened drinks, we need targeted research on the effect of non-nutritive sweeteners on health outcomes in people with diabetes and in the whole population

Most dietary guidelines are derived from evidence from Western countries. Research is needed to better understand the specific aetiological factors that link diet/nutrition and diabetes and its complications in different regions and different ethnic groups. This requires investment in developing prospective cohorts and building capacity to undertake research in low and middle income settings and in immigrant ethnic groups. Up-to-date, evidence based dietary guidelines are needed that are locally relevant and readily accessible to healthcare professionals, patients, and the public in different regions of the world. Greater understanding is also needed about the dietary determinants of type 2 diabetes and its complications at younger ages and in those with lower body mass index in some ethnic groups

We need investment in medical education to train medical students and physicians in lifestyle interventions, including incorporating nutrition education in medical curricula

Individual, collective, and upstream factors are important. Issuing dietary guidance does not ensure its adoption or implementation. Research is needed to understand the individual and societal drivers of and barriers to healthy eating. Educating and empowering individuals to make better dietary choices is an important strategy; in particular, the social aspects of eating need attention as most people eat in family or social groups and counselling needs to take this into account. Equally important is tackling the wider determinants of individual behaviour—the “foodscape”, sociocultural and political factors, globalisation, and nutrition transition

Key messages

Considerable evidence supports a common set of dietary approaches for the prevention and management of type 2 diabetes, but uncertainties remain

Weight management is a cornerstone of metabolic health but diet quality is also important

Low carbohydrate diets as the preferred choice in type 2 diabetes is controversial. Some guidelines maintain that no single ideal percentage distribution of calories from different macronutrients (carbohydrates, fat, or protein) exists, but there are calls to review this in light of emerging evidence on the potential benefits of low carbohydrate diets for weight management and glycaemic control

The quality of carbohydrates such as refined versus whole grain sources is important and should not get lost in the debate on quantity

Recognition is increasing that the focus of dietary advice should be on foods and healthy eating patterns rather than on nutrients. Evidence supports avoiding processed foods, refined grains, processed red meats, and sugar sweetened drinks and promoting the intake of fibre, vegetables, and yoghurt. Dietary advice should be individually tailored and take into account personal, cultural, and social factors

An exciting recent development is the understanding that type 2 diabetes does not have to be a progressive condition but instead there is potential for remission with dietary intervention

Acknowledgments

We thank Sue Brown as a patient representative of Diabetes UK for her helpful comments and insight into this article.

Contributors and sources: The authors have experience and research interests in the prevention and management of type 2 diabetes (NGF, AM, VM, RT, WY), in guideline development (NGF, AM, VM, WY), and in nutritional epidemiology (NGF, VM). Sources of information for this article included published dietary guidelines or medical nutrition therapy guidelines for diabetes, and systematic reviews and primary research articles based on randomised clinical trials or prospective observational studies. All authors contributed to drafting this manuscript, with NGF taking a lead role and she is also the guarantor of the manuscript. All authors gave intellectual input to improve the manuscript and have read and approved the final version.

Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following: NGF receives funding from the Medical Research Council Epidemiology Unit (MC_UU_12015/5). NGF is a member (unpaid) of the Joint SACN/NHS-England/Diabetes-UK Working Group to review the evidence on lower carbohydrate diets compared with current government advice for adults with type 2 diabetes and is a member (unpaid) of ILSI-Europe Qualitative Fat Intake Task Force Expert Group on update on health effects of different saturated fats. AM received honorarium and research funding from Herbalife and Almond Board of California. VM has received funding from Abbott Health Care for meal replacement studies, the Cashew Export Promotion Council of India, and the Almond Board of California for studies on nuts. RT has received funding from Diabetes UK for the Diabetes Remission Clinical Trial and he is a member (unpaid) of the Joint SACN/NHS-England/Diabetes-UK Working Group to review the evidence on lower carbohydrate diets compared to current government advice for adults with type 2 diabetes. WY has received funding from the Veterans Affairs for research projects examining a low carbohydrate diet in patients with diabetes.

Provenance and peer review: Commissioned, externally peer reviewed

This article is one of a series commissioned by The BMJ . Open access fees for the series were funded by Swiss Re, which had no input in to the commissioning or peer review of the articles. The BMJ thanks the series advisers, Nita Forouhi and Dariush Mozaffarian, for valuable advice and guiding selection of topics in the series.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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ADA-funded researchers use the money from their awards to conduct critical diabetes research. In time, they publish their findings in order to inform fellow scientists of their results, which ensures that others will build upon their work. Ultimately, this cycle drives advances to prevent diabetes and to help people burdened by it. In 2018 alone, ADA-funded scientists published over 200 articles related to their awards!

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Next, Dr. Delong wants to determine if HIPs can serve as a biomarker or possibly even targeted to prevent or treat type 1 diabetes. Baker, R. L., Rihanek, M., Hohenstein, A. C., Nakayama, M., Michels, A., Gottlieb, P. A., Haskins, K., & Delong, T. (2019). Hybrid Insulin Peptides Are Autoantigens in Type 1 Diabetes. Diabetes , 68 (9), 1830–1840.

Understanding the biology of body-weight regulation in children

Determining the biological mechanisms regulating body-weight is important for preventing type 2 diabetes. The rise in childhood obesity has made this even more urgent. Behavioral studies have demonstrated that responses to food consumption are altered in children with obesity, but the underlying biological mechanisms are unknown. This year, Dr. Schur tested changes in brain and hormonal responses to a meal in normal-weight and obese children. Results from her study show that hormonal responses in obese children are normal following a meal, but responses within the brain are reduced. The lack of response within the brain may predispose them to overconsumption of food or difficulty with weight-loss.

With this information at hand, Dr. Schur wants to investigate how this information can be used to treat obesity in children and reduce diabetes.

Roth, C. L., Melhorn, S. J., Elfers, C. T., Scholz, K., De Leon, M. R. B., Rowland, M., Kearns, S., Aylward, E., Grabowski, T. J., Saelens, B. E., & Schur, E. A. (2019). Central Nervous System and Peripheral Hormone Responses to a Meal in Children. The Journal of Clinical Endocrinology and Metabolism , 104 (5), 1471–1483.

A novel molecule to improve continuous glucose monitoring

To create a fully automated artificial pancreas, it is critical to be able to quantify blood glucose in an accurate and stable manner. Current ways of continuously monitoring glucose are dependent on the activity of an enzyme which can change over time, meaning the potential for inaccurate readings and need for frequent replacement or calibration. Dr. Wang has developed a novel molecule that uses a different, non-enzymatic approach to continuously monitor glucose levels in the blood. This new molecule is stable over long periods of time and can be easily integrated into miniaturized systems.

Now, Dr. Wang is in the process of patenting his invention and intends to continue research on this new molecule so that it can eventually benefit people living with diabetes.

Wang, B. , Chou, K.-H., Queenan, B. N., Pennathur, S., & Bazan, G. C. (2019). Molecular Design of a New Diboronic Acid for the Electrohydrodynamic Monitoring of Glucose. Angewandte Chemie (International Ed. in English) , 58 (31), 10612–10615.

Addressing the legacy effect of diabetes

Several large clinical trials have demonstrated the importance of tight glucose control for reducing diabetes complications. However, few studies to date have tested this in the real-world, outside of a controlled clinical setting. In a study published this year, Dr. Laiteerapong found that indeed in a real-world setting, people with lower hemoglobin A1C levels after diagnosis had significantly lower vascular complications later on, a phenomenon known as the ‘legacy effect’ of glucose control. Her research noted the importance of early intervention for the best outcomes, as those with the low A1C levels just one-year after diagnosis had significantly lower vascular disease risk compared to people with higher A1C levels.

With these findings in hand, physicians and policymakers will have more material to debate and determine the best course of action for improving outcomes in people newly diagnosed with diabetes.

Laiteerapong, N. , Ham, S. A., Gao, Y., Moffet, H. H., Liu, J. Y., Huang, E. S., & Karter, A. J. (2019). The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study). Diabetes Care , 42 (3), 416–426.

A new way to prevent immune cells from attacking insulin-producing beta-cells

Replacing insulin-producing beta-cells that have been lost in people with type 1 diabetes is a promising strategy to restore control of glucose levels. However, because the autoimmune disease is a continuous process, replacing beta-cells results in another immune attack if immunosorbent drugs are not used, which carry significant side-effects. This year, Dr. Song reported on the potential of an immunotherapy he developed that prevents immune cells from attacking beta-cells and reduces inflammatory processes. This immunotherapy offers several potential benefits, including eliminating the need for immunosuppression, long-lasting effects, and the ability to customize the treatment to each patient.

The ability to suppress autoimmunity has implications for both prevention of type 1 diabetes and improving success rates of islet transplantation.

Haque, M., Lei, F., Xiong, X., Das, J. K., Ren, X., Fang, D., Salek-Ardakani, S., Yang, J.-M., & Song, J . (2019). Stem cell-derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes. JCI Insight , 4 (7).

A new target to improve insulin sensitivity

The hormone insulin normally acts like a ‘key’, traveling through the blood and opening the cellular ‘lock’ to enable the entry of glucose into muscle and fat cells. However, in people with type 2 diabetes, the lock on the cellular door has, in effect, been changed, meaning insulin isn’t as effective. This phenomenon is called insulin resistance. Scientists have long sought to understand what causes insulin resistance and develop therapies to enable insulin to work correctly again. This year, Dr. Summers determined an essential role for a molecule called ceramides as a driver of insulin resistance in mice. He also presented a new therapeutic strategy for lowering ceramides and reversing insulin resistance. His findings were published in one of the most prestigious scientific journals, Science .

Soon, Dr. Summers and his team will attempt to validate these findings in humans, with the ultimate goal of developing a new medication to help improve outcomes in people with diabetes.

Chaurasia, B., Tippetts, T. S., Mayoral Monibas, R., Liu, J., Li, Y., Wang, L., Wilkerson, J. L., Sweeney, C. R., Pereira, R. F., Sumida, D. H., Maschek, J. A., Cox, J. E., Kaddai, V., Lancaster, G. I., Siddique, M. M., Poss, A., Pearson, M., Satapati, S., Zhou, H., … Summers, S. A. (2019). Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science (New York, N.Y.) , 365 (6451), 386–392.

Determining the role of BPA in type 2 diabetes risk

Many synthetic chemicals have infiltrated our food system during the period in which rates of diabetes has surged. Data has suggested that one particular synthetic chemical, bisphenol A (BPA), may be associated with increased risk for developing type 2 diabetes. However, no study to date has determined whether consumption of BPA alters the progression to type 2 diabetes in humans. Results reported this year by Dr. Hagobian demonstrated that indeed when BPA is administered to humans in a controlled manner, there is an immediate, direct effect on glucose and insulin levels.

Now, Dr. Hagobian wants to conduct a larger clinical trial including exposure to BPA over a longer period of time to determine precisely how BPA influences glucose and insulin. Such results are important to ensure the removal of chemicals contributing to chronic diseases, including diabetes.

Hagobian, T. A. , Bird, A., Stanelle, S., Williams, D., Schaffner, A., & Phelan, S. (2019). Pilot Study on the Effect of Orally Administered Bisphenol A on Glucose and Insulin Response in Nonobese Adults. Journal of the Endocrine Society , 3 (3), 643–654.

Investigating the loss of postmenopausal protection from cardiovascular disease in women with type 1 diabetes

On average, women have a lower risk of developing heart disease compared to men. However, research has shown that this protection is lost in women with type 1 diabetes. The process of menopause increases rates of heart disease in women, but it is not known how menopause affects women with type 1 diabetes in regard to risk for developing heart disease. In a study published this year, Dr. Snell-Bergeon found that menopause increased risk markers for heart disease in women with type 1 diabetes more than women without diabetes.

Research has led to improved treatments and significant gains in life expectancy for people with diabetes and, as a result, many more women are reaching the age of menopause. Future research is needed to address prevention and treatment options.

Keshawarz, A., Pyle, L., Alman, A., Sassano, C., Westfeldt, E., Sippl, R., & Snell-Bergeon, J. (2019). Type 1 Diabetes Accelerates Progression of Coronary Artery Calcium Over the Menopausal Transition: The CACTI Study. Diabetes Care , 42 (12), 2315–2321.

Identification of a potential therapy for diabetic neuropathy related to type 1 and type 2 diabetes

Diabetic neuropathy is a type of nerve damage that is one of the most common complications affecting people with diabetes. For some, neuropathy can be mild, but for others, it can be painful and debilitating. Additionally, neuropathy can affect the spinal cord and the brain. Effective clinical treatments for neuropathy are currently lacking. Recently, Dr. Calcutt reported results of a new potential therapy that could bring hope to the millions of people living with diabetic neuropathy. His study found that a molecule currently in clinical trials for the treatment of depression may be valuable for diabetic neuropathy, particularly the type affecting the brain.

Because the molecule is already in clinical trials, there is the potential that it can benefit patients sooner than later.

Jolivalt, C. G., Marquez, A., Quach, D., Navarro Diaz, M. C., Anaya, C., Kifle, B., Muttalib, N., Sanchez, G., Guernsey, L., Hefferan, M., Smith, D. R., Fernyhough, P., Johe, K., & Calcutt, N. A. (2019). Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189. Diabetes , 68 (11), 2143–2154.

ADA-funded researcher studying link between ageing and type 2 diabetes

One of the most important risk factors for developing type 2 diabetes is age. As a person gets older, their risk for developing type 2 diabetes increases. Scientists want to better understand the relationship between ageing and diabetes in order to determine out how to best prevent and treat type 2 diabetes. ADA-funded researcher Rafael Arrojo e Drigo, PhD, from the Salk Institute for Biological Studies, is one of those scientists working hard to solve this puzzle.

Recently, Dr. Arrojo e Drigo published results from his research in the journal Cell Metabolism . The goal of this specific study was to use high-powered microscopes and novel cellular imaging tools to determine the ‘age’ of different cells that reside in organs that control glucose levels, including the brain, liver and pancreas. He found that, in mice, the cells that make insulin in the pancreas – called beta-cells – were a mosaic of both old and young cells. Some beta-cells appeared to be as old as the animal itself, and some were determined to be much younger, indicating they recently underwent cell division.

Insufficient insulin production by beta-cells is known to be a cause of type 2 diabetes. One reason for this is thought to be fewer numbers of functional beta-cells. Dr. Arrojo e Drigo believes that people with or at risk for diabetes may have fewer ‘young’ beta-cells, which are likely to function better than old ones. Alternatively, if we can figure out how to induce the production of younger, high-functioning beta-cells in the pancreas, it could be a potential treatment for people with diabetes.

In the near future, Dr. Arrojo e Drigo’s wants to figure out how to apply this research to humans. “The next step is to look for molecular or morphological features that would allow us to distinguish a young cell from and old cell,” Dr. Arrojo e Drigo said.

The results from this research are expected to provide a unique insight into the life-cycle of beta-cells and pave the way to novel therapeutic avenues for type 2 diabetes.

Watch a video of Dr. Arrojo e Drigo explaining his research!

Arrojo E Drigo, R. , Lev-Ram, V., Tyagi, S., Ramachandra, R., Deerinck, T., Bushong, E., … Hetzer, M. W. (2019). Age Mosaicism across Multiple Scales in Adult Tissues. Cell Metabolism , 30 (2), 343-351.e3.

Researcher identifies potential underlying cause of type 1 diabetes

Type 1 diabetes occurs when the immune system mistakenly recognizes insulin-producing beta-cells as foreign and attacks them. The result is insulin deficiency due to the destruction of the beta-cells. Thankfully, this previously life-threatening condition can be managed through glucose monitoring and insulin administration. Still, therapies designed to address the underlying immunological cause of type 1 diabetes remain unavailable.

Conventional approaches have focused on suppressing the immune system, which has serious side effects and has been mostly unsuccessful. The American Diabetes Association recently awarded a grant to Dr. Kenneth Brayman, who proposed to take a different approach. What if instead of suppressing the whole immune system, we boost regulatory aspects that already exist in the system, thereby reigning in inappropriate immune cell activation and preventing beta-cell destruction? His idea focused on a molecule called immunoglobulin M (IgM), which is responsible for limiting inflammation and regulating immune cell development.

In a paper published in the journal Diabetes , Dr. Brayman and a team of researchers reported exciting findings related to this approach. They found that supplementing IgM obtained from healthy mice into mice with type 1 diabetes selectively reduced the amount of autoreactive immune cells known to target beta-cells for destruction. Amazingly, this resulted in reversal of new-onset diabetes. Importantly, the authors of the study determined this therapy is translatable to humans. IgM isolated from healthy human donors also prevented the development of type 1 diabetes in a humanized mouse model of type 1 diabetes.

The scientists tweaked the original experiment by isolating IgM from mice prone to developing type 1 diabetes, but before it actually occurred. When mice with newly onset diabetes were supplemented with this IgM, their diabetes was not reversed. This finding suggests that in type 1 diabetes, IgM loses its capacity to serve as a regulator of immune cells, which may be contribute to the underlying cause of the disease.

Future studies will determine exactly how IgM changes its regulatory properties to enable diabetes development. Identification of the most biologically optimal IgM will facilitate transition to clinical applications of IgM as a potential therapeutic for people with type 1 diabetes.    Wilson, C. S., Chhabra, P., Marshall, A. F., Morr, C. V., Stocks, B. T., Hoopes, E. M., Bonami, R.H., Poffenberger, G., Brayman, K.L. , Moore, D. J. (2018). Healthy Donor Polyclonal IgM’s Diminish B Lymphocyte Autoreactivity, Enhance Treg Generation, and Reverse T1D in NOD Mice. Diabetes .

ADA-funded researcher designs community program to help all people tackle diabetes

Diabetes self-management and support programs are important adjuncts to traditional physician directed treatment. These community-based programs aim to give people with diabetes the knowledge and skills necessary to effectively self-manage their condition. While several clinical trials have demonstrated the value of diabetes self-management programs in terms of improving glucose control and reducing health-care costs, whether this also occurs in implemented programs outside a controlled setting is unclear, particularly in socially and economically disadvantaged groups.

Lack of infrastructure and manpower are often cited as barriers to implementation of these programs in socioeconomically disadvantaged communities. ADA-funded researcher Dr. Briana Mezuk addressed this challenge in a study recently published in The Diabetes Educator . Dr. Mezuk partnered with the YMCA to evaluate the impact of the Diabetes Control Program in Richmond, Virginia. This community-academic partnership enabled both implementation and evaluation of the Diabetes Control Program in socially disadvantaged communities, who are at higher risk for developing diabetes and the complications that accompany it.

Dr. Mezuk had two primary research questions: (1) What is the geographic and demographic reach of the program? and (2) Is the program effective at improving diabetes management and health outcomes in participants? Over a 12-week study period, Dr. Mezuk found that there was broad geographic and demographic participation in the program. The program had participants from urban, suburban and rural areas, most of which came from lower-income zip codes. HbA1C, mental health and self-management behaviors all improved in people taking part in the Greater Richmond Diabetes Control Program. Results from this study demonstrate the value of diabetes self-management programs and their potential to broadly improve health outcomes in socioeconomically diverse communities. Potential exists for community-based programs to address the widespread issue of outcome disparities related to diabetes.  Mezuk, B. , Thornton, W., Sealy-Jefferson, S., Montgomery, J., Smith, J., Lexima, E., … Concha, J. B. (2018). Successfully Managing Diabetes in a Community Setting: Evidence from the YMCA of Greater Richmond Diabetes Control Program. The Diabetes Educator , 44 (4), 383–394.

Using incentives to stimulate behavior changes in youth at risk for developing diabetes

Once referred to as ‘adult-onset diabetes’, incidence of type 2 diabetes is now rapidly increasing in America’s youth. Unfortunately, children often do not have the ability to understand how everyday choices impact their health. Could there be a way to change a child’s eating behaviors? Davene Wright, PhD, of Seattle Children’s Hospital was granted an Innovative Clinical or Translational Science award to determine whether using incentives, directed by parents, can improve behaviors related to diabetes risk. A study published this year in Preventive Medicine Reports outlined what incentives were most desirable and feasible to implement. A key finding was that incentives should be tied to behavior changes and not to changes in body-weight.

With this information in hand, Dr. Wright now wants to see if incentives do indeed change a child’s eating habits and risk for developing type 2 diabetes. She is also planning to test whether an incentive program can improve behavior related to diabetes management in youth with type 1 diabetes. Jacob-Files, E., Powell, J., & Wright, D. R. (2018). Exploring parent attitudes around using incentives to promote engagement in family-based weight management programs. Preventive Medicine Reports , 10 , 278–284.

Determining the genetic risk for gestational diabetes

Research has identified more than 100 genetic variants linked to risk for developing type 2 diabetes in humans. However, the extent to which these same genetic variants might affect a woman’s probability for getting gestational diabetes has not been investigated.

Pathway to Stop Diabetes ® Accelerator awardee Marie-France Hivert, MD, of Harvard University set out to answer this critical question. Dr. Hivert found that indeed genetic determinants of type 2 diabetes outside of pregnancy are also strong risk factors for gestational diabetes. This study was published in the journal Diabetes .

The implications? Because of this finding, doctors in the clinic may soon be able to identify women at risk for getting gestational diabetes and take proactive steps to prevent it. Powe, C. E., Nodzenski, M., Talbot, O., Allard, C., Briggs, C., Leya, M. V., … Hivert, M.-F. (2018). Genetic Determinants of Glycemic Traits and the Risk of Gestational Diabetes Mellitus. Diabetes , 67 (12), 2703–2709.

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Effect of Steviol Glycosides on Human Health with Emphasis on Type 2 Diabetic Biomarkers: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Camilla christine bundgaard anker, shamaila rafiq, per bendix jeppesen.

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Correspondence: [email protected] ; Tel.: +45-28-15-18-77

Received 2019 Jul 8; Accepted 2019 Aug 19; Collection date 2019 Sep.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/ ).

The natural sweetener from Stevia rebaudiana Bertoni, steviol glycoside (SG), has been proposed to exhibit a range of antidiabetic properties. The objective of this systematic review was to critically evaluate evidence for the effectiveness of SGs on human health, particularly type 2 diabetic (T2D) biomarkers, collecting data from randomized controlled trials (RCTs). Electronic searches were performed in PubMed and EMBASE and the bibliography of retrieved full-texts was hand searched. Using the Cochrane criteria, the reporting quality of included studies was assessed. Seven studies, nine RCTs, including a total of 462 participants were included. A meta-analysis was performed to assess the effect of SGs on following outcomes: BMI, blood pressure (BP), fasting blood glucose (FBG), lipids, and glycated hemoglobin (HbA1c). The meta-analysis revealed an overall significant reduction in systolic BP in favour of SGs between SG and placebo, mean difference (MD): −6.32 mm Hg (−7.69 to 0.46). The overall effect of BMI, diastolic BP, FBG, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) was a non-significant reduction in favour of SGs, and a non-significant increase in low-density lipoprotein cholesterol and triglyceride, while no significant effect of HbA1c was found. Heterogeneity was significant for several analyses. More studies investigating the effect of SGs on human health, particularly T2D biomarkers, are warranted.

Keywords: steviol glycosides, type 2 diabetes, fasting blood glucose, lipids, BMI, blood pressure, HbA1c

1. Introduction

Diabetes mellitus has been ranked as the sixth leading cause of disability [ 1 ]. The International Diabetes Federation (IDF) estimated a total of more than 425 million diabetics in the age range 20–79 worldwide in 2017, type 2 diabetes mellitus (T2DM) accounting for more than 90% of the overall cases. According to IDF, the number of T2DM incidences is expected to further increase to around 629 million by year 2045, making this metabolic disease a continuously increasing problem worldwide [ 2 , 3 ].

T2DM is a metabolic and multifactorial condition in that both genetic, epigenetic, and environmental factors, including diet and physical activity, contribute to the development of the disease [ 4 ]. In most cases, insulin resistance is present and precedes the development of T2DM by increasing the requirements for insulin, leading to insulin insufficiency in individuals whose β-cells have limited secretory reserve and is most often related to obesity, ageing, and physical inactivity [ 5 , 6 ]. Indeed, it is suggested that the case of insulin resistance as seen in many T2DM patients is the result of an increase in visceral adiposity [ 5 , 7 ]. As a consequence of the insulin deficiency, there is a reduced insulin-mediated glucose uptake from skeletal muscle and other peripheral target tissues and an increased glucose production from the liver, as a result of increased glucagon secretion from the α-cells, and free fatty acid mobilization from adipose tissue. Initially, this will cause postprandial hyperglycemia, eventually resulting in fasting hyperglycemia [ 7 , 8 ].

Left untreated, T2DM might eventually lead to secondary complications such as microvascular and macrovascular complication and cause morbidity and mortality [ 5 , 9 ].

Several chemical drugs have been developed in order to manage and treat T2DM of which metformin is the first drug of choice. Metformin affects insulin sensitivity to increase glucose uptake in the liver. Previously, glitazones have also been administered to type 2 diabetic patients to increase insulin sensitivity in muscles. However, due to severe side effects, these agents have almost been removed from the market. Furthermore, SGLT-2 and DPP-4 inhibitors have been introduced as antidiabetic agents. SGLT-2 inhibitors reduce the blood glucose by inhibiting SGLT-2 and thereby increasing the excretion of glucose in the urine. DPP-4 inhibitors stimulate the insulin secretion while inhibiting degradation of the insulinotropic hormone GLP-1, resulting in a blood glucose reduction. Some agents exhibit insulin-resistance-reducing effects and might reduce the requirement for insulin secretagogues such as sulfonylureas and meglitinides. However, none of the existing drugs have a completely healing effect, and most of the currently available chemical drugs are costly and cause side effects [ 6 , 10 ].

In the search of alternative treatments, natural products extracted from a number of herbal plants have been found to exhibit hypoglycemic activity [ 11 , 12 , 13 ]. The natural constituents in the leaves of the herb Stevia rebaudiana Bertoni have been closely investigated in a range of in vitro, in vivo, and human studies, some demonstrating the possession of Stevioside and other SGs of some antidiabetic capabilities in both humans [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] and rodents [ 26 , 27 , 28 , 29 , 30 , 31 , 32 ].

1.1. Stevia Rebaudiana Bertoni

The perennial shrub Stevia rebaudiana Bertoni belongs to the Asteraceae family native to South America, in particular Paraguay and Brazil. For decades, indigenous people have used extracts from the leaves of this sweet herb as sweetener to several foods and beverages and in medicines, e.g., for treatment of diabetes [ 33 ]. High-purity steviol glycoside extracts (≥95%) have been approved for use as food sweetener in several countries and regions, including the European Union and the United States. The sweet taste is a result of the presence of the natural constituents of the plant known as steviol glycosides (SGs) [ 34 , 35 ].

The SGs derived from the plant are four-ring diterpenes composed of an aglycone backbone called steviol to which various numbers and types of sugars are attached ( Figure 1 A). Presently, >40 SGs have been identified, Stevioside (4–13% wt:wt, Figure 1 B) and Rebaudioside A (Reb A—2–4% wt:wt, Figure 1 C) being the most abundant glycosides in the leaves of S. rebaudiana . Stevioside and Reb A are both non-caloric compounds ∼200–300 times sweeter than 0.4 M sucrose and are chemically very similar, differing only by one additional glucose moiety on Reb A. In general, SGs differ only in the number and type of monosaccharides attached to the aglycone [ 36 ].

Backbone structure of SGs ( A ), Stevioside ( B ), and Reb A ( C ).

1.1.1. Metabolism of Steviol Glycosides

Besides sharing similar chemical structure, SGs also experience the same metabolic fate. Due to the lack of capability of the enzymes and acid present in the upper gastrointestinal tract to digest SGs, SGs remains undigested and enter the colon where the microbiota is responsible for hydrolysis and degradation processes. The glycosidic linkages are cleaved and the sugar moieties removed, leaving behind the aglycone backbone, steviol. A large amount of steviol is quickly absorbed and transported to the liver where it is conjugated to glucuronic acid to form steviol glucuronide (SVG), the rest is excreted in the feces. Finally, the end product, SVG, is excreted via urine in humans and via bile in rats. Besides minor differences in the metabolism rate accounted for by the number of sugar moieties present, SGs are hydrolyzed to steviol at generally similar rates, regardless of the type or numbers of sugar moieties [ 37 , 38 , 39 , 40 ].

1.1.2. Effect of Steviol Glycosides on Health and Diabetes Biomarkers

A number of studies in both human and rodents have been conducted to investigate the effects of SGs on diabetes biomarkers such as blood pressure (BP), fasting blood glucose, and insulin etc., and it has been reported that SGs exhibit some antidiabetic capabilities.

1.2. Effect on Fasting Blood Glucose and Insulin

An early study by Curi et al. [ 41 ] showed a correlation between ingestion of extracts of S. rebaudiana Bertoni and suppression of plasma glucose and an increase in glucose tolerance in normal adult humans.

Subsequently, long-term human trials have been conducted, aiming to investigate the effect of 200–1500 mg/day orally administered stevioside [ 15 , 16 , 17 , 19 , 42 , 43 ] and 500–1000 mg/day Reb A [ 22 , 23 ] in a time period ranging from 3 days to 2 years on glycated hemoglobin (HbA1c), fasting blood glucose, and insulin in healthy, type 1 and type 2 diabetic, low-normotensive, hypertensive, and hyperlipidemic subjects. Neither of the investigated outcomes were found to be significantly changed when comparing intervention groups with control groups. However, it should be noted that the protocols of the studies enrolling diabetic subjects differed with some continuing their antidiabetic medications [ 15 , 23 ] and some ending before initiation of the study [ 22 , 43 ].

In one of these studies including diabetic subjects continuing their hypoglycemic medications [ 15 ], oral administration of 750 mg/day Stevioside for 3 months did not affect the blood glucose and HbA1c levels in both type 2 diabetics and normotensive/low-normotensive subjects. Although the Stevioside treatment was found not to exert any hypoglycemic effect in the subjects, a significant increase in fasting blood glucose concentration was indeed detected in the placebo group compared with baseline in subjects with type 1 diabetes mellitus, whereas the subjects consuming Stevioside managed to maintain the fasting blood glucose concentration during the 3 months study period.

Similar results were revealed in a study by Jeppesen et al. [ 43 ] where 55 type 2 diabetics ending their hypoglycemic medications at initiation of 1500 mg/day Stevioside treatment for 3 months. Both HbA1c and fasting blood glucose were found to be significantly increased for the placebo group ( p < 0.01 and p < 0.007, respectively) during the 3 months, whereas for the Stevioside group, no change was found in the measures ( p < 0.14 and p < 0.1, respectively).

A non-significant reduction in both HbA1c and fasting blood glucose levels in type 2 diabetic subjects post treatment of 1000 mg/day Reb A for 16 weeks was reported by Maki et al. [ 22 ]. However, a slight rise in HbA1c levels was observed in both Reb A and placebo groups and no difference in HbA1c changes for Reb A compared with placebo was observed. Moreover, the fasting insulin increased significantly in the Reb A group compared with placebo. However, the changes from baseline to treatment were not different between groups.

A study examined the effect of 1 g/day Stevia leaf powder for 60 days on fasting blood glucose in type 2 diabetic subjects [ 44 ]. Here, the volunteers were treated with Stevia leaf powder in preference to high-purity SGs as seen in the protocols of the other studies. Ritu et al. reported significantly reduced fasting blood glucose levels of diabetic subjects of the intervention groups 60 days post initiation of treatment compared with prior to intervention [ 44 ]. However, these results should be interpreted with caution, since crude Stevia leaf powder contain a number of other components which might influence and affect the results.

In a meta-analysis, Onakpoya and Heneghan [ 24 ] evaluated existing evidence for effectiveness on cardiovascular risk factors in adults, using data from RCTs. An evaluation of six of aforementioned studies showed a small but significant decrease in fasting blood glucose (−0.63 mmol/L, p < 0.00001). It is discussed whether this observation is of clinical relevance due to the limited extent of reduction [ 36 ].

According to Jeppesen et al. [ 43 ], one possible reason for these contrary findings compared to data from several animal studies is the enrollment of diabetic subjects who might have been at a late developmental stage of the disease, and consequently with limited β-cell function.

Although no evidence indicates a direct hypoglycemic or insulinotropic effect of Stevia and its SGs in both healthy and diabetic human subjects, findings suggest that a potential of these to maintain a static diabetic state exists at levels above ADI, i.e., 0–4 mg steviol equivalents (SEs)/kg bw/day [ 36 ].

1.3. Effect on Energy Intake and Weight Control

From findings that Stevia might possess beneficial effects on blood glucose and insulin levels in humans [ 18 , 41 ], it has been suggested that Stevia also might have a role in food intake regulation. To date, only two studies have investigated the effects of Stevia on satiety and food/energy intake [ 14 , 25 ].

In a randomized crossover study, Anton et al. tested the effects of two preloads containing either Stevia (580 kcal), aspartame (580 kcal), or sucrose (986 kcal) consumed 20 min prior to ad libitum test meals two times daily for three days on food intake and satiety, among other factors, in both lean and obese individuals [ 14 ]. A significant reduction in food intake over the entire day (including preloads) was observed in the Stevia group compared to the sucrose group. However, when excluding the preload calories from the analyses, no significant difference in food intake was observed. In addition, the investigators did not find any differences in satiety levels between the different conditions at any time point, all indicating that the participants did not compensate by eating more at the meals at lunch or dinner.

In a second randomized cross-over study, Tey et al. examined the effects of Stevia (0.33 g; Reb A) compared to sucrose (65 g) in liquid form on total daily energy intake in 30 healthy, relatively lean males [ 25 ]. The study beverage was consumed 1 h prior to an ad libitum study lunch. Stevia was found not to reduce the total daily energy intake, with 73% compensation of the energy obtained from sucrose. Neither did Stevia affect the satiety ratings. In fact, Stevia was shown to significantly increase the desire to eat, hunger, and prospective consumption ratings 30 min post treatment and immediately before consumption of the ad libitum lunch compared with the sucrose treatment. Additionally, the included subjects reported lower fullness for the Stevia treatment compared with the control.

When including findings from clinical trials investigating BMI and body weight as second outcomes, similar results are reported indicating no change in these measures post treatment of Stevia compared with placebo treatment [ 16 , 17 , 19 , 22 ].

1.4. Effect on Blood Pressure

In vivo studies have suggested the ability of intravenously administered Stevioside to cause a hypotensive effect [ 45 , 46 ]. However, it has been discussed whether the effects are the same after oral administration in humans, since the uptake of Stevioside has been shown to be extremely low as a consequence to its high molecular weight [ 42 , 47 ].

The effect of SGs on both systolic and diastolic blood pressure has been investigated in randomized clinical trials (RCTs) in both healthy (normotensive), hypertensive, and type 1 and type 2 diabetic adults. Geuns et al. [ 20 ] revealed that neither systolic blood pressure (SBP) or diastolic blood pressure (DBP) in healthy, normotensive volunteers were affected after oral administration of 750 mg/day Stevioside for 3 days. This in agreement with findings by Barriocanal et al. [ 15 ], demonstrating that oral administration of 750 mg/day Stevioside for 3 months does not exhibit any hypotensive effect in subjects with normal/low-normal BP levels. Likewise, the blood pressure of type 2 diabetic subjects was not affected by the administration of either 1000 mg/day Reb A for 16 weeks [ 22 ] or 750 mg/day [ 15 ] or 1500 mg/day [ 43 ] Stevioside for 3 months. However, for these studies, continuation of hypotensive medications among the hypertensive subjects during the study period was part of the protocol.

The possible hypotensive effect of Stevioside was investigated in two randomized, double-blinded, placebo-controlled studies including hypertensive subjects not ending treatment with BP reducing medications before study initiation [ 16 , 19 ]. In a study enrolling 168 subjects with mild essential hypertension, 1500 mg/day orally administrated Stevioside for two years was shown to significantly reduce the SBP and DBP compared with baseline in the Stevioside group [ 19 ]. A significant reduction was also observed when comparing the Stevioside group and the placebo group. Furthermore, it was reported that the blood pressure started decreasing ∼1 week after initiation of the Stevioside administration [ 19 ]. This agrees with findings by Chan et al. [ 16 ], conducting a similar study investigating the effectiveness and tolerability of 750 mg/day Stevioside in hypertensive patients. From this study, the reduction in BP was registered 7 days after initiation of the active treatment, and the hypotensive effect of Stevioside reached statistical significance after 3 months when comparing the Stevioside and the placebo group.

SGs were shown to cause a significant decrease in diastolic blood pressure (−2.24 mm Hg; p = 0.03) in a meta-analysis of seven RCTs [ 24 ]. However, non-significant results were obtained regarding SGs effect on systolic blood pressure, probably due to the observed significant heterogeneity between the included studies. As already stated, protocols of some of the included studies regarding continuation of blood pressure lowering and antidiabetic medications were not concordant, leading to inconsistency and incommensurability of the data presented in the studies.

1.5. Effect on Lipids

A few studies have included measures of lipids such as cholesterols, triacylglycerols (TAGs), and free fatty acids (FFAs) as part of the investigation of the effects of Stevia and SGs on human health and diabetic biomarkers [ 15 , 16 , 17 , 19 , 22 , 43 , 44 ].

Most of the existing literature indicate no effect of 200 mg/day–1500 mg/day Stevioside and 1000 mg/day Reb A on lipids in mild hypertensive, hypertensive, type 1 and type 2 diabetic, and healthy subjects when administered orally for 90 days to 2 years.

In one study enrolling 49 hyperlipidemic volunteers [ 17 ], administration of 200 mg/day Stevioside did not exert any hypolipidemic effect. A decrease in blood levels of total cholesterol and LDL values during the treatment was detected in both Stevioside and placebo groups; however, no change in BMI was reported.

When administering 1 g Stevia leaf powder for 60 days in type 2 diabetic subjects, the serum cholesterol, triglyceride, and very low-density lipoprotein-cholesterol (VLDL-C) levels were found to be significantly reduced [ 44 ].

1.6. Mechanism of Hypoglycemic, Insulinotropic, and Hypotensive Effects

To investigate the possible capability of SGs to induce a maintaining effect of glucose homeostasis, in vitro and animal studies have been conducted. SGs are suggested to exert hypoglycemic, insulinotropic, and glucagonostatic effects through direct or indirect action on mechanisms involving insulin secretion, signaling, and release; glucagon secretion, and release; regulation of key genes; and glucose absorption. It is obvious that the substitution of sucrose or other carbohydrates with non-caloric or non-nutritive sweeteners, such as SGs, will result in a lowering of the blood glucose concentrations and thereby a stable state of glycemia [ 48 ].

However, from studies observing diabetic Goto–Kakizaki (GK) rats [ 26 ] and streptozotocin (STZ)- or fructose-induced diabetic male Wistar rats [ 29 , 31 ], both intravenously and orally administered Stevioside was shown to exert antihyperglycemic, insulinotropic, and glucagonostatic actions, these effects being more prominent after a glucose load. In addition, in vitro insulin action on skeletal muscle glucose transport in both lean and obese Zucker rats has been shown to be improved by 0.01–0.1 mM Stevioside [ 49 ].

Jeppesen et al. [ 26 ] investigated the role of Stevioside in the management of glycemia in both the nonobese animal model of type 2 diabetes, GK rats, and normal Wistar rats. During an intravenous glucose tolerance test (GTT) with and without 0.2 g/kg Stevioside in anesthetized GK rats, Stevioside induced a significant reduction in blood glucose ( p < 0.05), an increase in insulin secretion ( p < 0.05), and a reduction in glucagon levels. No effect was observed in normal Wistar rats after administration of Stevioside. Jeppesen et al. [ 32 ] further showed that long-term administration of Stevioside at a dose of 0.025 g/kg/day resulted in suppression of plasma glucose after intra-arterial injection of a bolus of 2 g/kg glucose in GK rats (incremental AUC, p < 0.05). In addition, a higher first phase insulin response (incremental AUC, p < 0.05) was evident from the Stevioside-fed animals compared with the control group, causing a concomitant suppression of glucagon (incremental AUC, p < 0.05). However, no effect of the long-term administration on fasting blood glucose, insulin, and glucagon was reported. Similar observations were reported in a previous study by Jeppesen et al. [ 27 ], demonstrating the capability of Stevioside and the aglycone to potentiate insulin secretion from isolated mouse islets in a dose- and glucose-dependent manner.

Fructose-rich chow fed to normal Wistar rats induced a diabetic state in the animals which oral administration of 0.5 mg/kg to 5.0 mg/kg Stevioside seemed to overcome [ 31 ]. A single oral administration of 0.5 mg/kg Stevioside for 90 min decreased plasma glucose concentrations and lowered the glucose-insulin index (a measure of insulin resistance) during an intraperitoneal glucose tolerance test in the fructose-rich chow-fed rats. Repeated oral administration of 5.0 mg/kg Stevioside resulted in a significant decrease in plasma glucose ( p < 0.01) and a reduction in fasting plasma insulin in rats fed fructose-rich chow for four weeks. Furthermore, Stevioside improved insulin resistance induced by food, and delayed the induction of insulin resistance in the high-fructose chow fed animals together with a reported ability of increasing the insulin response, and thereby insulin sensitivity, in STZ-diabetic rats. Noteworthy, Stevioside (10 days after treatment) was found to improve insulin sensitivity in these rats more rapidly compared to metformin (15 days after treatment). Similar findings were reported by Chen et al. [ 29 ]. Stevioside administered via gastrogavage lowered the blood glucose levels in normal Wistar rats (in a dose dependent manner, 0.5 mg/kg to 5.0 mg/kg) and lowered high glucose levels in STZ-induced diabetic rats, and in fructose-induced diabetic rats. For both STZ-induced diabetic rats and fructose-induced diabetic rats, Stevioside treatment by gastrogavage lowered the blood glucose levels after just one day compared to rats in the control group.

In a nine-week intervention, Nordentoft et al. demonstrated that the more bioavailable Stevioside derivative, isosteviol (ISV), was capable of decreasing the glucose-insulin index, i.e., reducing insulin resistance, and preventing development of a severe state of diabetes when fed to genetically obese diabetic KKay mice at a dose of 20 mg/kg/day [ 30 ]. In addition, ISV was found to upregulate the gene expression of the GLUT2 glucose transporter protein gene transcript, key insulin-regulating genes and insulin transcription factors in pancreatic islets from KKAy control and ISV-treated mice, suggesting an enhanced glucose sensitivity as well as improved insulin expression and secretion in β-cells.

In vitro studies using the clonal β-cell line, INS-1, and isolated Noval Medical Research Institute (NMRI) mice islets, have demonstrated increased glucose-stimulated insulin secretion (GSIS) when chronically exposed to 1 µmol/L to Stevioside or steviol [ 32 ] or ISV at 10 −10 to 10 −6 mol/L [ 30 ]. Jeppesen et al. presumed these changes to be partially caused by the concomitant capability of Stevioside and steviol to induce proinsulin, insulin, and a range of genes involved in glycolysis together with an upregulation in gene expression of glucose responsive genes and improvement of nutrient-sensing mechanisms in the INS-1 cells treated with Stevioside or the aglycone. Chen et al. [ 29 ] suggested the hypoglycemic effects of Stevioside to be caused by the effect of Stevioside on gluconeogenesis. In fact, it was shown that daily oral treatment with Stevioside decreased mRNA and protein levels of a rate-limiting enzyme for gluconeogenesis, PEPCK in diabetic rats. Blood glucose levels might be regulated and reduced in diabetic rats through a decreasing effect of Stevioside on the gene expression of PEPCK in the liver to slow down gluconeogenesis. Interestingly, aqueous extract from S. rebaudiana Bertoni has been shown to affect several mitochondrial functions [ 50 ]. An inhibitory effect of aqueous extract from S. rebaudiana Bertoni on the adenosine triphosphate (ATP) phosphorylation and nicotinamide adenine dinucleotide (NADH)-oxidase activity in rat liver mitochondria was reported. This contributed to an inhibition of adenosine diphosphate (ADP)/ATP exchange, resulting in increased glycolysis and decreased gluconeogenesis.

In an additional study, Jeppesen et al. aimed to investigate the mechanism through which Stevioside and steviol (1 nmol/L to 1 mmol/L) exert an insulinotropic effect in INS-1 cells [ 27 ]. It was questioned whether the insulinotropic effects were mediated via the same mechanisms as the classic sulfonylureas, i.e., binding to receptor proteins on β-cells, blocking K ATP + -channels and depolarizing the β-cell plasma membrane, inducing insulin release. Interestingly, neither of the diterpenes were found to possess a blocking capability of the plasma membrane K ATP + -channels on β-cells, suggesting another mechanism to the insulinotropic effects than mediation via membrane depolarization as a consequence of closure of K ATP + -channels in the β-cell membrane. Recently, Philippaert et al. suggested that the molecular mechanism through which SGs exert their therapeutic effects is by a potentiation of transient receptor potential cation channel subfamily melastatin member 5 (TRPM5) channel activity in β-cells [ 28 ]. It was strongly suggested that this monovalent cation channel was essential for the biological action of steviol and SGs, from the finding that steviol and SGs potentiate glucose-induced Ca 2+ oscillations and thereby insulin release in WT pancreatic islets expressing TRPM5. Testing the effect of SGs on GSIS, led to the observations of Stevioside only being able to potentiate GSIS in WT islets, but not in Trpm5 −/− islets. Similarly, intraperitoneal injection of 2.5 g/kg glucose plus 200 mg/kg Stevioside in fasted anaesthetized mice resulted in a significantly higher plasma insulin level 30 min post injection of Stevioside in WT mice, whereas the same effect was absent in Trpm5 −/− mice. Acute oral administration of 0.5 mg/kg/day 2 h before a glucose tolerance test (GTT), also resulted in blood glucose values being significantly reduced after Stevioside treatment in WT mice, whereas no similar effect was evident from Trpm5 −/− mice. The same effects were observed in alloxan-diabetic WT-recipient mice receiving WT islets, but not in WT-recipient mice receiving Trpm5 −/− islets. In addition, Stevioside was reported to possess a glucose intolerance preventive effect in WT mice receiving a high-fat diet plus Stevioside compared to a high-fat diet, solely (control). Again, this effect was absent in Trpm5 −/− mice, where no difference between control and the Stevioside-treated group was seen. However, expression of TRPM5 in human β-cells is relatively low, and almost absent, why further studies need to be conducted to elucidate the mechanism underlying the effects of SGs in humans [ 51 ].

Intravenous administration of Stevioside has been shown to induce a blood pressure reduction in hypertensive rats [ 45 ] as well as an increased water, sodium, and potassium excretion [ 46 ], suggesting a vasodilating effect of Stevioside on the kidney, eventually leading to a reduction in blood pressure. In contrast to a relatively high degree of evidence supporting the hypoglycemic and insulinotropic effects of SGs and the mechanism thereof, evidence for the exact mechanism underlying the hypotensive effect of SGs is lacking. However, it has been reported that the antihypertensive mechanism of Stevioside depends on the inhibition of Ca 2+ -influx from extracellular fluid [ 52 ].

The purpose for this systematic review was to evaluate the existing evidence on the effectiveness of SGs, in particular Stevioside and Reb A, on diabetic biomarkers including fasting blood glucose and insulin, lipids (cholesterol and TAGs), BP, body weight, and BMI.

2. Materials and Methods

2.1. search strategy.

Electronic searches were performed in the databases PubMed and EMBASE in the time period of August to October 2018 using search terms such as Stevia, Stevioside, steviol glycoside, insulin release, antihyperglycemic agent, fasting blood glucose, triglycerides, HDL, LDL, cholesterol, BMI, systolic blood pressure, diastolic blood pressure, and glycated hemoglobin. In PubMed, the search terms were searched as MeSH terms. All synonyms and other common used terms for interventions and outcomes were included in the search. In order to be included in this review, it was required that the study design of the studies was double-blinded, randomized, controlled trials (RCTs). For inclusion purposes, it was required that the RCTs investigated the effectiveness of orally administered SG in human participants ≥18 years. In addition, the RCTs had to include a control group receiving placebo matching the intervention. Studies on SGs combined with other dietary supplements were excluded. All studies meeting the specified inclusion criteria were included in this review, without any restrictions regarding age, duration, or lifestyle adjustments. However, articles presented in languages other than English were not included. No criteria for study participants were made, thus trials in which both type 1 and 2 diabetic, hypertensive, and healthy subjects participated, were included. The outcomes of interest for this systematic review and meta-analysis were markers of type 2 diabetes, including fasting blood glucose, systolic blood pressure, diastolic blood pressure, total cholesterol, LDL, HDL, glycated hemoglobin (HbA1c), triglycerides, and BMI.

Since it has been reported that the various SGs share the same metabolic pathway and fate [ 37 , 38 ], SGs are also expected to produce similar physiological effects. Thus, no inclusion criteria for a specific SG was set.

2.2. Risk of Bias Assessment

The risk of bias was assessed using the Cochrane Collaboration’s tool. Study data concerning risk of bias was extracted and included in characteristics of the studies in RevMan 5.3. Each study was evaluated for unclear, low, or high risk of bias in the following criteria: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other possible bias [ 53 ].

2.3. Data Extraction

Studies obtained from the electronic searches were considered for inclusion on the basis of title and abstract and by in-depth review of the full-text articles. Seventeen articles were selected for assessment of eligibility by two reviewers (S.R. and C.C.B.A.) for a final decision. Due to the unpublished data of Δmean and the associated SD, mean ± SD data of post-treatment for intervention and placebo groups from each included study was extracted according to number of participants and intervention effect for each outcome of interest. Baseline data between groups was checked for significant differences. Data from post-treatment was excluded in case of significant differences between group preintervention. If specified in mM, fasting blood glucose, total cholesterol, HDL, LDL, and TAG data was converted to mg/dL [ 54 ].

2.4. Statistical Analysis

Mean ± SD data of post-treatment for intervention and placebo groups was pooled in RevMan 5.3 [ 55 ] to compare changes after intervention between intervention and placebo groups by inverse variance and random effects model. Mean differences and 95% CI across studies were obtained by producing forest plots. In studies presenting data as mean ± SEM, SDs were derived from the reported SEMs by use of the RevMan calculator tool. Heterogeneity was investigated using I 2 statistic; values of 25%, 50%, and 75% indicated low, medium, and high statistical heterogeneity, respectively. I 2 > 50% indicated significant heterogeneity.

For a proper investigation of the effect of Stevioside on diabetic biomarkers, subgroups were produced, in which studies including diabetic subjects and studies including nondiabetic subjects were analyzed independently of each other. If data was adequate, further categorial subgroup and sensitivity analyses were performed.

Six hundred and seventy-seven nonduplicate studies were obtained from electronic searches, out of which 17 eligible studies were identified ( Figure 2 ). A total of 10 studies were excluded due to incompatible data ( n = 4 [ 14 , 21 , 22 , 41 ]) and inappropriate study design ( n = 6 [ 25 , 42 , 44 , 56 , 57 , 58 ]). Seven studies comprising nine RCTs and a total of 462 participants were included in this review [ 15 , 16 , 17 , 18 , 19 , 43 , 59 ]. All studies were of parallel design except one [ 18 ], and placebo-controlled by administration of placebo matching the intervention ( Table 1 ). Three RCTs included participants with hypertension [ 16 , 19 , 59 ], two of which included subjects with mild hypertension [ 19 , 60 ], four RCTs included diabetic participants [ 15 , 18 , 43 ], of which one included type 1 diabetic subjects [ 15 ], one RCT included untreated hyperlipidemic patients [ 17 ], while only one RCT included healthy subjects [ 15 ]. The SG Stevioside was used as intervention for all studies at a daily dose varying from 200–1500 mg. Variations were observed in number of times the supplements (both intervention and placebo) were administered per day. The duration of Stevioside or placebo administration ranged from 4 h to 2 years.

Flow chart for the number of studies screened, assessed for eligibility, and included in meta-analysis examining the effects of SGs on human health.

Characteristics of included randomized controlled trials (RCTs).

BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; FBG: fasting blood glucose; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TAG: triglyceride; HbA1c: glycated hemoglobin; T1D: type 1 diabetes; T2D: type 2 diabetes. a Three RCTs in one study. Group 1: T1D; Group 2: T2D; Group 3: Healthy. b Cross-over trial.

The contents of placebos varied between studies and were specified in only three studies, including maize starch [ 18 , 43 ] and talcum [ 17 ]. For the rest of the included studies, “matching placebo” was the only annotation regarding contents of placebos. Additionally, lifestyle adjustments also varied across the studies, and the majority of included studies did not specify their sources of funding. Discrepancies between studies were observed by assessing the risk of bias ( Figure 3 ). Two studies adequately reported randomization and allocation concealment procedures, and four studies adequately reported blinding of participants and personnel, while only one study adequately reported blinding of outcome assessors. Other biases, such as continuation of medicine, were detected in several of the studies. However, the majority of included studies lacked information regarding the assessed biases.

Risk of bias summary of studies included in meta-analysis examining the effect of SGs on human health. Adequate reporting is marked by either green (no bias) or red (bias). Nonadequate information about the bias in question is marked by “?”.

3.1. Effect of Steviol Glycosides on BMI

A total of five studies (seven RCTs, n = 401) were included in the meta-analysis of BMI ( Figure 4 ). No overall effect on BMI was found between administration of SGs and placebo (MD: −0.46, CI: −0.95–0.04). For subgroup analysis, the meta-analysis of BMI included four studies (four RCTs, n = 187) in the nondiabetic group and two studies (three RCTs, n = 214) in the diabetic group. In nondiabetic subjects, BMI was not affected by the administration of SGs for 90 days–1 year (MD: −0.43, 95% CI: −1.63–0.76, p = 0.48). Meta-analysis of the diabetes subgroup also revealed a non-significant effect of SG administration for 3 months–2 years. A trend towards a lower BMI was observed (MD: −0.53, CI: −1.15–0.08, p = 0.09); however, this did not reach statistical significance. Some heterogeneity was reported to be present in the nondiabetic subgroup ( I 2 = 33%, p = 0.21). No significant heterogeneity was found in neither nondiabetic or diabetes subgroups ( I 2 = 0%, p = 0.51). Sensitivity analysis showed two studies significantly contributing to the heterogeneity of the nondiabetic group [ 17 , 60 ].

Effect of SGs on BMI (kg/m 2 ) CI: confidence interval; MD: mean difference; RCTs: randomized controlled trials; SD: standard deviation.

3.2. Effect of Steviol Glycosides on Blood Pressure

Six studies (seven RCTs, n = 403) reported adequate and compatible data for statistical analyses ( Figure 5 ). Meta-analysis of these RCTs showed a significant difference in SBP when comparing SGs and placebo (MD: −6.32 mm Hg, CI: −10.17 to −2.46, p = 0.001). However, heterogeneity was reported, although not significant ( I 2 = 34.9%, p = 0.22). Subgroup analysis of four RCTs and three RCTs for the nondiabetic and diabetic group, respectively, revealed only a significant change in SBP in the nondiabetic subgroup between SGs and placebo (MD: −7.62 mm Hg, CI: −12.10, −3.13, p = 0.0009). No significant difference was observed in the diabetic subgroup (MD: −2.85 mm Hg, CI: −8.90 to 3.21, p = 0.36). Significant heterogeneity was reported in the nondiabetic subgroup (I 2 = 75%, p = 0.007), while no heterogeneity was evident from the diabetic subgroup ( I 2 = 0%, p = 0.83). Sensitivity analyses revealed differences in outcome when comparing only studies including hypertensive subjects. In fact, further subgroup analysis of the effect of SGs on SBP in nondiabetic hypertensive subjects (two RCTs, n = 268), revealed a significant reduction in systolic blood pressure (MD: −10.78 mm Hg, CI: −12.84 to −8.72, p < 0.00001) with non-significant heterogeneity between the studies ( I 2 = 24%, p = 0.25).

Effect of SGs on systolic blood pressure (SBP, mmHg) CI: confidence interval; MD: mean difference; RCTs: randomized controlled trials; SD: standard deviation.

An additional RCT was included in the meta-analysis of DBP, which was excluded in the analysis of SBP due to significant baseline differences between groups. Thus, six studies (eight RCTs, n = 494) were included in the meta-analysis concerning the effects of SGs on DBP ( Figure 6 ). No overall effect was found when combining all studies (MD: −3.62 mm Hg, CI: −7.69 to 0.49, p = 0.08) and significant heterogeneity was found ( I 2 = 91%, p < 0.00001). Subgroup analyses showed non-significant differences for both nondiabetic (MD: −5.07 mm Hg, CI: −10.88 to 0.74, p = 0.09) and diabetic subgroups (MD: −1.72 mm Hg, CI: −4.84 to 1.41, p = 0.28). No heterogeneity was found between studies included in the diabetic subgroup analysis, while significant heterogeneity was reported between studies included in the nondiabetic subgroup analysis ( I 2 = 95%, p < 0.00001). Comparing only studies including nondiabetic, hypertensive subjects revealed the same findings as to when comparing nondiabetic subjects regardless of blood pressure.

Effect of SGs on diastolic blood pressure (DBP, mmHg) CI: confidence interval; MD: mean difference; RCTs: randomized controlled trials; SD: standard deviation.

3.3. Effect of Steviol Glycosides on Fasting Blood Glucose

Meta-analysis of six studies (8 RCTs, n = 438) showed no significant difference in FBG in favour of SG ( Figure 7 ; MD: −2.63 mg/dL, CI: −7.77 to 2.51, p = 0.32). Significant heterogeneity was found between the included studies ( I 2 = 74%, p = 0.0004). Likewise, when analyzing on the basis of subgroups, diabetic status was shown not to affect the direction of the results (nondiabetic subgroup: MD: −2.60 mg/dL, CI: −5.61 to 0.42, p = 0.09 and diabetic subgroup: MD: −44.01, CI: −120.41 to 32.38, p = 0.26). Significant heterogeneity was reported for both groups ( I 2 = 47%, p = 0.11 and I 2 = 89%, p < 0.0001, respectively). One RCT included type 1 diabetic subjects. Performing a sensitivity analysis, leaving these data out, resulted in a decreased heterogeneity. Furthermore, by conducting a subgroup analysis including studies prohibiting any type of medications (four RCTs, n = 216), including antihypertensive and antidiabetic medications, no significant difference in FBG was observed (MD: −1.19, CI: −4.23 to 1.85, p = 0.44). However, no heterogeneity was observed between included studies ( I 2 = 0%, p = 0.64).

Effect of SGs on fasting blood glucose (FBG, mg/dL) CI: confidence interval; MD: mean difference; RCTs: randomized controlled trials; SD: standard deviation.

3.4. Effect of Steviol Glycosides on Cholesterol

A non-significant difference in total cholesterol between SG and placebo ( Figure 8 ; MD: −1.27 mg/dL, CI: −6.56 to 4.02, p = 0.64) was revealed by a meta-analysis of six studies (eight RCTs, n = 438). Analysis of five RCTs ( n = 355) including nondiabetic subjects (MD: −1.59 mg/dL, CI: −7.46 to 4.28, p = 0.60) and 3 RCTs ( n = 83) including diabetic subjects (MD: 0.10 mg/dL, CI: −12.09 to 12.30, p = 0.99) did not change the direction of meta-analytic results. No heterogeneity was found between studies included in the subgroup analysis of nondiabetic subjects ( I 2 = 0%, p = 0.79). The same was evident from the subgroup analysis of diabetic subjects ( I 2 = 0%, p = 0.52).

Effect of SGs on total cholesterol (mg/dL) CI: confidence interval; MD: mean difference; RCTs: randomized controlled trials; SD: standard deviation.

Similar findings were observed for LDL-C and HDL-C ( Figure 9 ; Figure 10 , respectively).

Effect of SGs on low-density lipoprotein cholesterol (LDL-C, mg/dL) CI: confidence interval; MD: mean difference; RCTs: randomized controlled trials; SD: standard deviation.

Effect of SGs on high-density lipoprotein cholesterol (HDL-C, mg/dL) CI: confidence interval; MD: mean difference; RCTs: randomized controlled trials; SD: standard deviation.

However, while no heterogeneity was observed between studies included in the meta-analysis of LDL-C, heterogeneity was reported between studies included in the diabetic subgroup analysis of HDL-C ( Figure 10 ).

Sensitivity analysis revealed that the study by Barriocanal et al. (RCT including type 2 diabetics) significantly contributed to the heterogeneity of the diabetic subgroup. By removing the data from the analysis, the HDL-C was found to be significantly decreased in favour of SG (MD: −7.63 mg/dL, CI: −11.41 to −3.85, p < 0.0001).

Meta-analysis of six studies (seven RCTs, n = 422) showed an overall non-significant difference in TAGs between SGs and placebo ( Figure 11 ; MD: 3.65 mg/dL, CI: −5.70 to 13.01, p = 0.44). Subgroup analyses did not change the direction of results in neither nondiabetic (MD: 2.83 mg/dL, CI: −6.82 to 12.48, p = 0.58) or diabetic subgroups (MD: 10.45 mg/dL, CI: −43.32 to 64.22, p = 0.70). No heterogeneity was found between studies in the nondiabetic subgroup ( I 2 = 0%, p = 0.57). However, heterogeneity was found for the diabetic subgroup ( I 2 = 26%, p = 0.25).

Effect of SGs on triglycerides (TAGs, mg/dL) CI: confidence interval; MD: mean difference; RCTs: randomized controlled trials; SD: standard deviation.

3.5. Effect of Steviol Glycosides on Glycated Hemoglobin

Three studies (five RCTs, n = 127) reported adequate data for statistical analysis. Meta-analysis of these RCTs showed a non-significant difference in HbA1c between SGs and placebo ( Figure 12 ; MD: 0.00%, CI: −0.24 to 0.25, p = 0.98). Subgroup analyses did not change the direction of the outcome (nondiabetic subjects: MD: 0.07%, CI: −0.20 to 0.34, p = 0.63 and diabetic subjects: MD: −0.30%, CI: −0.89 to 0.29, p = 0.31). No heterogeneity was found between studies included in the overall analysis ( I 2 = 0%, p = 0.54) or in the subgroup analyses of nondiabetic ( I 2 = 0%, p = 0.49) or diabetic subjects ( I 2 = 0%, p = 0.50).

Effect of SGs on glycated hemoglobin (HbA1c, %) CI: confidence interval; MD: mean difference; RCTs: randomized controlled trials; SD: standard deviation.

4. Discussion

This systematic review and meta-analysis suggest that administration of SGs causes non-significant reductions in BMI, diastolic blood pressure, fasting blood glucose, total cholesterol, and HDL-C in nondiabetic subjects. Even though the data did not reach statistical significance, it is worth mentioning that SG administration tended to reduce the diastolic blood pressure ( p = 0.09). A non-significant increase in TAGs in favour of placebo was also observed in non-diabetic subjects. Furthermore, a significant decrease in systolic blood pressure in favour of SGs was found in both overall and subgroup analysis of non-diabetic subjects, although the heterogeneity was found to be significant. However, when exclusively comparing data from long-term studies including non-diabetic, hypertensive subjects, a significant reduction with no heterogeneity between studies was observed. Only two long-term studies included non-diabetic, hypertensive subjects.

In the diabetic subgroup, a non-significant increase in favour of placebo in LDL-C was suggested. Also, non-significant reductions in BMI in favour of SGs was observed. However, this decrease tended to reach statistical significance ( p = 0.09).

Non-significant reductions in favour of SGs of systolic blood pressure, diastolic blood pressure, fasting blood glucose, HbA1c, and HDL-C were suggested in diabetic subjects. Furthermore, non-significant increases in favour of placebo of total cholesterol and LDL were evident from this meta-analysis. Our results also showed an increasing effect of SGs on LDL-C and TAGs.

Our findings partially corroborate the findings from a previous systematic review and meta-analysis, suggesting beneficial effects of Stevioside on cardiovascular risk factors [ 24 ]. Similarities in the included articles exist between the systematic review and meta-analysis by Onakpoya et al. and the current study. However, two papers investigating the effect of Reb A on several outcomes of interest included in the study by Onakpoya et al. were excluded from this study due to incompatible data. Thus, only studies using Stevioside as intervention were included. Interestingly, Onakpoya et al. reported a non-significant effect of Reb A on outcomes such as SBP, DBP, fasting blood glucose, and lipid profile. Also, one additional trial not available from the previous systematic review and meta-analysis was included in the current study. In addition, this study further developed this area of investigation by another approach. We aimed to investigate the effect of SGs on human health, particularly diabetes biomarkers, including BMI, SBP, DBP, FBG, total cholesterol, LDL-C, HDL-C, TAGs, and HbA1c.

Similar to the observations by Onakpoya et al., significant heterogeneity was found in some of the overall analyses in the current meta-analysis. Thus, the results from this systematic review and meta-analysis should be interpreted with caution. Substantial variations were observed in trial design, variation in daily doses of Stevioside, duration of intervention, and differences in protocols regarding lifestyle, including continuation of antihypertensive and antidiabetic medications across included studies. However, some of the subgroup analyses showed small or no heterogeneity, indicating true directions of the results of this intervention.

Since the effects of SGs have been investigated on a variety of outcomes in both humans and animals, and it has been reported that SGs exhibit both hypotensive, hypoglycemic, and hypolipidemic actions, the purpose for this study was to gather data from clinical trials and compare these.

From clinical trials, it has been suggested that administration of Stevia and SGs do not exhibit any body weight or BMI-lowering effect compared with placebo treatment, consistent with this meta-analysis [ 16 , 17 , 19 , 22 ]. Additionally, no effects of Stevia affecting satiety and energy intake to a significant extent have been reported [ 14 , 25 ], suggesting the non-caloric profile of SGs being responsible for the possible reduction in body weight or BMI if presented [ 48 ]. Most of the included studies incorporated lifestyle adjustments regarding diet and physical activity into their study procedure, which might have affected the results since these factors play a crucial role in affecting weight and BMI profiles of the subjects.

From a previous systematic review, Stevia intake was found to produce an increase in blood pressure when combining findings from studies performed for 1–3 months. In contrast, a lowering of blood pressure in hypertensive patients consuming Stevia for 1–2 years was reported [ 59 ]. In a 2-year study, consumption of 1500 mg/day Stevioside was found to contribute to healthy blood pressure regulation by inducing vasorelaxation [ 61 ]. Further antihypertensive effects of Stevia have been reported by Tomas et al., showing a systolic and diastolic blood pressure decreasing effect in mild-hypertensive subjects by administration of 750 mg Stevia [ 62 ]. Asides from the reported effect sizes for the reduction in blood pressures appear small, even small reductions may be beneficial in the prevention and management of hypertension.

Even though hypoglycemic effects and the underlying mechanisms of SGs are well established to some extent from several animal studies as already reported [ 26 , 27 , 28 , 29 , 31 , 32 ], no indications of reductions of blood glucose levels or in HbA1c in favour of SGs was found from the current study. No reductions in blood glucose levels or HbA1c were expected for non-diabetics from findings showing a stimulation in insulin release only at high glucose concentrations [ 26 , 27 ]. Thus, it is suggested that Stevioside elicits its beneficial effect by stimulating insulin release only in the diabetic state. Unexpectedly, no significant reductions of blood glucose levels in favour of SGs were found from subgroup analysis of diabetic subjects. However, due to the inconsistency between protocols across the included studies, some diabetic subjects were allowed to continue their antidiabetic medications, while other prohibited this medication before initiation of intervention, which might have affected the results to a great extent.

The same is applicable for the results of the lipid profile. Administration of a range of oral antihyperglycemic medications have been shown to affect the lipid profile in type 2 diabetics [ 63 ]. In previous studies, Stevioside alone or in combination with soy-protein isolate has been shown to decrease plasma lipids in the type 2 diabetic GK rat [ 64 ] and in high-fat diet fed mice [ 65 ]. Sharma et al. studied the effect of consumption of Stevia extract on 20 selected hypercholesterolemic women, and found a significant reduction in cholesterol, TAGs, and LDL-C, and a significant increase in HDL-C [ 66 ]. Only one of the included studies dealt with hyperlipidemic subjects, possibly explaining the obtained results. Significant differences were not found from the systematic review and meta-analysis by Onakpoya et al., suggesting that the results from animal studies do not translate to noticeable changes in humans. The duration of the included studies might have affected the results, hence why studies with a longer duration are of interest. Findings from animal studies have shown Stevia supplements to reduce TAGs [ 67 ], while this is not found from the current study. Actually, the contrary was observed from the overall analysis and the subgroup analysis of non-diabetic subjects. Unfortunately, only two studies concerning type 2 diabetics were included, meaning no statistically appropriate outcome was achieved.

Due to inconsistencies between study protocols regarding regulations in lifestyle such as diet and physical activity, the majority of these findings should be interpreted with caution, since lifestyle changes might improve the cardiovascular risk profile [ 68 , 69 ]. It is uncertain whether these lifestyle adjustments exclusively led to the observed small changes in some of the outcomes or enhanced or blunted the effects of SGs.

It would have been preferable to perform additional subgroup analyses to further elucidate the true effects of SGs on the outcomes. However, due to the limited quantity of included studies and the resultant limited number of participants, this was assessed not to be sufficient. To be able to perform true and statistically comparable subgroup analyses, it was determined beforehand that three or more studies presenting adequate data for statistical analysis should be included. For some of the outcomes, this was not the case, hence no conclusions should be made from these subgroup analyses. To be able to achieve as many subgroup analyses as possible, one RCT including T1D patients was included in the subgroup analyses of diabetic subjects. Due to major differences in etiology and pathogenesis between T1D and T2D [ 70 ], bias might have occurred. In addition, for future aspects, ∆mean and the associated SDs should be extracted from the articles rather than comparing placebo and intervention post-treatment data. The fact that the current meta-analysis was conducted on the basis of the post-treatment data might have resulted in exclusion of important data.

Onakpoya et al. requested information and missing data from trial investigators of included studies, and imputed SDs [ 71 ] from reported p values or upper limits for the significance levels, assuming that the SDs for each outcome reported were the same in both intervention and comparator groups, which might have resulted in bias [ 24 ]. To further improve this systematic review and meta-analysis, missing data should be requested from trial investigators.

Lastly, it is noteworthy that the majority of the clinical trials included in the current study did not aim to investigate the effects of SGs on the outcomes of interest. Rather, the efficacy and tolerability of SGs were examined to be able to confirm or deny the possible harmful effects of SGs in hypertensive or diabetic subjects.

Further clinical trials, in particular RCTs, investigating the effects of Stevioside are required. The trials should investigate the effects of diabetic biomarkers and include diabetic subjects, last for more than 6 months, and prohibit antidiabetic medications if possible. Furthermore, the diabetic subjects included in the trials should be newly diagnosed to avoid limited beta cell function of the patients. Studies should include descriptions of the placebo interventions [ 72 ].

5. Conclusions

From this systematic review and meta-analysis including data from published RCTs, Stevioside is suggested to generate reductions in blood pressure, in particular in SBP. Differences in favour of SGs of other outcomes were also evident, but not to a significant extent. Since the majority of included studies are based on safety of SG as a sweetener rather than a pharmaceutical treatment, the doses used are probably not high enough to induce any physiological changes.

In addition, continuation of antidiabetic and antihypertensive medications might have affected the final outcomes of the individual studies and thereby the overall outcome of the current study. Further clinical trials including diabetic subjects are warranted.

Acknowledgments

The authors would like to thank Max Lambert for the software support. Thanks to Aarhus University and Aarhus University Hospital for the opportunity to conduct study.

Author Contributions

Conceptualization, C.A. and P.B.J.; methodology, C.A. and P.B.J.; validation, C.A., S.R.; formal analysis, C.A.; writing—review and editing, C.A., S.R. and P.B.J.; visualization, C.A.; supervision, P.B.J.; project administration, P.B.J.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Type 1 diabetes FAQs

Endocrinologist Yogish Kudva, M.B.B.S., answers the most frequently asked questions about type 1 diabetes.

Hi, I'm Dr. Yogish C Kudva. I'm an endocrinologist at Mayo Clinic and I'm here to answer some of the important questions you may have about type one diabetes.

The best current treatment for type one diabetes is an automated insulin delivery system. This system includes a continuous glucose monitor, insulin pump, and a computer algorithm that continually adjusts insulin responding to the continuous glucose monitoring signal. The patient still has to enter information about the amount of carbohydrate he or she eats at mealtimes to provide the meal time related insulin.

Testing using a glucose meter is not enough because glucose measurements in people with type one diabetes, vary from normal to low and normal to high very rapidly in the course of a day, a continuous glucose monitor is needed to assess whether treatment is effective and also to determine how to improve treatment.

Current guidelines recommend use of a continuous glucose monitor. The percentage of time that is spent daily with glucose between 70 and 180 milligram per deciliter is the main measurement of appropriate treatment. This percentage should be 70% or higher daily. In addition, percentage of time spent with glucose below 70 should be less than four percent and greater than 250 should be less than five percent. Clearly, hemoglobin A1C testing to evaluate adequacy of treatment is not enough.

In certain people with type one diabetes transplantation can be undertaken. This could be pancreas transplantation or transplantation of insulin making cells called islet. Islet transplantation is considered research in the US. Pancreas transplantation is available as a clinical treatment. These patients with hypoglycemia unawareness may benefit from a pancreas transplant. People with type one diabetes who develop recurrent diabetic ketoacidosis may also benefit from a pancreas transplant. People with type one diabetes who have developed kidney failure, could have their lives transformed by transplantation of both the pancreas and the kidney.

There is active research going on to prevent type one diabetes from happening in children and adults who are less than 45 years old. People who are eligible for such research studies are people who have a positive antibody test for type one diabetes and are willing to be in such studies. The treatment being tested is medication that suppresses the immune system. Willing participants would be randomized to receive immune suppressive treatment or placebo treatment. Placebo looks like the medication, but does not do the same thing in the body. Initial research studies have been successful in decreasing the risk of development of type one diabetes in people that have received the immune system suppressing treatment and therefore, larger studies are now being undertaken.

Try to be informed about research going on and treatments that may be approved for type one diabetes. You can get this information through already available publications. Make sure that at least annually you see a physician who is an expert on your disorder. Never hesitate to ask your medical team any questions or concerns you have. Being informed makes all the difference. Thanks for your time and we wish well.

Type 1 diabetes symptoms often start suddenly and are often the reason for checking blood sugar levels. Because symptoms of other types of diabetes and prediabetes come on more gradually or may not be easy to see, the American Diabetes Association (ADA) has developed screening guidelines. The ADA recommends that the following people be screened for diabetes:

• Anyone with a body mass index higher than 25 (23 for Asian Americans), regardless of age, who has additional risk factors. These factors include high blood pressure, non-typical cholesterol levels, an inactive lifestyle, a history of polycystic ovary syndrome or heart disease, and having a close relative with diabetes.
• Anyone older than age 35 is advised to get an initial blood sugar screening. If the results are normal, they should be screened every three years after that.
• Women who have had gestational diabetes are advised to be screened for diabetes every three years.
• Anyone who has been diagnosed with prediabetes is advised to be tested every year.
• Anyone who has HIV is advised to be tested.

Tests for type 1 and type 2 diabetes and prediabetes

A1C test . This blood test, which doesn't require not eating for a period of time (fasting), shows your average blood sugar level for the past 2 to 3 months. It measures the percentage of blood sugar attached to hemoglobin, the oxygen-carrying protein in red blood cells. It's also called a glycated hemoglobin test.

The higher your blood sugar levels, the more hemoglobin you'll have with sugar attached. An A1C level of 6.5% or higher on two separate tests means that you have diabetes. An A1C between 5.7% and 6.4% means that you have prediabetes. Below 5.7% is considered normal.

• Random blood sugar test. A blood sample will be taken at a random time. No matter when you last ate, a blood sugar level of 200 milligrams per deciliter (mg/dL) — 11.1 millimoles per liter (mmol/L) — or higher suggests diabetes.
• Fasting blood sugar test. A blood sample will be taken after you haven't eaten anything the night before (fast). A fasting blood sugar level less than 100 mg/dL (5.6 mmol/L) is normal. A fasting blood sugar level from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is considered prediabetes. If it's 126 mg/dL (7 mmol/L) or higher on two separate tests, you have diabetes.

Glucose tolerance test . For this test, you fast overnight. Then, the fasting blood sugar level is measured. Then you drink a sugary liquid, and blood sugar levels are tested regularly for the next two hours.

A blood sugar level less than 140 mg/dL (7.8 mmol/L) is normal. A reading of more than 200 mg/dL (11.1 mmol/L) after two hours means you have diabetes. A reading between 140 and 199 mg/dL (7.8 mmol/L and 11.0 mmol/L) means you have prediabetes.

If your provider thinks you may have type 1 diabetes, they may test your urine to look for the presence of ketones. Ketones are a byproduct produced when muscle and fat are used for energy. Your provider will also probably run a test to see if you have the destructive immune system cells associated with type 1 diabetes called autoantibodies.

Your provider will likely see if you're at high risk for gestational diabetes early in your pregnancy. If you're at high risk, your provider may test for diabetes at your first prenatal visit. If you're at average risk, you'll probably be screened sometime during your second trimester.

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Depending on what type of diabetes you have, blood sugar monitoring, insulin and oral drugs may be part of your treatment. Eating a healthy diet, staying at a healthy weight and getting regular physical activity also are important parts of managing diabetes.

Treatments for all types of diabetes

An important part of managing diabetes — as well as your overall health — is keeping a healthy weight through a healthy diet and exercise plan:

Healthy eating. Your diabetes diet is simply a healthy-eating plan that will help you control your blood sugar. You'll need to focus your diet on more fruits, vegetables, lean proteins and whole grains. These are foods that are high in nutrition and fiber and low in fat and calories. You'll also cut down on saturated fats, refined carbohydrates and sweets. In fact, it's the best eating plan for the entire family. Sugary foods are OK once in a while. They must be counted as part of your meal plan.

Understanding what and how much to eat can be a challenge. A registered dietitian can help you create a meal plan that fits your health goals, food preferences and lifestyle. This will likely include carbohydrate counting, especially if you have type 1 diabetes or use insulin as part of your treatment.

Physical activity. Everyone needs regular aerobic activity. This includes people who have diabetes. Physical activity lowers your blood sugar level by moving sugar into your cells, where it's used for energy. Physical activity also makes your body more sensitive to insulin. That means your body needs less insulin to transport sugar to your cells.

Get your provider's OK to exercise. Then choose activities you enjoy, such as walking, swimming or biking. What's most important is making physical activity part of your daily routine.

Aim for at least 30 minutes or more of moderate physical activity most days of the week, or at least 150 minutes of moderate physical activity a week. Bouts of activity can be a few minutes during the day. If you haven't been active for a while, start slowly and build up slowly. Also avoid sitting for too long. Try to get up and move if you've been sitting for more than 30 minutes.

Treatments for type 1 and type 2 diabetes

Treatment for type 1 diabetes involves insulin injections or the use of an insulin pump, frequent blood sugar checks, and carbohydrate counting. For some people with type 1 diabetes, pancreas transplant or islet cell transplant may be an option.

Treatment of type 2 diabetes mostly involves lifestyle changes, monitoring of your blood sugar, along with oral diabetes drugs, insulin or both.

Monitoring your blood sugar

Depending on your treatment plan, you may check and record your blood sugar as many as four times a day or more often if you're taking insulin. Careful blood sugar testing is the only way to make sure that your blood sugar level remains within your target range. People with type 2 diabetes who aren't taking insulin generally check their blood sugar much less often.

People who receive insulin therapy also may choose to monitor their blood sugar levels with a continuous glucose monitor. Although this technology hasn't yet completely replaced the glucose meter , it can lower the number of fingersticks necessary to check blood sugar and provide important information about trends in blood sugar levels.

Even with careful management, blood sugar levels can sometimes change unpredictably. With help from your diabetes treatment team, you'll learn how your blood sugar level changes in response to food, physical activity, medications, illness, alcohol and stress. For women, you'll learn how your blood sugar level changes in response to changes in hormone levels.

Besides daily blood sugar monitoring, your provider will likely recommend regular A1C testing to measure your average blood sugar level for the past 2 to 3 months.

Compared with repeated daily blood sugar tests, A1C testing shows better how well your diabetes treatment plan is working overall. A higher A1C level may signal the need for a change in your oral drugs, insulin regimen or meal plan.

Your target A1C goal may vary depending on your age and various other factors, such as other medical conditions you may have or your ability to feel when your blood sugar is low. However, for most people with diabetes, the American Diabetes Association recommends an A1C of below 7%. Ask your provider what your A1C target is.

People with type 1 diabetes must use insulin to manage blood sugar to survive. Many people with type 2 diabetes or gestational diabetes also need insulin therapy.

Many types of insulin are available, including short-acting (regular insulin), rapid-acting insulin, long-acting insulin and intermediate options. Depending on your needs, your provider may prescribe a mixture of insulin types to use during the day and night.

Insulin can't be taken orally to lower blood sugar because stomach enzymes interfere with insulin's action. Insulin is often injected using a fine needle and syringe or an insulin pen — a device that looks like a large ink pen.

An insulin pump also may be an option. The pump is a device about the size of a small cellphone worn on the outside of your body. A tube connects the reservoir of insulin to a tube (catheter) that's inserted under the skin of your abdomen.

Continuous glucose monitor and insulin pump

A continuous glucose monitor, on the left, is a device that measures your blood sugar every few minutes using a sensor inserted under the skin. An insulin pump, attached to the pocket, is a device that's worn outside of the body with a tube that connects the reservoir of insulin to a catheter inserted under the skin of the abdomen. Insulin pumps are programmed to deliver specific amounts of insulin automatically and when you eat.

A continuous glucose monitor, on the left, is a device that measures blood sugar every few minutes using a sensor inserted under the skin. An insulin pump, attached to the pocket, is a device that's worn outside of the body with a tube that connects the reservoir of insulin to a catheter inserted under the skin of the abdomen. Insulin pumps are programmed to deliver specific amounts of insulin continuously and with food.

A tubeless pump that works wirelessly is also now available. You program an insulin pump to dispense specific amounts of insulin. It can be adjusted to give out more or less insulin depending on meals, activity level and blood sugar level.

A closed loop system is a device implanted in the body that links a continuous glucose monitor to an insulin pump. The monitor checks blood sugar levels regularly. The device automatically delivers the right amount of insulin when the monitor shows that it's needed.

The Food and Drug Administration has approved several hybrid closed loop systems for type 1 diabetes. They are called "hybrid" because these systems require some input from the user. For example, you may have to tell the device how many carbohydrates are eaten, or confirm blood sugar levels from time to time.

A closed loop system that doesn't need any user input isn't available yet. But more of these systems currently are in clinical trials.

Oral or other drugs

Sometimes your provider may prescribe other oral or injected drugs as well. Some diabetes drugs help your pancreas to release more insulin. Others prevent the production and release of glucose from your liver, which means you need less insulin to move sugar into your cells.

Still others block the action of stomach or intestinal enzymes that break down carbohydrates, slowing their absorption, or make your tissues more sensitive to insulin. Metformin (Glumetza, Fortamet, others) is generally the first drug prescribed for type 2 diabetes.

Another class of medication called SGLT2 inhibitors may be used. They work by preventing the kidneys from reabsorbing filtered sugar into the blood. Instead, the sugar is eliminated in the urine.

Transplantation

In some people who have type 1 diabetes, a pancreas transplant may be an option. Islet transplants are being studied as well. With a successful pancreas transplant, you would no longer need insulin therapy.

But transplants aren't always successful. And these procedures pose serious risks. You need a lifetime of immune-suppressing drugs to prevent organ rejection. These drugs can have serious side effects. Because of this, transplants are usually reserved for people whose diabetes can't be controlled or those who also need a kidney transplant.

Bariatric surgery

Some people with type 2 diabetes who are obese and have a body mass index higher than 35 may be helped by some types of bariatric surgery . People who've had gastric bypass have seen major improvements in their blood sugar levels. But this procedure's long-term risks and benefits for type 2 diabetes aren't yet known.

Treatment for gestational diabetes

Controlling your blood sugar level is essential to keeping your baby healthy. It can also keep you from having complications during delivery. In addition to having a healthy diet and exercising regularly, your treatment plan for gestational diabetes may include monitoring your blood sugar. In some cases, you may also use insulin or oral drugs.

Your provider will monitor your blood sugar level during labor. If your blood sugar rises, your baby may release high levels of insulin. This can lead to low blood sugar right after birth.

Treatment for prediabetes

Treatment for prediabetes usually involves healthy lifestyle choices. These habits can help bring your blood sugar level back to normal. Or it could keep it from rising toward the levels seen in type 2 diabetes. Keeping a healthy weight through exercise and healthy eating can help. Exercising at least 150 minutes a week and losing about 7% of your body weight may prevent or delay type 2 diabetes.

Drugs — such as metformin, statins and high blood pressure medications — may be an option for some people with prediabetes and other conditions such as heart disease.

Signs of trouble in any type of diabetes

Many factors can affect your blood sugar. Problems may sometimes come up that need care right away.

High blood sugar

High blood sugar ( hyperglycemia in diabetes ) can occur for many reasons, including eating too much, being sick or not taking enough glucose-lowering medication. Check your blood sugar level as directed by your provider. And watch for symptoms of high blood sugar, including:

• Urinating often
• Feeling thirstier than usual
• Blurred vision
• Tiredness (fatigue)
• Irritability

If you have hyperglycemia, you'll need to adjust your meal plan, drugs or both.

Increased ketones in your urine

Diabetic ketoacidosis is a serious complication of diabetes. If your cells are starved for energy, your body may begin to break down fat. This makes toxic acids known as ketones, which can build up in the blood. Watch for the following symptoms:

• Stomach (abdominal) pain
• A sweet, fruity smell on your breath
• Shortness of breath

You can check your urine for excess ketones with a ketones test kit that you can get without a prescription. If you have excess ketones in your urine, talk with your provider right away or seek emergency care. This condition is more common in people with type 1 diabetes.

Hyperglycemic hyperosmolar nonketotic syndrome

Hyperosmolar syndrome is caused by very high blood sugar that turns blood thick and syrupy.

Symptoms of this life-threatening condition include:

• A blood sugar reading over 600 mg/dL (33.3 mmol/L)
• Extreme thirst
• Vision loss
• Hallucinations

This condition is seen in people with type 2 diabetes. It often happens after an illness. Call your provider or seek medical care right away if you have symptoms of this condition.

Low blood sugar (hypoglycemia)

If your blood sugar level drops below your target range, it's known as low blood sugar ( diabetic hypoglycemia ). If you're taking drugs that lower your blood sugar, including insulin, your blood sugar level can drop for many reasons. These include skipping a meal and getting more physical activity than normal. Low blood sugar also occurs if you take too much insulin or too much of a glucose-lowering medication that causes the pancreas to hold insulin.

Check your blood sugar level regularly and watch for symptoms of low blood sugar, including:

• Heart palpitations
• Slurred speech

Low blood sugar is best treated with carbohydrates that your body can absorb quickly, such as fruit juice or glucose tablets.

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Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

Diabetes is a serious disease. Following your diabetes treatment plan takes total commitment. Careful management of diabetes can lower your risk of serious or life-threatening complications.

• Commit to managing your diabetes . Learn all you can about diabetes. Build a relationship with a diabetes educator. Ask your diabetes treatment team for help when you need it.
• Choose healthy foods and stay at a healthy weight. If you're overweight, losing just 7% of your body weight can make a difference in your blood sugar control if you have prediabetes or type 2 diabetes. A healthy diet is one with plenty of fruits, vegetables, lean proteins, whole grains and legumes. And limit how much food with saturated fat you eat.

Make physical activity part of your daily routine. Regular physical activity can help prevent prediabetes and type 2 diabetes. It can also help those who already have diabetes to maintain better blood sugar control. A minimum of 30 minutes of moderate physical activity — such as brisk walking — most days of the week is recommended. Aim for at least 150 minutes of moderate aerobic physical activity a week.

Getting regular aerobic exercise along with getting at least two days a week of strength training exercises can help control blood sugar more effectively than does either type of exercise alone. Aerobic exercises can include walking, biking or dancing. Resistance training can include weight training and body weight exercises.

Also try to spend less time sitting still. Try to get up and move around for a few minutes at least every 30 minutes or so when you're awake.

Lifestyle recommendations for type 1 and type 2 diabetes

Also, if you have type 1 or type 2 diabetes:

• Identify yourself. Wear a tag or bracelet that says you have diabetes. Keep a glucagon kit nearby in case of a low blood sugar emergency. Make sure your friends and loved ones know how to use it.
• Schedule a yearly physical and regular eye exams. Your regular diabetes checkups aren't meant to replace yearly physicals or routine eye exams. During the physical, your provider will look for any diabetes-related complications and screen for other medical problems. Your eye care specialist will check for signs of eye damage, including retinal damage (retinopathy), cataracts and glaucoma.

Keep your vaccinations up to date. High blood sugar can weaken your immune system. Get a flu shot every year. Your provider may recommend the pneumonia and COVID-19 vaccines, as well.

The Centers for Disease Control and Prevention (CDC) also currently recommends hepatitis B vaccination if you haven't previously had it and you're an adult ages 19 to 59 with type 1 or type 2 diabetes.

The most recent CDC guidelines suggest vaccination as soon as possible after diagnosis with type 1 or type 2 diabetes. If you are age 60 or older, have been diagnosed with diabetes, and haven't previously received the vaccine, talk to your provider about whether it's right for you.

• Pay attention to your feet. Wash your feet daily in lukewarm water. Dry them gently, especially between the toes. Moisturize with lotion, but not between the toes. Check your feet every day for blisters, cuts, sores, redness or swelling. Talk to your provider if you have a sore or other foot problem that doesn't heal quickly on its own.
• Control your blood pressure and cholesterol. Eating healthy foods and exercising regularly can help control high blood pressure and cholesterol. Drugs may be needed, too.
• Take care of your teeth. Diabetes may leave you prone to more-serious gum infections. Brush and floss your teeth at least twice a day. And if you have type 1 or type 2 diabetes, schedule regular dental exams. Talk to your dentist right away if your gums bleed or look red or swollen.
• If you smoke or use other types of tobacco, ask your provider to help you quit. Smoking increases your risk of many diabetes complications. Smokers who have diabetes are more likely to die of cardiovascular disease than are nonsmokers who have diabetes. Talk to your provider about ways to stop smoking or to stop using other types of tobacco.

If you drink alcohol, do so responsibly. Alcohol can cause either high or low blood sugar. This depends on how much you drink and if you eat at the same time. If you choose to drink, do so only in moderation — one drink a day for women and up to two drinks a day for men — and always with food.

Remember to include the carbohydrates from any alcohol you drink in your daily carbohydrate count. And check your blood sugar levels before going to bed.

• Take stress seriously. The hormones your body may make in response to long-term stress may prevent insulin from working properly. This will raise your blood sugar and stress you even more. Set limits for yourself and prioritize your tasks. Learn relaxation techniques. And get plenty of sleep.

Alternative medicine

Many substances have been shown to improve the body's ability to process insulin in some studies. Other studies fail to find any benefit for blood sugar control or in lowering A1C levels. Because of the conflicting findings, there aren't any alternative therapies that are currently recommended to help everyone to manage blood sugar.

If you decide to try any type of alternative therapy, don't stop taking the drugs that your provider has prescribed. Be sure to discuss the use of any of these therapies with your provider. Make sure that they won't cause bad reactions or interact with your current therapy.

Also, no treatments — alternative or conventional — can cure diabetes. If you're using insulin therapy for diabetes, never stop using insulin unless directed to do so by your provider.

Coping and support

Living with diabetes can be difficult and frustrating. Sometimes, even when you've done everything right, your blood sugar levels may rise. But stick with your diabetes management plan and you'll likely see a positive difference in your A1C when you visit your provider.

Good diabetes management can take a great deal of time and feel overwhelming. Some people find that it helps to talk to someone. Your provider can probably recommend a mental health professional for you to speak with. Or you may want to try a support group.

Sharing your frustrations and triumphs with people who understand what you're going through can be very helpful. And you may find that others have great tips to share about diabetes management.

Your provider may know of a local support group. You can also call the American Diabetes Association at 800-DIABETES ( 800-342-2383 ) or the Juvenile Diabetes Research Foundation at 800-533-CURE ( 800-533-2873 ).

Preparing for your appointment

You're likely to start by seeing your health care provider if you're having diabetes symptoms. If your child is having diabetes symptoms, you might see your child's health care provider. If blood sugar levels are very high, you'll likely be sent to the emergency room.

If blood sugar levels aren't high enough to put you or your child immediately at risk, you may be referred to a provider trained in diagnosing and treating diabetes (endocrinologist). Soon after diagnosis, you'll also likely meet with a diabetes educator and a registered dietitian to get more information on managing your diabetes.

Here's some information to help you get ready for your appointment and to know what to expect.

What you can do

• Be aware of any pre-appointment restrictions. When you make the appointment, ask if you need to do anything in advance. This will likely include restricting your diet, such as for a fasting blood sugar test.
• Write down any symptoms you're experiencing, including any that may seem unrelated.
• Write down key personal information, including major stresses or recent life changes. If you're monitoring your glucose values at home, bring a record of the glucose results, detailing the dates and times of testing.
• Make a list of any allergies you have and all medications, vitamins and supplements you're taking.
• Record your family medical history. Be sure to note any relatives who have had diabetes, heart attacks or strokes.
• Bring a family member or friend, if possible. Someone who accompanies you can help you remember information you need.
• Write down questions to ask your provider. Ask about aspects of your diabetes management you're unclear about.
• Be aware if you need any prescription refills. Your provider can renew your prescriptions while you're there.

Preparing a list of questions can help you make the most of your time with your provider. For diabetes, some questions to ask include:

• Are the symptoms I'm having related to diabetes or something else?
• Do I need any tests?
• What else can I do to protect my health?
• What are other options to manage my diabetes?
• I have other health conditions. How can I best manage these conditions together?
• Are there restrictions I need to follow?
• Should I see another specialist, such as a dietitian or diabetes educator?
• Is there a generic alternative to the medicine you're prescribing?
• Are there brochures or other printed material I can take with me? What websites do you recommend?

What to expect from your doctor

Your provider is likely to ask you many questions, such as:

• Can you describe your symptoms?
• Do you have symptoms all the time, or do they come and go?
• How severe are your symptoms?
• Do you have a family history of preeclampsia or diabetes?
• Tell me about your diet.
• Do you exercise? What type and how much?

Diabetes care at Mayo Clinic

• Ferri FF. Diabetes mellitus. In: Ferri's Clinical Advisor 2022. Elsevier; 2022. https://www.clinicalkey.com. Accessed May 7, 2022.
• Classification and diagnosis of diabetes: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S002.
• Papadakis MA, et al., eds. Diabetes mellitus. In: Current Medical Diagnosis & Treatment 2022. 61st ed. McGraw Hill; 2022. https://accessmedicine.mhmedical.com. Accessed May 4, 2022.
• Diabetes risk factors. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/basics/risk-factors.html. Accessed June 2, 2022.
• Cunningham FG, et al. Diabetes mellitus. In: Williams Obstetrics. 25th ed. McGraw-Hill Education; 2018. https://accessmedicine.mhmedical.com. Accessed June 2, 2022.
• Diabetes and DKA (ketoacidosis). American Diabetes Association. https://www.diabetes.org/diabetes/dka-ketoacidosis-ketones. Accessed May 4, 2022.
• Diabetes Canada Clinical Practice Guidelines Expert Committee. Complementary and alternative medicine for diabetes. Canadian Journal of Diabetes. 2018; doi:10.1016/j.jcjd.2017.10.023.
• Nimmagadda R. Allscripts EPSi. Mayo Clinic. June 16, 2022.
• Jameson JL, et al., eds. Diabetes mellitus: Diagnosis, classification and pathophysiology. In: Harrison's Principles of Internal Medicine. 20th ed. McGraw-Hill Education; 2018. https://accessmedicine.mhmedical.com. Accessed June 2, 2022.
• Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S009.
• Facilitating behavior change and well-being to improve health outcomes: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S005.
• AskMayoExpert. Type 1 diabetes mellitus. Mayo Clinic; 2021.
• Glycemic targets: Standards of Medical Care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S012.
• Comprehensive medical evaluation and assessment of comorbidities: Standards of Medical Care in Diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S004.
• Prevention or delay of type 2 diabetes and associated comorbidities: Standards of Medical Care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S003.
• Obesity and weight management for the prevention and treatment of type 2 diabetes: Standards of Medical Care in Diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S008.
• Diabetes technology. Standards of Medical Care in Diabetes — 2022. 2022; doi:10.2337/dc22-S007.

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Recent research suggests that walnuts might help to fend off diabetes, with the study highlighting a lower incidence of type 2 diabetes among individuals who nibble on a handful of walnuts every day. This extensive research, encompassing over 34,000 adults, indicates a possible reduction of up to 50 per cent in the risk of developing type 2 diabetes for adults who include walnuts in their daily diet compared to those who do not consume nuts.

On average, walnut eaters were found to be consuming about 1.5 tablespoons daily. If they doubled their walnut intake to three tablespoons each day, the prevalence of type 2 diabetes could potentially decrease by 47 per cent.

This quantity aligns closely with the recommended serving size for walnuts, which is four tablespoons or one ounce.

While the study didn't explore effects of walnut consumption beyond twice the usual intake, Dr Lenore Arab from the David Geffen School of Medicine at The University of California, Los Angeles, commented: "These findings provide more evidence for food-based guidance to help reduce the risk for diabetes."

She further added: "The strong connection we see in this study between walnut consumers and lower prevalence of type 2 diabetes is additional justification for including walnuts in the diet. Other research has shown that walnuts may also be beneficial for cognitive function and heart health.", reports Gloucestershire Live .

A study involving 34,121 adults aged between 18 and 85 has revealed that eating walnuts could lower the risk of type 2 diabetes. The research, which used data from the National Health and Nutrition Examination Survey (NHANES), asked participants about their diet and whether they had been diagnosed with or were taking medication for diabetes.

The study also assessed participants for diabetes using common lab tests including fasting plasma glucose and haemoglobin A1c. It was found that those who reported eating walnuts had a lower risk of type 2 diabetes compared to those who didn't eat any nuts, regardless of factors such as age, gender, race, education, BMI, and physical activity levels.

It's well known that people with diabetes often have high blood pressure, cholesterol, or triglycerides, which can increase the risk of heart disease and stroke. Previous studies have looked at the link between walnut consumption and cardiovascular health as well as diabetes.

The researchers suggested that the health benefits of walnuts could be due to them being a rich source of recommended polyunsaturated fat (13 grams per ounce), which includes the plant-based omega-3 fatty acid alpha-linolenic acid (2.5 grams per ounce).

The findings were published in the journal Diabetes Metabolism Research and Reviews.

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