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Review article, ketogenic diets and chronic disease: weighing the benefits against the risks.

• 1 Physicians Committee for Responsible Medicine, Washington, DC, United States
• 2 Brenda Davis Nutrition Consulting, Kelowna, BC, Canada
• 3 Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States
• 4 Department of Medicine, New York City Health + Hospitals/Bellevue, New York, NY, United States
• 5 College of Liberal and Professional Studies, University of Pennsylvania, Philadelphia, PA, United States
• 6 School of Public Health, Loma Linda University, Loma Linda, CA, United States
• 7 Adjunct Faculty, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, United States

Very-low-carbohydrate ketogenic diets have been long been used to reduce seizure frequency and more recently have been promoted for a variety of health conditions, including obesity, diabetes, and liver disease. Ketogenic diets may provide short-term improvement and aid in symptom management for some chronic diseases. Such diets affect diet quality, typically increasing intake of foods linked to chronic disease risk and decreasing intake of foods found to be protective in epidemiological studies. This review examines the effects of ketogenic diets on common chronic diseases, as well as their impact on diet quality and possible risks associated with their use. Given often-temporary improvements, unfavorable effects on dietary intake, and inadequate data demonstrating long-term safety, for most individuals, the risks of ketogenic diets may outweigh the benefits.

Introduction

Very-low-carbohydrate (ketogenic) diets have been promoted for weight loss and, less commonly, for other health reasons. This review summarizes the effects of a ketogenic diet on health conditions for which it has been promoted, as well as potential long-term effects on health.

The term “ketogenic diet” generally refers to a diet that is very low in carbohydrate, modest in protein, and high in fat. This mix of fuels aims to induce ketosis , or the production of ketone bodies that serve as an alternate energy source for neurons and other cell types that cannot directly metabolize fatty acids. Urinary ketone levels are often used as an indicator of dietary adherence ( 1 ).

Various ketogenic diets have been studied, as shown in Table 1 . The best defined and studied is sometimes called a “classic” ketogenic diet, referring to a very-low-carbohydrate diet that is generally medically supervised, with a 4:1 or 3:1 ratio, by weight, of dietary fat to combined dietary protein and carbohydrate ( 2 ).

Table 1 . Macronutrient composition of ketogenic diets.

Other variants allow more protein or carbohydrate ( 2 ). Ketogenic diets as typically implemented in scientific studies limit dietary carbohydrate to <50 g per day with varying amounts of fat and protein ( 3 , 4 ). “Low-carbohydrate diets” refer to carbohydrate intake below the recommended dietary allowance of 130 g/day ( 3 ), which may not be low enough to induce ketosis ( 5 ).

Effects on Nutrient Metabolism

During prolonged fasting, some tissues, such as muscle, can directly metabolize free fatty acids released from adipose stores. However, much of this fatty acid is converted into ketones in the liver, which can fuel otherwise-obligate glucose consumers like neurons, minimizing mobilization of body protein for gluconeogenesis. However, to induce the liver to make ketones in the fed state, carbohydrate intake must be minimized and fat intake increased. Protein utilization is also altered on a ketogenic diet; the body shunts as much protein as possible to gluconeogenesis, while the minimum necessary amount is used for tissue repair.

Effects on Diet Quality

Extreme carbohydrate restriction can profoundly affect diet quality, typically curtailing or eliminating fruits, vegetables, whole grains, and legumes and increasing consumption of animal products. Very-low-carbohydrate diets may lack vitamins, minerals, fiber, and phytochemicals found in fruits, vegetables, and whole grains ( 6 – 8 ). Low-carbohydrate diets are often low in thiamin, folate, vitamin A, vitamin E, vitamin B6, calcium, magnesium, iron, and potassium ( 9 ). In the absence of multivitamin supplements, individuals on low-carbohydrate diets are at risk of frank nutritional deficiencies ( 10 ). Even when consuming only nutrient-dense foods, a 4:1 ketogenic diet is reported to have multiple micronutrient shortfalls, often lacking in vitamin K, linolenic acid, and water-soluble vitamins excluding vitamin B12 ( 11 ).

Ketogenic diets are typically low in fiber needed not only for healthful intestinal function but also for microbial production of beneficial colonic short-chain fatty acids ( 12 ), which enhance nutrient absorption, stimulate the release of satiety hormones, improve immune function, and have anti-inflammatory and anti-carcinogenic effects ( 13 , 14 ). Inadequate intake of these microbiota-accessible carbohydrates found in plant cell walls also increases gut permeability, as bacteria extract the carbon they need from the mucus membrane that protects the gastrointestinal tract instead of fiber ( 15 ). The relative abundance of certain health-promoting, fiber-consuming bacteria has been found to be reduced in children consuming a ketogenic diet for epilepsy ( 16 ). It has been suggested that supplementation of ketogenic diets with fiber and non-digestible carbohydrates might be advisable ( 16 ), although data to confirm that supplementation could counteract the effects of very-low-carbohydrate diets on the gut microbiota are lacking.

Intake of other protective dietary components may also be insufficient, such as phytochemicals (e.g., flavanones and anthocyanins), which are not typically included in multivitamins and for which specific intake targets have not been established. Low-carbohydrate diets are also typically high in saturated fat and cholesterol ( 10 ).

Effects of Ketogenic Diets by Condition

Seizure disorders.

Worldwide, the lifetime prevalence of epilepsy is 7.6 per 1,000 people ( 17 ). According to a 2018 Cochrane Review, most affected individuals can eliminate seizures with medication, but about 30% cannot. Some one-third to one-half of people with drug-resistant epilepsy can reduce seizure frequency by at least 50% with a ketogenic diet ( 18 ). The lack of glucose available to fuel neurons is a possible mechanism for action ( 19 ).

Long-term adherence is challenging, as food choices are limited and adverse effects are common ( 18 ). Micronutrient supplementation is required. Potential health risks accompany the long-term use of such a diet, as described below. Research has shown that modified versions of the ketogenic diet allowing for more carbohydrates have also been somewhat effective in seizure reduction ( 19 ). Most studies have not been long term, large scale, nor conducted with adult participants; therefore, more research is needed.

Obesity and Weight Management

Ketogenic diets can induce weight loss ( 20 – 23 ). In a 2020 meta-analysis of 38 studies lasting 6–12 months and including 6,499 participants, low-carbohydrate diets, defined here as <40% of energy from carbohydrate, led to a small weight loss, compared with low-fat diets, defined as <30% of energy from fat (mean difference −1.30 kg; 95% CI, −2.02 to −0.57), with considerable variability between individuals and between studies. More than half of included studies met criteria for a general ketogenic diet, as defined in Table 1 , for part or all of the low-carbohydrate intervention ( 24 ).

It has been proposed that weight loss on ketogenic diets may be due to reduced appetite ( 25 ), an effect also seen in those following balanced, very-low-energy diets (<800 kcal/day). Since ketosis occurs on both types of diets, though to a lesser degree with very-low-energy diets, it is speculated that ketosis itself may decrease hunger ( 26 ). However, findings from a recent trial by Hall et al. suggest that a low-fat vegan diet (10% energy from fat) may be more effective than a ketogenic diet in suppressing appetite ( 27 ). Energy expenditure has also been shown to increase on a ketogenic diet, at least in short-term studies ( 27 , 28 ).

In controlled trials, low-carbohydrate diets appear no more effective than other diets that similarly restrict calories ( 29 ), nor are they more effective than other dietary interventions, such as low-fat vegetarian diets, at inducing weight loss ( 30 , 31 ). A 2013 meta-analysis of randomized controlled trials testing very-low-carbohydrate ketogenic diets (≤50 g carbohydrate/day or ≤10% kcal from carbohydrates) against diets based on modest reductions in fat intake (<30% kcal from fat) for at least 1 year found that ketogenic diets led to marginally more weight loss than reduced-fat diets (weighted mean difference: −0.91 kg; 95% CI, −1.65 kg to −0.17 kg, p = 0.02). However, no statistically significant difference in amount of weight lost was seen between the 2 diets in trials following people for at least 2 years ( 3 ).

A 2017 meta-analysis of 9 trials echoed these findings. In studies <12 months long, low-carbohydrate diets (<130 g carbohydrate/day or <26% kcal from carbohydrates) were seen to lead to greater weight loss in people with type 2 diabetes relative to normal- or high-carbohydrate control diets (weighted mean difference: −1.18 kg; 95% CI, −2.32 kg to −0.04 kg; p = 0.04). No advantage was seen relative to control diets in studies of longer duration (weighted mean difference: −0.24 kg; 95% CI, −2.18 kg to 1.7 kg; p = 0.81) ( 32 ).

At least initially, ketogenic diets may slow fat loss. In a 2016 metabolic ward study by Hall et al., 17 overweight or obese men were provided a baseline diet (50% carbohydrate, 35% fat, and 15% protein, as a percent of energy) for 4 weeks, then a ketogenic diet (5% carbohydrate, 80% fat, 15% protein) for 4 weeks. For 2 weeks after switching from the baseline diet to the ketogenic diet, participants' weight loss accelerated—but fat loss slowed. The authors attributed the additional weight loss primarily to loss of body water. However, loss of body protein may have contributed; urinary nitrogen levels increased through day 11 on the ketogenic diet. In the final 2 weeks on the ketogenic diet, participants' rates of body weight and fat loss rebounded to a rate comparable to that on the baseline diet. As a result, study participants required 4 weeks on a ketogenic diet to lose the same average 0.5 kg of fat lost in the final 2 weeks on a baseline diet. It is not clear whether these effects have longer-term consequences ( 28 ).

The 2021 metabolic ward study by Hall et al. tested the effects of both an animal-based ketogenic diet (76% energy from fat, 10% carbohydrate) and a plant-based, low-fat diet (75% carbohydrate, 10% fat) on 20 weight-stable adults, mean age 29.9 years, mean BMI 27.8 kg/m 2 ( 27 ). Participants were randomized to each diet, which they consumed ad libitum for 2 weeks before immediately crossing over to the other diet. Ad libitum energy intake was 689 kcal/day lower on the low-fat, plant-based diet as compared to the ketogenic diet ( p < 0.0001). Reported hunger and satisfaction were similar between groups. Both diets induced weight loss: 1.77 ± 0.32 kg ( p < 0.0001) for the ketogenic diet vs. 1.09 ± 0.32 kg ( p = 0.003) for the low-fat diet. However, most of the weight lost on the ketogenic diet came from fat-free mass (-1.61 ± 0.27 kg; p < 0.0001); this was not the case with the low-fat diet (−0.16 ± 0.27 kg; p = 0.56). Fat mass did not significantly change during either the first or second week of the ketogenic diet, while the low-fat diet led to significant losses in body fat after both the first and second weeks. This suggests that low-fat, plant-based diets may control appetite better than ketogenic diets. These results also add to evidence suggesting that the rapid initial weight loss observed on ketogenic diets is due predominantly to loss of fat-free mass (e.g., body water, glycogen, protein, and contents of the gastrointestinal tract) ( 27 ).

Type 1 Diabetes

Although ketogenic diets can improve glycemia in pediatric patients with type 1 diabetes, they are generally not used in this population due to the risk of malnutrition, failure to thrive, reduced bone density, hyperlipidemia, poor sleep, amenorrhea, and hypoglycemia. In addition, mood and behavior may be adversely affected ( 33 ).

In adults with type 1 diabetes, both favorable and unfavorable outcomes have been observed. A small study of 11 adults with type 1 diabetes reported that a ketogenic diet improved blood glucose control ( 34 ). However, the ketogenic diet triggered more frequent and extreme hypoglycemic episodes (6.3 episodes per week compared to 1–2 episodes per week typically reported for those following conventional or otherwise unspecified diets). The majority of participants also developed dyslipidemia. Lipid changes are of particular concern in individuals with diabetes, who are already at heightened risk of cardiovascular events ( 34 ).

A comprehensive review strongly discouraged sustained ketosis or hyperketonemia in individuals with type 1 diabetes ( 35 ). Due to metabolic irregularities associated with type 1 diabetes, ketone production is elevated, and ketone clearance is diminished. Individuals with elevated ketones are at increased risk for complications of the microvasculature, brain, kidney, and liver compared to those with normal ketone levels. In type 1 diabetes, hyperketonemia is associated with oxidative stress, inflammation, non-alcoholic fatty liver disease, and insulin resistance ( 35 ).

Type 2 Diabetes

Ketogenic diets depress appetite, promote weight loss, reduce blood glucose values, and decrease HbA1c in the short term ( 21 , 36 – 43 ). Some studies have reported improved insulin sensitivity ( 40 ); the effect appears to be dependent on loss of fat mass ( 44 ). In the abovementioned metabolic ward study in which 17 overweight or obese men were provided a baseline diet (50% carbohydrate) for 4 weeks and then a ketogenic diet (5% carbohydrate) for 4 weeks, during the ketogenic diet phase, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and C-reactive protein increased significantly, while fasting insulin and triglycerides decreased. While on the ketogenic diet, insulin sensitivity was impaired when participants were challenged with a baseline diet meal (50% carbohydrates) ( 45 ).

In the 2021 metabolic ward trial by Hall et al. comparing the effects of an animal-based ketogenic diet and a plant-based, low-fat diet, the plant-based diet had a greater glycemic load and predictably resulted in higher postprandial glucose and insulin levels than the ketogenic diet. However, glucose tolerance, as determined by an oral glucose tolerance test at the end of each phase, was compromised during the ketogenic phase (average 2-h glucose was 142.6 mg/dL) compared to the plant-based phase (average 2-h blood glucose was 108.5 mg/dL). In addition, high-sensitivity C-reactive protein, a marker of inflammation, was substantially higher while on the ketogenic diet compared to the plant-based diet (2.1 vs. 1.2 mg/L; p = 0.003), although not significantly different from baseline ( 27 ).

Another low-carbohydrate diet trial that followed individuals for 1 year found that insulin sensitivity was improved at 6 months but returned to baseline at 1 year ( 22 ). In healthy men, a ketogenic diet (83% fat and 2% carbohydrate) reduced insulin's ability to suppress endogenous glucose production ( 46 ).

A recent meta-analysis showed that reductions in hemoglobin A1c achieved with carbohydrate-restricted diets typically wane after a few months and that such diets are not more effective than other diets ( 47 ).

In other clinical trials with ketogenic diets, diabetes medications are frequently reduced or eliminated ( 21 , 36 – 43 ). The beneficial effects of ketogenic diets for people with type 2 diabetes are attributable primarily to weight loss, with benefits appearing to wane over time ( 48 , 49 ). Few additional negative impacts on global measures of health have been reported in short-term studies on type 2 diabetes ( 21 , 37 , 40 ). Long-term effects have not been elucidated ( 49 ).

The prospective Nurses' Health Study found no link between diets lower in carbohydrate and incident type 2 diabetes in women, although those consuming the most vegetable protein and fat had an 18% lower risk ( 50 ). The Health Professionals Follow-Up Study found that men consuming diets low in carbohydrate and high in animal protein and fat had a 37% higher risk of being diagnosed with type 2 diabetes than those who scored lowest for this diet style. Those emphasizing vegetable protein and fat on low-carbohydrate diets did not experience increased risk, and for men under 65 years of age, diabetes risk was 22% lower ( 51 ).

Dietary staples in ketogenic diets include concentrated fats, meat, poultry, fish, eggs, and cheese, all of which have been associated with increased diabetes risk ( 52 – 56 ). These foods can be high in saturated fat, cholesterol, chemical contaminants, pro-oxidants such as heme iron, and inflammatory compounds such as N-glycolylneuraminic acid (Neu5Gc) and endotoxins. Conversely, foods consistently associated with reduced diabetes risk, including fruits, legumes, whole grains, and several vegetables, are minimized or eliminated ( 52 – 56 ).

Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a serious condition where excess fat is stored in hepatocytes, causing steatosis, which can progress to non-alcoholic steatohepatitis and increase the risk of hepatocellular carcinoma ( 57 – 60 ). Worldwide, the prevalence of NAFLD in adults is estimated to be 25.2%, ranging from a low of 13.5% in Africa to a high of 31.8% in the Middle East, with North America at 24.1% ( 61 ). The risk of NAFLD is significantly higher in individuals who have obesity or type 2 diabetes (43–92%) ( 57 , 58 , 62 ).

Hepatic triacylglycerol comes from three sources: de novo lipogenesis, primarily from glucose; lipolysis of stored triglyceride from adipose tissue; and diet-derived fats ( 58 ). Most (60–80%) triglyceride is from adipose tissue, 15% is from diet, and 5% is from de novo lipogenesis in healthy people. Triglyceride from de novo lipogenesis is much higher (26%) in individuals with NAFLD ( 63 ). Fat derived from de novo lipogenesis and adipose tissue is accelerated by insulin resistance ( 63 ).

Several clinical trials have compared low-fat and low-carbohydrate hypocaloric diets in overweight or obese adults and found similar reductions in intrahepatic fat ( 64 – 66 ). Ketogenic diets typically increase intake of saturated fat, cholesterol, and animal protein, all of which are associated with insulin resistance, oxidative stress, and an exacerbated flow of free fatty acids to hepatocytes ( 57 , 62 , 63 , 67 ).

In epidemiological studies, diets high in saturated fat, trans fat, simple sugars, and animal protein (especially from red and processed meat) ( 57 ) and low in dietary fiber and omega-3 fatty acids ( 62 , 68 ) are thought to contribute to NAFLD. In the Rotterdam Study, those consuming the most animal protein were 54% more likely to have NAFLD than those consuming the least (OR 1.54, 95% CI, 1.20–1.98) ( 68 ). Dietary components associated with reduced NAFLD risk include whole grains, nuts and seeds, monounsaturated fats, omega-3 fatty acids, vegetable protein, prebiotic fiber, probiotics, resveratrol, coffee, taurine, and choline ( 57 ). In the Tzu Chi Health Study, replacing one serving of soy with fish (or meat) was associated with a 12–13% increased risk of NAFLD. Whole grain intake had an inverse relationship with NAFLD, and those following a vegetarian diet had a 21% lower risk of NAFLD ( 69 ).

Lifestyle modifications, particularly diet change, weight loss, and exercise, are the primary modality for treating NAFLD ( 57 , 62 , 63 ). Lifestyle interventions that promote weight loss have been found to reduce liver fat and improve aminotransferase concentrations and insulin sensitivity ( 48 , 57 , 58 , 62 , 63 , 68 ). It has been suggested that achieving ketosis may have a benefit in ameliorating fatty liver ( 63 ), but the studies supporting this are limited and typically also restrict energy intake. Long-term safety and specific clinical outcomes have not been determined.

Some have suggested ketogenic diets for cancer patients ( 70 ) based on the so-called “Warburg effect,” whereby cancer cells increase glucose uptake and upregulate glycolysis even in the presence of oxygen, preferentially fermenting glucose to lactate ( 71 ). By nearly eliminating available glucose, ketogenic diets theoretically stress cancer cells.

Few clinical trials have tested this. A 2018 systematic review of ketogenic diets for the management of gliomas found no randomized clinical trials and just 6 published case series/reports. While the authors could not evaluate the effectiveness of ketogenic diets for cancer survival, they noted that minimal adverse events were reported, suggesting ketogenic diets may be safe in this population ( 72 ).

A 2020 systematic review analyzed 13 studies of ketogenic diets as a complementary therapy for standard treatments in a variety of cancers. Studies analyzed were small ( n = 2–44); 9 were prospective and 6 were controlled, but just 2 were randomized, and ketogenic diet prescriptions differed between studies. Diet-related adverse events were uncommon and mostly minor, and the diet had a beneficial effect on body composition. Findings were mixed for both overall survival and progression-free survival; beneficial effects were seen in four studies ( 73 ). A possible explanation for the lack of a consistent survival benefit is demonstrated in in vitro research suggesting that ketone utilization by cancer cells increases expression of genes associated with high metastatic potential ( 74 ). Given potential benefits for body composition, large, well-designed, randomized clinical trials are needed to determine the safety and effectiveness of ketogenic diets in cancer treatment ( 72 , 73 ).

Long-term data on cancer outcomes with ketogenic diets are lacking. However, food components typical of a ketogenic diet, such as red and processed meats, are linked to increased cancer risk ( 75 – 77 ). Whole grains, fruits, and vegetables are linked to a lower risk of both cancer and all-cause mortality ( 78 , 79 ), yet, with the exception of non-starchy vegetables, these foods are commonly avoided on ketogenic diets. For example, in one study of a ketogenic diet for type 2 diabetes, researchers encouraged unlimited meat, poultry, seafood, and eggs, while cutting intake of whole grains, fruits, and starchy vegetables and limiting intake of salad vegetables and non-starchy vegetables ( 21 ).

Alzheimer's Disease

By 2050, it is projected that 13.8 million people in the U.S. will have Alzheimer's disease (AD) ( 80 ). Given the brain's inability to efficiently utilize glucose in AD, some have proposed ketones as an alternate fuel source for these individuals ( 81 ). As reviewed by Włodarek in 2019, small trials have found that increasing blood ketones by supplementing with medium-chain triglycerides does improve some measures of cognitive function in AD, although not necessarily in those with the APOEε4 genotype ( 82 ).

No long-term data on ketogenic diets for AD are available, although small, short-term trials have been conducted. A 3-month, weight-maintaining ketogenic diet intervention improved cognition in subjects with mild-to-moderate AD ( n = 15), but improvements were lost after a 1-month washout period ( 83 ). A 6-week trial of a ketogenic diet in subjects with mild cognitive impairment led to improved memory relative to a control diet (50% of energy from carbohydrates); follow-up data were not available. However, the ketogenic diet was substantially lower in calories, which may have independently reduced insulin resistance ( 84 ). In a 2020 review of short-term ketogenic diet and ketone supplement studies in older adults, including those with no dysfunction, mild cognitive impairment, and AD, 6 of 9 controlled trials with clinical endpoints found significant cognitive improvements in the intervention groups, while other trials did not. Whether cognitive gains would be maintained upon discontinuation of the diet/supplement remains unknown due to lack of long-term follow-up ( 85 ).

Saturated fat intake, which typically increases on a ketogenic diet, is strongly associated with AD risk. In the Chicago Health and Aging Project, high saturated fat intake was linked to a 2- to 3-fold increased risk of incident AD ( 86 ). A 2016 review of international data found that consuming meats, eggs, high-fat dairy such as butter and cheese, and sweets was linked to an increased risk of AD ( 87 ). Aside from sweets, consumption of these foods generally increases on a ketogenic diet.

Polyphenol-rich plant foods such as fruits and vegetables are associated with lower AD risk ( 88 ) and diets focusing on whole plant foods and limiting animal foods and processed foods, such as the MIND diet, are proven to reduce AD risk ( 89 ). Thus, by providing ketones that can be metabolized by neurons in AD, a ketogenic diet could improve symptoms in the short term, but the diet's nutritional profile could increase risk over the long-term in healthy individuals.

Cardiovascular Disease

The effect of low-carbohydrate diets on plasma lipid concentrations is a major concern. It has long been established that weight loss by any means causes a reduction in total cholesterol of about 2 mg/dL per kilogram lost ( 90 ). However, low-carbohydrate diets are often an exception to that rule. In a 2002 6-month study of a very-low-carbohydrate “Atkins” diet by Westman et al., 12 (29%) of the 41 participants had LDL-C elevations. The average increase was 18 mg/dL ( 91 ). In a similar 6-month study by Yancy, 30% of participants had LDL-C increases > 10% ( 92 ).

In a trial published in 2003 by Foster et al., LDL-C rose 6.2% in a group of low-carbohydrate dieters at 3 months ( 22 ). For comparison, LDL-C dropped by 11.1% during this same time period in participants following a conventional low-calorie diet. In a 2004 1-year study, those on a low-carbohydrate diet increased their mean LDL-C from 112 to 120 mg/dL ( 93 ). In 2018, Hallberg ( 94 ) reported a mean 10% rise in LDL-C in individuals following low-carbohydrate diets, an elevation that persisted during 2 years of follow-up ( 95 ). A recent meta-analysis of 5 studies showed that, in individuals with type 2 diabetes, ketogenic diets led to, on average, no substantial change in LDL-C ( 96 ).

It is important to note that changes reported in group means do not reflect the change for any given individual. In the 2002 study cited above, while the mean LDL-C increase was 18 mg/dL, one participant's LDL-C concentration increased from 123 to 225 mg/dL ( 91 ). In the Yancy study, one participant's LDL-C increased from to 219 mg/dL. Another experienced an LDL-C rise from 184 to 283 mg/dL, and a third developed chest pain and was subsequently diagnosed with coronary heart disease ( 92 ). In the Foster study, the standard deviation for the change in LDL-C was 20.4%, indicating that while LDL-C decreased for some, for many participants, LDL-C rose dramatically ( 22 ).

Negative effects on blood lipids have also been seen in healthy individuals. A 2018 pilot study of young, fit adults (average age 31) found that 12 weeks on a ketogenic diet led to a weight loss of 3.0 kg in the ketogenic group, with no significant weight change in the control group. However, despite significant weight loss, LDL-C increased by 35% in the ketogenic group ( p = 0.048), from 114 mg/dL at baseline to 154 mg/dL at 12 weeks ( 97 ).

Some have suggested that LDL-C or LDL particle concentration elevations are of no concern if the increase is mainly in larger LDL particles. There are two problems with this rationale: First is the problem of heterogeneity noted above (i.e., individuals may have significant worsening of their lipid profiles that are not reflected by mean figures). Second, LDL is potentially atherogenic regardless of particle size ( 98 , 99 ). Data supporting this concern come from the Women's Health Study, a randomized, placebo-controlled trial of low-dose aspirin and vitamin E. As part of the study, LDL particle size was assessed. The hazard ratio for incident cardiovascular disease associated with large LDL particles was 1.44 (indicating a 44% increased risk). For small LDL, it was 1.63 (a 63% increased risk). Both were highly statistically significant. In other words, large LDL particles were strongly atherogenic, albeit less so than small LDL ( 100 ).

It has also been proposed that the risk elevation associated with increased LDL-C concentrations may be neutralized to the extent that high-density lipoprotein cholesterol (HDL-C) also rises. However, both Mendelian randomization trials and studies using HDL-elevating agents have not shown benefit regarding cardiovascular risk. In the former category are studies that have examined individuals with naturally occurring genetic variants associated with elevated plasma HDL-C concentrations. These genetic traits are not associated with reduced risk of myocardial infarction unless they also reduce LDL-C ( 101 ).

Treatment-induced HDL-C elevations were examined in a meta-analysis of 108 studies including 299,310 participants, which found no associated reduction in the risk of coronary heart disease events, coronary disease mortality, or total mortality ( 102 ). The LDL-C/HDL-C ratio was not a better predictor of cardiovascular outcomes than LDL-C alone, and the authors recommended using LDL-C, rather than HDL-C or a ratio of the two, as the therapeutic target.

Kidney Health

The evidence of the renal-specific effects of ketogenic diets is limited but worth noting, especially in the context of the unclear long-term benefits of such diets for diabetes and obesity ( 103 ). For those without chronic kidney disease (CKD), one of the biggest potential risks of the ketogenic diet is the development of kidney stones, a finding that has been frequently noted in the pediatric epilepsy literature ( 104 , 105 ). The ketogenic diet's emphasis on high-fat, animal-based foods while excluding many fruits and vegetables promotes a urinary milieu for kidney stones. Dietary animal protein consumption is a well-established promoter of kidney stones ( 106 ). The acidosis caused by the ketogenic diet may also encourage stone formation by lowering urinary citrate and pH levels while increasing urinary calcium levels.

Another potential risk of animal-based ketogenic diets for those without CKD is the development of CKD through the consumption of animal fat and protein. In observational studies of populations eating Western diets, high animal fat consumption, as is common with ketogenic diets, has been associated with increased risk of developing albuminuria ( 107 ). In a prospective study of nearly 12,000 people over 23 years, high animal protein consumption was associated with a 23% increased hazard ratio of incident CKD ( 108 ). Other observational studies of animal protein have shown similar findings ( 109 , 110 ).

For those with CKD, the high protein content in some ketogenic diets is of concern. While “classic” ketogenic diets are not necessarily high in protein, those used for weight loss often meet the definition of a high-protein diet (>1.5 g/kg/d) by encouraging dieters to consume 1.2–2.0 g/kg/d. Compared to control diets with higher protein content, low protein consumption has been associated with a reduction in the rate of kidney function decline in a meta-analysis of 14 randomized controlled trials ( 111 ). High protein consumption facilitates hyperfiltration, a phenomenon of increased blood flow to the glomerulus, which is thought to lead to long-term damage in those with CKD ( 112 ). Finally, the acid load from the ketogenic diet may worsen metabolic acidosis and kidney disease in those with CKD ( 113 ). The ketogenic diet's acid load comes from the foods consumed (especially those from animal-based sources), ketoacids associated with ketone production, and from the lack of natural alkali found in fruits and vegetables that are often avoided in the ketogenic diet. As such, the ketogenic diet requires further research regarding its long-term renal safety in those with and without CKD.

Pre-pregnancy and Pregnancy

Approximately 40% of pregnancies in the United States are unplanned ( 114 ). Low-carbohydrate diets followed prior to conception or during the periconceptual period are associated with an increased risk of birth defects and gestational diabetes, respectively.

The National Birth Defects Prevention Study found that women who reported consuming low-carbohydrate diets in the year prior to conception (daily carbohydrate intake ≤5th percentile of control mothers, or ~95 g carbohydrate/day) were 30% more likely to have an infant with a neural tube defect (95% CI, 1.02–1.67), specifically anencephaly (OR 1.35; 95% CI, 0.90–2.02) and spina bifida (OR 1.28; 95% CI, 0.95–1.72) ( 115 ). For unplanned pregnancies in particular, effect estimates for carbohydrate-restricted diets showed an 89% increased risk of neural tube defects (95% CI, 1.28–2.79) ( 115 ).

Use of folate supplements may not mitigate the risk seen with low-carbohydrate diets. In the above study, there was no effect measure modification by folic acid supplement use ( 115 ). A 2019 study conducted using data that predated the era of folate-fortified grain products also found an increase in neural tube defects in the offspring of women consuming low-carbohydrate diets in the periconceptual period (OR 2.0; 95% CI, 1.2–3.4), suggesting other factors were contributing ( 116 ).

A prospective cohort study evaluating gestational diabetes risk scored women's diets for adherence to a low-carbohydrate diet pattern and dietary fat source. After adjusting for multiple variables including BMI, women consuming the least carbohydrate had a 27% higher risk of gestational diabetes compared to those consuming the most (RR 1.27; 95% CI, 1.06–1.51, p = 0.03). A stronger association was seen for women following a low-carbohydrate diet pattern high in animal products; they had a 36% higher risk of gestational diabetes (RR 1.36; 95% CI, 1.13–1.64, p = 0.003). A vegetable-based low-carbohydrate dietary pattern was not associated with increased risk ( 117 ).

Adverse Effects of Ketogentic Diets

The most restrictive ketogenic diets used for epilepsy can cause fatigue, headache, nausea, constipation, hypoglycemia, and acidosis, especially within the first few days to weeks of following the diet ( 2 ). Dehydration, hepatitis, pancreatitis, hypertriglyceridemia, hyperuricemia, hypercholesterolemia, hypomagnesemia, and hyponatremia can also occur ( 82 , 118 ).

A study of 300 users of online forums found that self-administered ketogenic diets may be accompanied by a temporary cluster of symptoms frequently termed “keto flu,” which includes headache, fatigue, nausea, dizziness, “brain fog,” gastrointestinal discomfort, decreased energy, feeling faint, and heartbeat alterations ( 119 ). In endurance athletes, 3.5 weeks on a ketogenic diet led to unfavorable effects on markers of bone modeling and remodeling ( 120 ).

Longer-term effects can include decreased bone mineral density, nephrolithiasis, cardiomyopathy, anemia, and neuropathy of the optic nerve ( 82 , 121 ). Ketogenic diets have low long-term tolerability, and are not sustainable for many individuals ( 48 , 49 ). Diets low in carbohydrate have also been associated with an increased risk of all-cause mortality ( 122 ), although recent data suggest that lower-carbohydrate diets can be linked to either higher or lower mortality risk, depending on the quality of the carbohydrate they contain and whether they rely more on animal protein and saturated fat or plant protein and unsaturated fat, respectively ( 123 ).

Ketogenic diets reduce seizure frequency in some individuals with drug-resistant epilepsy. These diets can also reduce body weight, although not more effectively than other dietary approaches over the long term or when matched for energy intake. Ketogenic diets can also lower blood glucose, although their efficacy typically wanes within the first few months.

Very-low-carbohydrate diets are associated with marked risks. LDL-C can rise, sometimes dramatically. Pregnant women on such diets are more likely to have a child with a neural tube defect, even when supplementing folic acid. And these diets may increase chronic disease risk: Foods and dietary components that typically increase on ketogenic diets (eg, red meat, processed meat, saturated fat) are linked to an increased risk of CKD, cardiovascular disease, cancer, diabetes, and Alzheimer's disease, whereas intake of protective foods (eg, vegetables, fruits, legumes, whole grains) typically decreases. Current evidence suggests that for most individuals, the risks of such diets outweigh the benefits.

Author Contributions

LC and NDB contributed to the organization of the manuscript, reviewed, and approved the submitted version. LC composed the outline and drafted the manuscript. LC, BD, SJ, MJ, JP, MN, and NDB wrote sections of the manuscript. All authors had full access to data and revised and approved the manuscript for publication.

This work was funded by the Physicians Committee for Responsible Medicine.

Conflict of Interest

LC is an employee of the Physicians Committee for Responsible Medicine in Washington, DC, a non-profit organization providing educational, research, and medical services related to nutrition. LC also declares that a trust for her benefit previously held stock in 3M, Abbot Labs, AbbVie, Johnson and Johnson, Mondelez, Nestle, and Walgreens; she is the author of a food and nutrition blog, Veggie Quest; and she is former publications editor and current chair for the Women's Health Dietetic Practice Group within the Academy of Nutrition and Dietetics. MJ and JP received compensation from the Physicians Committee for Responsible Medicine while working on this manuscript. MN is an employee of the Physicians Committee for Responsible Medicine. NDB is an Adjunct Professor of Medicine at the George Washington University School of Medicine. He serves without compensation as president of the Physicians Committee for Responsible Medicine and Barnard Medical Center in Washington, DC, non-profit organizations providing educational, research, and medical services related to nutrition. He writes books and articles and gives lectures related to nutrition and health and has received royalties and honoraria from these sources.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: ketogenic diet, very-low-carbohydrate diet, low-carbohydrate diet, obesity, disease prevention

Citation: Crosby L, Davis B, Joshi S, Jardine M, Paul J, Neola M and Barnard ND (2021) Ketogenic Diets and Chronic Disease: Weighing the Benefits Against the Risks. Front. Nutr. 8:702802. doi: 10.3389/fnut.2021.702802

Received: 29 April 2021; Accepted: 10 June 2021; Published: 16 July 2021.

Reviewed by:

Copyright © 2021 Crosby, Davis, Joshi, Jardine, Paul, Neola and Barnard. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Lee Crosby, LCrosby@pcrm.org

• Research article
• Open access
• Published: 25 May 2023

Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials

• Chanthawat Patikorn 1 , 2 ,
• Pantakarn Saidoung 1 ,
• Tuan Pham 3 ,
• Pochamana Phisalprapa 4 ,
• Yeong Yeh Lee 5 ,
• Krista A. Varady 6 ,
• Sajesh K. Veettil 1 &
• Nathorn Chaiyakunapruk 1 , 7  

BMC Medicine volume  21 , Article number:  196 ( 2023 ) Cite this article

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Systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported the benefits of ketogenic diets (KD) in various participants such as patients with epilepsy and adults with overweight or obesity . Nevertheless, there has been little synthesis of the strength and quality of this evidence in aggregate.

To grade the evidence from published meta-analyses of RCTs that assessed the association of KD, ketogenic low-carbohydrate high-fat diet (K-LCHF), and very low-calorie KD (VLCKD) with health outcomes, PubMed, EMBASE, Epistemonikos, and Cochrane database of systematic reviews were searched up to February 15, 2023. Meta-analyses of RCTs of KD were included. Meta-analyses were re-performed using a random-effects model. The quality of evidence per association provided in meta-analyses was rated by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) criteria as high, moderate, low, and very low.

We included 17 meta-analyses comprising 68 RCTs (median [interquartile range, IQR] sample size of 42 [20–104] participants and follow-up period of 13 [8–36] weeks) and 115 unique associations. There were 51 statistically significant associations (44%) of which four associations were supported by high-quality evidence (reduced triglyceride ( n  = 2), seizure frequency ( n  = 1) and increased low-density lipoprotein cholesterol (LDL-C) ( n  = 1)) and four associations supported by moderate-quality evidence (decrease in body weight, respiratory exchange ratio (RER), hemoglobin A 1c , and increased total cholesterol). The remaining associations were supported by very low (26 associations) to low (17 associations) quality evidence. In overweight or obese adults, VLCKD was significantly associated with improvement in anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, and total cholesterol. K-LCHF was associated with reduced body weight and body fat percentage, but also reduced muscle mass in healthy participants.

Conclusions

This umbrella review found beneficial associations of KD supported by moderate to high-quality evidence on seizure and several cardiometabolic parameters. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether the short-term effects of KD will translate to beneficial effects on clinical outcomes such as cardiovascular events and mortality.

Peer Review reports

Ketogenic diets (KD) have received substantial attention from the public primarily due to their ability to produce rapid weight loss in the short run [ 1 , 2 ]. The KD eating pattern severely restricts carbohydrate intake to less than 50 g/day while increasing protein and fat intake [ 3 , 4 , 5 , 6 ]. Carbohydrate deprivation leads to an increase in circulating ketone bodies by breaking down fatty acids and ketogenic amino acids. Ketones are an alternative energy source from carbohydrates that alter physiological adaptations. These adaptions have been shown to produce weight loss with beneficial health effects by improving glycemic and lipid profiles [ 7 , 8 ]. KD has also been recommended as a nonpharmacological treatment for medication-refractory epilepsy in children and adults [ 8 , 9 ]. Evidence suggests that KD has reduced seizure frequency in patients with medication-refractory epilepsy, and even allowing some patients to reach complete and sustained remission. 11 However, the exact anticonvulsive mechanism of KD remains unclear [ 10 , 11 ].

Several systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported on the use of KD in patients with obesity or type 2 diabetes mellitus (T2DM) to control weight and improve cardiometabolic parameters [ 1 , 12 , 13 , 14 , 15 ], in patients with refractory epilepsy to reduce seizure frequency [ 16 ], and in athletes to control weight and improve performance [ 17 ]. To date, there has been little synthesis of the strength and quality of this evidence in aggregate. This umbrella review therefore aims to systematically identify relevant meta-analyses of RCTs of KD, summarize their findings, and assess the strength of evidence of the effects of KD on health outcomes.

The protocol of this study was registered with PROSPERO (CRD42022334717). We reported following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (Additional file 1 ) [ 18 ]. Difference from the original review protocol is described with rationale in Additional file 2 : Table S1.

Search strategy and eligibility criteria

We searched PubMed, EMBASE, Epistemonikos, and the Cochrane database of systematic reviews (CDSR) from the database inception to February 15, 2023 (Additional file 2 : Table S2). No language restriction was applied. Study selection was independently performed in EndNote by two reviewers (C.P. and PS). After removing duplicates, the identified articles' titles and abstracts were screened for relevance. Full-text articles of the potentially eligible articles were retrieved and selected against the eligibility criteria. Any discrepancies were resolved by discussion with the third reviewer (SKV).

We included studies that met the following eligibility criteria: systematic reviews and meta-analyses of RCTs investigating the effects of any type of KD on any health outcomes in participants with or without any medical conditions compared with any comparators. When more than 1 meta-analysis was available for the same research question, we selected the meta-analysis with the largest data set [ 19 , 20 , 21 ]. Articles without full-text and meta-analyses that provided insufficient or inadequate data for quantitative synthesis were excluded.

Data extraction and quality assessment

Two reviewers (CP and PS) independently performed data extraction and quality assessment (Additional file 2 : Method S1). Discrepancies were resolved with consensus by discussing with the third reviewer (SKV). We used AMSTAR- 2 -A Measurement Tool to Assess Systematic Reviews- to grade the quality of meta-analyses as high, moderate, low, or critically low by assessing the following elements, research question, a priori protocol, search, study selection, data extraction, quality assessment, data analysis, interpretation, heterogeneity, publication bias, source of funding, conflict of interest [ 22 ].

Data synthesis

For each association, we extracted effect sizes (mean difference [MD], the standardized mean difference [SMD], and risk ratio [RR]) of individual studies included in each meta-analysis and performed the meta-analyses to calculate the pooled effect sizes and 95% CIs using a random-effects model under DerSimonian and Laird [ 23 ], or the Hartung-Knapp- Sidik-Jonkman approach for meta-analyses with less than five studies [ 24 ].  p  < 0.05 was considered statistically significant in 2-sided tests. Heterogeneity was evaluated using the I 2 statistic. The evidence for small-study effects was assessed by the Egger regression asymmetry test [ 25 ]. Statistical analyses were conducted using Stata version 16.0 (StataCorp). We presented effect sizes of statistically significant associations with the known or estimated minimally clinically important difference (MCID) thresholds for health outcomes [ 14 , 26 , 27 , 28 , 29 , 30 ].

We assessed the quality of evidence per association by applying the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluations) in five domains, including (1) risk of bias in the individual studies, (2) inconsistency, (3) indirectness, (4) imprecision, and (5) publication bias [ 31 ]. We graded the strength of evidence (high, moderate, low, and very low) using GRADEpro version 3.6.1 (McMaster University).

Sensitivity analyses

Sensitivity analyses were performed by excluding small-size studies (< 25 th percentile) [ 32 ] and excluding primary studies having a high risk of bias rated by the Cochrane’s risk of bias 2 tool (RoB 2) for RCTs from the identified associations [ 19 , 20 , 21 , 33 ].

Seventeen meta-analyses were included (Fig.  1 and Additional file 2 : Table S3) [ 1 , 2 , 15 , 16 , 17 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. These meta-analyses comprised 68 unique RCTs with a median (interquartile range, IQR) sample size per RCT of 42 (20–104) participants and a median (IQR) follow-up period of 13 (8–36) weeks. The quality of meta-analyses assessed using AMSTAR-2 found that none were rated as high confidence, 2 (12%) as moderate confidence, 2 (12%) as low confidence, and 13 (76.0%) as critically low confidence (Table 1 and Additional file 2 : Table S4).

Study selection flow of meta-analyses. Abbreviation: CDSR, Cochrane database of systematic review

Types of KD identified in this umbrella review were categorized as (1) KD, which limits carbohydrate intake to < 50 g/day or < 10% of the total energy intake (TEI) [ 35 ], (2) ketogenic low-carbohydrate, high-fat diet (K-LCHF), which limits carbohydrate intake to < 50 g/day or < 10% of TEI with high amount of fat intake (60–80% of TEI) [ 38 , 46 ], (3) very low-calorie KD (VLCKD), which limits carbohydrate intake to < 30–50 g/day or 13–25% of TEI with TEI < 700–800 kcal/day, and (4) modified Atkins diet (MAD), which generally limits carbohydrate intake to < 10 g/day while encouraging high-fat foods [ 15 , 47 ]. Meta-analyses of long-chain triglyceride KD, medium-chain triglyceride KD, and low glycemic index treatment were not identified.

Description and summary of associations

We identified 115 unique associations of KD with health outcomes (Additional file 2 : Table S5). The median (IQR) number of studies per association was 3 [ 4 , 5 , 6 ], and the median (IQR) sample size was 244 (127–430) participants. Outcomes were associated with KD types, including 40 (35%) KD, 18 (16%) K-LCHF, 13 (11%) VLCKD, 25 (22%) KD or K-LCHF, 5 (4%) KD or VLCKD, 1 (1%) KD or MAD, and 13 (11%) KD, K-LCHF, or VLCKD.

The associations involved 40 (35%) anthropometric measures (i.e., body weight, body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], waist circumference, muscle mass, fat mass, body fat percentage, and visceral adipose tissue), 37 (32%) lipid profile outcomes (i.e., triglyceride, total cholesterol, high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]), 22 (19%) glycemic profile outcomes (i.e., hemoglobin A 1c [HbA 1c ], fasting plasma glucose, fasting insulin, and homeostatic model assessment of insulin resistance [HOMA-IR]), 6 (5%) exercise performance (i.e., maximal heart rate, respiratory exchange ratio [RER], maximal oxygen consumption (VO 2 max), 5 (4%) blood pressure outcomes (i.e., systolic blood pressure [SBP], diastolic blood pressure [DBP], and heart rate), 1 (1%) outcome associated with seizure frequency reduction ≥ 50% from baseline, and 3 other outcomes (i.e., serum creatinine, C-peptide, and C-reactive protein). In addition, there is 1 association (1%) of adverse events.

Participants in the identified associations included 68 (59%) associations in adults with overweight or obesity with or without T2DM or dyslipidemia, 15 (13%) athletes or resistance-trained adults, 12 (10%) adults with T2DM, 11 (10%) healthy participants ≥ 16 years old, 8 (7%) cancer patients, and 1 (1%) in children and adolescents with epilepsy.

Using GRADE, 115 associations were supported by very low strength of evidence ( n  = 66, 57%), with the remaining being low ( n  = 36, 31%), moderate ( n  = 9, 8%), and high quality of evidence ( n  = 4, 3%) (Additional file 2 : Table S5). Almost half, or 44% (51 associations), were statistically significant based on a random-effects model, of which 51% (26 associations) were supported by a very low level of evidence, followed by low (17 associations [33%]), moderate (4 associations [8%]), and high (4 associations [8%]) levels of evidence. Overall beneficial outcomes associated with KD were BMI [ 37 , 42 ], body weight [ 1 , 2 , 35 , 36 , 37 , 41 ], waist circumference [ 37 , 42 ], fat mass [ 37 , 42 ], body fat percentage [ 38 , 40 ], visceral adipose tissue [ 37 ], triglyceride [ 1 , 2 , 36 , 42 ], HDL-C [ 1 , 2 , 42 ], HbA 1c  [ 2 , 34 , 35 ],  HOMA-IR [ 2 , 42 ], DBP [ 1 ], seizure frequency reduction ≥ 50% from baseline [ 16 ], and respiratory exchange ratio [ 17 , 39 ]. Adverse outcomes associated with KD were reduced muscle mass [ 37 , 38 ], and increased LDL-C [ 2 , 35 ], and total cholesterol [ 2 , 17 ]. In terms of safety, one association showed no significant increase in adverse events (e.g., constipation, abdominal pain, and nausea) with KD [ 44 ].

Eight out of 13 associations supported by moderate to high-quality evidence were statistically significant (Table 2 ). There were 4 statistically significant associations supported by high-quality evidence, including the following: (1) KD or MAD for 3–16 months was associated with a higher proportion of children and adolescents with refractory epilepsy achieving seizure frequency reduction ≥ 50% from baseline compared with regular diet (RR, 5.11; 95% CI, 3.18 to 8.21) [ 16 ], (2) KD for 3 months was associated with reduced triglyceride in adults with T2DM compared with regular diet (MD, -18.36 mg/dL; 95% CI, -24.24 to -12.49, MCID threshold 7.96 mg/dL) [ 14 , 35 ], (3) KD for 12 months was associated with reduced triglyceride in adults with T2DM compared with regular diet (MD, -24.10 mg/dL; 95% CI, -33.93 to -14.27, MCID threshold 7.96 mg/dL) [ 14 , 35 ], and (4) KD for 12 months was associated with increased LDL-C in adults with T2DM compared with regular diet (MD, 6.35 mg/dL; 95% CI, 2.02 to 10.69, MCID threshold 3.87 mg/dL) [ 14 , 35 ]. In addition, there were 4 statistically significant associations supported by moderate-quality evidence: (1) KD for 3 months was associated with reduced HbA 1c in adults with T2DM compared with regular diet (MD, -0.61%; 95% CI, -0.82 to -0.40, MCID threshold 0.5%) [ 14 , 35 ], (2) VLCKD for 4–6 weeks was associated with reduced body weight in T2DM adults with overweight or obesity compared with a low-fat diet or regular diet (MD, -9.33 kg; 95% CI, -15.45 to -3.22, MCID threshold 4.40 kg) [ 14 , 15 ], (3) K-LCHF for 4–6 weeks was associated with reduced respiratory exchange ratio in athletes compared with a high-carbohydrate diet (SMD, -2.66; 95% CI, -3.77 to -1.54) [ 39 ], and (4) K-LCHF for 11–24 weeks was associated with increased total cholesterol in athletes compared with regular diet (MD, 1.32 mg/dL; 95% CI, 0.64 to 1.99) [ 14 , 17 ].

Types of KD showed different effects on health outcomes with changes more than the MCID thresholds in different populations (Fig.  2 ). KD or MAD for 3–16 months was associated with a 5-times higher proportion of children and adolescents with refractory epilepsy achieving seizure frequency reduction ≥ 50% from baseline compared with a regular diet (RR, 5.11; 95% CI, 3.18 to 8.21) [ 16 ]. In healthy participants, K-LCHF for 3–12 weeks could reduce body weight by 3.68 kg (95% CI, -4.45 to -2.90) but also significantly reduced muscle mass by 1.27 kg (95% CI, -1.83 to -0.70, MCID threshold 1.10 kg) [ 14 , 26 , 38 ]. In adults with T2DM, KD for 3–12 months was found to have significant associations with changes more than the MCID thresholds, including reduction of triglyceride and HbA 1c ; however, KD for 12 months led to a clinically meaningful increase in LDL-C by 6.35 mg/dL (95% CI, 2.02 to 10.69, MCID threshold 3.87 mg/dL) [ 14 , 35 ]. In adults with overweight or obesity and/or metabolic syndrome, VLCKD for 4–6 weeks demonstrated a clinically meaningful weight loss of 9.33 kg (95% CI, -15.45 to -3.22, MCID threshold 4.40 kg) [ 14 , 15 ]. VLCKD for 3–96 weeks led to a clinically meaningful improvement in BMI, body weight, waist circumference, triglyceride, fat mass, and insulin resistance, while preserving muscle mass [ 42 ].

Associations of Types of Ketogenic Diet with Health Outcomes. Abbreviations: BMI, body mass index, DBP, diastolic blood pressure; GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; HbA 1c , hemoglobin A 1c ; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model of insulin resistance; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TEI, total energy intake

Excluding RCTs with small sizes in 7 associations found that the strength of evidence of one association was downgraded to very low quality, i.e., KD for 12 months, and the increase of LDL-C in adults with T2DM compared with a control diet. Another association was downgraded to low quality, i.e., KD for 12 months and the reduction of triglyceride in adults with T2DM compared with the control diet (Additional file 2 : Table S6). The remaining associations retained the same rank.

This umbrella review was performed to systematically assess the potential associations of KD and health outcomes by summarizing the evidence from meta-analyses of RCTs. Sensitivity analyses were performed to provide additional evidence from high-quality RCTs, which further increased the reliability of results. We identified 115 associations of KD with a wide range of outcomes. Most associations were rated as low and very low evidence according to the GRADE criteria because of serious imprecision and large heterogeneity in findings, and indirectness due to a mix of different interventions and comparators.

Our findings showed that KD or MAD resulted in better seizure control in children and adolescents with medication-refractory epilepsy (approximately a third of cases) for up to 16 months [ 10 , 11 , 16 ]. Anti-epileptic mechanisms of KD remain unknown but are likely multifactorial. Enhanced mitochondrial metabolism and an increase in ketone bodies or reduction in glucose across the blood–brain barrier resulted in synaptic stabilization [ 48 , 49 , 50 ]. Other mechanisms include an increase in gamma-aminobutyric acid (GABA) [ 51 ], more beneficial gut microbiome [ 52 ], less pro-inflammatory markers [ 53 ], and epigenetic modifications (e.g. beta-hydroxybutyrate [beta-OHB]) [ 54 ].

In adults, KD was associated with improved anthropometric measures, cardiometabolic parameters, and exercise performance. Our findings, however, demonstrated differences in the level of associations with type of KD. On the one hand, VLCKD is very effective in producing weight loss while preserving muscle mass in adults with overweight or obesity, with specific benefits on anthropometric and cardiometabolic parameters [ 15 , 42 ]. On the other hand, a significant portion of the weight loss seen in K-LCHF was due to muscle mass loss [ 17 , 38 ]. Overall KD was negatively associated with reduced muscle mass and increased LDL-C and total cholesterol.

Our findings demonstrated that KD could induce a rapid weight loss in the initial phase of 6 months, after which time further weight loss was hardly achieved [ 35 ]. Furthermore, weight loss induced by KD is relatively modest and appears comparable to other dietary interventions that are effective for short-term weight loss, e.g., intermittent fastingand Mediterranean diet [ 55 , 56 , 57 ].

KD is one of the dietary interventions employed by individuals to achieve rapid weight loss, which usually comes with reduced muscle mass [ 58 ]. However, KD has been hypothesized to preserve muscle mass following weight loss based on several mechanisms, including the protective effect of ketones and its precursors on muscle tissue [ 59 , 60 , 61 ], and increased growth hormone secretion stimulated by low blood glucose to increase muscle protein synthesis [ 58 , 62 , 63 ].

With regards to KD effects on lipid profiles, our results demonstrate an effective reduction in serum triglyceride levels with 3 months of lowered dietary carbohydrate intake, with even further reduction by month 12 [ 35 ]. Triglyceride levels are consistently shown to decrease after KD. Acute ketosis (beta-OHB ≈ 3 mM) due to ketone supplementation also shows decreases in triglycerides, indicating a potential effect of ketones on triglycerides independent of weight loss. One possible mechanism is the decreased very low-density lipoprotein content in the plasma due to low insulin levels. Due to a lack of insulin, lipolysis increases in fat cells [ 2 , 13 , 15 ]. Of note, the converse has also been observed as a phenomenon known as carbohydrate-induced hypertriglyceridemia, whereby higher dietary carbohydrate intake leads to higher serum triglycerides levels, potentially mediated by changes in triglyceride clearance and hepatic de novo lipogenesis rates [ 64 ]. Though our aggregate results also confirm an increase in LDL-C and total cholesterol with KD and K-LCHF, respectively, it is important to note that an increase in either of these levels does not necessarily signify a potentially deleterious cardiovascular end-point. This qualification derives from the fact that LDL particles are widely heterogeneous in composition and size, with small dense LDL particles being significantly more atherogenic than larger LDL particles [ 65 ]. Our observed aggregate effect of KD on cholesterol levels does not account for the difference in LDL particle size, nor does it distinguish the sources of dietary fat, which can also be a significant effector of LDL particle size distribution and metabolism [ 66 ].

Most RCTs of KD were conducted in patients with a limited group of participants, such as those with overweight, obesity, metabolic syndrome, cancer, and refractory epilepsy. In addition, most outcomes measured were limited to only surrogate outcomes. Thus, more clinical trials with a broader scope in populations and outcomes associated with KD would expand the role of KD in a clinical setting. For example, participant selection could be expanded from previous trials to include elderly patients, nonalcoholic fatty live disease (NAFLD) patients, and polycystic ovarian syndrome patients. Outcomes of interest of could be expanded to include (1) clinical outcomes such as cardiovascular events and liver outcomes, (2) short- and long-term safety outcomes such as adverse events (e.g., gastrointestinal, neurological, hepatic, and renal), eating disorder syndrome, sleep parameters, lipid profiles, and thyroid function and (3) other outcomes such as adherence and quality of life. More importantly, long-term studies are needed to investigate the sustainability of the clinical benefits of KD.

Our findings are useful to support the generation of evidence-based recommendations for clinicians contemplating use of KD in their patients, as well as for the general population. We further emphasize the importance of consultation with healthcare professionals before utilizing KD and any other dietary interventions. We demonstrated the benefits of KD on various outcomes in the short term. However, these improvements may prove difficult to sustain in the long term because of challenges in adherence. As for any diet interventions to achieve sustainable weight loss, factors of success include adherence, negative energy balance, and high-quality foods. Thus, communication and education with KD practitioners are important to ensure their adherence to the diet. Some individuals might benefit from switching from KD to other dietary interventions to maintain long-term weight loss.

Limitations

This umbrella review has several limitations. Firstly, we focused on published meta-analyses which confined us from assessing the associations of KD on outcomes and populations that were not included in existing meta-analyses. Secondly, most of the included meta-analyses were rated with AMSTAR-2 as critically low confidence, mainly due to a lack of study exclusion reasons, unexplained study heterogeneity, and unassessed publication bias. However, these domains unlikely affected our findings. Thirdly, we could not perform a dose–response analysis to understand the effects of different levels of carbohydrate intake on health outcomes because of insufficient details of carbohydrate intake reported in the meta-analyses. Fourthly, most RCTs of KD were limited to a relatively small number of participants with a short-term follow-up period, which limited our assessment of sustained beneficial effects after stopping KD. Lastly, due to decreased adherence, carbohydrate intake most likely increased across the course of the trials. For example, subjects in the KD arm of the A TO Z Weight Loss Study [ 67 ], started with a carbohydrate intake < 10 g/day but ended at 12 months with a carbohydrate intake accounting for 34% of TEI. In the DIRECT trial, subjects in the KD group started with carbohydrate intake of 20 g/day and ended at 12 months with 40% of TEI from carbohydrate intake [ 68 ]. Thus, we cannot be certain how the precise degree of ketosis contributed to the beneficial effects noted.

Beneficial associations of practicing KD were supported by moderate- to high-quality evidence, including weight loss, lower triglyceride levels, decreased HbA 1c , RER, and decreased seizure frequency. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether these short-term effects of KD will translate to beneficial effects on more long-term clinical outcomes such as cardiovascular events and mortality.

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary information files.

Abbreviations

Beta-hydroxybutyrate

Body mass index

Diastolic blood pressure

Gamma-aminobutyric acid

High-density lipoprotein cholesterol

Hemoglobin A 1c

Homeostatic model assessment of insulin resistance

Ketogenic low-carbohydrate high-fat diet

Ketogenic diets

Low-density lipoprotein cholesterol

Modified Atkins diet

Minimally clinically important difference

Nonalcoholic fatty liver disease

Randomized clinical trials

Respiratory exchange ratio

Systolic blood pressure

Type 2 diabetes mellitus

Total energy intake

Very low-calorie ketogenic diet

Maximal oxygen consumption

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The authors would like to acknowledge Thunchanok Ingkaprasert and Wachiravit Youngjanin for their editorial assistance.

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Chanthawat Patikorn, Pantakarn Saidoung, Sajesh K. Veettil & Nathorn Chaiyakunapruk

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Method S1. Data extraction. Table S1. Difference from original review protocol. Table S2. Search strategy. Table S3. Excluded studies with reasons.  Table S4. Quality assessment. Table S5. Summary of associations. Table S6. Sensitivity analyses. 

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Patikorn, C., Saidoung, P., Pham, T. et al. Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials. BMC Med 21 , 196 (2023). https://doi.org/10.1186/s12916-023-02874-y

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Effect of the ketogenic diet on glycemic control, insulin resistance, and lipid metabolism in patients with T2DM: a systematic review and meta-analysis

• Xiaojie Yuan 1   na1 ,
• Jiping Wang 1   na1 ,
• Shuo Yang 2   na1 ,
• Mei Gao 2 ,
• Lingxia Cao 2 ,
• Xumei Li 1 ,
• Dongxu Hong 1 ,
• Suyan Tian 3 &
• Chenglin Sun   ORCID: orcid.org/0000-0003-3570-1918 1 , 2  

Nutrition & Diabetes volume  10 , Article number:  38 ( 2020 ) Cite this article

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• Type 2 diabetes

At present, the beneficial effect of the ketogenic diet (KD) on weight loss in obese patients is generally recognized. However, a systematic research on the role of KD in the improvement of glycemic and lipid metabolism of patients with diabetes is still found scarce.

This meta-study employed the meta-analysis model of random effects or of fixed effects to analyze the average difference before and after KD and the corresponding 95% CI, thereby evaluating the effect of KD on T2DM.

After KD intervention, in terms of glycemic control, the level of fasting blood glucose decreased by 1.29 mmol/L (95% CI: −1.78 to −0.79) on average, and glycated hemoglobin A1c by 1.07 (95% CI: −1.37 to −0.78). As for lipid metabolism, triglyceride was decreased by 0.72 (95% CI: −1.01 to −0.43) on average, total cholesterol by 0.33 (95% CI: −0.66 to −0.01), and low-density lipoprotein by 0.05 (95% CI: −0.25 to −0.15); yet, high-density lipoprotein increased by 0.14 (95% CI: 0.03−0.25). In addition, patients’ weight decreased by 8.66 (95% CI: −11.40 to −5.92), waist circumference by 9.17 (95% CI: −10.67 to −7.66), and BMI by 3.13 (95% CI: −3.31 to −2.95).

KD not only has a therapeutic effect on glycemic and lipid control among patients with T2DM but also significantly contributes to their weight loss.

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Introduction.

Diabetes mellitus (DM) is the world’s leading cause for motility and morbidity, and the disease has become a major public health burden worldwide. It is estimated that the prevalence of diabetes in adults worldwide is over 300 million, and it will increase by 55% by 2035 1 . Obesity or overweight is one of the essential risk factors for diabetes and contributes to a twice-higher risk to develop DM 2 , 3 . Thus, dietary therapy aiming at weight loss is typically recommended in clinical practice 4 . Due to the fact that diabetes and its complications affect many aspects of physiology, the benefits of weight reduction are not limited to glycemic control but are also related to many cardiovascular risk factors such as blood pressure, high-density lipoprotein (HDL), total cholesterol (TC) and triglyceride (TG) 2 .

Medical nutrition, as part of the comprehensive treatment of DM with obesity with a primary goal of weight reduction, is the most simple, effective and economical choice of intervention. The dietary approach for body weight reduction can be obtained from many strategies, including a low-calorie diet, a very low-calorie diet, high-protein diet, and so on. Ketogenic diet (KD), which contains a very low level of carbohydrates (<55 g/d) with the main energy sources of lipid and protein, and which causes ketosis and simulates the physiological state of fasting, has been well reported to be effective for weight loss and glycemic control 4 , 5 , 6 , 7 , 8 , 9 . Previous meta-analyses have proved the efficacy of KD in body weight reduction 2 , 10 , 11 ; however, systemic reviews on the effect of KD on weight reduction and glycolipid metabolism in patients with DM are still limited. Westman et al. 12 and Partsalaki et al. 13 demonstrated that KD improved type 2 diabetes mellitus (T2DM) by reducing the glycemic response caused by carbohydrate and improving potential insulin resistance. Leonetti et al. 14 and Walton et al. 15 reported reduced TG and TC with increased HDL levels after KD consumption for a lipid profile. However, controversies are still existing; studies revealed that a low-carbohydrate, high-fat diet may exacerbate the lipid profile in patients with diabetes, although glycemic control improved with hypoglycemic medications 16 , 17 , 18 . Therefore, the purpose of the current review was to conduct a meta-analysis on the effects of a KD in patients with diabetes.

Considering the potential benefits of KD in diabetes management and weight reduction, and considering fasting blood glucose and glycated hemoglobin A1c (HbA1c) as common biomarkers for long-term glycemic control, HDL, LDL, TC, and TG levels are included in the current analysis to determine the changes of metabolic disorders in glucose and lipid metabolism. In addition, the homeostatic model assessment of insulin resistance (HOMA-IR) is considered as a reflection of insulin resistance reversal.

Materials and methods

Literature search.

In this meta-analysis, only studies published in English were considered, which were identified by searching the PubMed and MEDLINE databases. The keywords used for this literature search are T2DM or diabetes mellitus, ketogenic diet, obesity, and human. The search was finished on September 20, 2019. This meta-analysis was planned and performed according to the Preferred Reporting Items for Systemic Reviews (PRISM) guideline (Fig. 1 ).

Only studies published in English were considered, which were identified by searching the PubMed and MEDLINE databases. The keywords used for this literature search are T2DM or diabetes mellitus, ketogenic diet, obesity, and human. The search was finished on September 20, 2019.

Inclusive/exclusive criteria

Studies that met the following inclusive criteria were included: (1) the disease of interest is type II diabetes; (2) the therapeutic diet under consideration is KD; (3) the study was carried out on humans; animal experiments are not included; and (4) the summary statistics of the mean difference between before and after KD (if both means for before and after measurements are available, then we took the difference of these two statistics to obtain the desired mean difference), their corresponding standard error or 95% CI (according to this, the standard error was calculated) or p values (according to this, the corresponding t statistics and subsequently the standard error were calculated) are available.

Exclusive criteria: (1) case report studies were excluded; (2) meta-analysis or review studies were excluded; (3) studies on other diseases rather than type II diabetes were excluded; and (4) if only the respective mean and standard errors were available, such studies were excluded given it is hard to get an accurate estimation for the standard error of mean difference (since both measurements were on the same patient, they should be correlated to each other, and hence it is impossible to estimate this correlation).

Statistical analysis

The effects of KD on type II diabetes were estimated by the mean difference after KD versus before KD and their corresponding 95% CIs in random-effects meta-analysis models or fixed-effect meta-analysis models. To determine which model should be used, heterogeneity among studies was evaluated by the Cochrane’s Q statistic corresponding p values and the I 2 statistics. If the p value was <0.05 and I 2  > 0.5, a random-effect meta-analysis model was used. Otherwise, a fixed-effect meta-analysis model was chosen. Additionally, potential bias was assessed by using funnel plots, in which effect sizes versus standard errors were diagrammed. All statistical analysis was carried out in the R software, version 3.5 ( www.r-project.org ) 19 , 20 , 21 .

There are 13 studies included in this meta-analysis; the details of these 13 studies are presented in Table 1 . In total, 567 subjects were included in the final meta-analysis. From the perspective of glucose metabolism, lipid metabolism, and weight control, the effects of KD on T2DM were systemically reviewed by comparing the after-intervention measures with before-intervention measures of several biomarkers for the same patient. The variables used to surrogate for carbohydrate metabolism are included fasting glucose level and HbA1c; for lipid metabolism TC, TG, HDL and LDL; and for weight loss body weight, BMI and waist circumference. For all variables except BMI and waist, random-effect models were adopted according to the Q statistic p value and I 2 statistics.

Using the meta-analysis method, we found that the fasting blood glucose level was decreased 1.29 mmol/l (95% CI: −1.78 to −0.79) after the intervention of KD, compared to before such an intervention (based on ten articles that have the summary statistics for the difference between after- and before-intervention measures). As far as HbA1c is concerned, we found that the reduced proportion of HbA1c is more significant after the KD implementation, with a difference of −1.07% (95% CI: −1.37 to −0.78), which is regarded as the ideal therapeutic effect of drugs that is possible to be achieved on HbA1c. The forest plots for these two carbohydrates metabolism indices are given in Fig. 2 .

The reduced proportion of HbA1c is more significant after the KD implementation, which is regarded as the ideal therapeutic effect of drugs that is possible to be achieved on HbA1c.

In this study, eight articles investigated the effect of KD on the lipid metabolism of diabetic patients, but only five papers analyzed total cholesterol. It can be seen that after KD consumption, TG decreased by 0.72 mmol/L (95% CI: −1.01 to −0.43), TC decreased by 0.33 mmol/L (95% CI: −0.66 to −0.01), and LDL decreased by 0.05 mmol/L (95% CI: −0.25 to −0.15). On the other hand, HDL increased by 0.14 mmol/L (95% CI: 0.03−0.25). The forest plots for these four biomarkers are shown in Fig. 3 .

It can be seen that after KD consumption, TG, TC, and LDL decreased. On the other hand, HDL increased.

Regarding weight loss, many studies have demonstrated that KD has a positive effect by providing effective control over obesity. The results of our meta-analysis are consistent with previous results. Specifically, the average weight decreased by 8.66 kg (95% CI: −11.40 to −5.92), waist circumference reduced by 9.17 cm (95% CI: −10.67 to −7.66) and BMI reduced by 3.13 kg/m 2 (95% CI: −3.31 to −2.95), as shown in Fig. 4 .

Many studies have demonstrated that KD has a positive effect by providing effective control over obesity; our findings were consistent with the previous reports.

The American Diabetes Society (ADA) recommended physical activity, dietary management, and medical intake and other approaches should be applied simultaneously to manage blood glucose levels, and other abnormal metabolic factors. KD showed numerous health benefits to patients with T2DM 22 , 23 . KD provides energy through fat oxidation. When the human body experienced extreme hunger or very limited carbohydrate, the ketone body was produced and released to circulation by hepatic transformation of fatty acids 24 , 25 . Nutritional ketosis is different from severe pathological diabetic ketosis; the blood ketone body remained at 0.5−3.0 mmol/L with reduced blood glucose and normal blood pH, with no symptoms in nutritional ketosis 26 .

The possible mechanism for the health benefit of KD on patients with T2DM is that the extreme restriction of carbohydrate reduces the intestinal absorption of mono-saccharide, which leads to lower blood glucose level and reduces the fluctuation of blood glucose, and its effectiveness on regulating glucose metabolism was confirmed by a large body of evidence 27 , 28 . The current study analyzed 13 studies from literature focusing on diabetic patients; the results showed that the reduction of blood glucose ranges from 0.62 to 5.61 mmol/L. Higher reduction amplitudes were reported by Dashti 29 and Leonetti et al. 14 of 5.61 mmol/L (weight random 3.0%) and 3.87 mmol/L (weight random 1.2%), respectively; other reductions in blood glucose were all lower than 1.8 mmol/L. The possible reason for the higher reduction found in these two studies could be the higher blood glucose level included in the studies, and also that the average blood glucose concentration was above 10.0 mmol/L, leading to the possibility of a larger reduction; however, their contribution to the overall effect estimations in the meta-analysis was low. The average changes in fasting blood glucose after the KD consumption among the selected studies were −1.29 mmol/L, indicating the effectiveness of the KD in lowering fasting blood glucose.

No studies included in this meta-analysis evaluated the effect of KD on postprandial glucose level; unlike medications, dietetic therapy showed a long-term effect on glucose regulation 4 , 16 , and HbA1c was analyzed to evaluate the long-term effect of KD. HbA1c effectively reflects the blood glucose control in the past 2−3 months in patients with diabetes. It is reported that the risk of cardiac infarction and micro-vascular complications reduced by 14% and 37%, respectively, when HbA1c reduced by 1%. Therefore, the HbA1c level showed essential clinical significance in evaluating the blood glucose control, revealing the potential problems in the treatment and thereby guiding the therapeutic schedule 30 , 31 . Eight of the selected studies showed a reduction of HbA1c after KD consumption, the changes ranging from −0.6% to −3.3%; HbA1c reduced <1.5% in the majority of the studies included in the current analysis besides the study conducted by Walton (−3.3%; weight random 5.1%) 15 . The possible explanation for such strong improvement of HbA1c could be that Walton’s study had enrolled a limited number of patients and thus the compliance of patients to KD therapy can be guaranteed. Moreover, the studied subjects were newly diagnosed diabetic patients who were under dietary management without taking glucose-lowering medications; newly diagnosed subjects persist well in the study. Considering the causal factors comprehensively, the above study showed an ideal reduction in HbA1c. The average reduction of HbA1c was 1.07 in the current analysis of the selected eight studies, indicating that dietary management may also achieve the ideal therapeutic effects of medication.

HOMA-IR is considered as an indicator to evaluate the status of insulin resistance. Insulin resistance as a clinical characteristic of T2DM is closely related to obesity. Improving insulin resistance is one of the major targets in diabetes treatment 32 , 33 , 34 . However, studies focusing on the role of KD in the improvement of insulin resistance in patients with diabetes are very limited; most of the studies focused on the effect in obese subjects 35 , 36 . For instance, a controlled clinical trial aiming at the effects of KD consumption in obese people without diabetes revealed that HOMA-IR decreased by about 2.0 after KD consumption for 6 weeks 37 . The current analysis showed consistent changes in the studies that included HOMA-IR evaluation, with reduction ranging from −0.4 to −3.4; the reason for the significant reduction of 3.4 in the study by Tay et al. 38 is that the population included was obese diabetic patients with BMI higher than 30 kg/m 2 . Obesity is closely related to insulin resistance; KD consumption is confirmed to be effective in reducing body weight, and it is expected that KD may improve insulin resistance in obese diabetic patients 39 . During the ketogenesis, the sensitivity of the insulin receptor is promoted; therefore, KD not only ensures the supply of basic nutrients but also maintains a negative balance of energy, and reduces the fluctuation and reduction of insulin secretion caused by reduced carbohydrate intake as well, which eventually leads to improved insulin sensitivity 40 , 41 , 42 , 43 .

Consumption of KD not only improved glucose metabolism, but a large body of evidence has reported that KD improved lipid metabolism as well. Hussain et al. 4 reported that KD reduced TG and TC, and increased HDL level, thus ameliorating the status of dyslipidemia. In the present study, eight studies included showed results of lipid metabolism in diabetic patients after KD consumption; however, only five analyzed the TC levels. The current results showed the mean reduction of TG was 0.72 mmol/L, TC was 0.33 mmol/L, and LDL was 0.05 mmol/L, while the increase of HDL was 0.14 mmol/L. The higher amplitude of variation occurred in the Dashti et al. study 29 . This study reported that TG reduced by 3.67 mmol/L, TC reduced by 1.88 mmol/L, and LDL reduced by 1.78 mmol/L, while HDL increased by 0.14 mmol/L. Changes in the amplitude of the lipid biomarkers were all at the higher end in the above study. Both glucose and lipid metabolism showed great improvement after KD consumption in such a study; the characteristics of subjects recruited were closely correlated. The study recruited 31 obese subjects with hyperglycemia, dyslipidemia, and BMI over 30 kg/m 2 . The baseline TG, TC, and LDL were higher than those of typical patients with T2DM, which may contribute to the significant changes after the intervention. Consumption of KD showed a significant therapeutic effect in common patients with T2DM, including the Dashti 29 study. Disorders of lipid metabolism are particularly strong among patients with insulin resistance in T2DM. Dyslipidemia is lipotoxic to cells, leading to and/or aggravating insulin resistance. Its typical manifestation is the increase of TG and free fatty acid (FFA) 44 , 45 , 46 , 47 . Increased FFA is an independent pathogenic factor for insulin resistance and can possibly increase the risk for cardiovascular diseases 48 , 49 . Therefore, the improvement of dyslipidemia is beneficial for not only regulating insulin sensitivity but also controlling the occurrence and progression of diabetic complications 50 , 51 .

Numerous studies have confirmed the role of KD consumption in weight reduction in obese patients 35 , 36 , 37 , 40 , 41 , 42 , 43 , 52 ; the current meta-analysis focused on the effect of KD on weight reduction in obese diabetic patients. The results showed the average reduction of body weight was 8.66 kg, waist circumference was 9.17 cm, and BMI was 3.22 kg/m 2 , which were consistent with previous studies in nondiabetic patients. We also found that KD reduced systolic blood pressure by 4.30 (95% CI: −7.02 to 1.58) and diastolic blood pressure by 5.14 (95% CI: −10.18 to 0.10) in patients with T2DM, which possibly benefit from the improvement of body weight 51 .

Besides the mediation of glucose and lipid metabolism, KD may also benefit other clinical symptoms in diabetic patients, including insomnia, chills, constipation, pruritus, numbness of limbs, hypopsia, fatty liver, hypertension, and reduced cardiac function.

The potential side effects of KD were only mentioned in two of the studies 14 , 41 included in the meta-analysis; thus it is impossible to perform a systematic review in terms of the risks associated with KD consumption. Specifically, Goday and Leonetti’s 14 , 41 study investigated the adverse reactions of KD. Goday et al. 41 mentioned that fatigue, headache, nausea and vomiting were more common in the KD diet group after a 2-week intervention, while constipation and orthostatic hypotension were more common after 10 weeks. It was revealed by Leonetti et al. 14 that in the early stages of applying the KD, patients reported a sense of hunger, but it could be significantly alleviated with the progress of the intervention. Even though headache, nausea, vomiting, constipation, diarrhea, and other symptoms were reported during the study, the symptoms were mild and lasted for a short time, not relating to clinical practice.

Limitations

Only 13 studies were included in the current analysis, with limited studies focusing on the effect of KD in patients with T2DM worldwide. For instance, no analysis was conducted on HOMA-IR even though there was a trend of improvement; also, very limited literature was available. All studies included in this meta-analysis were carried out among Caucasian diabetic patients (no East Asians included); however, the majority of East Asian diabetic patients showed insulin resistance with central obesity and defect in insulin secretion. Therefore, clinical trials conducted among East Asians are highly desirable to confirm whether there is an improvement in the secretion function of islet cells other than improved regulation of glucose and lipid metabolism. Moreover, the current study analyzed the data without assigning studies into time duration due to the limited number of studies and the missing data of insulin and lipid biomarkers; in addition, the duration of the follow-up was decentralized into days, months, and years. The available studies concerning the effects of ketogenic diet in patients with diabetes are very limited; it is impossible to summarize a similar follow-up interval for statistical analysis of time points. However, the current results suggested that ketogenic diet consumption contributed to therapeutic effects despite the length of the term of intervention. The analysis of the difference before and after the intervention may also give credit to the clinical efficacy of the diet therapy. In current clinical practice, a majority of the patients have to use a combination of multiple drugs to improve their glycolipid metabolism. Drug therapy is a heavy mental and economical burden to patients. Given the fact that most of the patients are confused regarding a proper dietary therapy plan, it is essential to recommend a feasible dietary therapy plan to transmit a positive message to both patients with diabetes and physicians majored in the area of diabetes.

Based on a meta-analysis that systematically reviewed 13 relevant studies, we found that ketogenic diet can not only control fasting blood glucose and reduce glycosylated hemoglobin, but also improve lipid metabolism. Additionally, ketogenic diet can reduce BMI and body weight. Therefore, ketogenic diet may be used as part of the integrated management of type 2 diabetes.

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Acknowledgements

This study was supported by the Science Technology Department of Jilin Province (20180623006TC and 20200404213YY) and the Interdisciplinary Project of First Hospital of Jilin University (JDYYJC010) and Transformation Project of First Hospital of Jilin University (JDYYZH-1902019) and Education Department of Jilin Province (JJKH20190032KJ and JJKH20201081KJ).

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Department of Clinical Nutrition, First Hospital of Jilin University, 1 Xinmin Street, 130021, Changchun, Jilin, China

Xiaojie Yuan, Jiping Wang, Xumei Li, Dongxu Hong & Chenglin Sun

Department of Endocrinology and Metabolism, First Hospital of Jilin University, 1 Xinmin Street, 130021, Changchun, Jilin, China

Shuo Yang, Mei Gao, Lingxia Cao & Chenglin Sun

Division of Clinical Research, First Hospital of Jilin University, 1 Xinmin Street, 130021, Changchun, Jilin, China

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X.Y., J.W., S.Y., S.T. and C.S. were responsible for writing, M.G., L.C., X.L. and S.Y. were responsible for the literature collection and data management, D.H. and S.T. for statistical analysis, C.S. and S.T. are in charge of the overall research design and supervision.

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Yuan, X., Wang, J., Yang, S. et al. Effect of the ketogenic diet on glycemic control, insulin resistance, and lipid metabolism in patients with T2DM: a systematic review and meta-analysis. Nutr. Diabetes 10 , 38 (2020). https://doi.org/10.1038/s41387-020-00142-z

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Diet Review: Ketogenic Diet for Weight Loss

Finding yourself confused by the seemingly endless promotion of weight-loss strategies and diet plans? In this series , we take a look at some popular diets—and review the research behind them .

What is it?

The ketogenic or “keto” diet is a low-carbohydrate, fat-rich eating plan that has been used for centuries to treat specific medical conditions. In the 19 th century, the ketogenic diet was commonly used to help control diabetes. In 1920 it was introduced as an effective treatment for epilepsy in children in whom medication was ineffective. The ketogenic diet has also been tested and used in closely monitored settings for cancer, diabetes, polycystic ovary syndrome, and Alzheimer’s disease.

However, this diet is gaining considerable attention as a potential weight-loss strategy due to the low-carb diet craze, which started in the 1970s with the Atkins diet (a very low-carbohydrate, high-protein diet, which was a commercial success and popularized low-carb diets to a new level). Today, other low-carb diets including the Paleo, South Beach, and Dukan diets are all high in protein but moderate in fat. In contrast, the ketogenic diet is distinctive for its exceptionally high-fat content, typically 70% to 80%, though with only a moderate intake of protein.

How It Works

The premise of the ketogenic diet for weight loss is that if you deprive the body of glucose—the main source of energy for all cells in the body, which is obtained by eating carbohydrate foods—an alternative fuel called ketones is produced from stored fat (thus, the term “keto”-genic). The brain demands the most glucose in a steady supply, about 120 grams daily, because it cannot store glucose. During fasting, or when very little carbohydrate is eaten, the body first pulls stored glucose from the liver and temporarily breaks down muscle to release glucose. If this continues for 3-4 days and stored glucose is fully depleted, blood levels of a hormone called insulin decrease, and the body begins to use fat as its primary fuel. The liver produces ketone bodies from fat, which can be used in the absence of glucose. [1]

When ketone bodies accumulate in the blood, this is called ketosis. Healthy individuals naturally experience mild ketosis during periods of fasting (e.g., sleeping overnight) and very strenuous exercise. Proponents of the ketogenic diet state that if the diet is carefully followed, blood levels of ketones should not reach a harmful level (known as “ketoacidosis”) as the brain will use ketones for fuel, and healthy individuals will typically produce enough insulin to prevent excessive ketones from forming. [2] How soon ketosis happens and the number of ketone bodies that accumulate in the blood is variable from person to person and depends on factors such as body fat percentage and resting metabolic rate. [3]

What is ketoacidosis?

There is not one “standard” ketogenic diet with a specific ratio of macronutrients ( carbohydrates , protein , fat ). The ketogenic diet typically reduces total carbohydrate intake to less than 50 grams a day—less than the amount found in a medium plain bagel—and can be as low as 20 grams a day. Generally, popular ketogenic resources suggest an average of 70-80% fat from total daily calories, 5-10% carbohydrate, and 10-20% protein. For a 2000-calorie diet, this translates to about 165 grams fat, 40 grams carbohydrate, and 75 grams protein. The protein amount on the ketogenic diet is kept moderate in comparison with other low-carb high-protein diets, because eating too much protein can prevent ketosis. The amino acids in protein can be converted to glucose, so a ketogenic diet specifies enough protein to preserve lean body mass including muscle, but that will still cause ketosis.

Many versions of ketogenic diets exist, but all ban carb-rich foods. Some of these foods may be obvious: starches from both refined and whole grains like breads, cereals, pasta, rice, and cookies; potatoes, corn, and other starchy vegetables; and fruit juices. Some that may not be so obvious are beans , legumes, and most fruits. Most ketogenic plans allow foods high in saturated fat, such as  fatty cuts of meat , processed meats, lard, and butter, as well as sources of unsaturated fats , such as nuts, seeds, avocados, plant oils, and oily fish. Depending on your source of information, ketogenic food lists may vary and even conflict.

• Strong emphasis on fats at each meal and snack to meet the high-fat requirement. Cocoa butter, lard, poultry fat, and most plant fats (olive, palm, coconut oil) are allowed, as well as foods high in fat, such as avocado, coconut meat, certain nuts (macadamia, walnuts, almonds, pecans), and seeds (sunflower, pumpkin, sesame, hemp, flax).
• Some dairy foods may be allowed. Although dairy can be a significant source of fat, some are high in natural lactose sugar such as cream, ice cream, and full-fat milk so they are restricted. However, butter and hard cheeses may be allowed because of the lower lactose content.
• Protein stays moderate. Programs often suggest grass-fed beef (not grain-fed) and free-range poultry that offer slightly higher amounts of omega-3 fats, pork, bacon, wild-caught fish, organ meats, eggs, tofu, certain nuts and seeds.
• Most non-starchy vegetables are included: Leafy greens (kale, Swiss chard, collards, spinach, bok choy, lettuces), cauliflower, broccoli, Brussels sprouts, asparagus, bell peppers, onions, garlic, mushrooms, cucumber, celery, summer squashes.
• Certain fruits in small portions like berries. Despite containing carbohydrate, they are lower in “net carbs”* than other fruits.
• Other: Dark chocolate (90% or higher cocoa solids), cocoa powder, unsweetened coffee and tea, unsweetened vinegars and mustards, herbs, and spices.

Not Allowed

• All whole and refined grains and flour products, added and natural sugars in food and beverages, starchy vegetables like potatoes, corn, and winter squash.
• Fruits other than from the allowed list, unless factored into designated carbohydrate restriction. All fruit juices.
• Legumes including beans, lentils, and peanuts.
• Although some programs allow small amounts of hard liquor or low carbohydrate wines and beers, most restrict full carbohydrate wines and beer, and drinks with added sweeteners (cocktails, mixers with syrups and juice, flavored alcohols).

*What Are Net Carbs? “Net carbs” and “impact carbs” are familiar phrases in ketogenic diets as well as diabetic diets. They are unregulated interchangeable terms invented by food manufacturers as a marketing strategy, appearing on some food labels to claim that the product contains less “usable” carbohydrate than is listed. [6] Net carbs or impact carbs are the amount of carbohydrate that are directly absorbed by the body and contribute calories. They are calculated by subtracting the amount of indigestible carbohydrates from the total carbohydrate amount. Indigestible (unabsorbed) carbohydrates include insoluble fibers from whole grains, fruits, and vegetables; and sugar alcohols, such as mannitol, sorbitol, and xylitol commonly used in sugar-free diabetic food products. However, these calculations are not an exact or reliable science because the effect of sugar alcohols on absorption and blood sugar can vary. Some sugar alcohols may still contribute calories and raise blood sugar. The total calorie level also does not change despite the amount of net carbs, which is an important factor with weight loss. There is debate even within the ketogenic diet community about the value of using net carbs.

Programs suggest following a ketogenic diet until the desired amount of weight is lost. When this is achieved, to prevent weight regain one may follow the diet for a few days a week or a few weeks each month, interchanged with other days allowing a higher carbohydrate intake.

The Research So Far

The ketogenic diet has been shown to produce beneficial metabolic changes in the short-term. Along with weight loss, health parameters associated with carrying excess weight have improved, such as insulin resistance, high blood pressure, and elevated cholesterol and triglycerides. [2,7] There is also growing interest in the use of low-carbohydrate diets, including the ketogenic diet, for type 2 diabetes. Several theories exist as to why the ketogenic diet promotes weight loss, though they have not been consistently shown in research: [2,8,9]

• A satiating effect with decreased food cravings due to the high-fat content of the diet.
• A decrease in appetite-stimulating hormones, such as insulin and ghrelin, when eating restricted amounts of carbohydrate.
• A direct hunger-reducing role of ketone bodies—the body’s main fuel source on the diet.
• Increased calorie expenditure due to the metabolic effects of converting fat and protein to glucose.
• Promotion of fat loss versus lean body mass, partly due to decreased insulin levels.

The findings below have been limited to research specific to the ketogenic diet: the studies listed contain about 70-80% fat, 10-20% protein, and 5-10% carbohydrate. Diets otherwise termed “low carbohydrate” may not include these specific ratios, allowing higher amounts of protein or carbohydrate. Therefore only diets that specified the terms “ketogenic” or “keto,” or followed the macronutrient ratios listed above were included in this list below. In addition, though extensive research exists on the use of the ketogenic diet for other medical conditions, only studies that examined ketogenic diets specific to obesity or overweight were included in this list. ( This paragraph was added to provide additional clarity on 5.7.18. )

• A meta-analysis of 13 randomized controlled trials following overweight and obese participants for 1-2 years on either low-fat diets or very-low-carbohydrate ketogenic diets found that the ketogenic diet produced a small but significantly greater reduction in weight, triglycerides, and blood pressure, and a greater increase in HDL and LDL cholesterol compared with the low-fat diet at one year. [10] The authors acknowledged the small weight loss difference between the two diets of about 2 pounds, and that compliance to the ketogenic diet declined over time, which may have explained the more significant difference at one year but not at two years (the authors did not provide additional data on this).
• A systematic review of 26 short-term intervention trials (varying from 4-12 weeks) evaluated the appetites of overweight and obese individuals on either a very low calorie (~800 calories daily) or ketogenic diet (no calorie restriction but ≤50 gm carbohydrate daily) using a standardized and validated appetite scale. None of the studies compared the two diets with each other; rather, the participants’ appetites were compared at baseline before starting the diet and at the end. Despite losing a significant amount of weight on both diets, participants reported less hunger and a reduced desire to eat compared with baseline measures. The authors noted the lack of increased hunger despite extreme restrictions of both diets, which they theorized were due to changes in appetite hormones such as ghrelin and leptin, ketone bodies, and increased fat and protein intakes. The authors suggested further studies exploring a threshold of ketone levels needed to suppress appetite; in other words, can a higher amount of carbohydrate be eaten with a milder level of ketosis that might still produce a satiating effect? This could allow inclusion of healthful higher carbohydrate foods like whole grains, legumes, and fruit. [9]
• A study of 39 obese adults placed on a ketogenic very low-calorie diet for 8 weeks found a mean loss of 13% of their starting weight and significant reductions in fat mass, insulin levels, blood pressure, and waist and hip circumferences. Their levels of ghrelin did not increase while they were in ketosis, which contributed to a decreased appetite. However during the 2-week period when they came off the diet, ghrelin levels and urges to eat significantly increased. [11]
• A study of 89 obese adults who were placed on a two-phase diet regimen (6 months of a very-low-carbohydrate ketogenic diet and 6 months of a reintroduction phase on a normal calorie Mediterranean diet) showed a significant mean 10% weight loss with no weight regain at one year. The ketogenic diet provided about 980 calories with 12% carbohydrate, 36% protein, and 52% fat, while the Mediterranean diet provided about 1800 calories with 58% carbohydrate, 15% protein, and 27% fat. Eighty-eight percent of the participants were compliant with the entire regimen. [12] It is noted that the ketogenic diet used in this study was lower in fat and slightly higher in carbohydrate and protein than the average ketogenic diet that provides 70% or greater calories from fat and less than 20% protein.

Potential Pitfalls

Following a very high-fat diet may be challenging to maintain. Possible symptoms of extreme carbohydrate restriction that may last days to weeks include hunger, fatigue, low mood, irritability, constipation, headaches, and brain “fog.” Though these uncomfortable feelings may subside, staying satisfied with the limited variety of foods available and being restricted from otherwise enjoyable foods like a crunchy apple or creamy sweet potato may present new challenges.

Some negative side effects of a long-term ketogenic diet have been suggested, including increased risk of kidney stones and osteoporosis, and increased blood levels of uric acid (a risk factor for gout). Possible nutrient deficiencies may arise if a variety of recommended foods on the ketogenic diet are not included. It is important to not solely focus on eating high-fat foods, but to include a daily variety of the allowed meats, fish, vegetables, fruits, nuts, and seeds to ensure adequate intakes of fiber, B vitamins, and minerals (iron, magnesium, zinc)—nutrients typically found in foods like whole grains that are restricted from the diet. Because whole food groups are excluded, assistance from a registered dietitian may be beneficial in creating a ketogenic diet that minimizes nutrient deficiencies.

Unanswered Questions

• What are the long-term (one year or longer) effects of, and are there any safety issues related to, the ketogenic diet?
• Do the diet’s health benefits extend to higher risk individuals with multiple health conditions and the elderly? For which disease conditions do the benefits of the diet outweigh the risks?
• As fat is the primary energy source, is there a long-term impact on health from consuming different types of fats (saturated vs. unsaturated) included in a ketogenic diet?
• Is the high fat, moderate protein intake on a ketogenic diet safe for disease conditions that interfere with normal protein and fat metabolism, such as kidney and liver diseases?
• Is a ketogenic diet too restrictive for periods of rapid growth or requiring increased nutrients, such as during pregnancy, while breastfeeding, or during childhood/adolescent years?

Bottom Line

Available research on the ketogenic diet for weight loss is still limited. Most of the studies so far have had a small number of participants, were short-term (12 weeks or less), and did not include control groups. A ketogenic diet has been shown to provide short-term benefits in some people including weight loss and improvements in total cholesterol, blood sugar, and blood pressure. However, these effects after one year when compared with the effects of conventional weight loss diets are not significantly different. [10]

Eliminating several food groups and the potential for unpleasant symptoms may make compliance difficult. An emphasis on foods high in  saturated fat  also counters recommendations from the Dietary Guidelines for Americans and the American Heart Association and may have adverse effects on blood LDL cholesterol. However, it is possible to modify the diet to emphasize foods low in saturated fat such as olive oil, avocado, nuts, seeds, and fatty fish.

A ketogenic diet may be an option for some people who have had difficulty losing weight with other methods.  The exact ratio of fat, carbohydrate, and protein that is needed to achieve health benefits will vary among individuals due to their genetic makeup and body composition. Therefore, if one chooses to start a ketogenic diet, it is recommended to consult with one’s physician and a dietitian to closely monitor any biochemical changes after starting the regimen, and to create a meal plan that is tailored to one’s existing health conditions and to prevent nutritional deficiencies or other health complications. A dietitian may also provide guidance on reintroducing carbohydrates once weight loss is achieved.

A modified carbohydrate diet following the Healthy Eating Plate model may produce adequate health benefits and weight reduction in the general population. [13]

• Low-Carbohydrate Diets
• David Ludwig clears up carbohydrate confusion
• The Best Diet: Quality Counts
• Other Diet Reviews
• Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr . 2013 Aug;67(8):789.
• Paoli A. Ketogenic diet for obesity: friend or foe?. Int J Environ Res Public Health . 2014 Feb 19;11(2):2092-107.
• Gupta L, Khandelwal D, Kalra S, Gupta P, Dutta D, Aggarwal S. Ketogenic diet in endocrine disorders: Current perspectives. J Postgrad Med . 2017 Oct;63(4):242.
• von Geijer L, Ekelund M. Ketoacidosis associated with low-carbohydrate diet in a non-diabetic lactating woman: a case report. J Med Case Rep . 2015 Dec;9(1):224.
• Shah P, Isley WL. Correspondance: Ketoacidosis during a low-carbohydrate diet. N Engl J Med . 2006 Jan 5;354(1):97-8.
• Marcason W. Question of the month: What do “net carb”, “low carb”, and “impact carb” really mean on food labels?. J Am Diet Assoc . 2004 Jan 1;104(1):135.
• Schwingshackl L, Hoffmann G. Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis. J Acad Nutr Diet . 2013 Dec 1;113(12):1640-61.
• Abbasi J. Interest in the Ketogenic Diet Grows for Weight Loss and Type 2 Diabetes. JAMA . 2018 Jan 16;319(3):215-7.
• Gibson AA, Seimon RV, Lee CM, Ayre J, Franklin J, Markovic TP, Caterson ID, Sainsbury A. Do ketogenic diets really suppress appetite? A systematic review and meta‐analysis. Obes Rev . 2015 Jan 1;16(1):64-76.
• Bueno NB, de Melo IS, de Oliveira SL, da Rocha Ataide T. Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr . 2013 Oct;110(7):1178-87.
• Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, Proietto J. Ketosis and appetite-mediating nutrients and hormones after weight loss. Eur J Clin Nutr . 2013 Jul;67(7):759.
• Paoli A, Bianco A, Grimaldi KA, Lodi A, Bosco G. Long term successful weight loss with a combination biphasic ketogenic mediterranean diet and mediterranean diet maintenance protocol. Nutrients . 2013 Dec 18;5(12):5205-17.
• Hu T, Mills KT, Yao L, Demanelis K, Eloustaz M, Yancy Jr WS, Kelly TN, He J, Bazzano LA. Effects of low-carbohydrate diets versus low-fat diets on metabolic risk factors: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol . 2012 Oct 1;176(suppl_7):S44-54.

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The Ketogenic Diet: Evidence for Optimism but High-Quality Research Needed

Affiliation.

• 1 New Balance Foundation Obesity Prevention Center, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
• PMID: 31825066
• PMCID: PMC7269727
• DOI: 10.1093/jn/nxz308

For >50 y, dietary guidelines in the United States have focused on reducing intakes of saturated and total fat. However, rates of obesity and diabetes rose markedly throughout this period, with potentially catastrophic implications for public health and the economy. Recently, ketogenic diets have received substantial attention from the general public and nutrition research community. These very-low-carbohydrate diets, with fat comprising >70% of calories, have been dismissed as fads. However, they have a long history in clinical medicine and human evolution. Ketogenic diets appear to be more effective than low-fat diets for treatment of obesity and diabetes. In addition to the reductions in blood glucose and insulin achievable through carbohydrate restriction, chronic ketosis might confer unique metabolic benefits of relevance to cancer, neurodegenerative conditions, and other diseases associated with insulin resistance. Based on available evidence, a well-formulated ketogenic diet does not appear to have major safety concerns for the general public and can be considered a first-line approach for obesity and diabetes. High-quality clinical trials of ketogenic diets will be needed to assess important questions about their long-term effects and full potential in clinical medicine.

Keywords: Alzheimer disease; cancer; cardiovascular disease; diabetes; ketogenic diet; ketones; low-carbohydrate diet; low-fat diet; obesity; vegan diet.

Copyright © The Author(s) 2019.

• Blood Glucose / metabolism
• Diet, Ketogenic*
• Dietary Carbohydrates / administration & dosage
• Insulin / blood
• Insulin Resistance
• Nutrition Policy
• Obesity / diet therapy*
• Obesity / metabolism
• Weight Loss
• Blood Glucose
• Dietary Carbohydrates

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Pilot study shows ketogenic diet improves severe mental illness

A small clinical trial led by Stanford Medicine found that the metabolic effects of a ketogenic diet may help stabilize the brain.

April 1, 2024 - By Nina Bai

A study led by researchers at Stanford Medicine showed that diet can help those with serious mental illness. nishihata

For people living with serious mental illness like schizophrenia or bipolar disorder, standard treatment with antipsychotic medications can be a double-edged sword. While these drugs help regulate brain chemistry, they often cause metabolic side effects such as insulin resistance and obesity, which are distressing enough that many patients stop taking the medications.

Now, a pilot study led by Stanford Medicine researchers has found that a ketogenic diet not only restores metabolic health in these patients as they continue their medications, but it further improves their psychiatric conditions. The results, published March 27 in Psychiatry Research , suggest that a dietary intervention can be a powerful aid in treating mental illness.

“It’s very promising and very encouraging that you can take back control of your illness in some way, aside from the usual standard of care,” said Shebani Sethi , MD, associate professor of psychiatry and behavioral sciences and the first author of the new paper.

Making the connection

Sethi, who is board certified in obesity and psychiatry, remembers when she first noticed the connection. As a medical student working in an obesity clinic, she saw a patient with treatment-resistant schizophrenia whose auditory hallucinations quieted on a ketogenic diet.

That prompted her to dig into the medical literature. There were only a few, decades-old case reports on using the ketogenic diet to treat schizophrenia, but there was a long track record of success in using ketogenic diets to treat epileptic seizures.

“The ketogenic diet has been proven to be effective for treatment-resistant epileptic seizures by reducing the excitability of neurons in the brain,” Sethi said. “We thought it would be worth exploring this treatment in psychiatric conditions.”

A few years later, Sethi coined the term metabolic psychiatry, a new field that approaches mental health from an energy conversion perspective.

Shebani Sethi

In the four-month pilot trial, Sethi’s team followed 21 adult participants who were diagnosed with schizophrenia or bipolar disorder, taking antipsychotic medications, and had a metabolic abnormality — such as weight gain, insulin resistance, hypertriglyceridemia, dyslipidemia or impaired glucose tolerance. The participants were instructed to follow a ketogenic diet, with approximately 10% of the calories from carbohydrates, 30% from protein and 60% from fat. They were not told to count calories.

“The focus of eating is on whole non-processed foods including protein and non-starchy vegetables, and not restricting fats,” said Sethi, who shared keto-friendly meal ideas with the participants. They were also given keto cookbooks and access to a health coach. 

The research team tracked how well the participants followed the diet through weekly measures of blood ketone levels. (Ketones are acids produced when the body breaks down fat — instead of glucose — for energy.) By the end of the trial, 14 patients had been fully adherent, six were semi-adherent and only one was non-adherent.

The participants underwent a variety of psychiatric and metabolic assessments throughout the trial.

Before the trial, 29% of the participants met the criteria for metabolic syndrome, defined as having at least three of five conditions: abdominal obesity, elevated triglycerides, low HDL cholesterol, elevated blood pressure and elevated fasting glucose levels. After four months on a ketogenic diet, none of the participants had metabolic syndrome.

On average, the participants lost 10% of their body weight; reduced their waist circumference by 11% percent; and had lower blood pressure, body mass index, triglycerides, blood sugar levels and insulin resistance.

“We’re seeing huge changes,” Sethi said. “Even if you’re on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, the insulin resistance. I think that’s very encouraging for patients.”

The participants reported improvements in their energy, sleep, mood and quality of life.

The psychiatric benefits were also striking. On average, the participants improved 31% on a psychiatrist rating of mental illness known as the clinical global impressions scale, with three-quarters of the group showing clinically meaningful improvement. Overall, the participants also reported better sleep and greater life satisfaction.

“The participants reported improvements in their energy, sleep, mood and quality of life,” Sethi said. “They feel healthier and more hopeful.”

The researchers were impressed that most of the participants stuck with the diet. “We saw more benefit with the adherent group compared with the semi-adherent group, indicating a potential dose-response relationship,” Sethi said.

Alternative fuel for the brain

There is increasing evidence that psychiatric diseases such as schizophrenia and bipolar disorder stem from metabolic deficits in the brain, which affect the excitability of neurons, Sethi said.

The researchers hypothesize that just as a ketogenic diet improves the rest of the body’s metabolism, it also improves the brain’s metabolism.

“Anything that improves metabolic health in general is probably going to improve brain health anyway,” Sethi said. “But the ketogenic diet can provide ketones as an alternative fuel to glucose for a brain with energy dysfunction.”

Likely there are multiple mechanisms at work, she added, and the main purpose of the small pilot trial is to help researchers detect signals that will guide the design of larger, more robust studies.  

As a physician, Sethi cares for many patients with both serious mental illness and obesity or metabolic syndrome, but few studies have focused on this undertreated population.

She is the founder and director of the metabolic psychiatry clinic at Stanford Medicine.

“Many of my patients suffer from both illnesses, so my desire was to see if metabolic interventions could help them,” she said. “They are seeking more help. They are looking to just feel better.”

Researchers from the University of Michigan; the University of California, San Francisco; and Duke University contributed to the study.

The study was supported by Baszucki Group Research Fund, the Kuen Lau Fund and the Obesity Treatment Foundation.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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What you need to know about the ketogenic diet

If you’ve been considering options to improve your health, you may have heard about the popular ketogenic diet — also known as the keto diet. But did you know that today’s latest diet trend isn’t all that new? In fact, one of the reasons the ketogenic diet was originally developed in the 1920s was to treat epilepsy. 1

The ketogenic diet is currently drawing mass appeal. Studies have shown this diet can aid with overall metabolic health, including weight loss, lipid profiles, glucose levels, and insulin sensitivity — and could stave off feelings of hunger. 2-6

So, is the ketogenic diet the right option for you?

The ketogenic diet explained

This low-carbohydrate diet, typically containing 0 to 50 grams of carbs a day, shares some similarities with other low-carb diets, like Paleo or Atkins. However, it’s not a high-protein diet, and instead focuses on eating higher-fat foods. The aim of the ketogenic diet is to reduce your carbohydrate intake so that your body uses fat as a primary fuel — rather than using carbohydrates. How does the ketogenic diet do this? By replacing processed foods containing refined carbohydrates such as bread, pasta, potatoes, and rice, which can cause an unhealthy rise in blood sugar in some people.

Instead of eating foods containing carbs, the ketogenic diet calls for eating higher fat, nutrient dense foods. This includes meats, cheeses, eggs, and oil-rich plants such as avocados, olives, and nuts — and non-industrial fruit oils such as olive oil or coconut oil. Vegetables include non-starchy ones, such as leafy greens, broccoli, cauliflower, and cabbage.

When the diet is followed, your body will begin to use fat as a source of energy, which can result in weight loss. But the greater impact for many people can be improved metabolic health. 3 Better metabolic health can mean lower blood pressure, better lipid profiles, lower blood sugar levels, and a decrease in body fat.

The challenges of a ketogenic diet

While the ketogenic diet has its benefits, it can be difficult to cut carbs, including starches and some types of fruit — even while substituting for more filling options. And it can be easy to focus on the wrong kinds of higher-fat foods, like those that are ultra-processed. Some experts recommend foods containing more monounsaturated and polyunsaturated fat, often found in plant-based foods or certain fish, such as salmon.

Is the ketogenic diet right for you?

There is no one-size-fits-all approach to managing your health. What works for one person may not work for you, and what works in the short term may not work in the long term. Some diets could even be dangerous depending on your health history, genetic makeup, or if you have a chronic condition like diabetes, cancer, or heart disease (because you may need to change the dosage or slowly taper off current medications).

As an advocate for your personal health and well-being, your doctor can help you develop healthy eating patterns. They can also encourage a plan that contains a variety of nutritious, high-quality unprocessed foods tailored to helping your health. Your doctor will also take your personal and cultural preferences, dietary restrictions and allergies, and budget into consideration.

Bottom line: When it comes to any diet or major lifestyle change, it’s best to talk to your doctor first. They may recommend something like the ketogenic diet or a low-carb diet — or they may not. It all depends on you, your body type, and your medical history. So, if you’re considering a weight-loss program or looking to improve your metabolic health, work with your doctor to create a plan that will help you thrive.

1  EH Kossoff and HS Wang, "Dietary therapies for epilepsy," Biomedical Journal , January–February 2013, http://www.ncbi.nlm.nih.gov/pubmed/23515147 

2  Laura R. Saslow et al., "Twelve-month outcomes of a randomized trial of a moderate-carbohydrate versus very low-carbohydrate diet in overweight adults with type 2 diabetes mellitus or prediabetes," Nutrition & Diabetes , December 21, 2017, http://www.nature.com/articles/s41387-017-0006-9 

3  RD Feinman et al., "Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base," Nutrition , January 31, 2015, http://www.ncbi.nlm.nih.gov/pubmed/25287761 

4  Amy L. McKenzie et al., "A Novel Intervention Including Individualized Nutritional Recommendations Reduces Hemoglobin A1c Level, Medication Use, and Weight in Type 2 Diabetes," JMIR Diabetes , March 7, 2017, http://diabetes.jmir.org/2017/1/e5/ 

5  A.A. Gibson et al., "Do ketogenic diets really suppress appetite? A systematic review and meta analysis," Obesity Reviews , November 17, 2014, http://doi.wiley.com/10.1111/obr.12230 

6  SJ Hallberg et al., "Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study," Diabetes Therapy , April 9, 2018, http://www.ncbi.nlm.nih.gov/pubmed/29417495 

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May 12, 2024

Shark Tank Keto Gummies: Where to Buy and What You Need to Know

“Have you heard about those new keto gummies that were featured on Shark Tank?” Emily’s voice buzzed with excitement as she leaned across the table at the café. “They’re supposed to be amazing for anyone trying to stay on a keto diet!” Mark raised an eyebrow, curiosity piqued. “Keto gummies, really? How do they work, and where can I get them?”

This interaction mirrors the conversations happening nationwide as Shark Tank Keto Gummies gained popularity. This article will delve into everything you need to know about these supplements, from their effectiveness to where you can buy them.

What Are Shark Tank Keto Gummies?

Shark Tank Keto Gummies are dietary supplements formulated to support the ketogenic diet, which drastically reduces carbohydrate intake in favor of fat and moderate protein. These gummies are crafted to help the body maintain the state of ketosis, where it burns fat instead of carbohydrates for energy. Typically, they contain key ingredients like beta-hydroxybutyrate (BHB) salts, which are exogenous ketones meant to boost the body’s natural ketone production. By introducing these exogenous ketones, the gummies aim to facilitate quicker entry into ketosis, helping individuals overcome the challenges of dietary restrictions and energy dips commonly associated with the initial stages of the keto diet.

How Do Keto Gummies Aid Ketosis?

The primary mechanism through which keto gummies aid in achieving ketosis is by supplying the body with ready-to-use ketone bodies. When ingested, the BHB salts in keto gummies bypass the liver and go directly into the bloodstream, providing an immediate source of energy for cells, particularly brain cells, which can use ketones more efficiently than fatty acids. This can not only help reduce the feelings of fatigue and brain fog associated with the early stages of ketosis but also assist in diminishing the body’s demand for glucose, thus maintaining a state of ketosis. It’s important to note, however, that while these supplements can support ketosis, optimal results still depend significantly on adhering to a proper ketogenic diet.

Are Shark Tank Keto Gummies Effective?

The effectiveness of Shark Tank Keto Gummies can vary from person to person, largely depending on dietary habits and lifestyle. Clinical studies suggest that exogenous ketones, like those found in keto gummies, can indeed increase ketone body concentrations in the blood, potentially aiding those on a ketogenic diet in maintaining ketosis. However, they are not a magic solution; effective weight management and health improvements still require comprehensive dietary and lifestyle changes. Users often report benefits such as improved energy levels and reduced appetite, which can significantly contribute to the overall success of the diet.

Where to Buy Shark Tank Keto Gummies?

Shark Tank Keto Gummies are available through various online platforms, including official product websites, health supplement stores, and major e-commerce sites like Amazon. To avoid counterfeit products and ensure authenticity, it’s crucial to purchase these gummies from reputable sources. Prices and product formulations can vary widely, so it’s advisable to compare options, read customer reviews, and perhaps even consult healthcare professionals before making a purchase to ensure the product meets your specific dietary needs and health conditions.

Side Effects and Considerations

While generally safe for most people, Shark Tank Keto Gummies can cause side effects, particularly if taken in excess or without proper adherence to dietary guidelines. Potential side effects include gastrointestinal distress, such as nausea and diarrhea, which are common with the intake of exogenous ketones. Furthermore, because these products are designed to alter nutrient metabolism, individuals with underlying health conditions or those on medication should consult a healthcare provider to prevent possible adverse interactions.

Real Customer Reviews

Exploring real customer reviews can offer valuable insights into the practical benefits and drawbacks of Shark Tank Keto Gummies. Many users praise the supplements for helping them sustain energy levels and manage appetite, which are critical for maintaining a strict ketogenic diet. However, some reviews point out that results can vary, highlighting the importance of setting realistic expectations and understanding that supplements alone are not a substitute for dietary discipline and regular physical activity.

How to Incorporate Keto Gummies into Your Diet

To maximize the benefits of Shark Tank Keto Gummies, integrate them into a well-planned ketogenic diet. Begin with a lower dose to assess your body’s response and gradually increase as needed, always considering your overall carbohydrate intake and nutritional balance. These gummies should complement, not replace, a nutritionally rich keto diet. Regular physical activity and sufficient hydration are also crucial to enhance the effectiveness of the gummies and promote overall health.

Alternatives to Shark Tank Keto Gummies

For those who may not find Shark Tank Keto Gummies suitable, there are alternatives. Other ketogenic supplements, such as MCT oil, collagen peptides, and keto-friendly snack bars, can offer similar benefits. These alternatives might be preferable for individuals looking for variety in their supplementation or those with specific dietary restrictions.

FAQs about Shark Tank Keto Gummies

How long does it take for shark tank keto gummies to work.

The onset of action for keto gummies can vary, but some users report feeling effects as soon as 30 minutes after consumption. Consistent use combined with a strict keto diet is crucial for best results.

Can I take keto gummies if I’m not on a strict keto diet?

While designed for those on a ketogenic diet, keto gummies might still offer benefits such as reduced appetite or increased energy for those not strictly adhering to keto. However, the effects may be less pronounced.

Are there any allergens in Shark Tank Keto Gummies?

Product formulations vary, but common allergens include gelatin, which is derived from animal products. Always check the label for allergen information.

How often should I take keto gummies?

Most manufacturers recommend taking one to two gummies per day. Follow the instructions on the package or consult with a healthcare provider.

Where can I find scientific studies on keto gummies?

Scientific studies on keto supplements, including gummies, can be found in medical journals and databases such as PubMed. Research specific to brands featured on Shark Tank may also be available on their official websites.

This comprehensive guide to Shark Tank Keto Gummies provides all the essential information needed to make an informed decision. Whether you’re looking to enhance your keto journey or just curious about this popular supplement, remember to prioritize quality and consult with healthcare professionals.

More Topics about Shark Tank Keto Gummies:

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