research paper on vildagliptin

Vildagliptin in clinical practice: a review of literature

Affiliation.

1 Central Manchester University Hospitals Foundation Trust, Department of Medicine, Manchester, M13 9WL, UK.
PMID: 19874253
DOI: 10.1517/14656560903302265

Vildagliptin is the second member of the DPP-IV inhibitor class of drugs licensed for the treatment of type 2 diabetes mellitus (T2DM). The novel action of these drugs has promoted a new outlook in the pathobiology of T2DM. This review undertakes to examine the clinical studies published to date, with the aim of evaluating the position of vildagliptin among the drugs that are now available to treat this common dysmetabolic state.

Publication types

Research Support, Non-U.S. Gov't
Adamantane / analogs & derivatives*
Adamantane / pharmacokinetics
Adamantane / pharmacology
Adamantane / therapeutic use
Blood Glucose / analysis
Diabetes Mellitus, Type 2 / drug therapy
Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics
Dipeptidyl-Peptidase IV Inhibitors / pharmacology
Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
Islets of Langerhans / drug effects
Nitriles / pharmacokinetics
Nitriles / pharmacology
Nitriles / therapeutic use*
Pyrrolidines / pharmacokinetics
Pyrrolidines / pharmacology
Pyrrolidines / therapeutic use*
Vildagliptin
Blood Glucose
Dipeptidyl-Peptidase IV Inhibitors
Pyrrolidines

An official website of the United States government

Official websites use .gov A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Publications
Account settings
Advanced Search
Journal List

Data on vildagliptin and vildagliptin plus metformin combination in type-2 diabetes mellitus management

Biplab bandyopadhyaya, b harish darla, mahesh abhyankar, santosh revankar.

Author information
Article notes
Copyright and License information

Dr.Mahesh Abhyankar [email protected]

Received 2021 Feb 28; Revised 2021 Mar 15; Accepted 2021 Mar 18; Collection date 2021.

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.

It is of interest to evaluate the clinical effectiveness and safety of vildagliptin as monotherapy and combination therapy of vildagliptin and metformin for the management of type 2 diabetes mellitus (T2DM) patients in Indian settings. The study included patients with T2DM (aged >18 years) receiving vildagliptin monotherapy and vildagliptin in combination with metformin therapy of various strengths. Data related to demographics, risk factors, medical history, glycated hemoglobin (HbA1c) levels, and medical therapies were retrieved from medical records. Out of 9678 patients (median age, 52.0 years), 59.1% were men. A combination of vildagliptin and metformin (50/500 mg) was the most commonly used therapy (54.8%), and the median duration of therapy was 24.0 months. The predominant reason for selecting vildagliptin therapy was to improve HbA1c levels (87.8%). A total of 87.5% of patients required dosage up-titration. Vildagliptin therapy was used in patients with T2DM and associated complications (peripheral neuropathy, CAD, nephropathy, retinopathy, autonomous neuropathy, stroke/TIA, and peripheral artery disease). Among 5175 patients who experienced body weight changes, a majority of patients showed a loss of weight (68.6%). The target glycemic control was achieved in 95.3% of patients. The mean HbA1c levels were significantly decreased post-treatment (mean change: 1.34%; p<0.001). Adverse events were reported in 0.4% of patients. Physicians rated the majority of patients as good to excellent on the global evaluation of efficacy and tolerability scale (98.9%, each). Vildagliptin as monotherapy and combination therapy of vildagliptin and metformin was an effective therapy in reducing HbA1c helps in achieving target glycemic control, and was well tolerated in Indian patients with T2DM continuum.

Keywords: Antidiabetic therapy, DPP4i, glycemic control, hypertension

The poor glycemic control, long duration of illness, and the ethnicity of the population contribute to the increased susceptibility to diabetes associated complications [ 1 ]. Indian individuals with T2DM are highly susceptible to the risk of developing macrovascular complications with a 40% higher risk of mortality due to cardiovascular diseases, as compared to the White populations [ 2 - 4 ]. Moreover, the prevalence of comorbidities in Indian patients with diabetes is high along with peripheral vascular disease, hypertension, ocular diseases, and dyslipidemia as the most common comorbidities [ 5 - 8 ]. Therefore, early diagnosis of diabetes and improved glycemic control will aid in alleviating the risk factors of these patients. The American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the India-specific diabetes management guidelines recommend the use of metformin along with lifestyle changes as first-line therapy for diabetes management [ 9 - 11 ]. Targeted glycemic levels may not be achieved by metformin or other oral antidiabetic drugs (OADs) monotherapy. Hence, considering diabetes as a progressive disease, combination therapies of metformin with other oral antidiabetic drugs (OADs) are recommended [ 9 - 11 ]. Moreover, if patients fail to achieve target glycemic levels with monotherapy, the combination therapies of metformin with other OADs and/or insulin are recommended [ 9 - 11 ]. Vildagliptin is a second-generation dipeptidyl peptidase-4 (DPP-4) inhibitor [ 12 ] and evidence suggests potential mechanisms of synergy between metformin and vildagliptin [ 13 , 14 ]. The clinical efficacy and safety of vildagliptin monotherapy or in combination with metformin have been demonstrated in several studies. Globally, the effectiveness, tolerability, and low discontinuation rates of vildagliptin monotherapy and combination therapy of vildagliptin and metformin are reported in several real-world studies [ 15 - 17 ]. However, there is a need for evidence from India demonstrating the overall clinical benefits of glycemic control and weight reduction with vildagliptin monotherapy [ 18 ] or vildagliptin and metformin combination therapy for diabetes [ 19 , 20 ]. Therefore, it is of interest to document the treatment patterns, clinical effectiveness, and safety profile of vildagliptin monotherapy, vildagliptin, and metformin combination therapy for the management of the T2DM continuum in India.

This retrospective, multi-centric, observational real-world study was conducted across 365 Indian healthcare centers having medical records of adult patients with T2DM who had received vildagliptin alone or as an add-on to metformin therapy. The study was conducted in accordance with the ethical principles that are consistent with the Declaration of Helsinki, International Conference on Harmonization-Good Clinical Practices, and the applicable legislation on non-interventional studies. Approval for the study protocol from an Independent Ethics Committee was obtained before the study initiation.

Study population:

Patients of either sex, aged >18 years and who had received vildagliptin monotherapy or fixed-dose combination of vildagliptin and metformin (IR-Immediate Release) for the treatment of T2DM were identified. The patients' treatment information was sourced from the treating physician under an agreement. Patients having incomplete data files were excluded from the study. According to the investigator's discretion, unsuitable patients or patient data were also not included in the study.

The study outcomes included the evaluation of change in glycated hemoglobin (HbA1c) levels and weight changes after the treatment with vildagliptin alone or in combination with metformin therapy of various strengths. In addition, demographics of patients receiving vildagliptin alone or in combination with metformin therapy of various strengths, duration of treatment, other OADs and/or insulin and any concomitant medication received during the study period, presence of any concurrent disease and, adverse events reported within past 12 months were assessed.

Statistical analysis:

Data were analyzed using Statistical Package for The Social Sciences (SPSS) software, version 23.0. Demographic characteristics were summarized with descriptive statistics including median and interquartile range (IQR) for continuous variables, and frequency and percentages for categorical variables. A comparison of qualitative and quantitative variables between the groups was done using the chi-square test and Mann-Whitney U test, respectively. A p-value <0.05 was considered statistically significant.

A total of 9678 patients with T2DM were included. The median (IQR) age was 52.0 (45.0-61.0) years and the majority of patients (45.4%) were from the age group of >40 to ≤60 years. The proportion of male patients (59.1%) was higher than female patients (40.9%). The majority of the patients were enrolled in urban and semi-urban areas (83.3%). The median body mass index (BMI) of the overall population was 27.0 kg/m2. The median duration of diabetes was 60.0 months. Family history of diabetes (49.4%) and sedentary lifestyle (44.0%) were the most common risk factors observed followed by obesity (37.6%), smoking (29.6%), and emotional stress (26.3%). The most commonly observed comorbidities were hypertension (68.7%) and dyslipidemia (47.1%) while peripheral neuropathy (44.6%) and coronary artery disease (CAD) (30.6%) were the most common complications observed in the study patients ( Table 1 ). The majority of patients (54.8%) received a combination of vildagliptin and metformin (50/500 mg) while 23.7% received vildagliptin monotherapy (50 mg), 15.1% received a combination of vildagliptin and metformin (50/1000 mg) and 6.4% received combination of vildagliptin and metformin (50/850 mg). Vildagliptin as monotherapy or combination therapy with metformin was used across a wide range of age groups from younger patients aged >18 years to elderly patients aged >60 years. Vildagliptin alone or in combination with metformin twice daily (BD) was the most frequently used dosage pattern (74.1%). The median duration of treatment (vildagliptin alone or in combination with metformin therapy) was 24.0 months ( Table 2 ). A majority of patients (94.7%) received sulfonylureas as the concomitant anti-diabetic medication. Insulin was administered to 944 (15.7%) patients. Among the concomitant non-diabetic medications, antihypertensives (60.4%) were the most common class of drugs followed by statins (31.6%) ( Table 2 ). The analysis revealed that the most common reason for selecting vildagliptin alone or in combination with metformin was to achieve an improvement in HbA1c levels (87.8%). Other common reasons included the control of fasting plasma glucose (45.4%) and postprandial plasma glucose (35.2%), low risk of hypoglycemia (49.8%), and weight neutrality (34.2%) ( Figure 1 ). A total of 1969 patients required dosage titration during the treatment, the majority of them (87.5%) required dosage up-titration ( Table 3 ). The most common reason given for titration was to improve HbA1c level (78.7%) as shown in Figure 1 . Before initiating the treatment, a total of 91.5% of patients were having poor glycemic control (HbA1c ≥7.5%) where 29.6% and 28.7% of the patients were having HbA1c levels in the range of 7.5-8.0% and 8.0-8.5%, respectively ( Table 3 ).[ Figure 2A ] presents the trend of vildagliptin monotherapy and combination therapy of vildagliptin and metformin with respect to HbA1c levels across the study population. The data suggested that the combination therapy of vildagliptin and metformin at 50/500 mg dose and vildagliptin monotherapy at 50 mg dose were the most commonly prescribed therapies in the patient population across a wide range of HbA1c levels from <7.5->10%. A total of 95.3% of patients achieved target glycemic control with vildagliptin monotherapy or vildagliptin and metformin combination therapy. The treatment with vildagliptin monotherapy or vildagliptin and metformin combination therapy significantly reduced the mean HbA1c levels by 1.34% [95% CI, 1.31-1.36]; p<0.001) when compared to the pre-treatment levels (8.62% vs. 7.28%) (Figure 2B). A total of 4503 (46.6%) patients experienced no change in body weight during treatment. Among 5175 (53.4%) patients who experienced body weight changes during therapy, majority of them (3551, 68.6%) had lost weight while the remaining 1624(31.4%) patients had gained weight. Of those who lost weight, more than half (N=2638) had a weight reduction in the range of 0-2 kg ( Table 3 ). A total of 44 patients (0.4%) reported adverse events with gastritis and dyspepsia being the most common adverse events (9, each) ( Table 3 ). Physicians rated the majority of patients as good to excellent on the global evaluation of efficacy and tolerability scale (98.9%, each) ( Figure 3 ). observed followed by obesity (37.6%), smoking (29.6%), and emotional stress (26.3%). The most commonly observed comorbidities were hypertension (68.7%) and dyslipidemia (47.1%) while peripheral neuropathy (44.6%) and coronary artery disease (CAD) (30.6%) were the most common complications observed in the study patients ( Table 1 ). The majority of patients (54.8%) received a combination of vildagliptin and metformin (50/500 mg) while 23.7% received vildagliptin monotherapy (50 mg), 15.1% received a combination of vildagliptin and metformin (50/1000 mg) and 6.4% received combination of vildagliptin and metformin (50/850 mg). Vildagliptin as monotherapy or combination therapy with metformin was used across a wide range of age groups from younger patients aged >18 years to elderly patients aged >60 years. Vildagliptin alone or in combination with metformin twice daily (BD) was the most frequently used dosage pattern (74.1%). The median duration of treatment (vildagliptin alone or in combination with metformin therapy) was 24.0 months ( Table 2 ). A majority of patients (94.7%) received sulfonylureas as the concomitant anti-diabetic medication. Insulin was administered to 944 (15.7%) patients. Among the concomitant non-diabetic medications, antihypertensives (60.4%) were the most common class of drugs followed by statins (31.6%) ( Table 2 ). The analysis revealed that the most common reason for selecting vildagliptin alone or in combination with metformin was to achieve an improvement in HbA1c levels (87.8%). Other common reasons included the control of fasting plasma glucose (45.4%) and postprandial plasma glucose (35.2%), low risk of hypoglycemia (49.8%), and weight neutrality (34.2%) ( Figure 1 ). A total of 1969 patients required dosage titration during the treatment, the majority of them (87.5%) required dosage up-titration ( Table 3 ). The most common reason given for titration was to improve HbA1c level (78.7%) as shown in Figure 1 . Before initiating the treatment, a total of 91.5% of patients were having poor glycemic control (HbA1c ≥7.5%) where 29.6% and 28.7% of the patients were having HbA1c levels in the range of 7.5-8.0% and 8.0-8.5%, respectively ( Table 3 ). Figure 2A presents the trend of vildagliptin monotherapy and combination therapy of vildagliptin and metformin with respect to HbA1c levels across the study population. The data suggested that the combination therapy of vildagliptin and metformin at 50/500 mg dose and vildagliptin monotherapy at 50 mg dose were the most commonly prescribed therapies in the patient population across a wide range of HbA1c levels from >7.5-<10%. A total of 95.3% of patients achieved target glycemic control with vildagliptin monotherapy or vildagliptin and metformin combination therapy. The treatment with vildagliptin monotherapy or vildagliptin and metformin combination therapy significantly reduced the mean HbA1c levels by 1.34% [95% CI, 1.31-1.36]; p<0.001) when compared to the pre-treatment levels (8.62% vs. 7.28%) ( Figure 2B ). A total of 4503 (46.6%) patients experienced no change in body weight during treatment. Among 5175 (53.4%) patients who experienced body weight changes during therapy, majority of them (3551, 68.6%) had lost weight while the remaining 1624(31.4%) patients had gained weight. Of those who lost weight, more than half (N=2638) had a weight reduction in the range of 0-2 kg (Table 3). A total of 44 patients (0.4%) reported adverse events with gastritis and dyspepsia being the most common adverse events (9, each) ( Table 3 ). Physicians rated the majority of patients as good to excellent on the global evaluation of efficacy and tolerability scale (98.9%, each) ( Figure 3 ). The median age was significantly higher in patients receiving vildagliptin 50 mg monotherapy (54.0 years) as compared to those receiving vildagliptin and metformin combinations (50/1000, 50/500, and 50/850 mg) (52.0 years, each) (p<0.001). The proportion of patients receiving combination therapy of vildagliptin and metformin 50/850 mg from age group >45-≤60 years (54.5%) was significantly higher compared to other treatment groups (p<0.001). The median (IQR) duration of diabetes was significantly higher in patients receiving a combination of vildagliptin and metformin 50/1000 mg (60.0 [36.0-108.0] months) than those receiving other therapies such as vildagliptin monotherapy 50 mg (60.0 [26.0-96.0] months), vildagliptin and metformin 50/500 mg combination therapy (60.0 [36.0-96.0] months) and vildagliptin and metformin 50/850 mg combination therapy (60.0 [36.0-84.0] months) (p<0.001). Vildagliptin or vildagliptin and metformin combinations were used in patients with T2DM with associated complications, like peripheral neuropathy, CAD, nephropathy, retinopathy, autonomous neuropathy, stroke/TIA, and PAD. In T2DM patients taking vildagliptin or vildagliptin and metformin combination therapy, the common comorbidity was hypertension and dyslipidemia observed in 64.4% to 71.1% and 45.5% to 50.7%, respectively. Obesity was observed in 42% of patients taking vildagliptin and metformin 50/1000 mg, while 25.1% to 26.3% in other dosage forms. NFALD was observed in 22.2 % of the patients taking vildagliptin 50 mg, while 3.4% to 7.2% in other dosage forms ( Table 4 ).

Table 1. Patient demographics and treatment related observations.

Table 2. observations related to various medications received across the study population..

Reasons for starting vildagliptin monotherapy or vildagliptin and metformin combination and titration of dosage during study period.

Table 3. Observations related to weight alterations, glycemic control, and adverse events.

A) The trend of vildagliptin monotherapy or vildagliptin and metformin combination dosage with respect to HbA1c levels. B) Mean change in HbA1c levels from pretreatment to post treatment.

Physical global evaluation for (A) Efficacy and (B) Tolerability of the treatment.

Table 4. Treatment wise patient demographics observations.

Discussion:.

This real-world study documented the clinical characteristics, and treatment patterns including dosage and duration of vildagliptin monotherapy or vildagliptin and metformin combination therapy in adult patients with T2DM across 365 clinical study centers in India. In addition, it also evaluated the effect of vildagliptin therapy on glycemic control and the safety profile of patients with the T2DM continuum. A majority of the patients were from urban areas and were middle-aged with a median age of 52.0 years. A high prevalence of disease in male patients, family history of diabetes, sedentary lifestyle, and obesity were the most commonly observed risk factors of T2DM in the present study. These findings are in line with previous Indian studies. According to the Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study, age, male sex, obesity, hypertension, and family history of diabetes were the independent risk factors for diabetes in both urban and rural areas. The study also reported a higher prevalence of diabetes in urban areas, especially among low socioeconomic groups [ 21 ]. Similarly, a recent 10-year prospective cohort study from Southern India reported that age >45 years, family history of T2DM, BMI ≥25 kg/m2, and presence of obesity as the risk factors for T2DM [ 22 ]. The presence of comorbidities in Indian patients with T2DM is well established in several previous studies [ 5 - [ 8 ]. Uncontrolled glycemia and chronic diabetes substantially contribute to the elevated risk of diabetes-associated complications. Therefore, comorbidities such as hypertension and dyslipidemia, and other complications pose a high risk of mortality for the Indian cohort of T2DM. A high prevalence of hypertension was observed in the present study population. The results corroborate with the observations from several other Indian studies reported that 20%-40% of patients have both diabetes and hypertension [ 22 - 24 ]. A joint consensus statement from the American and European Diabetes Associations recommends that DPP-4 inhibitor may be used if there is a need to avoid hypoglycemia or control the weight gain [ 10 ]. The use of vildagliptin has been approved in Indian patients for the treatment of T2DM as monotherapy or in combination with metformin, sulfonylureas, and thiazolidinediones, as well as with insulin [ 20 ]. In India, vildagliptin and metformin combination tablets are available in 50/500 mg, 50/850 mg, and 50/1000 mg doses [ 20 ]. The most commonly used therapy in the present study was the combination therapy of vildagliptin and metformin at 50/500 mg dose followed by vildagliptin monotherapy at 50 mg dose. Several real-world studies from India have reported the use of vildagliptin monotherapy (4%-18%) [ 25 , 26 ] and vildagliptin and metformin combination therapy (37%) [ 27 ] for the management of T2DM. About 70% of the present study cohort used the twice-daily formulation. In the present study, the use of vildagliptin either as monotherapy or combination therapy with metformin across a wide range of age groups (>18 years to >60 years) suggests the benefits of vildagliptin to a patient population of both younger and elder age groups. More than one-third of the patient population on vildagliptin therapy presented CAD as a complication. However, a meta-analysis of 17000 patients has provided evidence that supports the cardiovascular safety of vildagliptin [ 28 ]. Similarly, a real-world study by Williams et al. suggested that exposure to vildagliptin was not associated with an increased overall CVD risk or risk of myocardial infarction, acute coronary syndrome, stroke, and congestive heart failure when compared with other OADs [ 29 ]. In the present study, more than 70% of patients received concomitant anti-diabetic medications. Sulfonylureas were the most commonly prescribed anti-diabetic medications along with vildagliptin or vildagliptin and metformin combination therapies. A Japanese study reported that sulfonylurea (26.3%) was the second most commonly prescribed anti-diabetic drug after biguanide (54.6%) in patients with T2DM receiving vildagliptin monotherapy [ 17 ]. Several population-based studies in India have included patients who had comorbidities such as hypertension and dyslipidemia along with diabetes. Similarly, the present study also included patients with hypertension and dyslipidemia, and therefore, the most commonly prescribed concomitant medications were antihypertensives and statins [ 16 , 20 ]. The present study suggested that monotherapy of vildagliptin or combination therapy with metformin showed greater improvements in the mean HbA1c and greater reduction in the body weight. More than 90% of the patients had uncontrolled glycemic levels before treatment and good glycemic control achieved by 95.3% of patients after the treatment. These observations suggest the clinical effectiveness of vildagliptin monotherapy or vildagliptin and metformin combination therapy in achieving glycemic control and weight neutralization. A meta-analysis of 58 randomized controlled trials, DPP4-inhibitors, vildagliptin 50 mg BD, and linagliptin 10 mg QD, suggested a significant lowering effect on the glycemic indices in comparison to the placebo [ 30 ]. The 5-year long trial results suggest early intervention with vildagliptin plus metformin provides significant continuing benefits compared to the initial metformin monotherapy used for patients with newly diagnosed T2DM [ 31 ]. In the post-hoc analysis of an observational real-world EDGE study, Wangnoo et al. assessed the safety and efficacy of vildagliptin in combination with another OAD in 11,057 Indian patients with T2DM. Vildagliptin and metformin combination was used in more than 70% of the study population. The HbA1c reduction was in favor of vildagliptin usage, achieved in 68.5% in the vildagliptin cohort compared to the comparator cohort (56.8%), with an unadjusted OR of 1.65 (95% CI: 1.53, 1.79; p < 0.0001) [ 18 ]. In previous studies, vildagliptin or vildagliptin and metformin combination therapy was well tolerated [ 18 , 31 ]. These findings are in line with the current study results that have shown a smaller number of patients experiencing adverse events with these treatments. Physicians' global evaluation of efficacy and tolerability showed a majority of patients on a good to excellent scale (98.9%). Evidence from Indian literature suggests that, of all the combination of OADs, the combination of metformin and vildagliptin was prescribed by the majority of the physicians [ 27 , 32 ]. These observations support the use of vildagliptin as an add-on therapy to metformin and are the preferred choice of therapy by physicians in Indian settings. The present study has several limitations. Due to the retrospective nature of this study, several parameters such as the antidiabetic regimens used before vildagliptin or vildagliptin/metformin combination therapy and time of the previous visit could not be captured, which may have an indirect effect on the overall study results.

Vildagliptin with or without metformin was an effective therapy in reducing HbA1c that helped in achieving target glycemic control and was well tolerated in Indian patients with the T2DM continuum. The use of vildagliptin therapy in patients with comorbidities (hypertension and dyslipidemia), complications (peripheral neuropathy, CAD, nephropathy, and retinopathy), different age groups (younger to elderly patients), and physician acceptance suggests wide use of vildagliptin for each subgroup of the diabetic continuum in Indian settings.

Acknowledgments

We acknowledge Ms. Farida Hussain, Ms. Monal Patil, Mr. Smitabrata Dasgupta, and Ms. Annsusan Renji from USV Pvt Ltd for their assistance in carrying out the project. The medical writing support was provided by Dr. Sona Warrier from the scientific services team of USV Pvt Ltd and Ms. Snehal Khanolkar from Sqarona Medical Communications LLP (Mumbai). We acknowledge BioQuest Solutions Private Limited for their services in the conduction of the real-world study. This project has been funded by USV Pvt Ltd.

There are no conflicts of interest. We declare that Dr. Mahesh Abhyankar and Dr. Santosh Revankar are employees of USV Pvt Ltd.

Edited by P Kangueane

Citation: Das et al. Bioinformation 17(3):413-423 (2021)

1. Unnikrishnan R, et al. Nat Rev Endocrinol . 2016;12:357. doi: 10.1038/nrendo.2016.53. [ DOI ] [ PubMed ] [ Google Scholar ]
2. Ali MK, et al. Indian J Med Res . 2010;132:584. [ PMC free article ] [ PubMed ] [ Google Scholar ]
3. Mohan V, et al. J Diabetes Sci Technol . 2010;4:158. doi: 10.1177/193229681000400121. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
4. Forouhi NG, et al. Diabetologia . 2006;49:2580. doi: 10.1007/s00125-006-0393-2. [ DOI ] [ PubMed ] [ Google Scholar ]
5. Podder V, et al. J Neurosci Rural Pract . 2020;11:467. doi: 10.1055/s-0040-1709369. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
6. Joshi SR. Ann Glob Health . 2015;81:830. doi: 10.1016/j.aogh.2016.01.002. [ DOI ] [ PubMed ] [ Google Scholar ]
7. Jayakumari C, et al. Diabetes Spectr . 2020;33:299. doi: 10.2337/ds19-0046. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
8. Venugopal K, Mohammed MZ. Chrismed J Health Res . 2014;1:223. [ Google Scholar ]
9. https://care.diabetesjournals.org/content/42/Supplement_1 .
10. Davies MJ, et al. Diabetes Care . 2018;41:2669. doi: 10.2337/dci18-0033. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
11. Bajaj S. Int J Diabetes Dev Ctries . 2017;38:S1. doi: 10.1007/s13410-018-0604-7. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
12. Kalra S. J Assoc Physicians India . 2011;59:237. [ PubMed ] [ Google Scholar ]
13. Lindsay JR, et al. Diabet Med . 2005;22:654. doi: 10.1111/j.1464-5491.2005.01461.x. [ DOI ] [ PubMed ] [ Google Scholar ]
14. Ahren B, et al. Diabetes Obes Metab . 2011;13:193. doi: 10.1111/j.1463-1326.2010.01321.x. [ DOI ] [ PubMed ] [ Google Scholar ]
15. Melzer Cohen, et al. J Diabetes . 2018;10:68. [ Google Scholar ]
16. Chawla M, et al. Curr Med Res Opin . 2018;34:1605. doi: 10.1080/03007995.2018.1476333. [ DOI ] [ PubMed ] [ Google Scholar ]
17. Hayashi T, et al. Expert Opin Pharmacother . 2020;21:121. doi: 10.1080/14656566.2019.1685500. [ DOI ] [ PubMed ] [ Google Scholar ]
18. Wangnoo SK, et al. Indian Journal of Clinical Practice. . 2013;24:537. [ Google Scholar ]
19. Ved P, Shah S. Indian J Endocrinol Metab . 2012;16:S110.. doi: 10.4103/2230-8210.94258. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
20. Chatterjee S, Chatterjee S. J Diabetes . 2014;6:237. doi: 10.1111/1753-0407.12078. [ DOI ] [ PubMed ] [ Google Scholar ]
21. Anjana RM, et al. Lancet Diabetes Endocrinol . 2017;5:585. [ Google Scholar ]
22. Vijayakumar G, et al. BMC Public Health . 2019;19:14. doi: 10.1186/s12889-019-6445-6. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
23. Tripathy JP, et al. Diabetol Metab Syndr . 2017;9:8. doi: 10.1186/s13098-017-0207-3. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
24. Acharya AS, et al. J Assoc Physicians India . 2017;65:46. [ PubMed ] [ Google Scholar ]
25. Dutta D, et al. Indian J Endocrinol Metab . 2019;23:460. doi: 10.4103/ijem.IJEM_185_19. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
26. Chaudhary KP, et al. Int J Res Med Sci . 2019;7:669. [ Google Scholar ]
27. Ashutosh K, et al. Int J ClinExp Med . 2017;3:1. [ Google Scholar ]
28. McInnes G, et al. Diabetes Obes Metab . 2015;17:1085. doi: 10.1111/dom.12548. [ DOI ] [ PubMed ] [ Google Scholar ]
29. Williams R, et al. Diabetes Obes Metab . 2017;19:1473. doi: 10.1111/dom.12951. [ DOI ] [ PubMed ] [ Google Scholar ]
30. Ling J, et al. Acta Diabetol . 2019;56:249. doi: 10.1007/s00592-018-1222-z. [ DOI ] [ PubMed ] [ Google Scholar ]
31. Matthews DR, et al. Lancet . 2019;394:1519. doi: 10.1016/S0140-6736(19)32131-2. [ DOI ] [ PubMed ] [ Google Scholar ]
32. Saxena T, et al. Diabetes Metab Syndr . 2019;13:1209. doi: 10.1016/j.dsx.2019.01.007. [ DOI ] [ PubMed ] [ Google Scholar ]
View on publisher site
PDF (1.5 MB)
Collections

Add to Collections

An official website of the United States government

Official websites use .gov A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Publications
Account settings
Advanced Search
Journal List

Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes

Miyako kishimoto.

Author information
Article notes
Copyright and License information

Correspondence: Miyako Kishimoto, Department of Diabetes and Metabolic Medicine, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan, Tel +81 3 3202 7181, Fax +81 3 3207 1038, Email [email protected]

Collection date 2013.

This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

Dipeptidyl peptidase-4 (DPP-4) inhibitors have recently emerged as a new class of antidiabetic that show favorable results in improving glycemic control with a minimal risk of hypoglycemia and weight gain. Teneligliptin, a novel DPP-4 inhibitor, exhibits a unique structure characterized by five consecutive rings, which produce a potent and long-lasting effect. Teneligliptin is currently used in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea- or thiazolidine-class drugs. In adults, teneligliptin is orally administered at a dosage of 20 mg once daily, which can be increased up to 40 mg per day. Because the metabolites of this drug are eliminated via renal and hepatic excretion, no dose adjustment is necessary in patients with renal impairment. The safety profile of teneligliptin is similar to those of other available DPP-4 inhibitors. However, caution needs to be exercised when administering teneligliptin to patients who are prone to QT prolongation. One study has reported that the postprandial blood glucose-lowering effects of teneligliptin administered prior to breakfast were sustained throughout the day, and the effects observed after dinner were similar to those observed after breakfast or lunch. Thus, although clinical data for this new drug are limited, this drug shows promise in stabilizing glycemic fluctuations throughout the day and consequently suppressing the progression of diabetic complications. However, continued evaluation in long-term studies and clinical trials is required to evaluate the efficacy and safety of the drug as well as to identify additional indications for its clinical use.

Keywords: teneligliptin, DPP-4 inhibitor, diabetes

Introduction

Incretin hormones, 1 – 3 namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released from enteroendocrine cells and enhance insulin secretion. 1 , 2 , 4 – 6 Incretins are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), and have a very short half-life (t 1/2 ) as a result. DPP-4 inhibitors increase the levels of active GLP-1 and GIP by inhibiting DPP-4 enzymatic activity; thus, in patients with diabetes, these inhibitors improve hyperglycemia in a glucose-dependent manner by increasing serum insulin levels and decreasing serum glucagon levels. 7 – 13 Therefore, incretin-related agents such as DPP-4 inhibitors are promising drugs that can decrease glucose fluctuations in diabetic patients and have emerged as a new class of antidiabetic. The effect of these inhibitors on glycemic control when administered as monotherapy or in combination with other drugs has been investigated in multiple trials. 7 , 8 , 11 , 12 Moreover, DPP-4 inhibitors have shown favorable results in improving glycemic control with a minimal risk of hypoglycemia and weight gain. 14 – 19

In this review, a novel chemotype prolylthiazolidine-based DPP-4 inhibitor, teneligliptin (generic name: teneligliptin hydrobromide hydrate) is characterized. Teneligliptin was originally synthesized by Mitsubishi Tanabe Pharma Corporation (Osaka, Japan) and was the first drug of its kind to be synthesized in Japan. Mitsubishi Tanabe Pharma Corporation and Daiichi Sankyo Co, Ltd, (Tokyo, Japan) jointly sell the drug under the brand name TENERIA®.

Chemistry of teneligliptin

Despite their common mechanism of action, DPP-4 inhibitors show marked structural heterogeneity ( Figure 1 ). 20 DPP-4 inhibitors may be classified into peptidomimetic (ie, sitagliptin, vildagliptin, saxagliptin, and anagliptin) and non-peptidomimetic (ie, alogliptin and linagliptin) subtypes. Teneligliptin, {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H- pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl} (1,3-thiazolidin-3-yl) methanone hemipentahydrobromide hydrate exhibits a unique structure that is characterized by five consecutive rings ( Figure 2 ) 21 and is peptidomimetic. An X-ray co-crystal structure of teneligliptin with DPP-4 demonstrates that the key interaction occurs between the phenyl ring on the pyrazole and the S 2 extensive subsite of DPP-4, which not only enhances the potency of the drug but also increases its selectivity. 21

Structural heterogeneity of dipeptidyl peptidase-4 (DPP-4) inhibitors.

Chemical structure of teneligliptin.

According to the product information provided by the pharmaceutical company, teneligliptin inhibits human plasma DPP-4 activity and recombinant human DPP-4 activity in a concentration-dependent manner with half-maximal inhibitory concentrations (IC 50 ) of 1.75 (95% CI, 1.62–1.89) nmol/L and 0.889 (95% CI, 0.812–0.973) nmol/L, respectively. Furthermore, the IC 50 values of teneligliptin for DPP-8, DPP-9, and fibroblast activation protein (FAP) are 0.189, 0.150, and >10 μmol/L, respectively, all of which are more than 160 times the value for recombinant human DPP-4.

Metabolism and excretion

CYP3A4, a cytochrome P450 isozyme and flavin-containing monooxygenases (FMO1 and FMO3) play major roles in the metabolism of teneligliptin. In vitro, teneligliptin exhibits a weak inhibitory effect for CYP2D6, CYP3A4, and FMO; however, it demonstrates no inhibitory effect for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C8/9, CYP2C19, and CYP2E1. In addition, teneligliptin does not induce the expression of CYP1A2 or CYP3A4.

About 34.4% of teneligliptin is excreted unchanged via the kidney and the remaining 65.6% teneligliptin is metabolized and eliminated via renal and hepatic excretion; 216 hours after the administration of 14 C-labeled teneligliptin (20 mg), the cumulative excretion percentages of radioactive teneligliptin in urine and feces were 45.4% and 46.5%, respectively.

Clinical use

Since September 2012, teneligliptin has been commercially sold in Japan and has been used for the treatment of type 2 diabetes mellitus when patients do not show sufficient improvement after diet control and exercise or a combination of diet control, exercise, and sulfonylurea- or thiazolidine-class drugs. In adults, 20 mg of teneligliptin may be orally administered once daily. If this dosage is insufficient, the dosage is increased to 40 mg once daily.

Effects of teneligliptin on glycemic parameters

Teneligliptin is still a relatively new drug, and published clinical studies concerning this drug are sparse. However, a report by Eto et al 22 provides important novel data, particularly the finding that teneligliptin significantly improved 24-hour blood glucose control in Japanese patients with type 2 diabetes. Hereafter, the results of this particular report are summarized.

Effects on blood glucose level

To assess blood glucose control over 24 hours and the safety of teneligliptin at 10 and 20 mg doses, a randomized, double-blind, placebo-controlled, parallel-group study was conducted at four locations in Japan. 22 Japanese patients with type 2 diabetes mellitus that was inadequately controlled with diet and exercise were eligible to participate in the study. Among the 99 patients who participated, 32 were treated with a placebo, 34 were treated with teneligliptin at a dose of 10 mg, and 33 were treated with teneligliptin at a dose of 20 mg before breakfast for 4 weeks. The results revealed that both teneligliptin-treated groups showed significantly smaller 2-hour postprandial glucose (PPG), 24-hour mean glucose (MG), and fasting plasma glucose (FPG) values than the placebo group when the values at week 4 were compared to the baseline values.

The differences in the changes in 2-hour PPG after each meal between the teneligliptin (10 mg) and placebo groups were −50.7 ± 7.8, −34.8 ± 9.2, and −37.5 ± 7.5 mg/dL at breakfast, lunch, and dinner, respectively (least squares [LS] mean ± standard error [SE], P < 0.001 for all comparisons). The corresponding LS means ± SE for teneligliptin (20 mg) versus the placebo were −38.1 ± 7.8, −28.6 ± 9.2, and −36.1 ± 7.5 mg/dL, respectively ( P < 0.001, P < 0.01, and P < 0.001, respectively). Importantly, the postprandial blood glucose-lowering effects of teneligliptin administered before breakfast were sustained throughout the day, and the effects observed after dinner were similar to those observed after breakfast or lunch.

The changes in the 24-hour MG level from baseline were −34.7 ± 3.9, −30.9 ± 4.0, and −5.4 ± 4.0 mg/dL in the groups receiving 10 and 20 mg of teneligliptin and the placebo groups, respectively. Therefore, the differences between the teneligliptin-treated and placebo groups were −29.3 ± 5.3 and −25.5 ± 5.3 mg/dL for teneligliptin at doses of 10 and 20 mg, respectively (LS mean ± SE). These findings demonstrate that the 24-hour MG values significantly decreased in both teneligliptin-treated groups in comparison with the placebo group (both teneligliptin-treated groups, P < 0.001). In addition, when the 24–hour MG profiles were plotted, treatment with teneligliptin suppressed the increases in blood glucose levels over a 24-hour period in comparison with the effect of the placebo at week 4.

The changes in the FPG values from baseline were −20.7 ± 2.7, −20.5 ± 2.8, and −6.9 ± 2.8 mg/dL in the 10 mg and 20 mg groups of teneligliptin and the placebo groups, respectively. These results indicate the differences between the teneligliptin-treated and placebo groups, which were −13.8 ± 4.0 and −13.6 ± 4.0 mg/dL for teneligliptin at doses of 10 and 20 mg, respectively (LS mean ± SE). The decreases in the FPG values with teneligliptin at doses of 10 and 20 mg (both, P < 0.001) were statistically significant, compared with the placebo. However, there were no significant differences in the 2-hour PPG values after each meal, as well as in the 24-hour MG or FPG values between the 10 and 20 mg teneligliptin groups. These results indicate that the once-daily administration of teneligliptin before breakfast improved blood glucose control, even at dinnertime.

Effects on insulin

The area under the curve (AUC) 0–2h values for the postprandial insulin levels significantly increased after dinner in the teneligliptin 10 mg group ( P < 0.05), in comparison with the corresponding values in the placebo group, but not at other times in either group. The relative insulin concentrations were higher in the teneligliptin-treated groups because of the decreased blood glucose concentrations of the patients in these groups.

Effects on glucagon

In this study, the AUC 0–2h for the postprandial glucagon levels significantly decreased after breakfast and lunch as well as after dinner in the 20 mg teneligliptin group compared with the corresponding values in the placebo group. In addition, there were no significant differences in the insulin or glucagon concentrations between the two teneligliptin-dosage groups, although glucagon secretion was lower with teneligliptin treatment at 20 mg, particularly after dinner. Thus, the study concluded that teneligliptin effectively suppressed postprandial glucagon secretion after meals and improved postprandial hyperglycemia.

Pharmacokinetic and pharmacodynamic properties of teneligliptin

The plasma concentrations of teneligliptin after the administration of teneligliptin at dosages of 10 or 20 mg once daily for 4 weeks revealed a median time to maximum concentration (C max ) of 1.0 hour in both groups and a mean t 1/2 of 20.8 and 18.9 hours, respectively.

The maximum percentage of the inhibition in plasma DPP-4 activity was achieved within 2 hours after administration and was 81.3% and 89.7% in the 10 and 20 mg teneligliptin groups, respectively.

The active GLP-1 concentration in the plasma in the 10 mg and 20 mg teneligliptin groups was higher than that in the placebo group throughout the day, even at 24 hours after administration. The AUC 0–2h values for the active GLP-1 concentration after breakfast, lunch, and dinner were 8.0, 8.4, and 7.8 pmol ⋅ h/L, respectively, in the 10 mg teneligliptin group, and 8.3, 7.9, and 8.6 pmol ⋅ h/L, respectively, in the 20 mg teneligliptin group. Thus, the increase in AUC 0–2h for the active GLP-1 concentration after dinner was slightly greater in the 20 mg teneligliptin group than in the 10 mg teneligliptin group. Differences in the AUC 0–2h for the active GLP-1 concentration between both the teneligliptin-treated groups and the placebo group were statistically significant.

Safety and tolerability

The incidence of adverse events (AEs) was not significantly different between the teneligliptin and placebo groups in the study conducted by Eto et al 22 When AEs were rated by the investigators for intensity and potential relationship to the study drug, two drug-related AEs, increased levels of alanine aminotransferase and γ-glutamyltransferase, were observed in one patient (2.9%) treated with 10 mg of teneligliptin. No drug-related AEs occurred in the placebo or 20 mg teneligliptin groups. Furthermore, none of the patients in any of the groups experienced hypoglycemic symptoms or serious AEs. In addition, a pharmaceutical company provided information regarding domestic clinical studies that included 1183 patients, of which 118 patients (10.0%) experienced AEs, including abnormalities in clinical examination values such as levels of liver and kidney function, blood cell count, creatinine phosphokinase, and electrolytes. The main AEs included hypoglycemia (35 patients: 3.0%) and constipation (eleven patients: 0.9%). The pharmaceutical company also warned of serious AEs such as hypoglycemia, which could occur when other antidiabetic drugs were coadministered. In addition, they cautioned that intestinal obstruction could occur with an unknown frequency. GLP-1 is involved in gastrointestinal motility, 6 and the patients with intestinal obstruction had a past medical history of intestinal obstruction or abdominal surgery. Therefore, we should be cautious when administering incretin-related agents to patients with a history of these conditions. Continued assessment of AEs previously reported in clinical trials and post-market monitoring is required to determine the benefit/risk ratio for the drug.

According to a strict QT/QTc evaluation study and clinical studies for type 2 diabetes conducted in Japan and other countries, no AEs related to QT prolongation were detected with 40 mg/day of teneligliptin, which is the maximal dosage used in clinical practice. However, because when 160 mg/day of the drug was administered slight prolongation of the QTc interval was detected temporally at the high concentrations of the drug (around t max level), and also because some patients with diabetes have comorbid arrhythmia or ischemic heart diseases, teneligliptin may be used for a longer period and thus special caution is required in the administration of teneligliptin to patients who are prone to QT prolongation. In addition, the coadministration of teneligliptin with drugs known to cause QT prolongation on their own, such as class IA or class III antiarrhythmic drugs, should be performed with caution.

Long-term effects on glycemic control

In an independent clinical study (Phase II trial) conducted in Japan three hundred twenty-four patients with type 2 diabetes who did not achieve optimal glycemic control with diet and exercise treatment alone for more than 12 weeks were randomly allotted into the following groups: placebo, 10 mg teneligliptin, 20 mg teneligliptin, or 40 mg teneligliptin. The drugs were administered once daily for 12 weeks. After 12 weeks, the HbA 1c levels in the placebo group changed by +0.11% ± 0.05%, whereas those in the 10 mg teneligliptin, 20 mg teneligliptin, and 40 mg teneligliptin groups changed by −0.77% ± 0.05%, −0.80% ± 0.05%, and −0.91% ± 0.05%, respectively (LS mean ± SE). In a Phase III trial, 20 mg of teneligliptin was administered to 151 patients with type 2 diabetes who were treated with diet control and exercise treatment alone for more than 12 weeks. The dose of teneligliptin was increased to 40 mg in patients whose HbA 1c levels were greater than 7.3% at any time after week 24. At week 52, changes in the HbA 1c levels (mean ± standard deviation [SD]) were −0.63% ± 0.67%, compared to baseline.

Kadowaki and Kondo 23 conducted a double-blind placebo-controlled parallel-group study in 324 Japanese patients with type 2 diabetes randomized to receive different doses of teneligliptin or placebo once daily before breakfast for 12 weeks. The differences between the teneligliptin 10, 20, or 40 mg groups and the placebo group for the changes in HbA 1c levels were −0.9 (LS mean; 95% CI: −1.0, −0.7), −0.9 (−1.1, −0.7), and −1.0 (−1.2, −0.9)%, respectively (all, P < 0.001). The respective LS means for FPG were −17.8 (−23.4, −12.1), −16.9 (−22.6, −11.2), and −20.0 (−25.7, −14.3) mg/dL (all, P < 0.001). These results indicate that treatment with teneligliptin for 12 weeks provided significant and clinically meaningful reduction in the levels of HbA 1c and FPG across the dose range studied.

Continued evaluation in long-term studies and clinical practice are required to assess the long-term effects of this drug.

Effects of teneligliptin on lipid profiles

The lipid profile is an important determinant of cardiovascular risk in type 2 diabetes. It can affect antidiabetic therapy and is important in the clinical management of patients with type 2 diabetes. 20 , 24 – 26 Meta-analyses suggested a potential beneficial effect of DPP-4 inhibitors on cholesterol, which could contribute to a reduction in cardiovascular risk. 16 , 24 The administration of several DPP-4 inhibitors reduces postprandial triglyceride levels in humans, mice, and hamsters; however, its effects on postprandial free fatty acid levels are a matter of debate. 27 – 30 Fukuda-Tsuru et al 31 previously reported that a single administration of teneligliptin after an oral fat-loading test in Zucker fatty rats showed that teneligliptin at 1 mg/kg reduced the levels of postprandial triglycerides and free fatty acids and also increased the levels of GLP-1 and insulin. 32 , 33 GLP-1 inhibits the secretion of gastric lipase 34 and reduces intestinal triglyceride absorption and apo B and apo A-IV production, 28 , 35 and insulin suppresses lipolysis in adipose tissue, resulting in a reduction of the plasma free fatty acid levels; 36 therefore, the study speculated that the reduction in triglyceride and free fatty acid levels could be a consequence of the elevation of active GLP-1 and insulin levels. Furthermore, in Zucker fatty rats, the repeated administration of teneligliptin for 2 weeks reduced glucose excursions in an oral carbohydrate-loading test and decreased plasma triglyceride and free fatty acid levels under nonfasting conditions. Furthermore, these results were consistent with the findings of other previous reports on DPP-4 inhibitors in various rodent models such as db/db mice and streptozocin-induced diabetic rats. 37 – 40

Teneligliptin and renal impairment

The single administration of teneligliptin at 20 mg in patients with renal impairment revealed no remarkable changes in C max and t 1/2 corresponding to the level of renal impairment. Compared with healthy adult subjects, the AUC 0–∞ of subjects with mild renal impairment (50 ≤ creatinine clearance [Ccr] ≤ 80 mL/minute), moderate renal impairment (30 ≤ Ccr < 50 mL/minute), and severe renal impairment (Ccr < 30 mL/minute) was approximately 1.25 times, 1.68 times, and 1.49 times higher than that of healthy adult subjects, respectively. In addition, the AUC 0–43h of patients with end-stage renal failure was approximately 1.16 times higher than that of healthy adult subjects. In addition, 15.6% of the total administration dose of teneligliptin was eliminated via hemodialysis.

Teneligliptin and hepatic impairment

A single administration of teneligliptin 20 mg in patients with hepatic impairment revealed that the C max of subjects with mild hepatic impairment (Child-Pugh classification: 41 total score 5–6) and moderate hepatic impairment (Child–Pugh classification: total score 7–9) was approximately 1.25 times and 1.38 times that of healthy adult subjects, respectively. Compared to healthy adult subjects, the AUC 0–∞ of subjects with mild and moderate hepatic impairments was approximately 1.46 times and 1.59 times higher than that of healthy adult subjects, respectively. There have been no previous clinical studies using teneligliptin in patients with severe hepatic impairment (Child–Pugh classification: total score was greater than 9). Thus, specific caution is required when the drug is administered to patients with severe hepatic impairment.

Influence on body weight

Studies on the effect of DPP-4 inhibitors on body weight demonstrated variable results; however, these results were generally considered to be neutral. 14 , 16 , 42 – 44 In a Phase III trial, 20 mg of teneligliptin was administered to 151 patients with type 2 diabetes, who were previously treated with diet control and exercise treatment alone. The dose of teneligliptin was increased to 40 mg in patients with HbA 1c levels greater than 7.3% at any time after week 24. The mean body weight change of the patients at week 52 (mean ± SD) was +0.18 ± 2.14 kg ( P = 0.3254), which indicated that the effect of teneligliptin on body weight was neutral.

Gliptins in combination with other oral antidiabetic agents

Since DPP-4 inhibitors and metformin improve glycemic control via different, albeit potentially complementary, mechanisms, combination therapy with these two agents should provide effective and potentially additive glycemic control. 42 Studies using combination therapy of DPP-4 inhibitors and metformin (as one pill) showed favorable results in glycemic control because of favorable pharmacokinetic characteristics and complementary pharmacodynamic effects, which include enhanced incretin effect, suppressed hepatic glucose production, and improved peripheral insulin sensitivity. Moreover, in general, the combination of these drug into a single tablet improves patients’ compliance and often results in a lower cost of treatment. 14 , 45 , 46 Indeed several fixed-dose combinations have been developed and/or commercialized. 43 , 45

Furthermore, α-glucosidase inhibitors (α-GIs) reportedly enhanced GLP-1 responses and reduced the total GIP responses. 47 – 51 Considering the different but complementary mechanisms of action by which α-GIs and DPP-4 inhibitors lower glucose levels and increase GLP-1 action, combination therapy using these agents may provide a valuable means of treating diabetes. Using a continuous glucose-monitoring (CGM) system, 52 , 53 we previously reported the efficacy of combination therapy using miglitol and sitagliptin in patients with type 2 diabetes. 54

Several trials have also evaluated the efficacy and safety of adding a DPP-4 inhibitor to sulfonylurea, such as glimepiride or glyburide (glibenclamide), and have indicated a significant improvement in glycemic control. 43 , 55 Because hypoglycemic events may occur with the combination of DPP-4 inhibitors and sulfonylurea, caution should be taken to reduce the dose of sulfonylurea in order to minimize the risk of hypoglycemia.

When 20 mg of teneligliptin was administered to 96 patients with type 2 diabetes who were treated with glimepiride (1–4 mg per day) in addition to diet and exercise treatment, the changes in HbA 1c levels and fasting and the 2-hour postprandial blood glucose levels (LS mean ± SE) were −0.71% ± 0.06%, −17.3 ± 2.2 mg/dL, and −43.1 ± 4.4 mg/dL, respectively, from baseline at week 12.

From a theoretical standpoint, combination of DPP-4 inhibitors, which stimulate insulin secretion in a glucose-dependent manner and do not promote weight gain, and thiazolidinedione, which enhances peripheral insulin action and may cause weight gain, is an attractive and rational approach. 43 , 56 – 58 When 20 mg of teneligliptin was administered to 103 patients with type 2 diabetes who were treated with pioglitazone (15–30 mg per day) in addition to diet and exercise treatment, the changes in HbA 1c levels and fasting and 2-hour postprandial blood glucose levels (LS mean ± SE) were −0.94% ± 0.04%, −21.0 ± 1.9 mg/dL, and −56.9 ± 3.6 mg/dL, respectively, compared with that at baseline, at week 12.

Gliptin treatments in combination with insulin

The effectiveness of insulin injections has been previously established in various clinical studies; however, increasing the insulin dosage to achieve better glycemic control has been associated with an increased risk of hypoglycemia and weight gain. 59 To resolve these problems, combination therapy with insulin injection and oral medication is worth considering. Due to the different mechanisms and complementary effects of DPP-4 inhibitors and insulin, a combination of these agents would be a rational treatment option for insulin-treated patients. Favorable results with additional 0.3%–0.6% reductions in the HbA 1c levels have been reported in patients treated with both insulin and DPP-4 inhibitors. These patients demonstrated a low rate of hypoglycemia and a slight weight reduction. 43 , 55 We previously reported that the combination of sitagliptin and insulin therapy presented beneficial effects in stabilizing glycemic control by stimulating endogenous insulin secretion and suppressing glucagon secretion. 60 Vilsbøll et al previously reported in a 24-week study that the addition of sitagliptin to ongoing insulin therapy resulted in significant improvements in glycemic control, in comparison with the placebo treatment, by improving β-cell responsiveness. 61 The study concluded that, in patients with more advanced stages of the disease and β-cell failure, sitagliptin may still favorably affect glucose-dependent insulin secretion. Vildagliptin decreased HbA 1c levels in patients with poorly controlled type 2 diabetes with high doses of insulin, 62 and vildagliptin has also been reported to be beneficial for decreasing post-meal glucagon excursion in insulinopenic patients with type 1 diabetes; this effect was not secondary to a change in endogenous insulin secretion. 63 Taken together, these reports encourage further study of the use of incretin-related agents in insulin-treated patients with type 2 or type 1 diabetes. Teneligliptin is not currently approved for coadministration with insulin; however, a combination therapy of teneligliptin and insulin is quite promising for these aforementioned reasons.

Case presentation

A 68-year-old Japanese woman with a 7-year history of type 2 diabetes presented at our hospital (National Center for Global Health and Medicine, Tokyo, Japan) to be equipped with a CGM device (iPro®2; Medtronic Ltd, Watford, UK). 64 Her height was 148.6 cm and her body weight was 59.2 kg (body mass index 26.8 kg/m 2 ). Her hemoglobin A 1c and fasting C-peptide levels were 6.6% and 3.3 ng/mL, respectively, and she was on a treatment of 20 mg of gliclazide. On the first day of the CGM period, the patient was taking gliclazide alone. From day 2 through day 4, 20 mg of teneligliptin was also taken, before breakfast, in addition to gliclazide. During this period, she did not change her lifestyle remarkably, including the timing and amounts of her meals and the levels of her daily physical activities. Figure 3 shows the fluctuations in glucose levels measured using CGM during treatment with gliclazide alone (day 1) and gliclazide plus teneligliptin (days 2 to 4). The average and SD values of the CGM measurements on days 1, 2, 3, and 4 were 142 ± 26, 145 ± 20, 135 ± 15, and 126 ± 16 mg/dL, respectively, reflecting the attenuation of glucose fluctuations when teneligliptin was added to gliclazide. These findings clearly demonstrate the efficacy of combinatorial therapy using sulfonylurea such as gliclazide and teneligliptin in patients with type 2 diabetes.

Continuous glucose monitoring results during treatment with gliclazide alone (day 1) and gliclazide plus teneligliptin (days 2 to 4).

Notes: The symbols at the bottoms of the figures indicate the times of meals. The round symbols on or close to the wavy lines indicate the times and values of calibration.

Numerous clinical trials have demonstrated that DPP-4 inhibitors provide effective and consistent glycemic control with a good tolerability profile, including no severe hypoglycemia and weight gain. 7 , 8 , 11 – 19 , 42 – 45 Although different DPP-4 inhibitors are distinctive in their metabolic properties, excretion, recommended dosage, and daily dosage, and head-to-head clinical trials comparing the various DPP-4 inhibitors are scarce, the available data regarding indirect comparisons suggest that all available DPP-4 inhibitors have nearly the same efficacy and safety profile. 14 , 16 , 43 Thus, we may expect a similar efficacy and safety with the novel DPP-4 inhibitor, teneligliptin, although this drug requires careful long-term postmarketing surveillance and additional clinical trials to evaluate its efficacy and safety as well as to gain additional indications for its clinical use.

Acknowledgment

The author thanks Dr Mitsuhiko Noda for his comments regarding this paper.

The author reports no conflicts of interest in this work.

1. Drucker DJ. The role of gut hormones in glucose homeostasis. J Clin Invest. 2007;117:24–32. doi: 10.1172/JCI30076. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
2. Meier JJ, Nauck MA. Incretins and the development of type 2 diabetes. Curr Diab Rep. 2006;6:194–201. doi: 10.1007/s11892-006-0034-7. [ DOI ] [ PubMed ] [ Google Scholar ]
3. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87:1409–1439. doi: 10.1152/physrev.00034.2006. [ DOI ] [ PubMed ] [ Google Scholar ]
4. Kreymann B, Williams G, Ghatel MA, Bloom SR. Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet. 1987;2:1300–1304. doi: 10.1016/s0140-6736(87)91194-9. [ DOI ] [ PubMed ] [ Google Scholar ]
5. McIntosh CH, Widenmaier S, Kim SJ. Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP) Vitam Horm. 2009;80:409–471. doi: 10.1016/S0083-6729(08)00615-8. [ DOI ] [ PubMed ] [ Google Scholar ]
6. Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: similarities and differences. J Diabet Invest. 2010;1:8–23. doi: 10.1111/j.2040-1124.2010.00022.x. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
7. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91:4612–4619. doi: 10.1210/jc.2006-1009. [ DOI ] [ PubMed ] [ Google Scholar ]
8. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP. Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin. 2008;24:489–496. doi: 10.1185/030079908x261069. [ DOI ] [ PubMed ] [ Google Scholar ]
9. Xu L, Man CD, Charbonnel B, et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on beta-cell function in patients with type 2 diabetes: a model-based approach. Diabetes Obes Metab. 2008;10:1212–1220. doi: 10.1111/j.1463-1326.2008.00887.x. [ DOI ] [ PubMed ] [ Google Scholar ]
10. Brazg R, Xu L, Dalla Man C, Cobelli C, Thomas K, Stein PP. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes. Diabetes Obes Metab. 2007;9:186–193. doi: 10.1111/j.1463-1326.2006.00691.x. [ DOI ] [ PubMed ] [ Google Scholar ]
11. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–1705. doi: 10.1016/S0140-6736(06)69705-5. [ DOI ] [ PubMed ] [ Google Scholar ]
12. Deacon CF, Ahrén B, Holst JJ. Inhibitors of depeptidyl peptidase IV: a novel approach for the prevention and treatment of type 2 diabetes? Expert Opin Investig Drugs. 2004;13:1091–1102. doi: 10.1517/13543784.13.9.1091. [ DOI ] [ PubMed ] [ Google Scholar ]
13. Drucker DJ. Therapeutic potential of depeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2003;12:87–100. doi: 10.1517/13543784.12.1.87. [ DOI ] [ PubMed ] [ Google Scholar ]
14. Dicker D. DPP-4 inhibitors. Impact on glycemic control and cardiovascular risk factors. Diabetes Care. 2011;34(Suppl 2):S276–S278. doi: 10.2337/dc11-s229. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
15. Davidson JA. Advances in therapy for type 2 diabetes: GLP-1 receptor agonists and DPP-4 inhibitors. Cleve Clin J Med. 2009;76(Suppl 5):S28–S38. doi: 10.3949/ccjm.76.s5.05. [ DOI ] [ PubMed ] [ Google Scholar ]
16. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298:194–206. doi: 10.1001/jama.298.2.194. [ DOI ] [ PubMed ] [ Google Scholar ]
17. Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):1249–1255. doi: 10.1210/jc.2006-1882. [ DOI ] [ PubMed ] [ Google Scholar ]
18. Williams-Herman D, Round E, Swern AS, et al. Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis. BMC Endocr Disord. 2008;8:14. doi: 10.1186/1472-6823-8-14. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
19. Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ. 2012;344:e1369. doi: 10.1136/bmj.e1369. [ DOI ] [ PubMed ] [ Google Scholar ]
20. Baetta R, Corsini A. Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences. Drugs. 2011;71:1441–1467. doi: 10.2165/11591400-000000000-00000. [ DOI ] [ PubMed ] [ Google Scholar ]
21. Yoshida T, Akahoshi F, Sakashita H, et al. Discovery and preclinical profile of teneligliptin(3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg Med Chem. 2012;20(19):5705–5719. doi: 10.1016/j.bmc.2012.08.012. [ DOI ] [ PubMed ] [ Google Scholar ]
22. Eto T, Inoue S, Kadowaki T. Effects of once-daily teneligliptin on 24-h blood glucose control and safety in Japanese patients with type 2 diabetes mellitus: a 4-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2012;14:1040–1046. doi: 10.1111/j.1463-1326.2012.01662.x. [ DOI ] [ PubMed ] [ Google Scholar ]
23. Kadowaki T, Kondo K. Efficacy, safety and dose-response relationship of teneligliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2013 Mar 6; doi: 10.1111/dom.12092. Epub. [ DOI ] [ PubMed ] [ Google Scholar ]
24. Monami M, Lamanna C, Desideri CM, Mannucci E. DPP-4 inhibitors and lipids: systematic review and meta-analysis. Adv Ther. 2012;29:14–25. doi: 10.1007/s12325-011-0088-z. [ DOI ] [ PubMed ] [ Google Scholar ]
25. Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocrine Rev. 2008;29:351–366. doi: 10.1210/er.2007-0023. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
26. Sone H, Tanaka S, Tanaka S, et al. Japan Diabetes Complications Study Group Serum level of triglycerides is a potent risk factor comparable to LDL cholesterol for coronary heart disease in Japanese patients with type 2 diabetes: subanalysis of the Japan Diabetes Complications Study (JDCS) J Clin Endocrinol Metab. 2011;96:3448–3456. doi: 10.1210/jc.2011-0622. [ DOI ] [ PubMed ] [ Google Scholar ]
27. Ansar S, Koska J, Reaven PD. Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins. Cardiovasc Diabetol. 2011;10:61. doi: 10.1186/1475-2840-10-61. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
28. Hsieh J, Longuet C, Baker CL, et al. The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice. Diabetologia. 2010;53:552–561. doi: 10.1007/s00125-009-1611-5. [ DOI ] [ PubMed ] [ Google Scholar ]
29. Matikainen N, Mänttäri S, Schweizer A, et al. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia. 2006;49:2049–2057. doi: 10.1007/s00125-006-0340-2. [ DOI ] [ PubMed ] [ Google Scholar ]
30. Tremblay AJ, Lamarche B, Deacon CF, Weisnagel SJ, Couture P. Effect of sitagliptin therapy on postprandial lipoprotein levels in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13:366–373. doi: 10.1111/j.1463-1326.2011.01362.x. [ DOI ] [ PubMed ] [ Google Scholar ]
31. Fukuda-Tsuru S, Anabuki J, Abe Y, Yoshida K, Ishii S. A novel, potent, and long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, improves postprandial hyperglycemia and dyslipidemia after single and repeated administrations. Eur J Pharmacol. 2012;696(1–3):194–202. doi: 10.1016/j.ejphar.2012.09.024. [ DOI ] [ PubMed ] [ Google Scholar ]
32. Ionescu E, Sauter JF, Jeanrenaud B. Abnormal oral glucose tolerance in genetically obese (fa/fa) rats. Am J Physiol. 1985;248:E500–E506. doi: 10.1152/ajpendo.1985.248.5.E500. [ DOI ] [ PubMed ] [ Google Scholar ]
33. Pederson RA, White HA, Schlenzig D, Pauly RP, McIntosh CH, Demuth HU. Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. Diabetes. 1998;47:1253–1258. doi: 10.2337/diab.47.8.1253. [ DOI ] [ PubMed ] [ Google Scholar ]
34. Wøjdemann M, Wettergren A, Sternby B, et al. Inhibition of human gastric lipase secretion by glucagon-like peptide-1. Dig Dis Sci. 1998;43:799–805. doi: 10.1023/a:1018874300026. [ DOI ] [ PubMed ] [ Google Scholar ]
35. Qin X, Shen H, Liu M, et al. GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats. Am J Physiol Gastrointest Liver Physiol. 2005;288:G943–G949. doi: 10.1152/ajpgi.00303.2004. [ DOI ] [ PubMed ] [ Google Scholar ]
36. Mahler R, Statford WS, Tarrant ME, Ashmore J. The effect of insulin on lipolysis. Diabetes. 1964;13:297–302. [ PubMed ] [ Google Scholar ]
37. Moritoh Y, Takeuchi K, Asakawa T, Kataoka O, Odaka H. Combining a dipeptidyl peptidase-4 inhibitor, alogliptin, with pioglitazone improves glycaemic control, lipid profiles and beta-cell function in db/db mice. Br J Pharmacol. 2009;157:415–426. doi: 10.1111/j.1476-5381.2009.00145.x. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
38. Mu J, Woods J, Zhou YP, et al. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes. 2006;55:1695–1704. doi: 10.2337/db05-1602. [ DOI ] [ PubMed ] [ Google Scholar ]
39. Pospisilik JA, Martin J, Doty T, et al. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes. 2003;52:741–750. doi: 10.2337/diabetes.52.3.741. [ DOI ] [ PubMed ] [ Google Scholar ]
40. Sudre B, Broqua P, White RB, et al. Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male zucker diabetic fatty rats. Diabetes. 2002;51:1461–1469. doi: 10.2337/diabetes.51.5.1461. [ DOI ] [ PubMed ] [ Google Scholar ]
41. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus for bleeding esophageal varices. Br J Surg. 1973;60:646–654. doi: 10.1002/bjs.1800600817. [ DOI ] [ PubMed ] [ Google Scholar ]
42. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE, Sitagliptin 036 Study Group Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979–1987. doi: 10.2337/dc07-0627. [ DOI ] [ PubMed ] [ Google Scholar ]
43. Scheen AJ. A review of gliptins in 2011. Expert Opin Pharmacother. 2012;13:81–99. doi: 10.1517/14656566.2012.642866. [ DOI ] [ PubMed ] [ Google Scholar ]
44. Barnett A, Allsworth J, Jameson K, Mann R. A review of the effects of antihyperglycaemic agents on body weight: the potential of incretin targeted therapies. Curr Med Res Opin. 2007;23:1493–1507. doi: 10.1185/030079907x199691. [ DOI ] [ PubMed ] [ Google Scholar ]
45. Koliaki C, Doupis J. Linagliptin/Metformin fixed-dose combination treatment: a dual attack to type 2 diabetes pathophysiology. Adv Ther. 2012;29(12):993–1004. doi: 10.1007/s12325-012-0067-z. [ DOI ] [ PubMed ] [ Google Scholar ]
46. Genovese S, Tedeschi D. Effects of vildagliptin/metformin therapy on patient-reported outcomes: work productivity, patient satisfaction, and resource utilization. Adv Ther. 2013;30(2):152–164. doi: 10.1007/s12325-013-0001-z. [ DOI ] [ PubMed ] [ Google Scholar ]
47. Narita T, Katsuura Y, Sato T, et al. Miglitol induces prolonged and enhanced glucagon-like peptide-1 and reduced gastric inhibitory polypeptide responses after ingestion of a mixed meal in Japanese type 2 diabetic patients. Diabet Med. 2009;26:187–188. doi: 10.1111/j.1464-5491.2008.02651.x. [ DOI ] [ PubMed ] [ Google Scholar ]
48. Arakawa M, Ebato C, Mita T, et al. Miglitol suppresses the postprandial increases in interleukin 6 and enhances active glucagon-like peptide 1 secretion in viscerally obese subjects. Metabolism. 2008;57:1299–1306. doi: 10.1016/j.metabol.2008.04.027. [ DOI ] [ PubMed ] [ Google Scholar ]
49. Lee A, Patrick P, Wishart J, Horowitz M, Morley JE. The effects of miglitol on glucagon-like peptide-1 secretion and appetite sensations in obese type 2 diabetics. Diabetes Obes Metab. 2002;4:329–335. doi: 10.1046/j.1463-1326.2002.00219.x. [ DOI ] [ PubMed ] [ Google Scholar ]
50. Narita T, Yokoyama H, Yamashita R, et al. Comparison of the effects of 12-week administration of miglitol and voglibose on the responses of plasma incretins after a mixed meal in Japanese type 2 diabetic patients. Diabetes Obes Metab. 2012;14:283–287. doi: 10.1111/j.1463-1326.2011.01526.x. [ DOI ] [ PubMed ] [ Google Scholar ]
51. Aoki K, Kamiyama H, Yoshimura K, Shibuya M, Masuda K, Terauchi Y. Miglitol administered before breakfast increased plasma active glucagon-like peptide-1 (GLP-1) levels after lunch in patients with type 2 diabetes treated with sitagliptin. Acta Diabetol. 2012;49:225–230. doi: 10.1007/s00592-011-0322-9. [ DOI ] [ PubMed ] [ Google Scholar ]
52. Gross TM, Bode BW, Einhorn D, et al. Performance evaluation of the MiniMed continuous glucose monitoring system during patient home use. Diabetes Technol Ther. 2000;2:49–56. doi: 10.1089/152091500316737. [ DOI ] [ PubMed ] [ Google Scholar ]
53. Kaufman FR, Gibson LC, Halvorson M, Carpenter S, Fisher LK, Pitukcheewanont P. A pilot study of glucose measurements using the glucose sensor. Diabetes Care. 2002;25:1185–1191. [ Google Scholar ]
54. Kishimoto M, Noda M. A pilot study of the efficacy of miglitol and sitagliptin for type 2 diabetes with a continuous glucose monitoring system and incretin-related markers. Cardiovasc Diabetol. 2011;10:115. doi: 10.1186/1475-2840-10-115. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
55. Scheen AJ. DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials. Diabetes Metab. 2012;38(2):89–101. doi: 10.1016/j.diabet.2011.11.001. [ DOI ] [ PubMed ] [ Google Scholar ]
56. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–795. doi: 10.2337/db09-9028. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
57. Mikhail N. Combination therapy with DPP-4 inhibitors and pioglitazone in type 2 diabetes: theoretical consideration and therapeutic potential. Vasc Health Risk Manag. 2008;4:1221–1227. doi: 10.2147/vhrm.s3374. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
58. Rosenstock J, Kim SW, Baron MA, et al. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2007;9(2):175–185. doi: 10.1111/j.1463-1326.2006.00698.x. [ DOI ] [ PubMed ] [ Google Scholar ]
59. Mäkimattila S, Nikkilä K, Yki-Järvinen H. Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes mellitus. Diabetologia. 1999;42:406–412. doi: 10.1007/s001250051172. [ DOI ] [ PubMed ] [ Google Scholar ]
60. Kishimoto M, Noda M. Effect of the addition of sitagliptin and miglitol on insulin-treated type 2 diabetes. Diabetes Ther. 2012;3(1):11. doi: 10.1007/s13300-012-0011-x. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
61. Vilsbøll T, Rosenstock J, Yki-Järvinen H, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:167–177. doi: 10.1111/j.1463-1326.2009.01173.x. [ DOI ] [ PubMed ] [ Google Scholar ]
62. Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007;50:1148–1155. doi: 10.1007/s00125-007-0633-0. [ DOI ] [ PubMed ] [ Google Scholar ]
63. Foley JE, Ligueros-Saylan M, He YL, et al. Effect of vildagliptin on glucagon concentration during meals in patients with type 1 diabetes. Horm Metab Res. 2008;40:727–730. doi: 10.1055/s-2008-1078754. [ DOI ] [ PubMed ] [ Google Scholar ]
64. iPro®2 Professional CGM [homepage on the internet] Medtronic MiniMed Inc; 2013Available from: http://www.professional.medtronicdiabetes.com/hcp-products/ipro2 Accessed March 29, 2013 [ Google Scholar ]
View on publisher site
PDF (793.4 KB)
Collections

Add to Collections

Open access
Published: 22 August 2024

Vildagliptin promotes diabetic foot ulcer healing through autophagy modulation

Erik Biros 1 , 2 ,
Venkat Vangaveti 1 , 2 &
Usman Malabu 1 , 3

Diabetology & Metabolic Syndrome volume 16 , Article number: 204 ( 2024 ) Cite this article

333 Accesses

Metrics details

The study aimed to investigate the molecular mechanisms underlying the effects of Vildagliptin on the healing of diabetic foot ulcers (DFUs). The research compared patients who received 12 weeks of Vildagliptin treatment to those who did not. Various molecular markers associated with wound healing were measured. Wound fluid samples were collected from DFUs using a filter paper absorption technique, and total RNA was extracted for quantitative real-time PCR (qPCR). The results showed that the autophagy marker NUP62 was significantly downregulated in the Vildagliptin group at week 12 compared to baseline (median expression 0.57 vs. 1.28; P = 0.0234). No significant change was observed in the placebo group (median expression 1.61 vs. 1.48; P = 0.9102). Both groups showed substantial downregulation of RIPK3 , a necroptosis marker, at week 12 compared to their respective baselines. In addition to its effects on blood sugar levels, Vildagliptin may promote DFU healing by reducing autophagy in patients with diabetes.

Introduction

Diabetic foot ulcer (DFU) is a life-altering condition characterized by a non-healing wound on a foot, serving as a constant reminder of the diabetes complications. Diabetes affects around 530 million adults worldwide [ 1 ], and approximately a quarter of these individuals will develop DFU, which accounts for roughly 85% of lower limb amputations, leading to a dramatic decrease in quality of life and increased mortality [ 2 , 3 ]. The current standard of care for DFU primarily involves topical treatments that require frequent clinic visits and mechanical wound handling, often resulting in pain and a higher risk of infections [ 4 ]. These challenges underscore the urgent need for more effective and less invasive therapeutic strategies. In this context, oral medications simultaneously controlling blood sugar levels and promoting wound healing are particularly intriguing. Such treatments could improve patient outcomes and reduce the medication burden for diabetic patients, who are already at a higher risk of polypharmacy due to associated comorbidities [ 5 ].

Recent research has indicated that medications targeting the body’s natural incretin hormones, which stimulate insulin release, might also play a role in wound healing [ 6 ]. Vildagliptin, in particular, is a potent and selective inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme (DPP4i) [ 7 ]. DPP-4 rapidly degrades the gut’s incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which are responsible for insulin secretion upon glucose intake [ 8 ]. Notably, our recent observations suggest that DPP4i Vildagliptin not only aids in glycemic control but also improves DFU healing [ 6 ]. We hypothesize that Vildagliptin’s benefits extend beyond blood sugar regulation, influencing cellular processes vital for wound healing. Our analysis of wound fluid from DFU patients treated with Vildagliptin revealed significant changes in autophagy, a lysosome-dependent process that breaks down and recycles damaged cell components [ 9 ]. This study sheds light on the molecular mechanisms underlying Vildagliptin’s effectiveness in promoting DFU healing, providing a solid rationale for further investigation into its therapeutic potential.

Materials and methods

This study adhered to national and international guidelines, including the Guidance on Good Clinical Practice [CPMP/GCP/135/95] and the annotated version with Therapeutic Goods Administration (TGA) comments [DSEB, July 2000]. Additionally, it followed the NHMRC National Statement on Ethical Conduct in Human Research (2007) and complied with all other applicable Australian Commonwealth, State, or Territory laws or guidelines of Regulatory Authorities. The study also upheld ethical principles derived from the Declaration of Helsinki. Furthermore, the study protocol received approval from an independent ethics committee (IEC), specifically HREC/13/QTHS/65, and is registered under Trial Registration ACTRN12613000418774. After fully explaining the purpose and nature of all procedures, written consent was obtained from each patient or subject.

Patients and wound fluid sample collection

This study used samples from a large randomized, double-blind, placebo-controlled clinical trial described elsewhere [ 6 ]. The initial study included 50 participants, 25 randomly assigned to the placebo group and 25 to the treatment group. The inclusion criteria stated that the participants had to be adult males or females with type 2 diabetes who managed their condition through diet alone or non-DPP4i medication. All patients had a diabetes index foot ulcer graded at A1 or higher, according to the University of Texas Wound Classification System of Diabetic Foot Ulcers [ 10 ]. The primary exclusion criteria included type 1 diabetes and current index foot ulcer of any non-diabetic origin [ 6 ]. The trial compared the effectiveness of taking 100 mg of Vildagliptin per day, split into two 50 mg doses—one in the morning and one in the evening—along with the standard of care (SOC), with taking a placebo along with SOC. The treatment lasted 12 weeks, during which participants regularly visited their podiatry clinics. The duration and dosage used in the trial align with previous research [ 11 ]. The wound fluid samples were collected using filter paper absorption during the patient’s first and last visits to the podiatry clinic. The peri-wound area was gently cleaned with sterile saline to minimize contamination. A sterile filter paper disc of appropriate size was then gently applied to the wound bed, ensuring it was in contact with the wound fluid but not surrounding tissue/debris. The filter paper was left in place for approximately 1 min to allow sufficient absorption of the wound fluid. After removal, the filter paper was placed into a sterile 1.5 ml Eppendorf tube and immediately snap-froze in liquid nitrogen. The frozen samples were then stored at -80 °C until they could be assayed.

Molecular markers

We assessed a range of molecular markers to investigate various aspects of cellular processes. The following markers were evaluated:

(a) Proliferation: MKI67 (marker of proliferation Ki-67) and MCM2 (minichromosome maintenance complex component 2) (b) Senescence: GLB1 (galactosidase beta 1) and CDKN1A (cyclin-dependent kinase inhibitor 1 A) (c) Apoptosis: BAX (BCL2 associated X, apoptosis regulator) and BCL2 (BCL2 apoptosis regulator) (d) Necroptosis: RIPK3 (receptor-interacting serine/threonine kinase 3) and MLKL (mixed lineage kinase domain-like pseudokinase) (e) Energy metabolism: SIRT1 (sirtuin 1) and MT-CO3 (mitochondrially encoded cytochrome c oxidase III) (f) Autophagy: ATG7 (autophagy-related 7), NUP62 nucleoporin 62, also known as p62 (g): Mitophagy: PINK1 PTEN-induced kinase 1, PRKN parkin RBR E3 ubiquitin protein ligase (h): Four Yamanaka Factors related to pluripotency regulation: POU5F1 (OCT3/4), SOX2 (SRY-box transcription factor 2), KLF4 (KLF transcription factor 4), MYC (MYC proto-oncogene, bHLH transcription factor).

Gene expression

Quantitative real-time reverse transcription PCR (qPCR) assays were performed to assess the differential expression of selected markers in wound fluids of diabetic patients with DFU with and without Vildagliptin treatment. Total RNA was extracted using QIAzol lysis reagent (cat. no. 79306, Qiagen) and purified using the RNeasy Mini Kit (cat. no. 74104, Qiagen) following the manufacturer’s instructions. The relative expression of a gene in each sample was calculated using the concentration-Ct-standard curve method and normalized using the average expression of the ribosomal protein S13 ( RPS13 ) gene using the Rotor-Gene Q operating software version 2.0.24 (Qiagen). The one-step QuantiTect SYBR Green RT-PCR Kit (cat. no. 204243, Qiagen) was combined with the QuantiTect Primer Assays (Qiagen) following the manufacturer’s instructions with ten nanograms of total RNA as a template. The QuantiTect Primer Assays (Qiagen) were used for RPS13 (QT00224539), MKI67 (QT00014203), MCM2 (QT00070812), GLB1 (QT00066206), CDKN1A (QT00062090), BAX (QT00031192), RIPK3 (QT00046102), MLKL (QT00495117), SIRT1 (QT00051261), ATG7 (QT00008974), NUP62 (QT00064414), PINK1 (QT00056630), POU5F1 (QT00210840), SOX2 (QT00237601), and KLF4 (QT00061033). The SYBR Green PCR sense (5′-ATCCGTATTACTCGCATC-3′) and anti-sense (5′-TACTCTGAGGCTTGTAGG-3′) primers were designed for MT-CO3 (reference sequence NC_012920.1:9207–9990), BCL2 (sense 5′-TAACTCCTCTTCTTTCTC-3′ and anti-sense 5′-TACTTCATCACTATCTCC-3′; reference sequence NM_000633.3), PRKN (sense 5′-GACACCAGCATCTTCCAG-3′ and anti-sense 5′-GCACAGTCCAGTCATTCC-3′; reference sequence NM_004562.3), and MYC (sense 5′-ACACATCAGCACAACTACG-3′ and anti-sense 5′-CGCCTCTTGACATTCTCC-3′; reference sequence NM_002467.6) using the AlleleID software (PREMIER Biosoft). These primer pairs were manufactured and purchased from Merck. All reactions were independently repeated in duplicate to assess the repeatability of the results. The mean of the two raw values for each sample was used for analyses.

Statistical analysis

Data were analyzed using Stata/MP 16.0 (StataCorp LP, USA), and summary statistics are provided as a median (bold horizontal line) and interquartile range (whiskers). The Wilcoxon signed-rank test was used to compare gene expression between the first and last visit in patients with and without Vildagliptin treatment. The statistical significance was assumed at the conventional 5% level. All data points were graphed for the best visual inspection using GraphPad Prism 9 (GraphPad Software, USA).

Patients characteristics

Eight patients with Vildagliptin and nine receiving placebo from a larger clinical trial of 50 patients (25/group) were included in this analysis. The inclusion was based solely on the availability of the paired wound fluid samples at the beginning and end of the study. These patients had similar characteristics across all measured parameters, ensuring a comparable baseline for analysis (Table 1 ).

Differential changes in DFU surface area

DFU surface area, our crucial measure of wound size, significantly decreased in patients receiving Vildagliptin treatment. Compared to the baseline measurement, the average DFU surface area decreased by ~ 23% after twelve weeks of treatment (348 mm² vs. 265 mm², P = 0.0047; Table 2 ). Notably, all patients in the Vildagliptin group exhibited decreased DFU surface area at the end of the study (Supplementary Table 1 ).

In contrast, the placebo group did not experience a statistically significant change in average DFU surface area at the end of the study (147 mm² vs. 172 mm², P = 0.7855; see Table 2 ). One patient did not show any change, and the other two patients in the placebo group demonstrated an increased DFU surface area at the end of the study (refer to Supplementary Table 1 ).

Expression of cell proliferation and senescence markers

We assessed the differential gene expression of two cell proliferation markers, MKI67 and MCM2 . Both genes were similarly expressed in the Vildagliptin and placebo groups at the first and last visits ( P > 0.05; Fig. 1 A).

Expression of proliferation and senescence markers in patients with and without Vildagliptin treatment. Data show a similar expression of MKI67 and MCM2 proliferation markers (A) and GLB1 and CDKN1A senescence markers (B) in both groups. The median (bold horizontal line) and interquartile range (whiskers) are shown. Statistical significance was determined using the paired Wilcoxon signed rank. MKI67 , marker of proliferation Ki-67; MCM2 , minichromosome maintenance complex component 2; (b) GLB1 , galactosidase beta 1 and CDKN1A , cyclin dependent kinase inhibitor 1 A; V1, first visit (baseline); V last, last visit (week 12)

Similarly, there was no difference in the expression of two cell senescence markers, GLB1 and CDKN1A , between the first and last visit in both Vildagliptin and placebo groups ( P > 0.05; Fig. 1 B).

Expression of apoptosis, necroptosis, and cell energy metabolism markers

We assessed the differential expression of two genes critically involved in cell apoptosis, BAX and BCL2 . The results are presented as BAX to BCL2 ratio and showed no statistically significant difference between the first and last visits in both Vildagliptin and placebo groups ( P > 0.05; Fig. 2 A).

Expression of apoptosis, necroptosis, and energy metabolism markers in patients with and without Vildagliptin treatment. Data show a similar ratio of apoptosis markers BAX/BCL2 in both groups (A) , downregulation of necroptosis marker RIKK3 in both groups (B) , and similar expression of energy metabolism genes SIRT1 and MT-CO3 in both groups (C) . The median (bold horizontal line) and interquartile range (whiskers) are shown. Statistical significance was determined using the paired Wilcoxon signed rank. BAX , BCL2 associated X, apoptosis regulator; BCL2 , BCL2 apoptosis regulator; RIPK3 , receptor interacting serine/threonine kinase 3; MLKL , mixed lineage kinase domain like pseudokinase; SIRT1 , sirtuin 1; MT-CO3 , mitochondrially encoded cytochrome c oxidase III; V1, first visit (baseline); V last, last visit (week 12)

However, when we assessed cell necroptosis markers, we found that the expression of the RIPK3 gene was significantly reduced at the last visit compared to the first visit in the Vildagliptin group (median expression 1.14 vs. 1.97, P = 0.0156; Fig. 2 B) and placebo group (median expression 0.64 vs. 1.06, P = 0.0078; Fig. 2 B). The second marker of necroptosis, MLKL , was similarly expressed at both groups’ first and last visits ( P > 0.05; Fig. 2 B).

We also assessed two genes, SIRT1 and mitochondrially encoded MT-CO3 , which are crucial in cells’ energy metabolism. There were no differences between the first and last visits in both groups’ expression of these two genes ( P > 0.05; Fig. 2 C).

Expression of autophagy end mitophagy markers

We assessed the differential gene expression of two autophagy markers, ATG7 and NUP62 . The ATG7 gene was similarly expressed in the Vildagliptin and placebo groups at the first and last visits ( P > 0.05; Fig. 3 A). However, when we assessed the second autophagy marker NUP62 , we found that this gene was significantly downregulated at the last visit compared to the first visit in the Vildagliptin group (median expression 0.57 vs. 1.28, P = 0.0234; Fig. 3 A), representing ~ 55% reduction in the relative expression. However, this reduction at last compared with the first visit was not found in the placebo group (median expression 1.61 vs. 1.48, P = 0.9102; Fig. 3 A).

Expression of autophagy and mitophagy markers in patients with and without Vildagliptin treatment. Data show significant downregulation of the autophagy marker NUP62 in Vildagliptin but not in the placebo group (A) and similar expression of mitophagy markers PINK1 and PRKN in both groups (B) . The median (bold horizontal line) and interquartile range (whiskers) are shown. Statistical significance was determined using the paired Wilcoxon signed rank. ATG7 , autophagy related 7; NUP62 , nucleoporin 62; PINK1 , PTEN induced kinase 1; PRKN , parkin RBR E3 ubiquitin protein ligase; V1, first visit (baseline); V last, last visit (week 12)

When we assessed the differential gene expression of two cell mitophagy markers, PINK1 and PRKN , both genes were similarly expressed in the Vildagliptin and placebo groups at the first and last visits ( P > 0.05; Fig. 3 B).

Expression of Yamanaka factors

We assessed the differential gene expression of four Yamanaka pluripotency factors, which play a critical role in cellular plasticity. All transcription factors were similarly expressed in the Vildagliptin and placebo groups at the first and last visits ( P > 0.05; Fig. 4 ).

Expression of pluripotency Yamanaka factors in patients with and without Vildagliptin treatment. Data show similar expressions of all four Yamanaka factors in both Vildagliptin and placebo groups. The median (bold horizontal line) and interquartile range (whiskers) are shown. Statistical significance was determined using the paired Wilcoxon signed rank. POU5F1 ( OCT3/4 ), POU class 5 homeobox 1; SOX2 , SRY-box transcription factor 2; KLF4 , KLF transcription factor 4; MYC , MYC proto-oncogene, bHLH transcription factor. V1, first visit (baseline); V last, last visit (week 12)

DFUs are often challenging to treat, and these wounds can become stagnant even if the best available treatment is provided. Previous research has shown that medications primarily used to control blood sugar levels, such as DPP4i(s), may help heal DFUs [ 12 ]. Consistent with these findings, our last study of diabetic patients with DFU found that DPP4i Vildagliptin improved healing by approximately 35% compared to placebo [ 6 ]. Therefore, we investigated the molecular mechanisms by which Vildagliptin might promote wound healing.

Diabetes mellitus may lead to various microangiopathies, including DFUs, often due to undergoing endothelial cell (EC) dysfunction [ 13 , 14 ]. Interestingly, DPP-4i(s), including Vildagliptin, was found to protect from EC dysfunction [ 15 ]. Perhaps, even more importantly, the protective effect is seen even in a normoglycemic context where Vildagliptin attenuates EC dysfunction in a non-diabetic mouse model [ 16 ]. This significant finding suggests that Vildagliptin may also affect cellular processes beyond its canonical inhibition of DPP-4. To further elucidate these findings, we assessed the differential expression of selected genes critically involved in essential cellular functions, some of which were evaluated previously and sometimes in different contexts. For example, Pujadas and colleagues previously reported that another DPP4i, Teneligliptin, increases the proliferation of human umbilical vein endothelial cells (HUVEC) exposed to hyperglycemia [ 17 ]. However, we did not find any effect of DPP-4i Vildagliptin on levels of cell proliferation markers in wound fluid obtained from diabetic patients with DFU. Likewise, it is indicative that DPP4i(s) might attenuate EC senescence in vitro and animal models [ 18 , 19 ]. Still, we did not find a similar effect of Vildagliptin on the expression of senescence markers in DFU wound fluid in our patients.

Nevertheless, Zhao and colleagues reported that the DPP4 enzyme promotes EC apoptosis and autophagy [ 20 ]. Although vildagliptin did not affect the expression of apoptotic markers in our context, our findings suggest that it attenuates autophagy. This is consistent with a study by Zhao and colleagues [ 20 ]. Our results showed that Vildagliptin treatment for 12 weeks resulted in a more than twofold reduction in the mRNA levels of the autophagy marker nucleoporin 62 ( NUP62 or p62 ) in the DFU wound fluid. Autophagy is an essential physiological cell self-renewal process; however, if in excess, it can trigger so-called autophagic cell death due to excessive degradation of cellular content [ 21 , 22 ]. The effect of vildagliptin on NUP62/p62 mRNA levels may be due to its ability to control blood sugar levels, which indirectly affects autophagy. When cells are exposed to a high concentration of glucose, the level of O-linked N-acetylglucosamine (O-GlcNAc) modification of the p62 nucleoporin increases [ 23 ]. Nucleoporins, including p62, are constitutively O-GlcNAcylated [ 24 ]. These modifications protect them from ubiquitination, thus proteasomal degradation [ 24 ], a hallmark of autophagy [ 9 ]. Indeed, p62 is a receptor for intracellular cargo to be degraded by autophagy, including ubiquitinated proteins [ 25 , 26 ]. Hence, p62 is used as an autophagy marker.

An intriguing and somewhat unexpected finding emerged regarding the necroptosis marker RIPK3 . After twelve weeks, RIPK3 levels significantly decreased in the wound fluid of DFU patients from both the Vildagliptin and placebo arms. Necroptosis is often seen as harmful to wound healing because of its pro-inflammatory nature [ 27 ]. However, the decrease in a necroptosis marker in both groups, although not completely understood, may suggest reduced inflammation within DFU, possibly creating a more favorable environment for healing. It is worth noting that there was a slightly higher rate of DFU improvement in the Vildagliptin group (8 out of 8 patients) compared to the placebo group (6 out of 9 patients) at the end of the study. This finding warrants further investigation into the interplay between RIPK3 and Vildagliptin’s mechanism of action in wound healing.

Furthermore, this study establishes the utility of filter paper absorption for collecting wound fluid samples to monitor multiple healing biomarkers within DFU. This minimally invasive method provides biological material for detecting local changes that might not be reflected in the circulation [ 6 ].

Our study has limitations. Due to the primary clinical use of DFU wound fluid, we could only collect samples from a relatively small group of patients ( N = 17) who completed the 12-week treatment. While filter paper absorption is a patient-friendly method, it yields a lower sample volume than aspiration techniques. This limited volume necessitated qPCR, a highly sensitive method ideal for small samples. However, this approach focuses on gene expression and may not capture protein levels exactly. Despite these limitations, we could comprehensively evaluate 18 genes related to six critical cellular processes. Future studies with larger sample sizes could be more focused now and further substantiate our findings by incorporating protein testing methods. Second, given the filter paper absorption sampling, we expected more subtle differences in molecular marker expression within the collected samples because the DFUs had only partially closed by week 12. Finally, it is essential to note that wound fluid composition is complex and includes genetic material from various resident cell types, not just endothelial cells. Despite these limitations, our data provide valuable molecular insights into the ongoing processes within DFUs during the systemic administration of Vildagliptin.

Conclusions

Building upon previous evidence of Vildagliptin’s effectiveness in glycemic control and DFU healing, our study sheds light on a potential mechanism - autophagy modulation. We observed that Vildagliptin treatment influenced autophagy-related gene expression in DFU wound fluid, suggesting a novel pathway for its wound healing properties. While these findings are promising, further research is required to substantiate and expand these results.

Data availability

Data is provided within the manuscript.

Collaborators GBDD. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the global burden of Disease Study 2021. Lancet. 2023;402(10397):203–34.

Article Google Scholar

Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005;293(2):217–28.

Article CAS PubMed Google Scholar

Ikura K, et al. HDL cholesterol as a predictor for the incidence of lower extremity amputation and wound-related death in patients with diabetic foot ulcers. Atherosclerosis. 2015;239(2):465–9.

Baig MS et al. An overview of Diabetic Foot Ulcers and Associated problems with special emphasis on treatments with antimicrobials. Life (Basel), 2022. 12(7).

Thi Bui DH, et al. Polypharmacy among people living with type 2 diabetes mellitus in rural communes in Vietnam. PLoS ONE. 2021;16(4):e0249849.

Article CAS PubMed PubMed Central Google Scholar

Vangaveti VN, et al. Effects of vildagliptin on wound healing and markers of inflammation in patients with type 2 diabetic foot ulcer: a prospective, randomized, double-blind, placebo-controlled, single-center study. Diabetol Metab Syndr. 2022;14(1):183.

Ahren B, Foley JE. The islet enhancer vildagliptin: mechanisms of improved glucose metabolism. Int J Clin Pract Suppl, 2008(159): p. 8–14.

Panina G. The DPP-4 inhibitor vildagliptin: robust glycaemic control in type 2 diabetes and beyond. Diabetes Obes Metab. 2007;9(Suppl 1):32–9.

Galluzzi L, et al. Molecular definitions of autophagy and related processes. EMBO J. 2017;36(13):1811–36.

Darling JD, et al. Predictive ability of the Society for Vascular Surgery Wound, ischemia, and foot infection (WIfI) classification system after first-time lower extremity revascularizations. J Vasc Surg. 2017;65(3):695–704.

Article PubMed PubMed Central Google Scholar

Cai L, et al. The efficacy and safety of vildagliptin in patients with type 2 diabetes: a meta-analysis of randomized clinical trials. J Clin Pharm Ther. 2012;37(4):386–98.

Marfella R, et al. Dipeptidyl peptidase 4 inhibition may facilitate healing of chronic foot ulcers in patients with type 2 diabetes. Exp Diabetes Res. 2012;2012:p892706.

Chao CY, Cheing GL. Microvascular dysfunction in diabetic foot disease and ulceration. Diabetes Metab Res Rev. 2009;25(7):604–14.

Huang X, et al. Resveratrol promotes Diabetic Wound Healing via SIRT1-FOXO1-c-Myc signaling pathway-mediated angiogenesis. Front Pharmacol. 2019;10:421.

Gao P, et al. Activation of Transient Receptor Potential Channel Vanilloid 4 by DPP-4 (Dipeptidyl Peptidase-4) inhibitor vildagliptin protects against Diabetic Endothelial Dysfunction. Hypertension. 2020;75(1):150–62.

Aini K, et al. Vildagliptin, a DPP-4 inhibitor, attenuates endothelial dysfunction and Atherogenesis in nondiabetic apolipoprotein E-Deficient mice. Int Heart J. 2019;60(6):1421–9.

Pujadas G, et al. The dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin functions as antioxidant on human endothelial cells exposed to chronic hyperglycemia and metabolic high-glucose memory. Endocrine. 2017;56(3):509–20.

Chen Z, et al. Dipeptidyl peptidase-4 inhibition improves endothelial senescence by activating AMPK/SIRT1/Nrf2 signaling pathway. Biochem Pharmacol. 2020;177:113951.

Oeseburg H, et al. Glucagon-like peptide 1 prevents reactive oxygen species-induced endothelial cell senescence through the activation of protein kinase A. Arterioscler Thromb Vasc Biol. 2010;30(7):1407–14.

Zhao X, et al. Long noncoding RNA CA7-4 promotes autophagy and apoptosis via sponging MIR877-3P and MIR5680 in high glucose-induced vascular endothelial cells. Autophagy. 2020;16(1):70–85.

Lerena C, Calligaris SD, Colombo MI. Autophagy: for better or for worse, in good times or in bad times. Curr Mol Med. 2008;8(2):92–101.

Wirawan E, et al. Autophagy: for better or for worse. Cell Res. 2012;22(1):43–61.

Han I, Oh ES, Kudlow JE. Responsiveness of the state of O-linked N-acetylglucosamine modification of nuclear pore protein p62 to the extracellular glucose concentration. Biochem J. 2000;350(Pt 1):109–14.

Zhu Y, et al. Post-translational O-GlcNAcylation is essential for nuclear pore integrity and maintenance of the pore selectivity filter. J Mol Cell Biol. 2016;8(1):2–16.

Pankiv S, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007;282(33):24131–45.

Gatica D, Lahiri V, Klionsky DJ. Cargo recognition and degradation by selective autophagy. Nat Cell Biol. 2018;20(3):233–42.

Ye K, Chen Z, Xu Y. The double-edged functions of necroptosis. Cell Death Dis. 2023;14(2):163.

Download references

Acknowledgements

Not applicable.

We acknowledge the financial contribution of Novartis Australia for this study.

Author information

Authors and affiliations.

Translational Research in Endocrinology and Diabetes, College of Medicine and Dentistry, James Cook University, 1 James Cook Drive, Townsville, QLD, 4811, Australia

Erik Biros, Venkat Vangaveti & Usman Malabu

Townsville University Hospital, Townsville, Australia

Erik Biros & Venkat Vangaveti

Department of Diabetes and Endocrinology, Townsville University Hospital, Townsville, Australia

Usman Malabu

You can also search for this author in PubMed Google Scholar

Contributions

E.B., V.V., and U.M. conceptualized the work. E.B. performed gene expression analysis. E.B. and V.V. performed formal statistical analysis. E.B. wrote the main manuscript text. All authors reviewed the manuscript.

Corresponding author

Correspondence to Erik Biros .

Ethics declarations

Ethical approval.

The study protocol, informed consent form, and case report form (CRF) have been approved by an independent human research ethics committee (HREC) located at the Townsville Hospital and Health Service (THHS) under the registration number HREC/13/QTHS/65.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note.

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ .

Reprints and permissions

About this article

Cite this article.

Biros, E., Vangaveti, V. & Malabu, U. Vildagliptin promotes diabetic foot ulcer healing through autophagy modulation. Diabetol Metab Syndr 16 , 204 (2024). https://doi.org/10.1186/s13098-024-01444-3

Download citation

Received : 21 June 2024

Accepted : 09 August 2024

Published : 22 August 2024

DOI : https://doi.org/10.1186/s13098-024-01444-3

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Diabetic foot ulcer
Vildagliptin
Wound fluid
Wound healing

Diabetology & Metabolic Syndrome

ISSN: 1758-5996

Submission enquiries: [email protected]

IMAGES

(PDF) Optimization and Validation of HPLC Method for Simultaneous
(PDF) A VALIDATED RP-HPLC METHOD FOR SIMULTANEOUS DETERMINATION OF
Vildagliptin treatment improved learning and memory in the diabetic rat
VILDAGLIPTIN « New Drug Approvals
(PDF) A 16-week study to compare the effect of vildagliptin versus
(PDF) Efficacy of vildagliptin in combination with insulin in patients

VIDEO

Dr. Piyush Desai: Vildagliptin: The Pioneer Gliptin
Vildagard M tablet || Vildagliptin+Metformin combination tablet for diabetes patients
Vildagard Tablet
Unprecedented Reno-protective benefits of Dapagliflozin & Vildagliptin in T2DM management
vildagliptin and metformin hydrochloride /vildagliptin metformin 50/500/ vidalip m/
How To Say Vildagliptin

COMMENTS

Efficacy of a Combination of Metformin and Vildagliptin in Comparison
The various treatment-related attributes at follow-up visit are depicted in Table 2.Significantly greater reduction in HbA1c level was observed in metformin plus vildagliptin arm in comparison to metformin only arm (median: −0.5% vs 0%, respectively; p<0.001).Reduction in HbA1c level was slightly higher in males as compared to females in the combination group (males vs females: −0.6% vs ...
Profile of vildagliptin in type 2 diabetes: efficacy, safety, and
Vildagliptin posed a low risk of hypoglycemia when combined with pioglitazone or insulin,44,46,47 and the weight gain was more apparent in the vildagliptin/insulin group.46. Long-term benefit of vildagliptin. Vildagliptin showed long-term benefit for type 2 diabetes by preserving β-cell function and normalizing the lipid profile.
Effects of Vildagliptin on Glucose Control Over 24 Weeks in Patients
OBJECTIVE—We sought to evaluate the efficacy and safety of vildagliptin, a new dipeptidyl peptidase-4 inhibitor, added to metformin during 24 weeks of treatment in patients with type 2 diabetes.. RESEARCH DESIGN AND METHODS—This was a double-blind, randomized, multicenter, parallel group study of a 24-week treatment with 50 mg vildagliptin daily (n = 177), 100 mg vildagliptin daily (n ...
Expert eValuation of Efficacy and Rationality of Vildagliptin "EVER
Combining vildagliptin with low-dose metformin (−1.6%) may provide equivalent or superior HbA1c lowering without GI tolerability issues associated with higher doses of metformin (−1.8%). 16 A meta-analysis revealed that exenatide + metformin and vildagliptin + metformin had better efficacy in improving insulin sensitivity in T2DM patients ...
Clinical Safety and Tolerability of Vildagliptin
The introduction of vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, for the treatment of type 2 diabetes mellitus (T2DM) in 2007 provided clinicians with a novel and effective treatment option for lowering blood glucose, which neither caused weight gain nor increased the risk of hypoglycaemia. 1,2 However, looking back on early development, there were theoretical apprehensions ...
Vildagliptin: the evidence for its place in the treatment of type 2
Evidence review: Clear evidence shows that vildagliptin improves glycemic control (measured by glycosylated hemoglobin and blood glucose levels) more than placebo in adults with type 2 diabetes, either as monotherapy or in combination with metformin. Vildagliptin is as effective as pioglitazone and rosiglitazone, and slightly less effective ...
Vildagliptin: a new oral treatment for type 2 diabetes mellitus
Vildagliptin is a new oral antidiabetic agent that enhances pancreatic islet cell responsiveness to glucose. An extensive clinical program involving approximately 22,000 patients and 7000 patient-years of exposure to vildagliptin has shown that the agent is well tolerated and efficacious in improving glycemic control in patients with type 2 diabetes mellitus (T2DM).
Glycaemic durability of an early combination therapy with vildagliptin
The Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY) study was therefore designed as a 5-year efficacy and safety study, comparing an early combination therapy of metformin plus dipeptidyl peptidase-4 inhibitor vildagliptin with standard-of-care metformin monotherapy, defined as a traditional ...
Efficacy and Safety of a Fixed-Dose Combination of Vildagliptin and
Background Type 2 diabetes mellitus (T2DM) arises due to a range of pathological abnormalities, necessitating a combination therapy to achieve optimal glycemic control. Vildagliptin, an effective and selective DPP-4 inhibitor, and pioglitazone, an insulin sensitizer, offer distinct mechanisms of act …
Vildagliptin in clinical practice: a review of literature
Vildagliptin is the second member of the DPP-IV inhibitor class of drugs licensed for the treatment of type 2 diabetes mellitus (T2DM). The novel action of these drugs has promoted a new outlook in the pathobiology of T2DM. This review undertakes to examine the clinical studies published to date, wi …
Glycaemic durability of an early combination therapy with vildagliptin
Early intervention with a combination therapy of vildagliptin plus metformin provides greater and durable long-term benefits compared with the current standard-of-care initial metformin monotherapy for patients with newly diagnosed type 2 diabetes.
Sustained-Release Vildagliptin 100 mg in Type 2 Diabetes Mellitus: A
Vildagliptin is an effective and well-tolerated molecule throughout the diabetes continuum. Studies performed in India show its efficacy and safety in the presence of other comorbidities and diabetic complications, and across a spectrum of age groups. Both vildagliptin SR 100 mg QD and vildagliptin 50 mg BD showed similar DPP4 inhibition for 24 ...
Profile of vildagliptin in type 2 diabetes: efficacy, safety, and
Vildagliptin as an add-on therapy to metformin. Vildagliptin can work well with metformin. First, vildagliptin improves islet function by increasing the sensitivity of the α- and β-cells to glucose, Citation 25 whereas metformin reduces hepatic glucose and improves insulin resistance. Citation 31 It is rational to combine an agent primarily targeting insulin sensitivity within the pancreas ...
Cardiovascular safety and effectiveness of vildagliptin in patients
Vildagliptin has previously been shown not to inhibit the action of GIP, which is required to increase blood glucose levels during hypoglycemia [Citation 24], and data show that vildagliptin can prevent blood glucose fluctuations [Citation 25 - Citation 27]. These data support the suggestion that vildagliptin does not increase the risk of CV ...
Vasculoprotective Effects of Vildagliptin. Focus on Atherogenesis
Research suggests that vildagliptin is able to improve vasodilation in a variety of ways. In the van Poppel et al. (2011) study, 4 weeks of treatment with vildagliptin results in greater vasodilatation response to intra-arterially acetylcholine administration compared to acarbose . Acetylcholine stimulates endothelial muscarinic receptors ...
Method Development and Validation of Vildagliptin and Metformin HCl in
The percentage assay of vildagliptin was 98.06 % which showed good applicability. The following results indicate that the procedure is accurate, precise, and reproducible while being simple and ...
Vildagliptin: a new oral treatment for type 2 diabetes mellitus
Abstract. Vildagliptin is a new oral antidiabetic agent that enhances pancreatic islet cell responsiveness to glucose. An extensive clinical program involving approximately 22,000 patients and 7000 patient-years of exposure to vildagliptin has shown that the agent is well tolerated and efficacious in improving glycemic control in patients with type 2 diabetes mellitus (T2DM).
Data on vildagliptin and vildagliptin plus metformin combination in
According to the Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study, age, male sex, obesity, hypertension, and family history of diabetes were the independent risk factors for diabetes in both urban and rural areas. ... Vildagliptin and metformin combination was used in more than 70% of the study population. The HbA1c ...
Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes
Vildagliptin decreased HbA 1c levels in patients with poorly controlled type 2 diabetes with high doses of insulin, 62 and vildagliptin has also been reported to be beneficial for decreasing post-meal glucagon excursion in insulinopenic patients with type 1 diabetes; this effect was not secondary to a change in endogenous insulin secretion. 63 ...
Vildagliptin promotes diabetic foot ulcer healing through autophagy
The study aimed to investigate the molecular mechanisms underlying the effects of Vildagliptin on the healing of diabetic foot ulcers (DFUs). The research compared patients who received 12 weeks of Vildagliptin treatment to those who did not. Various molecular markers associated with wound healing were measured. Wound fluid samples were collected from DFUs using a filter paper absorption ...
Efficacy of a Combination of Metformin and Vildagliptin in Comparison
Background: Early use of combination therapy in diabetes patients may lead to sustained glycemic control and thereby reduce the progression of diabetic complications.

Vildagliptin in clinical practice: a review of literature

Publication types

Data on vildagliptin and vildagliptin plus metformin combination in type-2 diabetes mellitus management

Study population:

Statistical analysis:

Table 1. Patient demographics and treatment related observations.

Table 3. Observations related to weight alterations, glycemic control, and adverse events.

Table 4. Treatment wise patient demographics observations.

Acknowledgments

Similar articles

Add to Collections

Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes

Introduction

Chemistry of teneligliptin

Metabolism and excretion

Clinical use

Effects of teneligliptin on glycemic parameters

Effects on blood glucose level

Effects on insulin

Effects on glucagon

Pharmacokinetic and pharmacodynamic properties of teneligliptin

Safety and tolerability

Long-term effects on glycemic control

Effects of teneligliptin on lipid profiles

Teneligliptin and renal impairment

Teneligliptin and hepatic impairment

Influence on body weight

Gliptins in combination with other oral antidiabetic agents

Gliptin treatments in combination with insulin

Case presentation

Acknowledgment

Similar articles

Add to Collections

Vildagliptin promotes diabetic foot ulcer healing through autophagy modulation

Introduction

Materials and methods

Patients and wound fluid sample collection

Molecular markers

Gene expression

Statistical analysis

Patients characteristics

Differential changes in DFU surface area

Expression of cell proliferation and senescence markers

Expression of apoptosis, necroptosis, and cell energy metabolism markers

Expression of autophagy end mitophagy markers

Expression of Yamanaka factors

Conclusions

Data availability

Acknowledgements

Author information

Contributions

Corresponding author

Ethics declarations

Competing interests

Additional information

Electronic supplementary material

Supplementary Material 1

About this article

Share this article

Diabetology & Metabolic Syndrome

IMAGES

VIDEO

COMMENTS