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James E Foley - One of the best experts on this subject based on the ideXlab platform.
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Insights Into GLP-1 and GIP Actions Emerging From Vildagliptin Mechanism Studies in Man
Frontiers in Endocrinology, 2019Co-Authors: James E FoleyAbstract:Vildagliptin blocks glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) inactivation of the meal induced increases in GLP-1 and GIP so that elevated GLP-1 and GIP levels are maintained over 24 hours. The primary insulin secretion effect of Vildagliptin is to improve the impaired sensitivity of the β-cells to glucose in subjects with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and in patients with type 2 diabetes mellitus (T2DM); this effect was seen acutely and maintained over at least two years in patients with T2DM. Vildagliptin was also associated with improved β-cell function that is likely secondary to the improved metabolic state. Although there was no evidence of restoration of β-cell mass, the preponderance of the Vildagliptin data does indicate that for at least two years β-cell function was maintained in Vildagliptin treated patients but not in the untreated patients. Vildagliptin suppressed an inappropriate glucagon response to an oral glucose challenge in patients with T2DM, to a mixed meal challenge in patients with T2DM and type 1 diabetes mellitus, and to a mixed meal challenge in subjects with IGT and IFG. The improved glucagon response was maintained for at least 2 years in patients with T2DM and there was no change in the glucagon response in normoglycemic individuals. Vildagliptin lowered glucose levels into the normal range with increasing hypoglycemia but also appeared to protect against insulin therapy induced hypoglycemia. These hypoglycemic benefits appear to be secondary in large part to the improved sensitivity of both the β and α-cell to glucose. In the case of the α-cell, if glucose levels are high, GLP-1 attenuates the glucagon levels and if glucose levels are low, GIP increases glucagon levels. Vildagliptin reduces fatty acid flux from the adipocyte leading to reduced liver fat which in turn leads to increased glucose utilization. The reduced glycosuria and reduced lipo-toxicity associated with Vildagliptin therapy does not lead to weight gain presumably due to increased fat mobilization and oxidation during meals and to reduced fat extraction from the gut.
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quantification of the contribution of glp 1 to mediating insulinotropic effects of dpp 4 inhibition with Vildagliptin in healthy subjects and patients with type 2 diabetes using exendin 9 39 as a glp 1 receptor antagonist
Diabetes, 2016Co-Authors: Michael A Nauck, Yanling He, Lise Kjems, Jens J Holst, Carolyn F Deacon, Joachim Kind, Lars D Kothe, Matthias Broschag, James E FoleyAbstract:We wanted to quantify the contribution of GLP-1 as a mediator of therapeutic effects of DPP-4 inhibition (Vildagliptin), using the GLP-1 receptor antagonist exendin [9-39] in type 2 diabetic patients and in healthy subjects. 32 patients with type 2 diabetes and 29 age- and weight-matched healthy control subjects were treated, in randomized order, with 100 mg q.d. Vildagliptin or placebo for 10 days. Meal tests were performed (days 9 and 10), without and with a high dose intravenous infusion of exendin [9-39]. The main endpoint was the ratio of integrated insulin secretion rates (total AUC ISR ) and total AUC glucose over 4 h following the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and GIP and lowered glucose responses without changing AUC ISR /AUC glucose in healthy subjects. Vildagliptin significantly increased this ratio by 10.5 % in type 2-diabetic patients and exendin [9-39] reduced it (both p ISR /AUC glucose ratio achieved with exendin [9-39] was significantly smaller after Vildagliptin than after placebo treatment (p = 0.026) and was equivalent to 47 ± 5% of the increments due to Vildagliptin. Thus, other mediators appear to contribute significantly to the therapeutic effects of DPP-4 inhibition.
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Vildagliptin-insulin combination improves glycemic control in Asians with type 2 diabetes.
World Journal of Diabetes, 2013Co-Authors: Plamen Kozlovski, James E Foley, Valentina Lukashevich, Q Shao, Wolfgang KothnyAbstract:AIM: To assess the efficacy and safety of Vildagliptin 50 mg bid as add-on therapy to insulin in Asian patients with type 2 diabetes mellitus (T2DM). METHODS: This was a post hoc analysis of a subgroup of Asian patients from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in T2DM patients inadequately controlled by stable insulin therapy, with or without metformin. A total of 173 patients were randomized 1:1 to receive treatment with Vildagliptin 50 mg bid (n = 87) or placebo (n = 86) for 24 wk. Changes in HbA1c and fasting plasma glucose (FPG), from baseline to study endpoint, were analyzed using an analysis of covariance model. Change from baseline to endpoint in body weight was summarized by treatment. Safety and tolerability of Vildagliptin was also evaluated. RESULTS: After 24 wk, the difference in adjusted mean change in HbA1c between Vildagliptin and placebo was 0.82% (8.96 mmol/mol; P < 0.001) in Asian subgroup, 0.85% (9.29 mmol/mol; P < 0.001) in patients also receiving metformin, and 0.73% (7.98 mmol/mol; P < 0.001) in patients without metformin, all in favor of Vildagliptin. There was no significant difference in the change in FPG between treatments. Weight was stable in both treatment groups (+0.3 kg and -0.2 kg, for Vildagliptin and placebo, respectively). Overall, Vildagliptin was safe and well tolerated with similarly low incidences of hypoglycemia (8.0% vs 8.1%) and no severe hypoglycemic events were experienced in either group. CONCLUSION: In Asian patients inadequately controlled with insulin (with or without concomitant metformin), insulin-Vildagliptin combination treatment significantly reduced HbA1c compared with placebo, without an increase in risk of hypoglycemia or weight gain.
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improved glycaemic control with Vildagliptin added to insulin with or without metformin in patients with type 2 diabetes mellitus
Diabetes Obesity and Metabolism, 2013Co-Authors: Wolfgang Kothny, James E Foley, Q Shao, Plamen Kozlovski, Baptist Gallwitz, Valentina LukashevichAbstract:Aim The aim of this study is to assess the efficacy and safety of Vildagliptin 50 mg bid as add-on therapy to insulin in type 2 diabetes mellitus (T2DM). Methods This is a multicentre, double-blind, placebo-controlled, parallel group, clinical trial in T2DM patients inadequately controlled by stable insulin therapy, with or without metformin. Patients received treatment with Vildagliptin 50 mg bid or placebo for 24 weeks. Results In all, 449 patients were randomized to Vildagliptin (n = 228) or placebo (n = 221). After 24 weeks, the difference in adjusted mean change in haemoglobin A1c (HbA1c) between Vildagliptin and placebo was −0.7 ± 0.1% (p < 0.001) in the overall study population, −0.6 ± 0.1% (p < 0.001) in the subgroup also receiving metformin and −0.8 ± 0.2% (p < 0.001) in the subgroup without metformin. Vildagliptin therapy was well tolerated and had a similarly low incidence of hypoglycaemia compared with placebo (8.4 vs. 7.2%, p = 0.66) in spite of improved glycaemic control, and was not associated with weight gain. (+0.1 vs. −0.4 kg). Conclusions Vildagliptin 50 mg bid added to insulin significantly reduced HbA1c in patients with T2DM inadequately controlled by insulin, with or without metformin. Vildagliptin was well tolerated, with a safety profile similar to placebo. These results were achieved without weight gain or an increase in hypoglycaemia incidence or severity in spite of improved glycaemic control.
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clinical evidence and mechanistic basis for Vildagliptin s effect in combination with insulin
Vascular Health and Risk Management, 2013Co-Authors: Anja Schweizer, James E Foley, Wolfgang Kothny, Bo AhrenAbstract:Due to the progressive nature of type 2 diabetes, many patients need insulin as add-on to oral antidiabetic drugs (OADs) in order to maintain adequate glycemic control. Insulin therapy primarily targets elevated fasting glycemia but is less effective to reduce postprandial hyperglycemia. In addition, the risk of hypoglycemia limits its effectiveness and there is a concern of weight gain. These drawbacks may be overcome by combining insulin with incretin-based therapies as these increase glucose sensitivity of both the α- and β-cells, resulting in improved postprandial glycemia without the hypoglycemia and weight gain associated with increasing the dose of insulin. The dipeptidyl peptidase-IV (DPP-4) inhibitor Vildagliptin has also been shown to protect from hypoglycemia by enhancing glucagon counterregulation. The effectiveness of combining Vildagliptin with insulin was demonstrated in three different studies in which Vildagliptin decreased A1C levels when added to insulin therapy without increasing hypoglycemia. This was established with and without concomitant metformin therapy. Furthermore, the effectiveness of Vildagliptin appears to be greater when insulin is used as a basal regimen as opposed to being used to reduce postprandial hyperglycemia, since improvement in insulin secretion likely plays a minor role when relatively high doses of insulin are administered before meals. This article reviews the clinical experience with the combination of Vildagliptin and insulin and discusses the mechanistic basis for the beneficial effects of the combination. The data support the use of Vildagliptin in combination with insulin in general and, in line with emerging clinical practice, suggest that treating patients with Vildagliptin, metformin, and basal insulin could be an attractive therapeutic option.
Anja Schweizer - One of the best experts on this subject based on the ideXlab platform.
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cardiovascular and heart failure safety profile of Vildagliptin a meta analysis of 17 000 patients
Diabetes Obesity and Metabolism, 2015Co-Authors: G Mcinnes, Valentina Lukashevich, S Del Prato, Anja Schweizer, Q Shao, Marc Evans, Michael Stumvoll, Wolfgang KothnyAbstract:Aims To report the cardiovascular (CV) safety profile and heart failure (HF) risk of Vildagliptin from a large pool of studies, including trials in high-risk patients with type 2 diabetes mellitus (T2DM), such as those with congestive HF and/or moderate/severe renal impairment. Methods We conducted a retrospective meta-analysis of prospectively adjudicated CV events. Patient-level data were pooled from 40 double-blind, randomized controlled phase III and IV Vildagliptin studies. The primary endpoint was occurrence of major adverse CV events (MACEs; myocardial infarction, stroke and CV death). Assessments of the individual MACE components and HF events (requiring hospitalization or new onset) were secondary endpoints. The risk ratio (RR) of Vildagliptin (50 mg once- and twice-daily combined) versus comparators (placebo and all non-Vildagliptin treatments) was calculated using the Mantel–Haenszel (M–H) method. Results Of the 17 446 patients, 9599 received Vildagliptin (9251.4 subject-years of exposure) and 7847 received comparators (7317.0 subject-years of exposure). The mean age of the patients was 57 years, body mass index 30.5 kg/m2 (nearly 50% obese), glycated haemoglobin concentration 8.1% and T2DM duration 5.5 years. A MACE occurred in 83 (0.86%) Vildagliptin-treated patients and 85 (1.20%) comparator-treated patients, with an M-H RR of 0.82 [95% confidence interval (CI) 0.61–1.11]. Similar RRs were observed for the individual events. Confirmed HF events were reported in 41 (0.43%) Vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with an M–H RR 1.08 (95% CI 0.68–1.70). Conclusions This large meta-analysis indicates that Vildagliptin is not associated with an increased risk of adjudicated MACEs relative to comparators. Moreover, this analysis did not find a significant increased risk of HF in Vildagliptin-treated patients.
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Cardiovascular and heart failure safety profile of Vildagliptin: a meta‐analysis of 17 000 patients
Diabetes Obesity and Metabolism, 2015Co-Authors: G Mcinnes, Valentina Lukashevich, S Del Prato, Anja Schweizer, Q Shao, Marc Evans, Michael Stumvoll, Wolfgang KothnyAbstract:Aims To report the cardiovascular (CV) safety profile and heart failure (HF) risk of Vildagliptin from a large pool of studies, including trials in high-risk patients with type 2 diabetes mellitus (T2DM), such as those with congestive HF and/or moderate/severe renal impairment. Methods We conducted a retrospective meta-analysis of prospectively adjudicated CV events. Patient-level data were pooled from 40 double-blind, randomized controlled phase III and IV Vildagliptin studies. The primary endpoint was occurrence of major adverse CV events (MACEs; myocardial infarction, stroke and CV death). Assessments of the individual MACE components and HF events (requiring hospitalization or new onset) were secondary endpoints. The risk ratio (RR) of Vildagliptin (50 mg once- and twice-daily combined) versus comparators (placebo and all non-Vildagliptin treatments) was calculated using the Mantel–Haenszel (M–H) method. Results Of the 17 446 patients, 9599 received Vildagliptin (9251.4 subject-years of exposure) and 7847 received comparators (7317.0 subject-years of exposure). The mean age of the patients was 57 years, body mass index 30.5 kg/m2 (nearly 50% obese), glycated haemoglobin concentration 8.1% and T2DM duration 5.5 years. A MACE occurred in 83 (0.86%) Vildagliptin-treated patients and 85 (1.20%) comparator-treated patients, with an M-H RR of 0.82 [95% confidence interval (CI) 0.61–1.11]. Similar RRs were observed for the individual events. Confirmed HF events were reported in 41 (0.43%) Vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with an M–H RR 1.08 (95% CI 0.68–1.70). Conclusions This large meta-analysis indicates that Vildagliptin is not associated with an increased risk of adjudicated MACEs relative to comparators. Moreover, this analysis did not find a significant increased risk of HF in Vildagliptin-treated patients.
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clinical evidence and mechanistic basis for Vildagliptin s effect in combination with insulin
Vascular Health and Risk Management, 2013Co-Authors: Anja Schweizer, James E Foley, Wolfgang Kothny, Bo AhrenAbstract:Due to the progressive nature of type 2 diabetes, many patients need insulin as add-on to oral antidiabetic drugs (OADs) in order to maintain adequate glycemic control. Insulin therapy primarily targets elevated fasting glycemia but is less effective to reduce postprandial hyperglycemia. In addition, the risk of hypoglycemia limits its effectiveness and there is a concern of weight gain. These drawbacks may be overcome by combining insulin with incretin-based therapies as these increase glucose sensitivity of both the α- and β-cells, resulting in improved postprandial glycemia without the hypoglycemia and weight gain associated with increasing the dose of insulin. The dipeptidyl peptidase-IV (DPP-4) inhibitor Vildagliptin has also been shown to protect from hypoglycemia by enhancing glucagon counterregulation. The effectiveness of combining Vildagliptin with insulin was demonstrated in three different studies in which Vildagliptin decreased A1C levels when added to insulin therapy without increasing hypoglycemia. This was established with and without concomitant metformin therapy. Furthermore, the effectiveness of Vildagliptin appears to be greater when insulin is used as a basal regimen as opposed to being used to reduce postprandial hyperglycemia, since improvement in insulin secretion likely plays a minor role when relatively high doses of insulin are administered before meals. This article reviews the clinical experience with the combination of Vildagliptin and insulin and discusses the mechanistic basis for the beneficial effects of the combination. The data support the use of Vildagliptin in combination with insulin in general and, in line with emerging clinical practice, suggest that treating patients with Vildagliptin, metformin, and basal insulin could be an attractive therapeutic option.
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efficacy of Vildagliptin in combination with insulin in patients with type 2 diabetes and severe renal impairment
Vascular Health and Risk Management, 2013Co-Authors: Valentina Lukashevich, James E Foley, Anja Schweizer, Sheila Dickinson, Perhenrik Groop, Wolfgang KothnyAbstract:BACKGROUND: The purpose of this study was to evaluate the efficacy of Vildagliptin 50 mg once daily in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m(2)) and longstanding type 2 diabetes not adequately controlled with insulin therapy, which is a difficult-to-treat population, with limited therapeutic options and a high susceptibility to hypoglycemia. METHODS: This was a post hoc subanalysis of data obtained during a previously described randomized, double-blind, parallel-group, 24-week study comparing the efficacy and safety of Vildagliptin 50 mg once daily versus placebo in patients with type 2 diabetes and moderate or severe renal impairment. The present data derive from 178 patients with severe renal impairment (baseline estimated glomerular filtration rate approximately 21 mL/min/1.73 m(2), 100 randomized to Vildagliptin, 78 randomized to placebo), all of whom were receiving insulin therapy (alone or in combination with an oral antidiabetic agent) for longstanding type 2 diabetes (mean approximately 19 years). RESULTS: With Vildagliptin in combination with insulin, the adjusted mean change (AMΔ) in HbA(1c) from baseline (7.7% ± 0.1%) was -0.9% ± 0.4% and the between-treatment difference (Vildagliptin - placebo) was -0.6% ± 0.2% (P < 0.001). The percentage of patients achieving endpoint HbA(1c) < 7.0% was significantly higher with Vildagliptin than placebo (45.2% versus 22.8%, P = 0.008). When added to insulin, Vildagliptin and placebo had comparable hypoglycemic profiles and did not cause weight gain. Both treatments were similarly well tolerated, with comparable incidences of adverse events, serious adverse events, and deaths. CONCLUSION: When added to insulin therapy in patients with severe renal impairment and longstanding type 2 diabetes, Vildagliptin 50 mg once daily was efficacious, eliciting HbA(1c) reductions consistent with those previously reported for a patient population with much more recent onset of type 2 diabetes and normal renal function, and had a hypoglycemic profile comparable with placebo. Accordingly, Vildagliptin is a suitable treatment option for patients with advanced type 2 diabetes and impaired renal function who require insulin therapy and present a serious therapeutic challenge in clinical practice.
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Evidence to support the use of Vildagliptin monotherapy in the treatment of type 2 diabetes mellitus.
Vascular Health and Risk Management, 2012Co-Authors: Sylvie Dejager, Anja Schweizer, James E FoleyAbstract:The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, Vildagliptin, as monotherapy have been widely confirmed in a large body of clinical studies of up to 2 years’ duration in various populations with type 2 diabetes mellitus. This paper reviews the data supporting the use of Vildagliptin in monotherapy. Consideration based on baseline glycated hemoglobin levels and age is given to patient segments where metformin is not appropriate. In addition, although prediabetes is not an indication, this manuscript briefly reviews some of the existing data showing that the mechanisms at work in diabetic populations are active in patients currently classified as prediabetic, with impaired glucose tolerance or impaired fasting glucose. Finally, the rationale for Vildagliptin dosing frequency in monotherapy is discussed. In summary, this review aims to define where in community practice the use of Vildagliptin as monotherapy is most desirable, focusing on segments of the population with type 2 diabetes mellitus that might receive the greatest benefit from Vildagliptin in the management of their disease.
S Dejager - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of action of the dipeptidyl peptidase 4 inhibitor Vildagliptin in humans
Diabetes Obesity and Metabolism, 2011Co-Authors: Bo Ahren, S Dejager, Anja Schweizer, Edwin Bernard Villhauer, B E Dunning, James E FoleyAbstract:Inhibition of dipeptidyl peptidase-4 (DPP-4) by Vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycemia in type 2 diabetes, with low risk for hypoglycemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and to inhibit glucagon secretion in a glucose-dependent manner. At hypoglycemic levels, the counterregulatory glucagon response is enhanced relative to baseline by Vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycemia with low risk for hypoglycemia. Vildagliptin also suppresses postprandial triglyceride-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced triglyceride stores in non-fat tissues. The large body of knowledge on Vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.
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assessing the general safety and tolerability of Vildagliptin value of pooled analyses from a large safety database versus evaluation of individual studies
Vascular Health and Risk Management, 2011Co-Authors: Anja Schweizer, James E Foley, S Dejager, Wolfgang KothnyAbstract:AIM: Analyzing safety aspects of a drug from individual studies can lead to difficult-to-interpret results. The aim of this paper is therefore to assess the general safety and tolerability, including incidences of the most common adverse events (AEs), of Vildagliptin based on a large pooled database of Phase II and III clinical trials. METHODS: Safety data were pooled from 38 studies of ≥ 12 to ≥ 104 weeks' duration. AE profiles of Vildagliptin (50 mg bid; N = 6116) were evaluated relative to a pool of comparators (placebo and active comparators; N = 6210). Absolute incidence rates were calculated for all AEs, serious AEs (SAEs), discontinuations due to AEs, and deaths. RESULTS: Overall AEs, SAEs, discontinuations due to AEs, and deaths were all reported with a similar frequency in patients receiving Vildagliptin (69.1%, 8.9%, 5.7%, and 0.4%, respectively) and patients receiving comparators (69.0%, 9.0%, 6.4%, and 0.4%, respectively), whereas drug-related AEs were seen with a lower frequency in Vildagliptin-treated patients (15.7% vs 21.7% with comparators). The incidences of the most commonly reported specific AEs were also similar between Vildagliptin and comparators, except for increased incidences of hypoglycemia, tremor, and hyperhidrosis in the comparator group related to the use of sulfonylureas. CONCLUSIONS: The present pooled analysis shows that Vildagliptin was overall well tolerated in clinical trials of up to >2 years in duration. The data further emphasize the value of a pooled analysis from a large safety database versus assessing safety and tolerability from individual studies.
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clinical experience with Vildagliptin in the management of type 2 diabetes in a patient population 75 years a pooled analysis from a database of clinical trials
Diabetes Obesity and Metabolism, 2011Co-Authors: Anja Schweizer, James E Foley, S Dejager, Q Shao, Wolfgang KothnyAbstract:AIM: To report the experience with Vildagliptin in a patient population with type 2 diabetes mellitus (T2DM) ≥75 years. METHODS: Efficacy data from seven monotherapy and three add-on therapy to metformin studies, respectively, of ≥24 weeks duration were pooled; effects of 24 weeks of treatment with Vildagliptin (50 mg bid) in patients ≥75 years were assessed in these two pooled datasets. Safety data were pooled from 38 studies of ≥12 to ≥104 weeks duration; adverse events (AEs) profiles of Vildagliptin (50 mg bid) were evaluated relative to a pool of comparators; 301 patients ≥75 years were analysed. Data in patients <75 years are provided as a reference. RESULTS: Mean age of the elderly population was 77 years. Changes in haemoglobin A1c (HbA1c) with Vildagliptin in the patient group ≥75 years were -0.9% from a baseline of 8.3% in monotherapy (p < 0.0001) and -1.1% from a baseline of 8.5% in add-on therapy to metformin (p = 0.0004), and these reductions were similar to those seen in the younger patients. The corresponding weight changes in the elderly patients were -0.9 kg (p = 0.0277) and -0.2 kg [not significant (NS)], respectively, and no confirmed hypoglycaemic events, including no severe events, were reported. AEs, drug-related AEs, serious adverse events (SAEs) and deaths were reported with a lower frequency in older patients receiving Vildagliptin than comparators [133.9 vs. 200.6, 14.5 vs. 21.8, 8.8 vs. 16.5 and 0.0 vs. 1.7 events per 100 subject year exposure (SYE), respectively], and the incidence of discontinuations due to AEs was similar in the two groups (7.2 vs. 7.5 events per 100 SYE, respectively). The safety profile of Vildagliptin was overall similar in younger and older patients. CONCLUSIONS: Vildagliptin was effective and well-tolerated in type 2 diabetic patients ≥75 years (mean age 77 years).
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Vildagliptin add on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride with no weight gain results from a 2 year study
Diabetes Obesity and Metabolism, 2010Co-Authors: D R Matthews, James E Foley, A Couturier, S Dejager, Vivian Fonseca, Bo Ahren, Ele Ferrannini, B ZinmanAbstract:AIM: To show that Vildagliptin added to metformin is non-inferior to glimepiride in reducing HbA1c levels from baseline over 2 years. METHODS: A randomized, double-blind, active-comparator study of patients with type 2 diabetes mellitus inadequately controlled (HbA1c 6.5-8.5%) by metformin monotherapy. Patients received Vildagliptin (50 mg twice daily) or glimepiride (up to 6 mg/day) added to metformin. RESULTS: In all, 3118 patients were randomized (Vildagliptin, n = 1562; glimepiride, n = 1556). From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between Vildagliptin and glimepiride treatment: -0.1% (0.0%) and -0.1% (0.0%), respectively. The primary objective of non-inferiority was met. A similar proportion of patients reached HbA1c or =0.5% or HbA1c 0.3% above IR). Independent of disease duration, age was a predictor of effect sustainability. Fewer patients experienced hypoglycaemia with Vildagliptin (2.3% vs. 18.2% with glimepiride) with a 14-fold difference in the number of hypoglycaemic events (59 vs. 838). Vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline -0.3 (0.1) kg; between-group difference -1.5 kg; p < 0.001]. Overall, both treatments were well tolerated and displayed similar safety profiles. CONCLUSIONS: Vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain.
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comparison of Vildagliptin and metformin monotherapy in elderly patients with type 2 diabetes a 24 week double blind randomized trial
Diabetes Obesity and Metabolism, 2009Co-Authors: Anja Schweizer, S Dejager, Emanuele BosiAbstract:AIMS: The study evaluated the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor, Vildagliptin, and metformin in drug-naive elderly patients with type 2 diabetes. The primary objective was to demonstrate non-inferiority of Vildagliptin vs. metformin in glycated haemoglobin (HbA1c) reduction. METHODS: This was a double-blind, randomized, multicentre, active-controlled, parallel-group study of 24-week treatment with Vildagliptin (100 mg daily, n=169) or metformin (titrated to 1500 mg daily, n=166) in drug-naive patients with type 2 diabetes aged>or=65 years (baseline HbA1c 7-9%). RESULTS: Participants had a mean age of 71 years, known duration of diabetes of 3 years and mean baseline HbA1c of 7.7%. At end-point, Vildagliptin was as effective as metformin, improving HbA1c by -0.64+/-0.07% and -0.75+/-0.07%, respectively, meeting the predefined statistical criterion for non-inferiority (upper limit of 95% confidence interval for between-treatment difference
Wolfgang Kothny - One of the best experts on this subject based on the ideXlab platform.
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effects of Vildagliptin on ventricular function in patients with type 2 diabetes mellitus and heart failure a randomized placebo controlled trial
Jacc-Heart Failure, 2018Co-Authors: Valentina Lukashevich, Wolfgang Kothny, Geremia B Bolli, Plamen Kozlovski, John J V Mcmurray, Piotr Ponikowski, James D Lewsey, Henry KrumAbstract:Abstract Objectives This study sought to examine the safety of the dipeptidyl peptidase-4 inhibitor, Vildagliptin, in patients with heart failure and reduced ejection fraction. Background Many patients with type 2 diabetes mellitus have heart failure and it is important to know about the safety of new treatments for diabetes in these individuals. Methods Patients 18 to 85 years of age with type 2 diabetes and heart failure (New York Heart Association functional class I to III and left ventricular ejection fraction [LVEF] Results A total of 254 patients were randomly assigned to Vildagliptin (n = 128) or placebo (n = 126). Baseline LVEF was 30.6 ± 6.8% in the Vildagliptin group and 29.6 ± 7.7% in the placebo group. The adjusted mean change in LVEF was 4.95 ± 1.25% in Vildagliptin treated patients and 4.33 ± 1.23% in placebo treated patients, a difference of 0.62 (95% confidence interval [CI]: −2.21 to 3.44; p = 0.667). This difference met the predefined noninferiority margin of −3.5%. Left ventricular end-diastolic and end-systolic volumes increased more in the Vildagliptin group by 17.1 ml (95% CI: 4.6 to 29.5 ml; p = 0.007) and 9.4 ml (95% CI: −0.49 to 19.4 ml; p = 0.062), respectively. Decrease in hemoglobin A 1c from baseline to 16 weeks, the main secondary endpoint, was greater in the Vildagliptin group: −0.62% (95% CI: −0.93 to −0.30%; p Conclusions Compared with placebo, Vildagliptin had no major effect on LVEF but did lead to an increase in left ventricular volumes, the cause and clinical significance of which is unknown. More evidence is needed regarding the safety of dipeptidyl peptidase-4 inhibitors in patients with heart failure and left ventricular systolic dysfunction. (Effect of Vildagliptin on Left Ventricular Function in Patients With Type 2 Diabetes and Congestive Heart Failure; NCT00894868)
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cardiovascular and heart failure safety profile of Vildagliptin a meta analysis of 17 000 patients
Diabetes Obesity and Metabolism, 2015Co-Authors: G Mcinnes, Valentina Lukashevich, S Del Prato, Anja Schweizer, Q Shao, Marc Evans, Michael Stumvoll, Wolfgang KothnyAbstract:Aims To report the cardiovascular (CV) safety profile and heart failure (HF) risk of Vildagliptin from a large pool of studies, including trials in high-risk patients with type 2 diabetes mellitus (T2DM), such as those with congestive HF and/or moderate/severe renal impairment. Methods We conducted a retrospective meta-analysis of prospectively adjudicated CV events. Patient-level data were pooled from 40 double-blind, randomized controlled phase III and IV Vildagliptin studies. The primary endpoint was occurrence of major adverse CV events (MACEs; myocardial infarction, stroke and CV death). Assessments of the individual MACE components and HF events (requiring hospitalization or new onset) were secondary endpoints. The risk ratio (RR) of Vildagliptin (50 mg once- and twice-daily combined) versus comparators (placebo and all non-Vildagliptin treatments) was calculated using the Mantel–Haenszel (M–H) method. Results Of the 17 446 patients, 9599 received Vildagliptin (9251.4 subject-years of exposure) and 7847 received comparators (7317.0 subject-years of exposure). The mean age of the patients was 57 years, body mass index 30.5 kg/m2 (nearly 50% obese), glycated haemoglobin concentration 8.1% and T2DM duration 5.5 years. A MACE occurred in 83 (0.86%) Vildagliptin-treated patients and 85 (1.20%) comparator-treated patients, with an M-H RR of 0.82 [95% confidence interval (CI) 0.61–1.11]. Similar RRs were observed for the individual events. Confirmed HF events were reported in 41 (0.43%) Vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with an M–H RR 1.08 (95% CI 0.68–1.70). Conclusions This large meta-analysis indicates that Vildagliptin is not associated with an increased risk of adjudicated MACEs relative to comparators. Moreover, this analysis did not find a significant increased risk of HF in Vildagliptin-treated patients.
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Cardiovascular and heart failure safety profile of Vildagliptin: a meta‐analysis of 17 000 patients
Diabetes Obesity and Metabolism, 2015Co-Authors: G Mcinnes, Valentina Lukashevich, S Del Prato, Anja Schweizer, Q Shao, Marc Evans, Michael Stumvoll, Wolfgang KothnyAbstract:Aims To report the cardiovascular (CV) safety profile and heart failure (HF) risk of Vildagliptin from a large pool of studies, including trials in high-risk patients with type 2 diabetes mellitus (T2DM), such as those with congestive HF and/or moderate/severe renal impairment. Methods We conducted a retrospective meta-analysis of prospectively adjudicated CV events. Patient-level data were pooled from 40 double-blind, randomized controlled phase III and IV Vildagliptin studies. The primary endpoint was occurrence of major adverse CV events (MACEs; myocardial infarction, stroke and CV death). Assessments of the individual MACE components and HF events (requiring hospitalization or new onset) were secondary endpoints. The risk ratio (RR) of Vildagliptin (50 mg once- and twice-daily combined) versus comparators (placebo and all non-Vildagliptin treatments) was calculated using the Mantel–Haenszel (M–H) method. Results Of the 17 446 patients, 9599 received Vildagliptin (9251.4 subject-years of exposure) and 7847 received comparators (7317.0 subject-years of exposure). The mean age of the patients was 57 years, body mass index 30.5 kg/m2 (nearly 50% obese), glycated haemoglobin concentration 8.1% and T2DM duration 5.5 years. A MACE occurred in 83 (0.86%) Vildagliptin-treated patients and 85 (1.20%) comparator-treated patients, with an M-H RR of 0.82 [95% confidence interval (CI) 0.61–1.11]. Similar RRs were observed for the individual events. Confirmed HF events were reported in 41 (0.43%) Vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with an M–H RR 1.08 (95% CI 0.68–1.70). Conclusions This large meta-analysis indicates that Vildagliptin is not associated with an increased risk of adjudicated MACEs relative to comparators. Moreover, this analysis did not find a significant increased risk of HF in Vildagliptin-treated patients.
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Vildagliptin in renal impairment.
Journal of Nephrology, 2014Co-Authors: Neelesh Dongre, Wolfgang KothnyAbstract:We read with interest the article by Schernthaner and Schernthaner [1] entitled ‘‘Diabetic nephropathy: new approaches for improving glycemic control and reducing risk’’, published in the November/December 2013 edition of J Nephrol. While we commend the authors for highlighting this important topic, we are writing to draw attention to what we believe is potentially misleading information regarding the dipeptidyl peptidase-4 (DPP-4) inhibitor Vildagliptin (Galvus ) in this article. The authors state ‘‘Vildagliptin is not recommended for patients with moderate or severe renal impairment ... because of a scarcity of evidence in this setting’’, citing an earlier paper by Scheen [2]. Although Schernthaner and Schernthaner faithfully quote Dr. Scheen, neither article accurately represents the current labelling for Vildagliptin, approved in the European Union and elsewhere, relating to its use in renal impairment. In fact, the Galvus Summary of Product Characteristics [3] states that Vildagliptin may be used at the standard dosage (i.e. 50 mg twice daily) in patients with mild renal impairment (CrCl C50 ml/min), and that the recommended dosage for patients with moderate to severe renal impairment, or with end-stage renal disease, is 50 mg once daily. We are concerned that the authors’ statement may lead physicians to either avoid initiating Vildagliptin in patients who could potentially benefit from treatment, or, because of unfounded safety concerns, to unnecessarily alter medication in patients who are responding well to Vildagliptin. We believe Vildagliptin is an effective treatment option for patients with type 2 diabetes mellitus, and has a favorable benefit:risk ratio in patients with renal impairment when used in accordance with the product labelling.
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efficacy and safety of Vildagliptin in patients with type 2 diabetes mellitus inadequately controlled with dual combination of metformin and sulphonylurea
Diabetes Obesity and Metabolism, 2014Co-Authors: Valentina Lukashevich, S Del Prato, M Araga, Wolfgang KothnyAbstract:Aim The broadly used combination of metformin and sulphonylurea (SU) often fails to bring patients to glycaemic goal. This study assessed the efficacy and safety of Vildagliptin as add-on therapy to metformin plus glimepiride combination in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control. Methods A multicentre, double-blind, placebo-controlled study randomized patients to receive treatment with Vildagliptin 50 mg bid (n = 158) or placebo (n = 160) for 24 weeks. Results After 24 weeks, the adjusted mean change in haemoglobin A1c (HbA1c) was −1.01% with Vildagliptin (baseline 8.75%) and −0.25% with placebo (baseline 8.80%), with a between-treatment difference of −0.76% (p < 0.001). Significantly more patients on Vildagliptin achieved the HbA1c target <7% (28.3% vs. 5.6%; p < 0.001). The difference in fasting plasma glucose reduction between Vildagliptin and placebo was −1.13 mmol/l (p < 0.001). In subgroup of patients with baseline HbA1c ≤8%, Vildagliptin reduced HbA1c by 0.74% from baseline 7.82% (between-treatment difference: –0.97%; p < 0.001) with significantly more patients achieving the HbA1c target <7% (38.6% vs. 13.9%; p = 0.014). Vildagliptin was well tolerated with low incidence of hypoglycaemia, slightly higher than with placebo (5.1% vs. 1.9%) and no clinically relevant weight gain. Conclusions Vildagliptin significantly improved glycaemic control in patients with T2DM inadequately controlled with metformin plus glimepiride combination. The addition of Vildagliptin was well tolerated with low risk of hypoglycaemia and weight gain. This makes Vildagliptin an attractive treatment option for patients failing on metformin plus SU particularly in patients with baseline HbA1c ≤8%.
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Bioequivalence and food effect assessment for Vildagliptin/metformin fixed-dose combination tablets relative to free combination of Vildagliptin and metformin in Japanese healthy subjects.
International journal of clinical pharmacology and therapeutics, 2016Co-Authors: Sachiko Mita, Yanling He, Kenneth Kulmatycki, Shripad D. Chitnis, Atish Salunke, Wei Zhou, Hikoe SuzukiAbstract:Objective To assess the bioequivalence of Vildagliptin/metformin fixeddose combination (FDC) tablets (50/250 mg and 50/500 mg) to free combinations of Vildagliptin and metformin and the effect of food on the pharmacokinetics (PK) of Vildagliptin and metformin following administration of 50/500 mg FDC tablets. Methods Two openlabel, randomized, single-center, singledose, 2-period crossover studies were conducted in Japanese healthy male volunteers. Participants were administered Vildagliptin/ metformin FDC tablets (study I: 50/250 mg, study II: 50/500 mg) or their free combinations under fasted condition. Food effect (standard Japanese breakfast: fat, 20 - 30% with ~ 600 kcal in total) was assessed during an additional period in study II (50/500 mg). PK parameters (AUC, C(max), t(max), t(1/2)) were calculated for Vildagliptin and metformin. Results In both studies, Vildagliptin/metformin FDC tablets were bioequivalent to their respective free combinations. Administration of FDC tablets after meals had no effect on Vildagliptin PK parameters. The rate of absorption of metformin decreased when administered under fed condition, as reflected by a prolonged t(max) (3 hours in fasted state vs. 4 hours in fed state) and decrease in C(max) by 26%, however, the extent of absorption (AUC(last)) was similar to that in the fasted state. Conclusions Vildagliptin/metformin FDC tablets were bioequivalent to their free combinations. Food decreased the C(max) of metformin by 26%, while AUC(last) was unchanged, consistent with previous reports. No food effect was observed on the C(max) or AUC(last) of Vildagliptin. Thus, food had no clinically relevant effects on the PK of metformin or Vildagliptin.
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quantification of the contribution of glp 1 to mediating insulinotropic effects of dpp 4 inhibition with Vildagliptin in healthy subjects and patients with type 2 diabetes using exendin 9 39 as a glp 1 receptor antagonist
Diabetes, 2016Co-Authors: Michael A Nauck, Yanling He, Lise Kjems, Jens J Holst, Carolyn F Deacon, Joachim Kind, Lars D Kothe, Matthias Broschag, James E FoleyAbstract:We wanted to quantify the contribution of GLP-1 as a mediator of therapeutic effects of DPP-4 inhibition (Vildagliptin), using the GLP-1 receptor antagonist exendin [9-39] in type 2 diabetic patients and in healthy subjects. 32 patients with type 2 diabetes and 29 age- and weight-matched healthy control subjects were treated, in randomized order, with 100 mg q.d. Vildagliptin or placebo for 10 days. Meal tests were performed (days 9 and 10), without and with a high dose intravenous infusion of exendin [9-39]. The main endpoint was the ratio of integrated insulin secretion rates (total AUC ISR ) and total AUC glucose over 4 h following the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and GIP and lowered glucose responses without changing AUC ISR /AUC glucose in healthy subjects. Vildagliptin significantly increased this ratio by 10.5 % in type 2-diabetic patients and exendin [9-39] reduced it (both p ISR /AUC glucose ratio achieved with exendin [9-39] was significantly smaller after Vildagliptin than after placebo treatment (p = 0.026) and was equivalent to 47 ± 5% of the increments due to Vildagliptin. Thus, other mediators appear to contribute significantly to the therapeutic effects of DPP-4 inhibition.
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Pharmacokinetics of Vildagliptin in patients with varying degrees of renal impairment.
International journal of clinical pharmacology and therapeutics, 2013Co-Authors: Yanling He, Kenneth Kulmatycki, Monica Ligueros-saylan, Wei Zhou, Yiming Zhang, Christine Reynolds, Ann TaylorAbstract:OBJECTIVE: The kidney plays a key role in both the metabolism and excretion of Vildagliptin. This study was designed to investigate the effects of varying degrees of renal impairment (RI) on the pharmacokinetics of Vildagliptin. METHODS: A total of 96 subjects were enrolled, and each subject received Vildagliptin 50 mg dosed orally once daily for 14 days. Vildagliptin and metabolite concentrations in plasma and urine were measured on Days 1 and 14. RESULTS: Compared to age-, gender-, BMI-matched subjects with normal renal function, the mean AUC of Vildagliptin after 14 days in patients with mild, moderate, and severe RI increased by 40%, 71%, and 100%, respectively, and the Cmax of Vildagliptin showed similar and minimal increases of 37%, 32% and 36%, respectively. CONCLUSIONS: These pharmacokinetics results suggest that 50 mg once daily is an appropriate dose and recommended for patients with moderate and severe renal impairment.
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Pharmacokinetic and pharmacodynamic interaction of Vildagliptin and voglibose in Japanese patients with Type 2 diabetes.
International journal of clinical pharmacology and therapeutics, 2013Co-Authors: Masayuki Yamaguchi, Yanling He, Takami Saji, Sachiko Mita, Kenneth Kulmatycki, Kenichi Furihata, Kaneo SekiguchiAbstract:OBJECTIVE: To assess the extent of pharmacokinetic and pharmacodynamic interaction between Vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4) enzyme, and voglibose, an α-glucosidase inhibitor widely prescribed in Japan, when coadministered in Japanese patients with Type 2 diabetes. METHODS: In this open-label, randomized, 3-treatment, 3-period and 6-way crossover study, 24 Japanese patients with Type 2 diabetes received 50 mg Vildagliptin twice daily; 50 mg Vildagliptin twice daily co-administered with 0.2 mg voglibose three times daily; or 0.2 mg voglibose three times daily for 3 days in each period. Plasma concentrations of Vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin, and glucagon were determined from blood samples collected at steady state. RESULTS: Exposure to Vildagliptin 50 mg (area under the concentration-time curve from 0 to 12 hours (AUCτ,ss)) and maximum plasma concentration at steady state (Cmax,ss) was reduced by 23% and 34% respectively with co-administration of voglibose. The percentage of DPP-4 inhibition by Vildagliptin remained unchanged when Vildagliptin was given alone or co-administered with voglibose; maximum inhibition was 98.3 ± 1.4% (mean ± SD) for Vildagliptin alone and 97.4 ± 1.1% with co-administration. Coadministration of Vildagliptin and voglibose led to a greater increase in the active GLP-1 plasma concentration than did Vildagliptin alone (geometric mean ratio 1.63 (90% CI, 1.30, 2.03), p = 0.0007). The combination of Vildagliptin and voglibose also led to a significantly lower plasma glucose levels (p < 0.0001). CONCLUSIONS: Plasma Vildagliptin levels were decreased when voglibose was co-administered, although DPP- 4 inhibition remained unchanged. Co-administration led to significantly better pharmacodynamic response compared with each treatment alone, including higher active GLP-1 and lower glucose levels. The results indicate that this coadministration may be beneficial in the clinical situation. Vildagliptin and voglibose treatments, alone or when co-administered, were well tolerated in Japanese patients with Type 2 diabetes.
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clinical pharmacokinetics and pharmacodynamics of Vildagliptin
Clinical Pharmacokinectics, 2012Co-Authors: Yanling HeAbstract:Vildagliptin is an orally active, potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor, shown to be effective and well tolerated in patients with type 2 diabetes mellitus (T2DM) as either monotherapy or in combination with other anti-diabetic agents. Vildagliptin possesses several desirable pharmacokinetic properties that contribute to its lower variability and low potential for drug interaction. Following oral administration, Vildagliptin is rapidly and well absorbed with an absolute bioavailability of 85%. An approximately dose-proportional increase in exposure to Vildagliptin over the dose range of 25–200 mg has been reported. Food does not have a clinically relevant impact on the pharmacokinetics of Vildagliptin, and it can be taken without regard to food. Vildagliptin is minimally bound to plasma proteins (9.3%) and, on the basis of a volume of distribution of 71 L, it is considered to distribute extensively into extra vascular spaces. Renal clearance of Vildagliptin (13L/h) accounts for 33% of the total body clearance after intravenous administration (41 L/h). The primary elimination pathway is hydrolysis by multiple tissues/organs. The DPP-4 enzyme contributes to the formation of the major hydrolysis metabolite, LAY 151; therefore, Vildagliptin is also a substrate of DPP-4. Vildagliptin has a low potential for drug interactions, as cytochrome P450 (CYP) enzymes are minimally (<1.6%) involved in the overall metabolism. Clinical pharmacokinetic studies have reported the lack of drug interaction with several drugs (metformin, pioglitazone, glyburide, simvastatin, amlodipine, valsartan, ramipril, digoxin and warfarin) that are likely to be frequently co-administered to patients with T2DM. In particular, Vildagliptin does not affect the pharmacokinetics of pioglitazone, glyburide, warfarin and simvastatin; therefore, it is not expected to affect the pharmacokinetics of a drug that is a substrate for CYP2C8, CYP2C9 or CYP3A4. In the elderly, Vildagliptin exposure increases by approximately 30%, which is considered to be mostly attributable to compromised renal function in the elderly population and is not considered to be clinically relevant. Vildagliptin has been demonstrated to be efficacious, safe and well tolerated in elderly patients with T2DM without dose adjustment. In subjects with varying degrees of renal impairment, Vildagliptin exposure increases by approximately 2-fold; however, the increase in the exposure does not correlate with the severity of renal impairment. The lack of a clear correlation between the increased exposure and the severity of renal impairment is considered to be attributable to the fact that the kidneys contribute to both the excretion and the hydrolysis metabolism of Vildagliptin. Hepatic impairment, gender, body mass index (BMI) and ethnicity do not have an influence on the pharmacokinetics of Vildagliptin. These findings suggest that Vildagliptin can be used in a diverse patient population without dose adjustment.