Association between vildagliptin and risk of angioedema, foot ulcers, skin lesions, hepatic toxicity, and serious infections in patients with type 2 diabetes mellitus: A European multidatabase, noninterventional, postauthorization safety study.

OBJECTIVES: This noninterventional, multidatabase, analytical cohort study explored whether vildagliptin is associated with an increased risk of specific safety events of interest, namely angioedema, foot ulcers, or skin lesions, adverse hepatic events, or serious infections compared with other noninsulin antidiabetic drugs (NIADs) using real-world data from five European electronic healthcare databases. DESIGN: Patients with type 2 diabetes mellitus aged ≥18 years on NIAD treatment were included between January 2005 and June 2014. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the outcomes of interest were estimated using negative binomial regression. PATIENTS: Approximately 2.8% of the included patients (n = 738 054) used vildagliptin at any time during the study, with an average follow-up time of 1.4 years. RESULTS: The adjusted IRRs (vildagliptin vs. other NIADs) were in the range of 0.87-3.71 (angioedema), 0.73-1.19 (foot ulcers), 0.37-1.18 (skin lesions), 0.24-1.14 (composite of foot ulcer or skin lesions), 0.29-0.55 (serious hepatic events), and 0.59-1.04 (serious infections), with no lower bound of the 95% CIs > 1. CONCLUSIONS: Overall, there was no increased risk of the events of interest in association with vildagliptin use compared with other NIADs.

Pancreatic safety of vildagliptin in patients with type 2 diabetes mellitus: A European, noninterventional, postauthorization safety study.

This cohort study assessed the pancreatic safety of vildagliptin versus other noninsulin antidiabetic drugs (NIADs) based on data from five European electronic health care databases. Patients with type 2 diabetes aged ≥18 years on NIAD treatment were enrolled. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated separately for acute pancreatitis and pancreatic cancer for vildagliptin (± other NIADs) compared with other NIADs using negative binomial regression. Approximately 2.8% of the enrolled patients (n = 738 054) used vildagliptin during the study, with an average follow-up time of 1.4 years. For acute pancreatitis, adjusted IRRs ranged between 0.89 andt 2.58 with all corresponding 95% CIs crossing 1. For pancreatic cancer adjusted IRRs ranged from 0.56 to 3.64, with the lower limit of 95% CIs >1 in some analyses. Post hoc sensitivity analyses taking latency time into account markedly lowered the risk estimates with corresponding 95% CIs crossing 1. Overall, the results do not suggest an increased pancreatitis risk with vildagliptin, while the observation for pancreatic cancer have to be interpreted carefully as this study was not designed to assess pancreatic cancer and rather be explained by certain underlying limitations including latency -time, chance findings and/or bias and confounding.

Effects of Vildagliptin on Ventricular Function in Patients With Type 2 Diabetes Mellitus and Heart Failure: A Randomized Placebo-Controlled Trial.

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] <0.40) were randomized to 52 weeks treatment with vildagliptin 50 mg twice daily (50 mg once daily if treated with a sulfonylurea) or matching placebo. The primary endpoint was between-treatment change from baseline in echocardiographic LVEF using a noninferiority margin of -3.5%. 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 A1c 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 < 0.001; -6.8 mmol/mol; 95% CI: -10.2 to -3.3 mmol/mol). 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).

Estimands: A More Strategic Approach to Study Design and Analysis.

Do we always precisely define the treatment effects that our clinical trial will estimate? Our tenet is that this is not always done, or is done inadequately. This lack of clarity can result in a misalignment among trial objectives, trial design, and statistical methods. We will discuss these challenges and present an improved framework using estimands that is proposed in a draft International Council for Harmonization (ICH) E9 addendum.

Cardiovascular safety of vildagliptin in patients with type 2 diabetes: A European multi-database, non-interventional post-authorization safety study.

The aim of this non-interventional, multi-database, analytical cohort study was to assess the cardiovascular (CV) safety of vildagliptin vs other non-insulin antidiabetic drugs (NIADs) using real-world data from 5 European electronic healthcare databases. Patients with type 2 diabetes aged ≥18 years on NIAD treatment were enrolled. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the outcomes of interest (myocardial infarction [MI], acute coronary syndrome [ACS], stroke, congestive heart failure [CHF], individually and as a composite) were estimated using negative binomial regression. Approximately 2.8% of the enrolled patients (n = 738 054) used vildagliptin at any time during the study, with an average follow-up time of 1.4 years, resulting in a cumulative current vildagliptin exposure of 28 330 person-years. The adjusted IRRs (vildagliptin [±other NIADs] vs other NIADs) were in the range of 0.61 to 0.97 (MI), 0.55 to 1.60 (ACS), 0.02 to 0.77 (stroke), 0.49 to 1.03 (CHF), and 0.22 to 1.02 (composite CV outcomes). The IRRs and their 95% CIs were close to 1, demonstrating no increased risk of adverse CV events, including the risk of CHF, with vildagliptin vs other NIADs in real-world conditions.

Effect of race and ethnicity on vildagliptin efficacy: A pooled analysis of phase II and III studies.

AIMS: To determine the impact of race and ethnicity on the efficacy, body weight and hypoglycaemia incidence with vildagliptin treatment in patients with type 2 diabetes mellitus using patient-level data from the vildagliptin clinical trial programme. METHODS: Data from 22 randomized, placebo-controlled global and local (Japan, China) registration studies of vildagliptin (50 mg once-daily or twice-daily) of ≥12-week duration were analysed by race (Caucasian [n = 2764] and Asian [n = 2232]) and by ethnicity (Japanese, Chinese, and Indian). The placebo-subtracted differences in the change in glycated haemoglobin (HbA1c) and body weight from baseline to week 12 or week 24 were evaluated by race or ethnicity using repeated measure analysis of unstructured covariance. Hypoglycaemia incidences were summarized using descriptive statistics. RESULTS: The HbA1c reduction from baseline with vildagliptin was similar across the racial/ethnic subgroups (-0.83% ± 0.02% to -1.01% ± 0.05%). Placebo-corrected HbA1c reduction was similar between Caucasian (-0.68% ± 0.03%) and Asian (-0.80% ± 0.03%) patients ( P value for interaction = .56); analysis by race and ethnicity showed better efficacy ( P < .02) in Japanese patients. Japanese patients were drug-naïve and treated with a single oral anti-diabetes drug only; they showed no response to placebo. Weight neutrality of vildagliptin was demonstrated in all groups (0.47 ± 0.11 kg to -0.29 ± 0.08 kg). Hypoglycaemic events (≥1) were infrequent in all ethnic subgroups. CONCLUSIONS: The glycaemic efficacy of vildagliptin was similar in Caucasian and Asian patients. The slightly better efficacy observed in Japanese patients was driven by the absence of placebo effect and might be explained by their earlier stage of diabetes compared to other subgroups.

Vildagliptin as add-on therapy to insulin improves glycemic control without increasing risk of hypoglycemia in Asian, predominantly Chinese, patients with type 2 diabetes mellitus.

BACKGROUND: The aim of the present study was to investigate the efficacy and safety of vildagliptin added onto insulin with or without metformin in an Asian, predominantly Chinese, population with type 2 diabetes mellitus (T2DM). METHODS: In this 24-week, multicenter, double-blind, placebo-controlled trial, patients with T2DM inadequately controlled (HbA1c 7.5%-11.0%) on stable therapy with long-acting, intermediate-acting, or premixed insulin, with or without concomitant metformin, were randomized to receive vildagliptin 50 mg b.i.d. or placebo. RESULTS: Of 293 patients randomized, 146 received vildagliptin and 147 received placebo treatment. At baseline, the overall mean age of patients was 58.1 years, mean T2DM duration was 11.3 years, and mean HbA1c was 8.7%. The adjusted mean (±SE) change in HbA1c at Week 24 in the vildagliptin and placebo groups was -1.08 ± 0.12% and -0.38 ± 0.12%, respectively (between-treatment difference -0.70 ± 0.16%; P < 0.001). The between-group difference in fasting plasma glucose was -0.43 ± 0.38 mmol/L (P = 0.259). Significantly, more patients achieved HbA1c <7.0% with vildagliptin than with placebo (23.6% vs. 11.2%; P = 0.006). The incidence of adverse events in the vildagliptin and placebo groups was 43.8% and 46.3%, whereas that of serious adverse events was 3.4% and 6.8%, respectively. The frequency of hypoglycemia was lower in the vildagliptin than placebo group (2.7% vs. 5.4%). CONCLUSION: The addition of vildagliptin 50 mg b.i.d. significantly improved glycemic control without an increased risk of hypoglycemia in Asian, predominantly Chinese, patients with T2DM inadequately controlled on insulin, with or without metformin.

Comparison of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment: a randomised clinical trial.

AIMS/HYPOTHESIS: There are limited data comparing dipeptidyl peptidase-4 (DPP-4) inhibitors directly. We compared the safety and efficacy of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment (RI). METHODS: This study was a parallel-arm, randomised, multicentre, double-blind, 24 week study conducted in 87 centres across Brazil and the USA. Patients with type 2 diabetes, either drug naive or treated with any glucose-lowering agents, who had inadequate glycaemic control (HbA1c 6.5-10.0% [48-86 mmol/mol]) and an estimated GFR <30 ml min(-1) [1.73 m](-2) were randomised (via interactive voice response technology) to vildagliptin 50 mg once daily or sitagliptin 25 mg once daily. These doses are recommended in this patient population and considered maximally effective. Participants, investigators and the sponsor were blinded to group assignment. Efficacy endpoints included change in HbA1c and fasting plasma glucose (FPG) at all visits and the primary safety endpoint was assessment of treatment-emergent adverse events. RESULTS: In total, 148 patients were randomised, 83 to vildagliptin and 65 to sitagliptin. All patients were analysed. After 24 weeks, the adjusted mean change in HbA1c was -0.54% (5.9 mmol/mol) from a baseline of 7.52% (59 mmol/mol) with vildagliptin and -0.56% (6.1 mmol/mol) from a baseline of 7.80% (62 mmol/mol) with sitagliptin (p = 0.874). FPG decreased by 0.47 ± 0.37 mmol/l with vildagliptin and increased by 0.16 ± 0.43 mmol/l with sitagliptin (p = 0.185). Both treatments were well tolerated with overall similar safety profiles. CONCLUSIONS/INTERPRETATION: At their recommended doses for severe RI, vildagliptin (50 mg once daily) compared with sitagliptin (25 mg once daily) demonstrated similar efficacy and both drugs were well tolerated. This study provides further support for the use of DPP-4 inhibitors in patients with severe RI. TRIAL REGISTRATION: ClinicalTrials.gov NCT00616811 (completed) FUNDING: This study was planned and conducted by Novartis.

Efficacy and safety of a single-pill combination of vildagliptin and metformin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial.

INTRODUCTION: The use of dipeptidyl peptidase-4 inhibitors in combination with metformin is increasing in Japanese patients with type 2 diabetes mellitus (T2DM), but no single-pill combination (SPC) is currently available in Japan. The objective of this study was to assess the efficacy and safety of vildagliptin/metformin SPC in Japanese patients with T2DM inadequately controlled with vildagliptin monotherapy. METHODS: This was a 14-week, randomized, double-blind, parallel-group, placebo-controlled trial. 171 patients with T2DM inadequately controlled [HbA1c (glycosylated hemoglobin) 7.0-10.0%] with vildagliptin 50 mg twice daily (bid) were randomized (2:1) to receive either a vildagliptin/metformin SPC (n = 115) or matching vildagliptin/placebo SPC (n = 56). RESULTS: Baseline demographics and background characteristics were generally comparable between the treatment groups. The change in HbA1c [mean ± standard error (SE)] was -0.8 ± 0.1% in the vildagliptin/metformin SPC (baseline HbA1c, 7.9 ± 0.1%) group and 0.1 ± 0.1% in the vildagliptin/placebo SPC (baseline HbA1c, 8.0 ± 0.1%) group, with a between-treatment difference of -1.0 ± 0.1% (P <0.001) in favor of the vildagliptin/metformin SPC group. The proportion of patients achieving target HbA1c <7.0% was significantly higher with vildagliptin/metformin SPC compared with vildagliptin/placebo SPC (45.8% vs. 13.5%, P <0.001). The overall incidences of adverse events (AEs) were 43.5% in the vildagliptin/metformin SPC and 67.9% in the vildagliptin/placebo SPC group. The incidences of serious AEs were low in both the treatment groups (0.9% vs. 3.6%, respectively). Body weight remained constant throughout the study in both the treatment groups. There were no deaths or hypoglycemic events during the study. CONCLUSIONS: Switching Japanese patients with T2DM requiring treatment intensification, from vildagliptin monotherapy to a vildagliptin/metformin SPC (50/250 or 50/500 mg) was efficacious and safe, eliciting significant reduction in HbA1c without increased risk of hypoglycemia and weight gain.

Vildagliptin added to sulfonylurea improves glycemic control without hypoglycemia and weight gain in Chinese patients with type 2 diabetes mellitus.

OBJECTIVE: The aim of the present study was to assess the efficacy and safety of vildagliptin as add-on to sulfonylurea therapy in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea monotherapy. METHODS: The 24-week randomized double-blind placebo-controlled study compared vildagliptin 50 mg, q.d., with placebo as add-on to glimepiride in T2DM patients who were inadequately controlled (HbA1c 7.5%-11.0% [58-97 mmol/mol]) on a stable dose of sulfonylurea for ≥12 weeks before study entry. RESULTS: In all, 279 patients were randomized to receive either vildagliptin (n = 143) or placebo (n = 136). At baseline, overall mean age was 58.5 years, body weight 68.1 kg, duration of diabetes 6.9 years and daily glimepiride dose 3.3 mg. After 24 weeks, the adjusted mean change (AMΔ) in HbA1c was -0.7% (-8 mmol/mol; baseline 8.6%, 70 mmol/mol) in the vildagliptin group and -0.2% (-2 mmol/mol; baseline 8.7%, 72 mmol/mol) in the placebo group, with a treatment difference of -0.5% (-5 mmol/mol; P < 0.001). The between-group difference in AMΔ in fasting plasma glucose was -0.4 mmol/L (P = 0.160). There was a slight, but not significant, decrease in body weight in both groups. No hypoglycemic events were reported in either group, including those patients reaching HbA1c <7.0%. Patients in the vildagliptin and placebo groups reported low and comparable incidences of adverse events (14.0% vs. 17.8%) and serious adverse events (0.7% in each group). CONCLUSION: Vildagliptin 50 mg, q.d., added to sulfonylurea monotherapy is effective in Chinese patients with T2DM, without increasing the risk of hypoglycemia and weight gain.