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

Studies in rodents with the DPP-4 inhibitor vildagliptin to evaluate possible drug-induced pancreatic histological changes that are predictive of pancreatitis and cancer development in man.

Aim: The present report summarizes rodent studies with vildagliptin, relevant to predicting pancreatitis or pancreatic cancer in man. Research design and Methods: As part of the regulatory development program for vildagliptin, a rodent toxicity program included two 104 week rodent (mouse and rat) carcinogenicity studies that were conducted according to guidelines assigned in FDA’s Draft Guidance for Industry. Results: Vildagliptin exposure in animals was evaluated for its effects on endocrine and exocrine pancreas. Two-year carcinogenicity studies were conducted in rats at oral doses up to 900 mg/kg (approximately 200 times the human exposure at the maximum recommended dose) and in mice at oral doses up to 1,000 mg/kg (up to 240 times the human exposure at the maximum recommended dose). The results from these studies demonstrate the expected preservation and growth of the endocrine beta cells with no significant findings in the exocrine acinar pancreas. There was no evidence of inflammatory infiltrates characteristic of pancreatitis, no palpable mass detection based on gross examination or any microscopic findings indicative of pancreatic islet cell (endocrine), acinar cell (exocrine) or ductal (exocrine) neoplasia in rat or mouse. Conclusions: Evaluation of vildagliptin in two-year preclinical carcinogenicity studies in both rats and mice indicate that while vildagliptin results in pharmacological benefits to the endocrine pancreas, this was not associated with any evidence of pancreatitis, pancreatic islet cell, acinar cell or ductal neoplasia. These data predict no increased risk of pancreatic cancer in man. Keywords: adverse effects, dipept

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

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

This non-interventional, multi-database, analytical cohort study assessed the cardiovascular (CV) safety of vildagliptin vs. other non-insulin antidiabetic drugs (NIADs) using real-world data from five 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 (95% 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 0.61-0.97 (MI), 0.55-1.60 (ACS), 0.02-0.77 (stroke), 0.49-1.03 (CHF), and 0.22-1.02 (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 under real-world conditions