Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large Phase III type 2 diabetes population

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2010-06, Vol.12 (6), p.485-494
• Main Authors: Schweizer, A, Dejager, S, Foley, J.E, Couturier, A, Ligueros-Saylan, M, Kothny, W
• Format: Article
• Language: English
• Subjects: Adamantane - administration & dosage; Adamantane - adverse effects; Adamantane - analogs & derivatives; Cardiovascular diseases; cardiovascular risk; Cerebral infarction; Cerebrovascular Disorders - chemically induced; Cerebrovascular Disorders - drug therapy; Clinical Trials, Phase III as Topic; Coronary artery disease; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetic Angiopathies - chemically induced; Diabetic Angiopathies - drug therapy; dipeptidyl peptidase-4; Dipeptidyl-Peptidase IV Inhibitors - administration & dosage; Dipeptidyl-Peptidase IV Inhibitors - adverse effects; Female; Gender; Heart diseases; Humans; Ischemia; Male; Meta-analysis; Middle Aged; Nitriles - administration & dosage; Nitriles - adverse effects; Pyrrolidines - administration & dosage; Pyrrolidines - adverse effects; Randomized Controlled Trials as Topic; Risk groups; Safety; Transient ischemic attack
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2010.01215.x

Aim: To assess the cardiovascular and cerebrovascular (CCV) safety of the dipeptidyl peptidase-IV inhibitor vildagliptin. Methods: Data were pooled from 25 Phase III studies of vildagliptin, used either as monotherapy or combination therapy, with durations of 12 weeks to ≥ 2 years. The safety of vildagliptin [50 mg qd (N = 1393) or 50 mg bid (N = 6116)] was assessed relative to a pool of all comparators [both placebo and active comparators (N = 6061)]. CCV events were adjudicated in a prospective, blinded fashion by an independent CCV adjudication committee. Meta-analysis of confirmed CCV events was performed with Mantel-Haenszel risk ratios (RRs); categories included in the composite endpoint were acute coronary syndrome, transient ischaemic attack (with imaging evidence of infarction), stroke and CCV death. Subgroup analyses by age (< and ≥ 65 years), gender and cardiovascular (CV) risk status [high CV risk status defined as a previous history of events in the Standard MedDRA Queries of ischaemic heart disease, cardiac failure, ischaemic cerebrovascular conditions and/or embolic/thrombotic events, arterial) were also carried out. In addition, unadjusted and exposure-adjusted incidences are presented for both the composite endpoint and its components. Results: Relative to all comparators, the RRs for the composite endpoint were < 1 for both vildagliptin 50 mg qd [RR = 0.88; 95% CI (0.37, 2.11)] and vildagliptin 50 mg bid [RR = 0.84; 95% CI (0.62, 1.14)]. The results were consistent across subgroups defined by age, gender and CV risk status, including the higher CV risk subgroups of elderly patients [RR for vildagliptin 50 mg bid vs. all comparators = 1.04; 95% CI (0.62, 1.73)], males [RR = 0.87; 95% CI (0.60, 1.24)] or patients with a high CV risk status [RR = 0.78; 95% CI (0.51, 1.19)]. The exposure-adjusted incidences of each component of the composite endpoint for vildagliptin 50 mg bid were also lower than or similar to those of all comparators. Conclusions: In a large meta-analysis, vildagliptin was not associated with an increased risk of adjudicated CCV events relative to all comparators in the broad population of type 2 diabetes including patients at increased risk of CCV events.