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

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 > or = 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 ( or = 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.