Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large Phase III type 2 diabetes population.
OBJECTIVE
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 (< and > 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.
Novartis Pharma AG, Basel, Switzerland. anja.schweizer@novartis.com
A
A
Schweizer
S
S
Dejager
J E
JE
Foley
A
A
Couturier
M
M
Ligueros-Saylan
W
W
Kothny
D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D002561:Cerebrovascular Disorders / Q000139:chemically induced* / Q000188:drug therapy; D017326:Clinical Trials, Phase III as Topic; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000139:chemically induced* / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D000077597:Vildagliptin
D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane