Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors were the first class of new antidiabetic drugs to be studied using modern cardiovascular safety trials, as mandated by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Trials with saxagliptin, alogliptin and sitagliptin satisfied the safety criteria with no increase in major cardiovascular adverse events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. No reduction in MACE was demonstrated in these trials, and an unexpected increase in the secondary outcome of hospitalisation for heart failure was observed in the SAVOR-TIMI 53 trial with saxagliptin.
Unusually, linagliptin was studied in two separate safety trials: CARMELINA compared linagliptin with placebo and CAROLINA compared linagliptin with glimepiride. In both trials MACE events were similar in the linagliptin and comparator groups, and no significant differences were observed in rates of hospitalisation for heart failure. These trials provide evidence of cardiovascular safety for linagliptin but show no clear cardiovascular benefits, and indirectly provide evidence of cardiovascular safety for the sulfonylurea glimepiride.