Dipeptidyl peptidase-4 inhibitors and cardiovascular safety

Recent cardiovascular outcome trials confirm the safety of the dipeptidyl peptidase-4 inhibitors, but new questions emerge

In 2007, a meta-analysis of clinical trial data implicated the blood glucose-lowering drug rosiglitazone as unexpectedly increasing, rather than reducing, cardiovascular risk in patients with type 2 diabetes.1 This report proved controversial, but its major consequence was that the United States Food and Drug Administration (FDA) required the manufacturer of every new blood glucose-lowering therapy to conduct a postmarketing (Phase IV) cardiovascular safety study when there was no convincing evidence of non-inferiority or superiority over conventional agents, such as metformin and sulfonylureas, based on cardiovascular end point data collected in Phase II–III studies.2 In line with this requirement, the manufacturers of most incretin-based therapies, which comprise the glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins), have initiated Phase IV cardiovascular safety studies. The exceptions are the GLP-1 analogue exenatide, which was already registered and marketed in the US at the time the FDA requirement came into effect, and the DPP-4 inhibitor vildagliptin, whose manufacturer elected not to do such a study and therefore not to market the drug in the US.