Dipeptidyl peptidase 4 (
DPP4) inhibitors have been touted as promising
antihyperglycemic agents due to their beneficial effects on glycemia without inducing
hypoglycemia or
body weight gain and their good tolerability. Beyond their
glucose-lowering effects, numerous clinical trials and experimental studies have suggested that
DPP4 inhibitors may exert cardioprotective effects through their pleiotropic actions via
glucagon-like peptide 1-dependent mechanisms or involving other substrates. Since 2008, regulatory agencies have required an assessment of
cardiovascular disease (CVD) safety for the approval of all new anti-hyperglycemic agents, including
incretin-based
therapies. Three large prospective
DPP4 inhibitor trials with cardiovascular (CV) outcomes have recently been published. According to the
Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with
Diabetes Mellitus (SAVOR-TIMI 53) and EXamination of cArdiovascular outcoMes with
alogliptIN versus standard of carE in patients with
type 2 diabetes mellitus and
acute coronary syndrome (EXAMINE) trials,
DPP4 inhibitors, including
saxagliptin and
alogliptin, did not appear to increase the risk of CV events in patients with
type 2 diabetes and established CVD or high risk factors. Unexpectedly,
saxagliptin significantly increased the risk of hospitalization for
heart failure by 27%, a finding that has not been explained and that requires further exploration. More recently, the Trial Evaluating Cardiovascular Outcomes with
Sitagliptin (TECOS) trial demonstrated the CV safety of
sitagliptin, including assessments of the primary composite CV endpoint and hospitalization for
heart failure in patients with
type 2 diabetes and established CVD. The CV outcomes of an ongoing
linagliptin trial are expected to provide new evidence about the CV effects of a DPP4-inhibitor in patients with
type 2 diabetes.