Potential Cardiovascular Effects of the Glucagon-like Peptide-1 Receptor Agonists

In patients with type 2 diabetes, cardiovascular risk reduction represents an important clinical goal in light of the elevated risk of cardiovascular mortality in this patient population; thus, it is important that glucose-lowering drugs have no negative effects and potentially some positive effects on cardiovascular risk. The glucagon-like peptide-1 receptor agonists (GLP-1RAs), which were designed to resist degradation by the enzyme dipeptidyl peptidase-4, are among the newer glucose-lowering agents for the treatment of type 2 diabetes. There are a number of agents within this class, including exenatide, liraglutide, albiglutide, lixisenatide, and dulaglutide. Preclinical research efforts in animal models have identified a number of favorable cardiovascular effects of GLP-1RAs beyond glucose lowering. Although the underlying basis for these cardiovascular effects has not yet been elucidated, a number of potential mechanisms have been suggested. Accumulating data from randomized clinical trials and retrospective/post hoc pooled analyses of clinical trials support the favorable effects of GLP-1RAs on blood pressure and lipid profiles. Although some observations have suggested that GLP-1RAs may lead to an increase in heart rate, a recent post hoc analysis including 11 studies of exenatide once weekly versus active comparators or placebo shows that mean increases in heart rate are small and transient, increases are more common in patients with low baseline heart rate, and that heart rate elevations become less prevalent over time. In addition, no association was observed between major adverse cardiac events and small mean increases in heart rate. Individual clinical trials in patients with type 2 diabetes also have provided evidence of protection against post-myocardial infarction ischemic damage, as well as the ability to improve circulating biomarker levels. Forthcoming data from phase 3 and 4 cardiovascular outcome trials of GLP-1RAs will provide further insight into their cardiovascular safety and cardioprotective potential in various settings.