Long-acting GLP-1 receptor agonists: Findings and implications of cardiovascular outcomes trials

Cardiovascular disease (CVD) is a common and serious comorbidity of type 2 diabetes mellitus (T2DM), and cardiovascular (CV) risk assessment has become an important aspect of evaluating new therapies for T2DM before approval by the FDA. Since 2008, in order to establish safety, new therapies for T2DM have been required to demonstrate that they will not result in an unacceptable increase in CV risk. Studies performed for this purpose are termed CV outcome trials, or CVOTs. This article reviews CVOTs completed to date for the class of long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs; liraglutide, exenatide extended-release, albiglutide, dulaglutide, semaglutide injectable, semaglutide oral) and implications for clinical management of T2DM. All CVOTs have confirmed long-acting GLP-1RAs to be noninferior to (not worse than) placebo with regard to first occurrence of a primary outcome of three-point major adverse cardiovascular events (MACE; composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke). Further, a number of the studies demonstrated a statistically significant reduction in primary outcomes of three-point MACE with GLP-1RA treatment compared with placebo. As a result, the product labeling for liraglutide, semaglutide injectable, and dulaglutide has been updated with an indication for reducing the risk of MACE in adults with T2DM and established CVD (all) or multiple CV risk factors (dulaglutide only). These findings have brought about an exciting paradigm shift from concern about not inflicting CV harm to the exciting prospect of reducing risks of CV outcomes. Major diabetes care guidelines now encourage early consideration of GLP-1RA use in patients with atherosclerotic CVD.