Cardiovascular Outcome Trials of Incretin Therapy (Dipeptidyl Peptidase-4 Inhibitors/Glucagon-Like Peptide-1 Receptor Agonist)

In 2008, the United States Food and Drug Administration issued guidance which mandated long-term cardiovascular outcome trials (CVOTs) to assess the safety of new antidiabetic drugs for type 2 diabetes. Since 2008, three CVOTs that have studied dipeptidyl peptidase-4 (DPP-4) inhibitors and four CVOTs of a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) have been reported. Each of the completed CVOTs showed the noninferiority of respective drugs to placebo for primary CV composite endpoint. Among them, liraglutide and semaglutide showed a reduction of major adverse cardiovascular events. However, the mechanisms for the observed cardiovascular differences between DPP-4 inhibitors and GLP-1RA, and across individual GLP-1RA are not clearly understood. Therefore, this review will summarize the CVOTs of the DPP-4 inhibitors and GLP-1RA, interpretation of cardioprotective results of incretin-based therapy and the possible mechanism of action.