CARDIOVASCULAR OUTCOME TRIALS OF THE INCRETIN-BASED THERAPIES: WHAT DO WE KNOW SO FAR?

OBJECTIVE: Diabetes is a well-established pro-inflammatory state with an increased risk for cardiovascular (CV) diseases. In recent years, the number of different classes of agents for the treatment of type 2 diabetes has increased substantially, and while glycemic control is the major focus of these medications, CV safety has become of interest. Two incretin-based therapies are currently available: glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors.

METHODS: The literature was reviewed for information regarding the incretin-based therapies and their effects on the CV system.

RESULTS: Independent of their glucose-lowering action, incretin-based therapies may have incretin-dependent mechanisms that positively affect blood pressure, weight, and other markers of CV disease risk, and, in the case of DPP-4 inhibition, nonincretin-dependent actions such as improving endothelial function. Several CV outcomes trials (CVOTs) with incretin-based therapies have recently completed with no excess CV risk observed, and positive effects have been reported in at least 1 trial of GLP-1 RAs, with more studies ongoing. Results for the risk for heart failure with DPP-4 inhibitor use are mixed, but no increase has been demonstrated with GLP-1 RAs.

CONCLUSION: Future CVOTs will need to be redesigned to help address these questions in the context of the emerging scope of the underlying mechanisms of cardio-metabolic disease in populations with diabetes.

ABBREVIATIONS: A1C = hemoglobin A1C ACS = acute coronary syndrome CHD = coronary heart disease CI = confidence interval CV = cardiovascular CVOT = Cardiovascular Outcome Trial DPP-4 = dipeptidyl peptidase 4 FDA = U.S. Food and Drug Administration GIP = glucose-dependent insulinotropic polypeptide GLP-1 = glucagon-like protein 1 GLP-1 RA = glucagon-like protein 1 receptor agonist HF = heart failure HR = hazard ratio LVEF = left ventricular ejection fraction MACE = major adverse cardiovascular events MI = myocardial infarction T2D = type 2 diabetes.