Glucagon-like peptide-1 receptor agonists for diabetes mellitus: a role in cardiovascular disease.

2305 D iabetes mellitus, defined as a fasting plasma glucose of ≥126 mg/dL or a glycosylated hemoglobin A1c level (HbA1c) of ≥6.5%, afflicts ≈12.9% of adults in the United States and nearly 285 million adults worldwide. Diabetes mellitus is a major risk factor for the development of cardio-vascular disease, independently conferring a 2-fold excess risk of coronary heart disease and stroke. 3 Macrovascular events in diabetes mellitus remain the leading cause of mortality , and the burden of cardiovascular disease attributable to diabetes mellitus has increased over the past decade. 4 An increase in the prevalence of obesity has contributed to the rise in diabetes mellitus. Additionally, obesity independently increases the risk of cardiovascular disease in patients with diabetes mellitus. 5 Although strict glycemic control unequivocally reduces the microvascular complications of diabetes mellitus, the macrovascular benefits of intensive therapy have been difficult to establish, with conflicting results from large clinical trials. 6–9 Multifactorial strategies are recommended to reduce cardiovascular risk in diabetes mellitus through enhanced gly-cemic control, blood pressure reduction, lipid management, weight loss, and physical activity. 10 Unfortunately, despite aggressive interventions for hyperglycemia, <50% of patients achieve standard HbA1c targets with conventional therapy. 11 Polypharmacy is required to achieve glycemic control in the majority of patients within 3 years of diagnosis. 12 Although combinations of drug classes can synergistically target multiple pathophysiological defects, novel therapies are required to manage diabetes mellitus and mitigate cardiovascular risks. Dipeptidyl-peptidase IV (DPP-IV) inhibitor and glu-cagon-like peptide-1 (GLP-1) receptor agonist incretin therapies were developed to complement conventional treatment options for diabetes mellitus. Despite promising initial reports of cardioprotective effects, DPP-IV inhibitors have failed to demonstrate improved cardiovascular outcomes in large clinical trials. 13–15 Randomized studies to evaluate cardiovascular outcomes associated with GLP-1 receptor agonists are currently underway. This review presents an overview of GLP-1 receptor agonist therapy in the treatment of patients with type 2 diabetes mel-litus, focusing on the clinical evidence for currently available therapies, adverse effects, and the implications of therapy for patients at high risk of cardiovascular disease. Type 2 diabetes mellitus is associated with a complex array of metabolic derangements, principally characterized by a progressive hormonal failure of adequate insulin release from pancreatic β-cells. At first diagnosis of diabetes mellitus, β-cell function is typically 50% lower than baseline and progressively declines despite treatment. 16 Other pathophysiolog-ical defects include inappropriate glucagon release, aberrant hepatic glucose output, insulin resistance, increased lipolysis, and …