The current epidemics of excessive weight and type 2 diabetes mellitus (T2DM) cause significant morbidity and mortality. T2DM frequently coexists with excess weight as well as hypertension and dyslipidemia, placing a significant percentage of the population at an elevated risk of cardiovascular disease. Maintaining effective glycemic control is linked with a diminished risk of developing microvascular complications, and recent studies have shown it may also reduce overall macro vascular complications. Reduction of associated risk factors, including those related to excessive weight, high blood pressure, and dyslipidemia, are also necessary to meaningfully decrease cardiovascular risk. Agents that can improve glycemia with weight neutrality or weight loss could offer additional benefit to overweight patients with T2DM. Although the major pathophysiologic defects in T2DM are recognized to be beta-cell dysfunction and peripheral insulin resistance, derangements in the incretin system may contribute as well. Antidiabetes agents targeting this system include dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Both classes have been shown to significantly reduce hyperglycemia. GLP-1 receptor agonists also promote significant weight loss and have potentially beneficial effects on cardiovascular risk markers.