Incretin hormones, such as glucagon-like peptide-1 (GLP-1), play a crucial role in modulating insulin and glucagon secretion, as well as regulating appetite, gastric emptying, and pancreatic beta cell function. The pathophysiology of type 2 diabetes mellitus (T2DM) is complex and includes impaired incretin response, among other metabolic abnormalities. Incretin-based treatments for T2DM, such as GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, mimic or prolong the actions of incretin hormones and function in a glucose-dependent manner, thereby reducing hyperglycemia and avoiding hypoglycemia. There are important mechanistic differences between the GLP-1 receptor agonists and the DPP-4 inhibitors. DPP-4 inhibitors protect endogenous GLP-1 from DPP-4 degradation, thereby achieving a physiologic level of GLP-1. In contrast, GLP-1 receptor agonists act directly on the GLP-1 receptor, achieving a pharmacologic level of GLP-1 activity. These different mechanisms yield different effects on diabetes and weight loss. Incretin-based treatments may improve beta cell function, and, while not indicated for these effects, GLP-1 receptor agonists may also promote satiety, reduce weight, slow gastric emptying, and possibly improve hypertension and triglyceride levels; these characteristics are absent with DPP-4 inhibitors. Therefore, GLP-1 receptor agonists can be an appropriate clinical choice for glycemic control in patients with T2DM, especially in those who would benefit from weight loss or are prone to hypoglycemia.