A Comprehensive Review on Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: Mechanism, Therapeutic Applications, and Future Perspectives

Dipeptidyl peptidase 4 (DPP-4) inhibitors, or gliptins, are oral antidiabetic medications that enhance the production of incretin by inhibiting the degradation of endogenous “insulinotropic” GIP and GLP-1 in vivo (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide). Incretin hormones play a key role in the homeostasis of blood glucose and initiate the secretion of insulin in an incretin-dependent manner, while also inhibiting glucagon function. With DPP-4 inhibition, postprandial GIP and GLP-1 plasma levels are increased both in fasting and after meals, lowering the minimally hypoglycemic level of postprandial glycemic hunger. Their gastric emptying is also delayed, and they elicit satiety, which can negate their weight-neutral effects. DPP-4 inhibitors (pleiotropic) in addition to glycemic treatment exhibit pleiotropic characteristics (despite potential cardio- and/or normotensive effects). They have been associated with improved endothelial dysfunction, oxidative stress, and inflammation—all of which are essential in the prevention of diabetic complications. As for DPP-4 inhibitors (sitagliptin, a commonly used agent, saxagliptin, linagliptin, and alogliptin), they are commonly associated with mild to moderate side effects, with nasopharyngitis and gastrointestinal symptoms being the most prevalent among them. DPP-4 inhibitors play a prominent role due to their once-daily dosing, safety profile, and glucose-dependent mechanism of action, representing a standard in the management of type 2 diabetes. Their ability to tightly control blood glucose with minimal side effects, both in monotherapy and combination therapy, is why they are commonly employed. Determining whether they provide durable benefits in diabetic patients may require more research to answer questions regarding long-term cardiorenal outcomes.