Dipeptidyl Peptidase-4 Inhibition beyond Glycemic Control: Unraveling the Antihypertensive Effects of Sitagliptin

Dipeptidyl peptidase-4 (DPP-4) inhibitors have established their role as effective oral antidiabetic agents by enhancing endogenous incretin activity and improving glycemic control. However, growing evidence suggests that their pharmacological impact extends far beyond glucose regulation. Sitagliptin, one of the most widely used DPP-4 inhibitors, has emerged as a potential modulator of cardiovascular function, particularly blood pressure homeostasis. This review synthesizes current clinical, preclinical, and mechanistic insights into the antihypertensive effects of sitagliptin. Potential underlying mechanisms include natriuretic and vasodilatory actions mediated through GLP-1–dependent and independent pathways, attenuation of oxidative stress and inflammation, improved endothelial function, and modulation of the renin–angiotensin–aldosterone system. We also highlight inconsistencies in human data, dose-dependent variations, and the need to distinguish direct vascular effects from those secondary to metabolic improvements. Understanding these pleiotropic actions of sitagliptin may have important therapeutic implications for patients with type 2 diabetes and comorbid hypertension. Future well-designed trials are warranted to clarify its cardiovascular benefits, optimize treatment strategies, and guide patient selection.