Sitagliptin: A Comprehensive Review of Its Pharmacology, Clinical Development, Synthetic Evolution, and Analytical Approaches.

Abstract

Type 2 diabetes mellitus (T2DM) is a pathophysiological metabolic disorder characterized by insulin resistance, defective insulin secretion, and overproduction of glucose by the liver, which lead to chronic hyperglycemia and severe complications, such as cardiovascular disease, kidney injury, and neuropathy. Among the therapeutic options, incretin-based therapies have drawn considerable interest because of their capacity for stimulating glucose-dependent insulin secretion and inhibiting glucagon release. Sitagliptin is the first orally effective selective dipeptidyl peptidase-4 (DPP-4) inhibitor, enhances glycemic control by elevating the concentrations of active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Over the years, the route to sitagliptin has changed dramatically. The original process was a long multi-step sequence with modest yields and extensive waste generation. Later innovations brought in a more efficient, protecting group-free approach with rhodium-catalyzed asymmetric hydrogenation, which enhanced both yield and stereoselectivity. The latest industrial process uses an engineered biocatalyst, a transaminase enzyme, to produce sustainable large-scale supply with outstanding optical purity and very small environmental footprint. This review addresses the pharmacological profile, clinical evidence, evolution of synthesis, and analytical techniques concerning sitagliptin. It also emphasizes the drug as a paradigm for contemporary diabetes therapy and sustainable pharma manufacturing.