Indications
Sitagliptin is prescribed as an adjunct therapy to diet and exercise for enhancing glycemic control in adults with type 2 diabetes mellitus. It is not recommended for use in individuals with type 1 diabetes or those with a history of pancreatitis. Additionally, sitagliptin can be used in combination with other medications, such as metformin or ertugliflozin, to further improve glycemic outcomes.
Pharmacodynamics
Sitagliptin functions by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which results in increased levels of incretin hormones including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This inhibition leads to reduced glucagon levels and an enhanced insulin response to glucose, contributing to improved blood sugar regulation.
Absorption
Sitagliptin exhibits an oral bioavailability of 87%. Its pharmacokinetic profile is consistent regardless of food intake, indicating that it can be administered with or without meals. The maximum plasma concentration of sitagliptin is typically achieved approximately two hours post-dose.
Metabolism
Sitagliptin undergoes minimal metabolism, with 79% of the administered dose being excreted in the urine as the unchanged drug. The primary metabolic pathways are facilitated by the cytochrome P450 enzymes, mainly CYP3A4 and to a lesser extent CYP2C8. After 18 hours, 81% of the dose remains unchanged. Minor metabolites include the M1 through M6 forms, each representing a small percentage of the dose and resulting from various metabolic processes such as sulfation, desaturation, cyclization, glucuronidation, carbamoylation, and hydroxylation. Of note, M2 and M5 metabolites are isomers, with M2 being the cis and M5 the trans isomer.
Mechanism of Action
Sitagliptin functions by inhibiting the enzyme DPP-4, resulting in a deceleration of the inactivation of incretins, such as GLP-1 and GIP. Incretins play a crucial role in glucose homeostasis by being secreted throughout the day and increasing in response to meal intake. By reducing the degradation of incretins, sitagliptin enhances insulin production and reduces glucagon release, which occurs in a glucose-dependent manner. These mechanisms collectively contribute to improved blood glucose regulation, as evidenced by decreased levels of glycosylated hemoglobin (HbA1c).
