Indications
Linagliptin is prescribed for managing type II diabetes mellitus when used in combination with diet and exercise. It is not suitable for treating type I diabetes or diabetic ketoacidosis. In January 2020, the FDA approved a combination product containing empagliflozin, linagliptin, and metformin, aimed at enhancing glycemic control in adults with type II diabetes mellitus when used adjunctively with lifestyle modifications.
Pharmacodynamics
Administration of a 5mg oral dose of linagliptin achieves more than 80% inhibition of dipeptidyl peptidase 4 (DPP-4) for a duration of 24 hours or longer. This inhibition elevates levels of glucagon-like peptide 1 (GLP-1), which subsequently leads to reductions in glycosylated hemoglobin and fasting plasma glucose.
Absorption
Linagliptin exhibits an oral bioavailability of approximately 30%. This indicates that 30% of the administered dose reaches systemic circulation in an active form.
Metabolism
After oral administration, linagliptin is predominantly excreted unchanged, primarily via feces, with 90% of the dose appearing in both urine and feces. The major metabolite identified in plasma is CD1790, while M489 is the main metabolite recovered post-excretion. Additional metabolites result from processes such as oxidation, oxidative degradation, N-acetylation, glucuronidation, and cysteine adduct formation, though their structures remain undetermined. Cytochrome P450 3A4, aldo-keto reductases, and carbonyl reductases are involved in the metabolic processing of linagliptin.
Mechanism of Action
Linagliptin functions as a competitive and reversible inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). By inhibiting DPP-4, Linagliptin delays the degradation of incretin hormones, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These incretin hormones are essential for stimulating insulin secretion from the pancreatic beta cells while simultaneously inhibiting glucagon release. Consequently, this dual action serves to reduce glycogen breakdown in the liver and enhance insulin secretion in response to glucose levels.
