linagliptin

linagliptin
IUPAC name	8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione
Tradename	Tradjenta, others
CAS number	668270-12-0
DrugBank	DB08882
UNII	3X29ZEJ4R2
ATC prefix	A10
ATC suffix	BH05

linagliptin. It is a medication used for the treatment of type 2 diabetes mellitus as an adjunct to diet and exercise. Classified as a dipeptidyl peptidase-4 inhibitor, it works by increasing levels of incretin hormones, which stimulate the release of insulin from the pancreas and lower the production of glucagon. It is typically administered orally as a once-daily tablet and is often used in combination with other antidiabetic agents like metformin.

Medical uses

Linagliptin is indicated to improve glycemic control in adults with type 2 diabetes mellitus, as recommended by bodies like the American Diabetes Association. It can be used as monotherapy or in dual therapy with agents such as metformin, sulfonylureas, or pioglitazone, and in triple therapy regimens. Clinical trials, including the CARMELINA trial, have demonstrated its efficacy in lowering hemoglobin A1c levels. It is not indicated for the treatment of type 1 diabetes or diabetic ketoacidosis, and its use requires consideration of the patient's renal function due to its unique pharmacokinetic profile.

Adverse effects

Common adverse reactions include nasopharyngitis, hypoglycemia (particularly when combined with a sulfonylurea or insulin), and arthralgia. More serious but rare risks include severe joint pain, pancreatitis, and hypersensitivity reactions such as angioedema. Post-marketing reports have noted cases of bullous pemphigoid, leading to monitoring by agencies like the U.S. Food and Drug Administration and the European Medicines Agency. The risk of heart failure was specifically assessed in the CARMELINA and CAROLINA cardiovascular outcome trials.

Pharmacology

As a competitive, reversible inhibitor of the enzyme dipeptidyl peptidase-4, linagliptin increases concentrations of active incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. This enhances glucose-dependent insulin secretion from pancreatic beta cells and suppresses glucagon release from pancreatic alpha cells. It exhibits nonlinear pharmacokinetics due to high binding to dipeptidyl peptidase-4 and is primarily eliminated via the enterohepatic circulation, with minimal renal excretion, distinguishing it from other agents in its class.

Chemistry

Linagliptin is a xanthine-based molecule with a chemical structure featuring a quinazoline group. Its systematic name is 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione. It is a crystalline solid with low aqueous solubility and is formulated as a film-coated tablet. The compound was discovered and optimized by researchers at Boehringer Ingelheim through structure-activity relationship studies targeting the dipeptidyl peptidase-4 enzyme's active site.

History

Linagliptin was discovered and developed by the pharmaceutical company Boehringer Ingelheim in collaboration with Eli Lilly and Company. It received its first global approval from the U.S. Food and Drug Administration in May 2011, followed by approvals from the European Medicines Agency and other regulatory bodies worldwide. Its development was part of a broader research effort into dipeptidyl peptidase-4 inhibitors following the discovery of sitagliptin by Merck & Co.. Key clinical trials establishing its safety and efficacy include the CARMELINA cardiovascular outcomes trial.

Society and culture

Marketed under the brand name **Tradjenta** in the United States and **Trajenta** in many other countries, linagliptin is a significant product for Boehringer Ingelheim. Its availability and cost are subjects of discussion within healthcare systems like the National Health Service in the United Kingdom. The medication has been included in treatment guidelines from organizations such as the American Association of Clinical Endocrinologists. It is also part of fixed-dose combination products, such as with empagliflozin, marketed as **Glyxambi**.

Category:Dipeptidyl peptidase-4 inhibitors Category:Antidiabetic drugs Category:Boehringer Ingelheim