Introduction
Linagliptin is a DPP-4 inhibitor developed by Boehringer Ingelheim for the treatment of type II diabetes . Linagliptin differs from other DPP-4 inhibitors in that it has a non-linear pharmacokinetic profile, is not primarily eliminated by the renal system, and obeys concentration dependant protein binding.
Uses
Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to manage hyperglycemia in patients with type 2 diabetes mellitus.
Linagliptin is indicated for the treatment of type II diabetes in addition to diet and exercise. It should not be used to treat type I diabetes or in diabetic ketoacidosis. An extended-release combination product containing empagliflozin, linagliptin, and metformin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively with diet and exercise.
Associated Conditions
Pharmacodynamics
A 5mg oral dose of linagliptin results in >80% inhibition of dipeptidyl peptidase 4 (DPP-4) for ≥24 hours. Inhibition of DPP-4 increases the concentration of glucagon-like peptide 1 (GLP-1), leading to decreased glycosylated hemoglobin and fasting plasma glucose.
Mechanism of Action
Linagliptin is a competitive, reversible DPP-4 inhibitor. Inhibition of this enzyme slows the breakdown of GLP-1 and glucose-dependant insulinotropic polypeptide (GIP). GLP-1 and GIP stimulate the release of insulin from beta cells in the pancreas while inhibiting release of glucagon from pancreatic beta cells. These effects together reduce the breakdown of glycogen in the liver and increase insulin release in response to glucose.
Absorption
Oral bioavailability of linagliptin is 30%.
Volume of Distribution
A single intravenous dose of 5mg results in a volume of distribution of 1110L. However an intravenous infusion of 0.5-10mg results in a volume of distribution of 380-1540L.
Protein Binding
Linagliptin is 99% protein bound at a concentration of 1nmol/L and 75-89% protein bound at a concentration of >30nmol/L.
Route of Elimination
84.7% of linagliptin is eliminated in the feces and 5.4% is eliminated in the urine.
Half Life
The terminal half life of linagliptin is 155 hours.
Clearance
Total clearance of linagliptin is 374mL/min.
Toxicity
No dosage adjustment is necessary based on race, age, weight, sex, renal impairment, or hepatic impairment.
Studies of efficacy and safety in pediatric populations were not included in the original drug approval but recent clinical trials show linagliptin to be well tolerated in patients 10 to 18 years old.
Animal studies showed an increased risk of lymphoma in female rats at over 200 times the clinical dose. Aside from this effect, linagliptin was not shown to be mutagenic, clastogenic, or have an effect on fertility.
Food Interactions
- Avoid excessive or chronic alcohol consumption. Chronic or binge drinking can increase the risk of serious side effects.
- Take with or without food. High fat meals reduce the maximum concentration and increase the AUC, but not to a clinically significant extent.
Dosage
Patients with renal impairment: No dose adjustment required. Linagliptin can be taken with or without a meal at any time of the day.
