Evaluation of the potential for steady-state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects

Curr Med Res Opin. 2009 Aug;25(8):1963-72. doi: 10.1185/03007990903094361.


Objective: Linagliptin (BI 1356) is a novel, orally available inhibitor of dipeptidyl peptidase-4 (DPP-4). Linagliptin improves glycaemic control in type 2 diabetic patients by increasing the half-life of the incretin hormone glucagon-like peptide-1 (GLP-1). Linagliptin is expected to be used as monotherapy or in combination with other antihyperglycaemic agents. This study was conducted to investigate potential pharmacokinetic or pharmacodynamic interactions between linagliptin and metformin.

Methods: This randomised, monocentric, open-label, two-way crossover design study was conducted in 16 healthy male subjects. Linagliptin (10 mg/day) and metformin (850 mg three times daily) were each administered alone and concomitantly. The steady-state pharmacokinetics of linagliptin and metformin and the inhibition of DPP-4 activity were determined at the end of each dosing period.

Results: Co-administration of linagliptin had no apparent effect on metformin exposure (metformin AUC(tau,ss); geometric mean ratio [GMR] co-administration:individual administration was 1.01; 90% confidence interval [CI] was 0.89-1.14). Effects on maximum concentration (C(max,ss)) were small (GMR: 0.89; 90% CI: 0.78-1.00). Co-administration of metformin did not significantly affect C(max,ss) of linagliptin (GMR: 1.03; 90% CI: 0.86-1.24), but increased AUC(tau)(,ss) by 20% (GMR: 1.20; 90% CI: 1.07-1.34). Metformin alone had no effect on DPP-4 activity, and the inhibition of DPP-4 caused by linagliptin was not affected by concomitant administration of metformin. Tolerability was good whether linagliptin and metformin were administered alone or concomitantly. No serious adverse events occurred and the frequency of adverse events was low; 7 events in 6 subjects. The most frequent events were related to the gastrointestinal tract, as expected with metformin. Importantly, no subjects experienced signs or symptoms relating to episodes of hypoglycaemia.

Conclusion: In this small, multiple dose study carried out in healthy subjects, co-administration of linagliptin with metformin did not have a clinically relevant effect on the pharmacokinetics or pharmacodynamics of either agent. This study suggests linagliptin and metformin can safely be administered concomitantly in type 2 diabetes patients without dose adjustment; larger, longer-term clinical trials in diabetic patients are underway.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cross-Over Studies
  • Dipeptidyl-Peptidase IV Inhibitors / administration & dosage
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Interactions*
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology*
  • Linagliptin
  • Male
  • Metformin / administration & dosage
  • Metformin / pharmacokinetics*
  • Metformin / pharmacology*
  • Middle Aged
  • Purines / administration & dosage
  • Purines / pharmacokinetics*
  • Purines / pharmacology*
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacokinetics*
  • Quinazolines / pharmacology*
  • Young Adult


  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Purines
  • Quinazolines
  • Linagliptin
  • Metformin