Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study

Diabetes Obes Metab. 2011 Jan;13(1):65-74. doi: 10.1111/j.1463-1326.2010.01326.x.


Aim: To evaluate the efficacy and safety of the potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin administered as add-on therapy to metformin in patients with type 2 diabetes with inadequate glycaemic control.

Methods: This 24-week, randomized, placebo-controlled, double-blind, parallel-group study was carried out in 82 centres in 10 countries. Patients with HbA1c levels of 7.0-10.0% on metformin and a maximum of one additional antidiabetes medication, which was discontinued at screening, continued on metformin ≥1500 mg/day for 6 weeks, including a placebo run-in period of 2 weeks, before being randomized to linagliptin 5 mg once daily (n = 524) or placebo (n = 177) add-on. The primary outcome was the change from baseline in HbA1c after 24 weeks of treatment, evaluated with an analysis of covariance (ANCOVA).

Results: Mean baseline HbA1c and fasting plasma glucose (FPG) were 8.1% and 9.4 mmol/l, respectively. Linagliptin showed significant reductions vs. placebo in adjusted mean changes from baseline of HbA1c (-0.49 vs. 0.15%), FPG (-0.59 vs. 0.58 mmol/l) and 2hPPG (-2.7 vs. 1.0 mmol/l); all p < 0.0001. Hypoglycaemia was rare, occurring in three patients (0.6%) treated with linagliptin and five patients (2.8%) in the placebo group. Body weight did not change significantly from baseline in both groups (-0.5 kg placebo, -0.4 kg linagliptin).

Conclusions: The addition of linagliptin 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin resulted in a significant and clinically meaningful improvement in glycaemic control without weight gain or increased risk of hypoglycaemia.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Glycated Hemoglobin A / drug effects*
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / pharmacology
  • Linagliptin
  • Male
  • Metformin / administration & dosage*
  • Metformin / pharmacology
  • Middle Aged
  • Purines / administration & dosage*
  • Purines / pharmacology
  • Quinazolines / administration & dosage*
  • Quinazolines / pharmacology
  • Young Adult


  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Purines
  • Quinazolines
  • Linagliptin
  • Metformin