Efficacy and safety of linagliptin 2.5 mg twice daily versus 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, placebo-controlled trial

Abstract

Objective:

Glycaemic control in patients with type 2 diabetes (T2DM) is often not achieved or not sustained using monotherapy such as metformin, necessitating the addition of other antihyperglycaemic agents. Linagliptin, a dipeptidyl peptidase-4 inhibitor, is licensed for 5 mg once-daily dosing. As metformin is administered twice daily, a fixed-dose combination of these compounds would require twice-daily administration of linagliptin. This study evaluated whether 2.5 mg twice-daily dosing of linagliptin has comparable efficacy and safety to 5 mg once-daily dosing when given in addition to metformin twice daily in patients with inadequate glycaemic control.

Methods:

A total of 491 T2DM patients with glycated haemoglobin (HbA1c) 7.0–10.0% were randomised (5:5:1) to double-blind treatment with linagliptin 2.5 mg twice daily, 5 mg once daily or placebo, respectively, in addition to continuing metformin twice daily (≥1500 mg/day or maximally tolerated dose). The primary endpoint was change from baseline in HbA1c after 12 weeks. ClinicalTrials.gov, NCT01012037.

Results:

Mean baseline HbA1c for all patients was 7.97%. After 12 weeks, linagliptin 2.5 mg twice daily and 5 mg once daily both significantly reduced HbA1c (placebo-adjusted changes from baseline −0.74% (95% CI −0.97, −0.52) and −0.80% (95% CI −1.02, −0.58), respectively, both p < 0.0001). The treatment difference (twice daily - once daily) between the linagliptin regimens was 0.06 (95% CI −0.07, 0.19), the upper bound of which was less than the predefined noninferiority margin (0.35%). The overall incidence of adverse events with linagliptin 2.5 mg twice daily, 5 mg once daily and placebo was 43.0%, 34.8%, and 38.6% respectively. Hypoglycaemia was rare (3.1% with linagliptin 2.5 mg twice daily, 0.9% with 5 mg once daily, 2.3% with placebo) with no severe episodes. Study limitations include duration, patient population (mainly white) and absence of postprandial glucose data.

Conclusions:

Linagliptin 2.5 mg twice daily had non-inferior HbA1c-lowering effects after 12 weeks compared to 5 mg once daily, with comparable safety and tolerability, in T2DM patients inadequately controlled with metformin.

Trial registration: ClinicalTrials.gov identifier: NCT01012037.

Key words::

• Diabetes mellitus, type 2
• Dipeptidyl peptidase IV inhibitors
• Metformin
• Randomised controlled trial

Transparency

Declaration of funding

This study was sponsored by Boehringer Ingelheim, the manufacturer of linagliptin.

Declaration of financial/other relationships

S.A.R. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article. E.R. was an employee of Boehringer Ingelheim at the time this study was conducted. T.M., S.W-B. and H.-J.W. are employees of Boehringer Ingelheim. R.T. is a contract statistician working for Boehringer Ingelheim.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgements

The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Giles Brooke PhD of Envision Scientific Solutions during the preparation of this article.

Part of this study was presented at the 47th European Association for the Study of Diabetes Annual Meeting, Lisbon, Portugal, 12–16 September, 2011 (poster 831).