Efficacy and safety of liraglutide versus placebo added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes: a randomized, placebo-controlled trial

A Ahmann, H W Rodbard, J Rosenstock, J T Lahtela, L de Loredo, K Tornøe, A Boopalan, M A Nauck, NN2211-3917 Study Group, A Ahmann, H W Rodbard, J Rosenstock, J T Lahtela, L de Loredo, K Tornøe, A Boopalan, M A Nauck, NN2211-3917 Study Group

Abstract

Aim: To confirm the superiority, compared with placebo, of adding liraglutide to pre-existing basal insulin analogue ± metformin in adults with inadequately controlled type 2 diabetes [glycated haemoglobin (HbA1c) 7.0-10.0% (53-86 mmol/mol)].

Methods: In this 26-week, double-blind, parallel-group study, conducted in clinics or hospitals, 451 subjects were randomized 1 : 1 to once-daily liraglutide 1.8 mg (dose escalated from 0.6 and 1.2 mg/day, respectively, for 1 week each; n = 226) or placebo (n = 225) added to their pre-existing basal insulin analogue (≥20 U/day) ± metformin (≥1500 mg/day). After randomization, insulin adjustments above the pre-study dose were not allowed. The primary endpoint was HbA1c change.

Results: After 26 weeks, HbA1c decreased more with liraglutide [-1.3% (-14.2 mmol/mol)] than with placebo [-0.1% (-1.2 mmol/mol); p < 0.0001]. More subjects on liraglutide reached HbA1c targets: <7.0% (59% vs 14%; p < 0.0001) and ≤6.5% (43% vs 4%; p < 0.0001) using slightly less insulin (35.8 IU vs 40.1 IU). Greater decreases from baseline (estimated treatment differences vs placebo; p < 0.0001) occurred in fasting plasma glucose (-1.3 mmol/l), seven-point glucose profiles (-1.6 mmol/l), body weight (-3.1 kg) and systolic blood pressure (-5.0 mmHg). Transient gastrointestinal adverse events (nausea: 22.2% vs 3.1%) and minor hypoglycaemia (18.2% vs 12.4%) were more frequent with liraglutide than placebo, and pulse increased (4.5 beats/min) compared with placebo. No severe hypoglycaemia or pancreatitis occurred.

Conclusions: Adding liraglutide to a basal insulin analogue ± metformin significantly improved glycaemic control, body weight and systolic blood pressure compared with placebo. Typical gastrointestinal symptoms and minor hypoglycaemia were more frequent with liraglutide.

Keywords: GLP-1 analogue; glycaemic control; incretin therapy; insulin therapy; randomised trial; weight loss therapy.

© 2015 John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Primary and secondary outcomes from randomization to 26 weeks. Estimated mean change [standard error of the mean (s.e.m.)] in (A) glycated haemoglobin (HbA1c) and (B) fasting plasma glucose (FPG), (C) ratio of the mean basal insulin analogue dose to baseline and (D) estimated mean change (s.e.m.) body weight with liraglutide (closed circles) or placebo (open squares).

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