Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study

Summary

Background

The frequency of obesity has risen dramatically in recent years but only few safe and effective drugs are currently available. We assessed the effect of liraglutide on bodyweight and tolerability in obese individuals without type 2 diabetes.

Methods

We did a double-blind, placebo-controlled 20-week trial, with open-label orlistat comparator in 19 sites in Europe. 564 individuals (18–65 years of age, body-mass index 30–40 kg/m²) were randomly assigned, with a telephone or web-based system, to one of four liraglutide doses (1·2 mg, 1·8 mg, 2·4 mg, or 3·0 mg, n=90–95) or to placebo (n=98) administered once a day subcutaneously, or orlistat (120 mg, n=95) three times a day orally. All individuals had a 500 kcal per day energy-deficit diet and increased their physical activity throughout the trial, including the 2-week run-in. Weight change analysed by intention to treat was the primary endpoint. An 84-week open-label extension followed. This study is registered with ClinicalTrials.gov, number NCT00422058.

Findings

Participants on liraglutide lost significantly more weight than did those on placebo (p=0·003 for liraglutide 1·2 mg and p<0·0001 for liraglutide 1·8–3·0 mg) and orlistat (p=0·003 for liraglutide 2·4 mg and p<0·0001 for liraglutide 3·0 mg). Mean weight loss with liraglutide 1·2–3·0 mg was 4·8 kg, 5·5 kg, 6·3 kg, and 7·2 kg compared with 2·8 kg with placebo and 4·1 kg with orlistat, and was 2·1 kg (95% CI 0·6–3·6) to 4·4 kg (2·9–6·0) greater than that with placebo. More individuals (76%, n=70) lost more than 5% weight with liraglutide 3·0 mg that with placebo (30%, n=29) or orlistat (44%, n=42). Liraglutide reduced blood pressure at all doses, and reduced the prevalence of prediabetes (84–96% reduction) with 1·8–3·0 mg per day. Nausea and vomiting occurred more often in individuals on liraglutide than in those on placebo, but adverse events were mainly transient and rarely led to discontinuation of treatment.

Interpretation

Liraglutide treatment over 20 weeks is well tolerated, induces weight loss, improves certain obesity-related risk factors, and reduces prediabetes.

Funding

Novo Nordisk A/S, Bagsvaerd, Denmark.

Introduction

Over the past 20 years, the rate of obesity has risen three-fold and is more than 30% in some European countries.¹ Around 50% of all adults in Europe are classified as overweight.2, 3 Obesity increases the risk of hypertension, diabetes, and atherosclerosis, all risk factors for the leading cause of death worldwide—cardiovascular disease.4, 5 Moreover, obesity is associated with a reduced quality of life.6, 7 Few safe and effective drugs are currently available for the treatment of obesity. Therefore, alternative approaches to weight loss that are safe and well tolerated and that can lower the risks associated with obesity are needed.

Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue with a 97% structural homology to human GLP-1, a gut-derived incretin hormone. Native GLP-1 has a short elimination half-life of 1–2 min, whereas liraglutide has a long half-life of about 13 h and can be administered once a day by subcutaneous injection.8, 9 Liraglutide was initially developed for the treatment of type 2 diabetes mellitus and has shown benefits for glycaemic control at doses up to 1·8 mg a day.10, 11, 12, 13, 14 Because liraglutide causes a dose-dependent weight loss, decreasing the concentration of glycosylated haemoglobin (HbA_1c),13, 15, 16 as well as improving β-cell function11, 17, 18 and systolic blood pressure,¹³ it could be an attractive treatment option for both type 2 diabetes and obesity.

The underlying mechanisms that mediate the effects of weight reduction of liraglutide are most probably a combination of effects on the gastrointestinal tract and the brain. Native GLP-1 suppresses appetite and energy intake in both normal-weight and obese individuals,19, 20, 21 as well as in people with type 2 diabetes,22, 23, 24 and delays gastric emptying.25, 26 Weight loss and decreased food intake have also been shown in studies with liraglutide in minipigs and rats.27, 28, 29 Feeding frequency and meal size were reduced in the minipig obesity model during liraglutide treatment.²⁷ GLP-1 receptors are expressed in several brainstem nuclei involved in appetite regulation,²⁹ and subcutaneously administered liraglutide might also reach these sites.

Our aim was to assess the effect on bodyweight of liraglutide (at doses up to 3·0 mg per day), in combination with an energy-deficit low-fat diet and physical activity counselling, in obese individuals. Liraglutide was compared with the approved weight-loss agent orlistat, a gastrointestinal lipase inhibitor. The safety and tolerability of doses of liraglutide higher than those previously studied in individuals with type 2 diabetes were also assessed.