ArticlesEffects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study
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 (HbA1c),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.
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Patients
Men and women aged 18–65 years, with body-mass index (BMI) of 30–40 kg/m2, stable bodyweight (<5% reported change during the previous 3 months), and fasting plasma glucose of less than 7 mmol/L at run-in, were recruited from 19 clinical research sites in eight European countries. Key exclusion criteria included known type 1 or 2 diabetes mellitus, obesity induced by drug treatment, use of approved weight-lowering pharmacotherapy or participation in a clinical weight control study within the
Results
135 men and 429 women (n=564) were randomly assigned and 472 (84%) completed the trial (figure 1). Three individuals treated with liraglutide (1·2 mg, 2·4 mg, and 3·0 mg) were excluded from the intention-to-treat population because of missing post-baseline weight data. Major protocol deviations, not necessarily leading to withdrawal from study, included non-compliance with eligibility criteria (n=3), assessments at week 20 outside visit window (n=12), treatment compliance issues (n=7), and
Discussion
Treatment with liraglutide, in addition to an energy-deficit diet and exercise programme, led to a sustained, clinically relevant, dose-dependent weight loss that was significantly greater than that with placebo (all doses) and orlistat (vs liraglutide 2·4 mg and 3·0 mg). Mean weight loss with liraglutide 3·0 mg was 7·2 kg. Weight loss was accompanied by reductions in waist circumference, systolic and diastolic blood pressure, and frequency of both metabolic syndrome and prediabetes.
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