Benefit-Risk Assessment of Obesity Drugs: Focus on Glucagon-like Peptide-1 Receptor Agonists

The prevalence of obesity and related comorbidities is increasing worldwide. Furthermore, clinically meaningful body weight losses has proven difficult to achieve and especially to maintain through sustained lifestyle change in the form of diet and exercise. Pharmacotherapy against obesity is a non-invasive treatment as an adjunct to lifestyle changes, but approved anti-obesity drugs are currently few. This article reviews the major anti-obesity drugs and the benefit-risk profiles of the long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and semaglutide (a modified version of liraglutide with longer half-life and tripled receptor affinity). Generally, GLP-1 RAs are well tolerated and induce significant weight loss and lowering of comorbidities. Studies with liraglutide 3.0 mg/day have shown an average placebo-subtracted weight loss of 5.5 kg (range 4.6-5.9) in 1- to 3-year duration trials. One trial using semaglutide 0.4 mg once daily reported an average weight loss of 11.6% (~ 13.1 kg) after 1 year. Furthermore, semaglutide induced a ~ 6 percentage point larger placebo-subtracted body weight loss in a head-to-head comparison with liraglutide (11.6 vs. 5.5% weight loss, respectively). The safety profiles for both drugs were similar, with transient gastrointestinal disorders being the most commonly reported adverse events. The longest running trial and the most recent trials have not raised any new safety concerns. Long-term trials and post-marketing surveillance is warranted to fully assess both long-term efficacy and safety. Future combinational therapies of mimicked gut hormones involved in regulation of energy homeostasis and/or additional lifestyle change in the form of exercise might further improve efficacy.