Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark.
Drug Saf. 2019 Aug;42(8):957-971. doi: 10.1007/s40264-019-00812-7.
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.
肥胖症及相关合并症的患病率在全球范围内呈上升趋势。此外，临床意义上的体重减轻很难实现，尤其是通过饮食和运动等持续的生活方式改变来维持。肥胖症的药物治疗是一种非侵入性治疗方法，作为生活方式改变的辅助手段，但目前批准的抗肥胖症药物很少。本文综述了主要的抗肥胖症药物，以及长效胰高血糖素样肽-1 受体激动剂（GLP-1 RAs）利拉鲁肽和司美格鲁肽（利拉鲁肽的改良版本，半衰期更长，受体亲和力增加三倍）的获益-风险概况。一般来说，GLP-1 RAs 耐受性良好，可显著减轻体重并降低合并症的风险。利拉鲁肽 3.0mg/天的研究显示，1 至 3 年的试验中，平均安慰剂校正体重减轻 5.5kg（范围为 4.6-5.9）。一项使用司美格鲁肽 0.4mg 每日一次的试验报告称，1 年后平均体重减轻 11.6%（~13.1kg）。此外，在与利拉鲁肽的头对头比较中，司美格鲁肽诱导的安慰剂校正体重减轻幅度大了约 6 个百分点（分别为 11.6%和 5.5%的体重减轻）。两种药物的安全性谱相似，最常见的不良反应是短暂的胃肠道疾病。最长的运行试验和最近的试验没有提出任何新的安全问题。需要进行长期试验和上市后监测，以充分评估长期疗效和安全性。未来涉及调节能量平衡的模拟肠道激素的联合治疗以及以运动形式的额外生活方式改变可能会进一步提高疗效。
