The history of anti-obesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials.gov (2012-2024). We identified 53 phase 3 and phase 2 trials, with 36 emerging anti-obesity drugs or combinations thereof and four withdrawn or terminated trials. Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide, survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate. Completed phase 2 trials on incretin-based therapies showed a mean percent weight loss of 7.4-24.2%. Almost half of the drugs undergoing phase 2 trials were incretin analogs. The obesity drug pipeline is expanding rapidly, with the most promising results reported with incretin analogs. Data on mortality and obesity-related complications, such as cardio-renal-metabolic events, are needed. Moreover, long-term follow-up data on the safety and efficacy of weight maintenance with novel obesity pharmacotherapies, along with studies focused on under-represented populations, cost-effectiveness assessments, and drug availability, are needed to bridge the care gap for patients with obesity. Significance Statement Obesity is the epidemic of the 21st century. Except for the newer injectable medications, drugs with suboptimal efficacy have been available in the clinician's armamentarium. However, emerging alternatives of novel agents and combinations populate the obesity therapeutic pipeline. This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives.

中文翻译：

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新兴的肥胖药物疗法：系统评价。


抗肥胖药物疗法的历史充满了失望，常常与促进减肥的社会压力以及体重过重意味着缺乏意志力的信念纠缠在一起。然而，新兴的药物疗法类别带来了降低肥胖率的希望。这项针对超重/肥胖成人的 2 期和 3 期试验的系统综述通过搜索 Medline、Embase 和 ClinicalTrials，研究了新型减肥药物疗法与安慰剂/对照或食品和药物管理局批准的减肥药物的效果。政府（2012-2024）。我们确定了 53 项 3 期和 2 期试验，其中 36 种新兴抗肥胖药物或其组合，以及 4 项撤回或终止的试验。口服索马鲁肽 50 mg 是唯一已完成 3 期试验的药物。目前有 14 项正在进行的 3 期试验，涉及胰高血糖素样肽 1 (GLP-1) 受体激动剂 (RA)（ecnoglutide、orforglipron、TG103）、GLP-1 RA/胰岛淀粉样多肽激动剂 (CagriSema)、GLP-1/胰高血糖素 RA（ mazdutide、survodutide）、GLP-1/葡萄糖依赖性促胰岛素多肽和胰高血糖素 RA（瑞他鲁肽）、达格列净以及西布曲明/托吡酯组合。已完成的基于肠促胰岛素疗法的 2 期试验显示，平均体重减轻百分比为 7.4-24.2%。几乎一半正在进行二期试验的药物是肠促胰岛素类似物。肥胖药物管道正在迅速扩大，其中最有希望的结果是肠促胰岛素类似物。需要有关死亡率和肥胖相关并发症（例如心肾代谢事件）的数据。 此外，需要关于新型肥胖药物疗法维持体重的安全性和有效性的长期随访数据，以及针对代表性不足的人群、成本效益评估和药物可用性的研究，以弥合患者的护理差距与肥胖。意义陈述 肥胖是21世纪的流行病。除了较新的注射药物外，临床医生的军备库中还提供了疗效欠佳的药物。然而，新兴药物和组合的替代品正在填充肥胖治疗渠道。本系统综述确定了正在进行或已完成 2 期和 3 期临床试验的新兴药物疗法的状态和作用机制。本文提供的信息进一步加深了对肥胖管理的理解，意味着直接的临床影响并刺激了研究举措。