Profil Institute for Clinical Research, Chula Vista, CA, USA.
Center for Weight Management, Department of Diabetes and Endocrinology, Scripps Clinic Del Mar, San Diego, CA, USA.
Diabetes Obes Metab. 2016 Jun;18(6):558-70. doi: 10.1111/dom.12657.
Pharmacotherapy directed toward reducing body weight may provide benefits for both curbing obesity and lowering the risk of obesity-associated comorbidities; however, many weight loss medications have been withdrawn from the market because of serious adverse effects. Examples include pulmonary hypertension (aminorex), cardiovascular toxicity, e.g. flenfluramine-induced valvopathy, stroke [phenylpropanolamine (PPA)], excess non-fatal cardiovascular events (sibutramine), and neuro-psychiatric issues (rimonabant; approved in Europe, but not in the USA). This negative experience has helped mould the current drug development and approval process for new anti-obesity drugs. Differences between the US Food and Drug Administration (FDA) and the European Medicines Agency, however, in perceptions of risk-benefit considerations for individual drugs have resulted in discrepancies in approval and/or withdrawal of weight-reducing medications. Thus, two drugs recently approved by the FDA, i.e. lorcaserin and phentermine + topiramate extended release, are not available in Europe. In contrast, naltrexone sustained release (SR)/bupropion SR received FDA approval, and liraglutide 3.0 mg was recently approved in both the USA and Europe. Regulatory strategies adopted by the FDA to manage the potential for uncommon but potentially serious post-marketing toxicity include: (i) risk evaluation and mitigation strategy programmes; (ii) stipulating post-marketing safety trials; (iii) considering responder rates and limiting cumulative exposure by discontinuation if weight loss is not attained within a reasonable timeframe; and (iv) requiring large cardiovascular outcome trials before or after approval. We chronicle the adverse effects of anti-obesity pharmacotherapy and consider how the history of high-profile toxicity issues has shaped the current regulatory landscape for new and future weight-reducing drugs.
药物治疗旨在减轻体重，可能有益于控制肥胖和降低肥胖相关合并症的风险；然而，许多减肥药因严重不良反应已退出市场。例如，肺动脉高压（安非拉酮）、心血管毒性，如芬氟拉明引起的瓣膜病、中风[苯丙醇胺（PPA）]、非致命性心血管事件过多（西布曲明）和神经精神问题（利莫那班；在欧洲获得批准，但未在美国获得批准）。这段负面经历帮助塑造了目前新减肥药的开发和审批流程。然而，美国食品和药物管理局（FDA）和欧洲药品管理局（EMA）对个别药物风险-效益的看法存在差异，导致了减肥药的批准和/或撤市存在差异。因此，美国食品和药物管理局最近批准的两种药物，即lorcaserin 和 phentermine + topiramate extended release，在欧洲不可用。相比之下，纳曲酮缓释片（SR）/安非他酮 SR 获得了 FDA 的批准，利拉鲁肽 3.0mg 最近在美国和欧洲获得批准。FDA 采用的监管策略来管理罕见但潜在严重的上市后毒性的潜在风险，包括：（i）风险评估和缓解策略计划；（ii）规定上市后安全性试验；（iii）考虑应答率并在合理时间内未达到减肥目标时通过停药限制累积暴露；以及（iv）在批准前或批准后进行大型心血管结局试验。我们记录了抗肥胖药物治疗的不良反应，并考虑了高知名度毒性问题的历史如何塑造了新的和未来减肥药物的当前监管格局。
