Ioannides-Demos Lisa L, Proietto Joseph, Tonkin Andrew M, McNeil John J
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
Drug Saf. 2006;29(4):277-302. doi: 10.2165/00002018-200629040-00001.
Some of the medications used for weight loss in the management of obesity have been associated with unacceptable morbidity and mortality. Safety concerns have led to the withdrawal of aminorex, followed by the fenfluramines in 1997, and phenylpropanolamine (norephedrine) in 2000. Aminorex was associated with an increased prevalence of primary pulmonary hypertension (PPH), fenfluramines with an increased prevalence of PPH and valvulopathy, and phenylpropanolamine with an increased risk of haemorrhagic stroke. Several studies have investigated the safety of the fenfluramines, yet the benefit-risk profile has not been conclusively quantified. This is due to several deficiencies in the published studies, including a lack of data on the baseline prevalences of comorbid conditions in obese subjects, and potential confounders and biases in the study designs. Although several studies and systematic reviews support an increased risk of PPH and valvulopathy in patients who have taken fenfluramines, without knowledge of the background prevalence it is not possible to determine if the exposure preceded the outcome. The population at higher risk of these adverse effects includes those taking higher doses or with a longer duration of exposure to fenfluramines and those with pre-existing cardiac disease or a genetic predisposition. Patients exposed to fenfluramines continue to be monitored, with some follow-up studies indicating no overall worsening in valvulopathy over time. There are limited efficacy and safety data for amfepramone (diethylpropion) and phentermine and their approval for the management of obesity is limited to short-term use. Orlistat and sibutramine are the only currently approved medications for long-term management of obesity. Although the benefit-risk profiles of sibutramine and orlistat appear positive, sibutramine continues to be monitored because of long-term safety concerns. The safety and efficacy of currently approved drug therapies have not been evaluated in children and elderly patient populations and there is limited information in adolescents, whilst the long-term safety of current and potential new drug therapies in adults will require several years of postmarketing surveillance to fully elucidate their adverse effect profiles.
在肥胖症治疗中，一些用于减肥的药物与不可接受的发病率和死亡率相关。安全问题导致氨苯唑啉退市，随后1997年氟苯丙胺退市，2000年苯丙醇胺（去甲麻黄碱）退市。氨苯唑啉与原发性肺动脉高压（PPH）患病率增加有关，氟苯丙胺与PPH和瓣膜病患病率增加有关，苯丙醇胺与出血性中风风险增加有关。多项研究调查了氟苯丙胺的安全性，但获益风险情况尚未得到最终量化。这是由于已发表研究存在若干缺陷，包括缺乏肥胖受试者合并症基线患病率的数据，以及研究设计中存在潜在的混杂因素和偏差。尽管多项研究和系统评价支持服用氟苯丙胺的患者发生PPH和瓣膜病的风险增加，但在不知背景患病率的情况下，无法确定暴露是否先于结局。这些不良反应风险较高的人群包括服用高剂量或长期接触氟苯丙胺的人群以及患有心脏病或有遗传易感性的人群。接触氟苯丙胺的患者仍在接受监测，一些随访研究表明瓣膜病总体上并未随时间推移而恶化。安非拉酮（二乙胺苯丙酮）和苯丁胺的疗效和安全性数据有限，它们被批准用于肥胖症治疗仅限于短期使用。奥利司他和西布曲明是目前仅有的被批准用于肥胖症长期治疗的药物。尽管西布曲明和奥利司他的获益风险情况似乎是积极的，但由于长期安全性问题，西布曲明仍在接受监测。目前批准的药物疗法的安全性和有效性尚未在儿童和老年患者群体中进行评估，青少年中的信息有限，而目前和潜在的新药疗法在成人中的长期安全性将需要数年的上市后监测才能充分阐明其不良反应情况。
