Ioannides-Demos Lisa L, Proietto Joseph, McNeil John J
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.
Drugs. 2005;65(10):1391-418. doi: 10.2165/00003495-200565100-00006.
Pharmacotherapy for the management of obesity is primarily aimed at weight loss, weight loss maintenance and risk reduction, and has included thyroid hormone, amphetamines, phentermine, amfepramone (diethylpropion), phenylpropanolamine, mazindol, fenfluramines and, more recently, sibutramine and orlistat. These agents decrease appetite, reduce absorption of fat or increase energy expenditure. Primary endpoints used to evaluate anti-obesity drugs most frequently include mean weight loss, percentage weight loss and proportion of patients losing >or=5% and >or=10% of initial bodyweight. Secondary endpoints may include reduction in body fat, risk factors for cardiovascular disease and the incidences of diseases such as diabetes mellitus. Most pharmacotherapies have demonstrated significantly greater weight loss in patients on active treatment than those receiving placebo in short-term (<or=1 year) randomised controlled trials of pharmacological treatment in conjunction with a calorie-controlled diet or lifestyle intervention. The evidence of long-term efficacy is limited to sibutramine (2 years) and orlistat (4 years). These are the only drugs currently approved for the long-term management of obesity in adults. Sibutramine recipients randomised following 6 months' treatment to either sibutramine or placebo demonstrated significantly better weight maintenance at 2 years than those taking placebo (p<0.001), with >or=10% loss of initial bodyweight in 46% of patients. For patients taking orlistat, weight loss was 2.2 kg greater than those on placebo at 4 years (p<0.001), with significantly more patients achieving >or=10% loss of initial bodyweight (26.2% and 15.6%, respectively; p<0.001). Other drugs that have been evaluated for weight loss include ephedrine, the antidepressants fluoxetine and bupropion, and the antiepileptics topiramate and zonisamide. Two clinical trials with fluoxetine both reported no significant difference in weight loss compared with placebo at 52 weeks. Clinical trials evaluating ephedrine, bupropion, topiramate and zonisamide have demonstrated significantly greater weight loss than placebo but have been limited to 16-26 weeks' treatment. A major obstacle to the evaluation of the clinical trials is the potential bias resulting from low study completion rates. Completion rates varied from 52.8% of phentermine recipients in a 9-month study, to 40% of fenfluramine recipients in a 24-week comparative study with phentermine and 18% of amfepramone recipients in a 24-week study. One-year completion rates range from 51% to 73% for sibutramine and from 66% to 85% for orlistat. Other potential sources of bias include run-in periods and subsequent patient selection based on compliance or initial weight loss. Several potential new therapies targeting weight loss and obesity through the CNS pathways or peripheral adiposity signals are in early phase clinical trials. Over the next decade the drug treatment of obesity is likely to change significantly because of the availability of new pharmacotherapies to regulate eating behaviours, nutrient partitioning and/or energy expenditure.
肥胖管理的药物治疗主要旨在减轻体重、维持体重减轻以及降低风险，所涉及的药物包括甲状腺激素、苯丙胺、苯丁胺、安非拉酮（二乙丙胺苯丙酮）、苯丙醇胺、马吲哚、芬氟拉明，以及最近的西布曲明和奥利司他。这些药物可降低食欲、减少脂肪吸收或增加能量消耗。用于评估抗肥胖药物的主要终点指标最常包括平均体重减轻、体重减轻百分比以及体重减轻≥5%和≥10%初始体重的患者比例。次要终点指标可能包括体脂减少、心血管疾病风险因素以及糖尿病等疾病的发病率。在短期（≤1年）将药物治疗与热量控制饮食或生活方式干预相结合的随机对照试验中，大多数药物疗法显示，接受积极治疗的患者比接受安慰剂的患者体重减轻更为显著。长期疗效的证据仅限于西布曲明（2年）和奥利司他（4年）。这两种药物是目前仅有的被批准用于成人肥胖长期管理的药物。接受西布曲明治疗6个月后随机分为继续使用西布曲明或改用安慰剂的患者，在2年时体重维持情况明显优于服用安慰剂的患者（p<0.001），46%的患者初始体重减轻≥10%。对于服用奥利司他的患者，4年时体重减轻比服用安慰剂的患者多2.2千克（p<0.001），实现初始体重减轻≥10%的患者明显更多（分别为26.2%和15.6%；p<0.001）。其他经评估用于减肥的药物包括麻黄碱、抗抑郁药氟西汀和安非他酮，以及抗癫痫药托吡酯和唑尼沙胺。两项关于氟西汀的临床试验均报告，在52周时与安慰剂相比体重减轻无显著差异。评估麻黄碱、安非他酮、托吡酯和唑尼沙胺的临床试验显示，体重减轻明显大于安慰剂，但治疗期限仅限于16 - 26周。评估这些临床试验的一个主要障碍是研究完成率低可能导致的潜在偏差。完成率在一项9个月的研究中，服用苯丁胺的患者为52.8%；在一项与苯丁胺进行的24周对比研究中，服用芬氟拉明的患者为4%；在一项24周的研究中，服用安非拉酮的患者为18%。西布曲明的1年完成率在51%至73%之间，奥利司他的1年完成率在66%至85%之间。其他潜在的偏差来源包括导入期以及随后基于依从性或初始体重减轻情况进行的患者选择。几种通过中枢神经系统途径或外周肥胖信号靶向减肥和肥胖的潜在新疗法正处于早期临床试验阶段。在未来十年，由于有新的药物疗法可用于调节饮食行为、营养分配和/或能量消耗，肥胖的药物治疗可能会发生显著变化。
