Since 1995, the use of the prescription drugs fenfluramine or dexfenfluramine for weight loss had increased greatly to 14 million prescriptions in 1½ years. The increased interest in drug treatment of obesity derives from the poor long-term results often obtained with behavior therapy, including diet and physical activity, as noted earlier in this report. The rationale for the addition of drugs to these regimens is that a more successful weight loss and maintenance may ensue. However, as of September 1997, the FDA requested the voluntary withdrawal of fenfluramine and dexfenfluramine from the market, due to a reported association between valvular heart disease with the drugs dexfenfluramine and fenfluramine, alone or combined with phentermine (761). In November 1997, the FDA provided clearance for marketing the drug sibutramine hydrochloride monohydrate for the management of obesity, including weight loss and maintenance of weight loss when used in conjunction with a reduced-calorie diet. Due to the rapidly evolving information regarding the use of pharmacotherapy for weight loss, the panel decided to present their critique of those pharmacotherapy trials meeting their criteria for consideration.
Forty RCT articles evaluated the effect of pharmacotherapy on weight loss. In most studies, advice or behavioral therapy promoting reduced energy intake and increased physical activity was included in all treatment arms, including the placebo group.
Drugs that have been evaluated alone or in combination for at least 1 year by RCTs are phentermine, d,l-fenfluramine, dexfenfluramine, sibutramine, and orlistat. Two reports addressing dexfenfluramine (390, 506) represent a subset of a larger multicenter trial, the International Dexfenfluramine Study (INDEX trial) (507). Of the nine trials with dexfenfluramine, four had interventions of approximately 1 year, three of approximately 6 months, and two of 3 months. Most of the trials included a majority of white women, and some included persons with diabetes. Most of the trials have weight regain data. One RCT (508) evaluated the effect of dexfenfluramine versus placebo on patients who had been on an 8-week VLCD for an additional 24 weeks. One RCT (509) evaluated the effect of phentermine versus placebo on patients with osteoarthritis. One RCT (510) evaluated the effect of various doses of sibutramine on weight loss over a 24 week period. Two RCTs of 12 and 8 weeks in duration studied phenylpropanolamine versus placebo (511, 512). One used phenylpropanolamine with diet (512), and the other with diet, exercise, and behavior therapy (511). Phenylpropanolamine is available as an over-the-counter drug. The average weight loss after 8 weeks of treatment was 2.59 kg (5.7 lb) for the drug versus 1.07 kg (2.4 lb) for the placebo, a difference of 1.5 kg (3.3 lb) (511). Short-term, but not long-term (over 1 year), effectiveness has been documented.
Rationale: Data reporting the results of 52 weeks of drug treatment are available only for dexfenfluramine, orlistat, phentermine, d,l-fenfluramine, and sibutramine. The effect on weight loss from these drugs after 1 year is modest: 2.6 kg (5.7 lb) difference on average between dexfenfluramine and placebo (9.8 kg [21.6 lb] versus 7.2 kg [15.9 lb], baseline weights of 98.0 kg [216 lb] and 96.6 kg [213 lb]) (507). For sibutramine, a difference of 2.8 kg (6.2 lb) was seen at 1 year (4.4 kg [9.7 lb] versus 1.6 kg [3.5 lb]) (513). In another study of sibutramine, the difference was a net loss of 5.5 kg (12.1 lb) at 24 weeks with a 20 mg dose (510). In all of the weight loss studies that were up to 1 year in duration, the majority of the weight loss occurred in the first 6 months with a plateauing or actual increase in weight in the following 6 months (388, 389, 507, 514). For orlistat, a difference of 2.2 kg (4.9 lb) (4.3 kg [9.5 lb] versus 2.1 kg [4.6 lb]) was found in a 16-week study (407). After a 210-week study on phentermine and d,l-fenfluramine, participants averaged a weight loss of 1.4 kg (3.1 lb) from baseline weight at week 210 (395, 514).
There are no known pharmacologic agents whose specific effect is to reduce abdominal fat or to improve cardiorespiratory fitness. Any improvements in abdominal fat or fitness would be secondary to weight loss or other interventions.
Sibutramine and orlistat are approved for long-term use. Such drugs can then be used as an adjunct to modifications in behavior, including diet and physical activity. Drugs should be discontinued if significant weight loss is not achieved, i.e., a loss of <4 pounds in the first 4 weeks, or if serious adverse effects occur.