Long-Term Pharmacotherapy for Obesity
Division of Geriatrics and Nutritional Sciences, Center for Human Nutrition, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8031, St. Louis, MO 63110. E-mail: email@example.com
Obese patients unable to achieve significant weight loss with lifestyle changes alone may require drug therapy, and such therapy may be needed long term lest weight lost be regained. In the United States, only sibutramine and orlistat are available for the long-term treatment of obesity. Clinical trials have shown that both drugs can induce and maintain weight loss, even in patients with comorbid conditions such as hypertension or type 2 diabetes. Their use must be combined with behavior modification and a structured meal plan, however, for patients to reap the full benefits of such treatment.
Interest in pharmacotherapy for obesity continues to increase because it is so difficult to achieve successful long-term weight management with lifestyle modification alone. When drugs are used to treat obesity, however, long-term if not life-long therapy is usually required because obese persons who respond to drug treatment usually regain the weight that was lost once treatment is stopped. Of the prescription drugs that are available in the U.S. to treat obesity (Table 1), only two—sibutramine and orlistat—are approved for long-term use. They were approved by the U.S. Food and Drug Administration in 1996 and 1999, respectively, after undergoing extensive testing in randomized clinical trials. The other medications listed in Table 1 were approved before 1974 and, thus, did not undergo the rigorous evaluation in large, long-term studies that is now required.
Table 1. . Medications approved by the U.S. Food and Drug Administration to treat obesity
|Phendimetrazine tartrate||Bontril, Plegine, Prelu-2, X-Trozine|
|Phentermine||Ionamin, Adipex-P, Fastin, Oby-trim|
|Diethylpropion hydrochloride||Tenuate, Tenuate Dospan|
Sibutramine, a derivative of the amphetamine precursor β-phenethylamine, blocks presynaptic nerve terminal reuptake of norepinephrine, serotonin, and dopamine. Sibutramine increases feelings of satiation (level of fullness during a meal), thereby decreasing food intake. Although sibutramine is classified as a schedule IV drug, it does not have abuse potential.
Sibutramine causes a dose-dependent loss in body weight when given in doses ranging from 1 to 30 mg/d (1). The current recommended starting dose is 10 mg/d, which can be decreased or increased by 5 mg in those who do not tolerate or who do not respond adequately to the initial dose. Treatment with >15 mg/d is not recommended. Weight regain occurs promptly when treatment is stopped (2).
Several long-term (48 to 104 weeks) randomized controlled trials have evaluated the clinical efficacy of sibutramine in obese subjects (3, 4, 5, 6, 7). In one trial, subjects given sibutramine therapy lost ∼7% of their initial body weight at 1 year, compared with a weight loss of 2% in the placebo group (3, 4). In addition, about three to four times as many subjects randomized to sibutramine therapy lost ≥5% and ≥10% of their initial weight than those randomized to placebo. Intermittent sibutramine therapy may be just as effective as continuous daily therapy in achieving weight loss. Weight loss achieved after 1 year of intermittent sibutramine therapy (15 mg/d given during weeks 1 and 2, 19 to 30, and 37 to 48, with placebo given during weeks 13 to 18 and 31 to 36 when sibutramine was withdrawn) was equivalent to that attained with continuous sibutramine therapy (15 mg/d) (4). There was a small regain in weight during the periods when the drug was replaced by placebo, followed by weight loss when the drug was resumed.
Sibutramine has also been shown to help maintain weight loss induced by successful dieting or sibutramine therapy. In one study, obese subjects who lost ≥6 kg of their body weight after 4 weeks of treatment with a very low-calorie diet were randomized to 1 year of sibutramine treatment or placebo (5). Those treated with sibutramine lost an additional 5.2 kg, whereas those treated with placebo gained 0.5 kg. In the Sibutramine Trial of Obesity Reduction and Maintenance Trial, subjects who lost ≥5% of their body weight after 6 months of sibutramine therapy were randomized to either continuous sibutramine therapy or placebo for an additional 18 months (2). On average, placebo-treated subjects steadily regained weight, maintaining only 20% of their 6-month weight loss at the end of the trial. In contrast, subjects treated with sibutramine maintained 80% of their initial weight loss at the end of 2 years.
The use of sibutramine also has been evaluated in obese patients who had obesity-related medical complications of either medication-controlled hypertension (6) or type 2 diabetes (7). Although overall weight loss was less than that observed in studies conducted in subjects who did not have comorbid disease, weight loss with sibutramine therapy was greater than with placebo therapy. In studies conducted in patients with hypertension, changes in diastolic and systolic blood pressure were not as beneficial in sibutramine-treated than in placebo-treated patients, despite greater weight loss in the sibutramine-treated group.
The most common side effects of sibutramine are dry mouth, constipation, and insomnia. Sibutramine also increases heart rate and blood pressure. A dose of 10 to 15 mg/d increases heart rate by ∼4 to 6 beats/min and increases both systolic and diastolic blood pressure by ∼2 to 4 mm Hg. Larger increases in blood pressure or heart rate suggest that the dose should be reduced or therapy stopped altogether. The adverse effect of sibutramine on blood pressure can prevent the normal beneficial effects of weight loss on blood pressure (2).
Orlistat, a synthetic derivative of lipstatin, binds to intestinal lipases and impairs digestion of dietary triglycerides and vitamin esters (8). Less than 1% of ingested orlistat is absorbed, so it has no effect on systemic lipases (9). At the current recommended dose of 120 mg three times a day with meals, orlistat blocks the absorption of almost one-third of ingested fat; higher doses of orlistat are unlikely to increase fat malabsorption (10). It should be noted that the effect of orlistat on fat absorption can vary considerably from meal to meal, depending on how well orlistat mixes and remains with the fat content of the meal.
The clinical efficacy of orlistat has been evaluated in a number of long-term (1 to 4 years) randomized clinical trials (11, 12, 13, 14, 15, 16, 17, 18, 19). In general, subjects randomized to orlistat therapy lost ∼8% to 10% of their body weight at 1 year, compared with ∼4% to 6% in subjects randomized to placebo (11, 12, 13, 14, 15). Approximately thirty-five percent to 70% of orlistat-treated subjects lost ≥5% of their body weight, compared with 20% to 50% of placebo-treated subjects. A greater percentage of orlistat-treated subjects lost ≥10% of their body weight compared with placebo-treated subjects (∼30% to 40% vs. 10% to 25%, respectively). Data from a 4-year trial conducted in over 3000 obese subjects demonstrated that orlistat therapy and lifestyle intervention resulted in weight loss of 11% and 7% at 1 and 4 years, respectively, compared with 6% and 4% at 1 and 4 years for the group treated with placebo and lifestyle intervention (16). In addition, therapy with orlistat resulted in a 37% reduction in the cumulative incidence of new-onset type 2 diabetes, primarily by preventing the development of diabetes in patients who had impaired glucose tolerance.
It is usually more difficult to achieve weight loss in obese patients with type 2 diabetes than in obese patients without diabetes. Data from studies that evaluated the use of orlistat in obese patients with type 2 diabetes treated with sulfonylureas (17), metformin (18), or insulin (20) found that the percentage of patients who achieved a ≥5% or ≥10% reduction in body weight was two to three times higher among those receiving orlistat and diet therapy than those receiving placebo and diet therapy. However, weight loss in these studies was less than that observed in obese subjects who did not have diabetes.
Orlistat has a beneficial effect on serum cholesterol concentration that is independent of weight loss alone. The decrease in serum low-density lipoprotein cholesterol concentrations after weight loss with orlistat therapy is greater than after placebo therapy, even after adjusting for percentage weight loss (12, 13). The mechanism responsible for this additional lipid-lowering effect may be related to orlistat's effect in blocking both dietary cholesterol and triglyceride absorption (20).
The composite data from most randomized clinical trials demonstrate that more subjects treated with orlistat (∼75%) than placebo (∼50%) experience one or more gastrointestinal side effects, such as abdominal pain, flatulence, increased defecation, fecal urgency, and fatty/oily stool. Gastrointestinal events usually occurred early, within the first 4 weeks of therapy, were of mild or moderate intensity, and were limited to one or two episodes despite continued orlistat treatment. Approximately four percent of subjects treated with orlistat and 1% of subjects treated with placebo withdrew from the studies because of gastrointestinal complaints.
Small decreases in plasma fat-soluble vitamin concentrations, particularly vitamins D, E, and β-carotene, can occur but usually remain within the normal range without vitamin supplementation. However, ∼5% of patients may experience larger decreases in plasma vitamin concentrations (11, 12, 13); therefore, all treated patients should take a daily multivitamin supplement at a time when orlistat is not being ingested.
Orlistat can also impair the absorption of lipophilic medications. Subtherapeutic plasma cyclosporin concentrations have been reported in obese patients who began orlistat therapy after organ transplantation (21, 22, 23). Therefore, orlistat should not be taken for at least 2 hours before or after the ingestion of lipophilic medications, and plasma drug concentrations should be monitored, if possible, to ensure appropriate dosing.
Pharmacotherapy can enhance weight loss in selected obese patients. However, effective use of weight loss medications requires long-term therapy and monitoring. Moreover, pharmacotherapy alone is not as effective as pharmacotherapy given in conjunction with a comprehensive weight management program. For example, weight loss after 1 year of treatment with sibutramine, behavior modification, and a structured meal plan was approximately three times greater than that achieved with sibutramine therapy alone (24). Therefore, patients given drug treatment without other efforts to modify lifestyle are exposed to the full risks of drug treatment without the full medical benefits.
Currently, there are a large number of antiobesity drugs in different stages of development. These include medications that have already been approved by the FDA for other indications (e.g., topiramate, which is approved for specific seizure disorders), drugs that are currently in phase III clinical trials (e.g., rimonabant, which is a cannabinoid receptor antagonist), and drugs that are in the industry “pipeline” (e.g., centrally acting appetite suppressants, thermogenic agents, gut hormone modulators, novel lipase inhibitors, and metabolic regulators). As our understanding of the mechanisms that regulate food intake increases, it is likely that newer drugs will be developed that will provide a more diverse and more effective armamentarium to treat human obesity.