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Editorials |
Energy balance represents a battle between energy intake and energy expenditure. When intake is greater than expenditure, most of the excess energy is stored as triacylglycerols in adipose tissue. When energy intake is less than expenditure, adipose tissue triacylglycerols are mobilized to provide fuel for body tissues. Body fat mass determines the duration of survival during prolonged starvation; the longest reported fast was that of a 207-kg man who ingested only non-energy-containing fluids for 382 d and lost 61% (126 kg) of his initial weight without adverse consequences (1). Although obesity may be advantageous during starvation, excessive body fat is associated with a long list of serious medical complications. Until recently in our evolutionary history, we kept obesity at bay by maintaining a reasonable balance between our genes, which are geared to consume and store energy, and a harsh environment, which kept energy intake down and energy expenditure up. Nations that have become technologically evolved with labor-saving devices, sedentary jobs, and abundant food supplies have found that these technological successes have dealt a serious blow to the precarious energy balance equation. The United States and other industrialized countries are getting fatter (2) and obesity is a major and growing public health problem throughout the world.
The difficult process of implementing lifelong modifications in eating and physical activity behaviors is the cornerstone of obesity therapy. Loss of as little as 5–10% of initial body weight may improve several of the medical abnormalities associated with obesity, including diabetes, high blood pressure, and dyslipidemia (3). Therefore, a modest weight loss, as long as it is maintained, can have considerable clinical benefits. However, the ability to achieve long-term, modest weight loss with behavior modification therapy is limited, which has led to an increased interest in pharmacotherapy. Currently, 9 generic drugs have been approved by the Food and Drug Administration (FDA) for the treatment of obesity in the United States (Table 1
). These medications act by altering monoamine (norepinephrine, serotonin, or both) metabolism in the brain to suppress appetite. Sibutramine is the only drug approved by the FDA that has been evaluated in long-term (1-y), prospective randomized controlled trials (PRCTs) (5) and is currently the only drug approved for long-term use.
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30% (7). Therefore, orlistat therapy should induce weight loss if patients are compliant with treatment, the malabsorptive potency of the drug is maintained, and patients do not increase their food intake to compensate for malabsorbed energy.
The study reported by Hill et al (8) in this issue of the Journal is the fourth PRCT to evaluate the effectiveness of orlistat in treating obesity. More subjects (a total of 2631) have been involved in published, long-term (
1 y) clinical trials of orlistat than in clinical trials of any other obesity drug in history (8–11). Therefore, extensive information on the clinical effectiveness and side effects of orlistat is available in peer-reviewed articles. The data reported in 3 previous trials were remarkably consistent (9–11). After 1 y of treatment, about one-third more patients treated with 120 mg orlistat 3 times daily lost 5% of their initial body weight than did those treated with placebo, whereas about twice as many patients treated with orlistat lost 10% of their initial body weight than did those treated with placebo (Figure 1). As noted previously (12), patients with type 2 diabetes had a more difficult time losing weight than did those without diabetes. Patients treated with orlistat also showed improvements in obesity-related cardiovascular disease risk factors, including serum total cholesterol, LDL cholesterol, the ratio of LDL to HDL, glucose and insulin concentrations, and blood pressure (9–11). Moreover, orlistat had an additional beneficial effect on plasma lipids that was independent of weight loss alone. Presumably, this effect is related to the action of orlistat on the absorption of dietary fat.
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8% of their initial body weight entered a 12-mo PRCT and were randomly assigned to receive therapy with 1 of 3 doses of orlistat (120, 60, or 30 mg 3 times daily) or placebo. In addition, subjects were instructed to increase their energy intake by consuming a diet that was estimated to maintain their new body weight. A total of 1313 subjects were enrolled in the 6-mo weight-loss portion of the study; of these, 729 (56%) lost 8% of their initial body weight. Of the 729 subjects who entered the 12-mo PRCT, 537 (74% of those randomly assigned; 41% of those who entered the study initially) completed the 12-mo trial. Subjects randomly assigned to 120 mg orlistat, but not those who received 60 or 30 mg, experienced significantly greater total weight loss (8.2% of initial body weight) and less weight regain (32% of initial weight loss) than did subjects who received placebo (6.4% and 56%, respectively). Furthermore, 48% of patients treated with orlistat compared with 30% of patients treated with placebo regained25% or less of their initial weight loss; 24% of patients treated with orlistat compared with 16% of patients treated with placebo did not regain any weight or continued to lose weight.
It has been hypothesized that orlistat helps patients lose weight by causing malabsorption of ingested fat and by enhancing dietary fat restriction to avoid the gastrointestinal side effects of fat malabsorption. In fact, it has been suggested that orlistat is a behavior modification tool that acts as an "antabuse" for fat. However, the data in the study by Hill et al (8) suggest that the effect of orlistat on body weight can be completely accounted for by fat malabsorption alone, rather than by a modification of fat intake. Fecal fat measured in week 44 was 20 g/d more in the 120-mg orlistat group than in the placebo group, which represents an energy loss of 753 kJ/d (180 kcal/d) or 275 MJ/y (65700 kcal/y). If both groups ingested the same amount of energy and fat (as reported in their food records), the orlistat group should have weighed 8 kg less than the placebo-treated subjects at the end of 1 y, which is >3 times the observed difference in body weight between the 2 groups. These data suggest that patients treated with orlistat either do not take all their prescribed medication or increase their total energy intake.
Several issues are important for clinicians when considering how results from the orlistat clinical trials apply to clinical practice. First, in all 4 PRCTs orlistat was given as part of an obesity treatment program that included dietary and behavioral counseling. It is likely that patients who take drug therapy for obesity in conjunction with behavior modification do better than those who take drug therapy alone (13). Therefore, prescribing medications without involving patients in an organized effort to modify lifestyle will expose patients to all the side effects of drug treatment without the full benefits.
Second, clinicians who follow appropriate weight-management treatment guidelines can expect better overall weight maintenance outcomes in their practice than those reported by Hill et al (8). In the study by Hill et al, subjects were instructed to maintain their dietary intake but were not prescribed a reduced-energy diet, even when they were gaining weight. Continued efforts to modify dietary intake and physical activity should enhance long-term outcome.
Third, the data reported by Hill et al (8) suggest that the use of orlistat in obese patients who have lost 10% of their body weight after diet and behavior counseling gives these patients a 50-50 chance of not regaining >25% of their initial weight loss and a 1 in 4 chance of not regaining any weight at all at the end of 1 y. Unfortunately, this study does not help us determine in advance which patients are likely to be successful, so a trial of orlistat is necessary to identify those who will benefit from treatment.
Fourth, obesity is a chronic condition that requires long-term therapy. Therefore, the decision to initiate pharmacotherapy must be considered carefully because it is likely that patients who are fortunate enough to respond to orlistat treatment will require long-term therapy for a chance at long-term success. Although the 4 major orlistat clinical trials lasted 1–2 y, this may not be long enough to truly evaluate orlistat's long-term efficacy in managing body weight and decreasing obesity-related medical complications. We do not know how orlistat-treated patients will fare after 5 or 10 y of treatment.
The results of the study by Hill et al (8) and of previously published trials (9–11) show that orlistat deserves to be considered as an additional weapon in the war against obesity. However, these data also show that pharmacologic therapy has modest benefits and is not a quick fix for such a complex problem. The genetic component of human obesity, the redundant physiologic and molecular pathways that defend against negative energy balance, the psychologic factors involved in maintaining lifestyle habits, and the supportive nature of our environment make it difficult if not impossible for any pharmacologic approach to cure obesity. At present, we should consider all available tools in planning obesity treatment strategies. Orlistat may provide real benefits in properly selected patients.
FOOTNOTES
See corresponding article on 1108.
See corresponding editorial on 1059.
1 From the Department of Internal Medicine, Washington University School of Medicine, St Louis.
2 Reprints not available. Address correspondence to S Klein, Washington University School of Medicine, 660 South Euclid Avenue, Box 8127, St Louis, MO 63110-1093. E-mail: sklein{at}imgate.wustl.edu.
Editor's note: orlistat has now been approved by the FDA for the long-term treatment of obesity.
REFERENCES
This article has been cited by other articles:
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C. H Halsted Is blockade of pancreatic lipase the answer? Am. J. Clinical Nutrition, June 1, 1999; 69(6): 1059 - 1060. [Full Text] [PDF]
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