Drug treatments for obesity: orlistat, sibutramine, and rimonabant
Raj S Padwal, Sumit R Majumdar
Antiobesity treatment is recommended for selected patients in whom lifestyle modiﬁcation is unsuccessful. Two antiobesity drugs are currently licensed for long-term use. Orlistat, a gastrointestinal lipase inhibitor, reduces weight by around 3 kg on average and decreasesprogression to diabetes in high-risk patients; adverse gastrointestinal eﬀects are common. Sibutramine, a monoamine-reuptake inhibitor, results in mean weight losses of 4−5 kg, but is associated with increases in blood pressure and pulse rate. Rimonabant, the ﬁrst of the endocannabinoid receptor antagonists, reduces weight by 4−5 kg on average and improves waist circumference and concentrations of HDLcholesterol and triglyceride; however, an increased incidence of mood-related disorders has been reported. To date, all antiobesity drug trials have been limited by their high attrition rates and lack of long-term morbidity and mortality data. Other promising antiobesity drugs, including those acting within the central melanocortin pathway, are in development, but are years away from clinicaluse. In light of the lack of successful weight-loss treatments and the public-health implications of the obesity pandemic, the development of safe and eﬀective drugs should be a priority. However, as new drugs are developed we suggest that the assessment processes should include both surrogate endpoints (ie, weight loss) and clinical outcomes (ie, major obesity-related morbidity and mortality). Onlythen can patients and their physicians be conﬁdent that the putative beneﬁts of such drugs outweigh their risks and costs.
“The devil has put a penalty on all things we enjoy in life. Either we suﬀer in health or we suﬀer in soul or we get fat.” Albert Einstein, 1879−1955
Lancet 2007; 369: 71–77 Department of Medicine, University of Alberta Hospital, Edmonton, AB, Canada (R S Padwal MD, S RMajumdar MD) Correspondence to: Dr Raj Padwal, Department of Medicine, 2E3·22 Walter C Mackenzie HSC, University of Alberta Hospital, Edmonton, Alberta, Canada, AB T6G 2B7 email@example.com
Driven by the need to survive, and inﬂuenced by complex genetic, emotional, and sociocultural factors, the desire to eat is one of the strongest of human instincts. In food deprivation, powerfulorexigenic (appetite-stimulatory) responses are elicited.1 After weight loss, compensatory metabolic alterations resist further reductions in weight.2 However, there are no equally potent or eﬀective counter-regulatory mechanisms for decreasing food intake or increasing physical activity after chronic weight gain. Thus, in modern times, the obesity pandemic represents the inevitable consequence of placinga population preselected for eﬃcient fat storage into a sedentary environment of caloric overabundance. In such a setting, unless volitional control of energy intake and expenditure is consciously and persistently exercised, weight will gradually increase despite remarkably little net excess caloric intake.3 Over the past three decades, the consequences of this tendency to gain weight havebecome increasingly apparent. The International Obesity Task Force estimates that more than 300 million individuals worldwide are obese and an additional 800 million are overweight.4 For the ﬁrst time, the number of overweight individuals in the world is equivalent to the number underweight.5 Unless current trends are reversed, the health-related and economic consequences will be enormous. Successfulmaintenance of the lifestyle changes needed for optimum bodyweight, although possible in some individuals,6 is uncommon7 and the current methods for lifestyle modiﬁcation (alone) as a treatment for obesity are widely regarded as ineﬀective. Antiobesity pharmacotherapy is a potentially important adjunctive treatment to lifestyle modiﬁcation. The ideal
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