Since eating behavior is an expression of endocrine, neurophysiologic, and psychological processes, prevention and treatment of obesity are complex. It is not surprising that there is considerable scientific and financial interest in developing pharmacologic therapy for the condition. Although obesity can be defined as excess adipose tissue, it is currently quantitated by means of the body mass index (BMI), calculated from BMI = weight (in kilograms)/height2 (in meters). Using this measure, a normal BMI is defined as 18.5–24.9; overweight, 25–29.9; obese, 30–39.9; and morbidly obese (ie, at very high risk), ≥ 40.
Some extremely muscular individuals may have a BMI higher than 25 and no excess fat; however, the BMI scale generally correlates with the degree of obesity and with risk. Although the cause of obesity can be simply stated as energy intake (dietary calories) exceeding energy output (resting metabolism plus exercise), the actual physiology of weight control is extremely complex, and the pathophysiology of obesity is still poorly understood. Many hormones and neuronal mechanisms regulate intake (appetite, satiety), processing (absorption, conversion to fat, glycogen, etc), and output (thermogenesis, muscle work). The fact that a large number of hormones reduce appetite might appear to offer many targets for weight-reducing drug therapy, but despite intensive research, no available pharmacologic therapy has succeeded in maintaining a weight loss of over 10% for 1 year. Furthermore, the social and psychological aspects of eating are powerful influences that are independent of or only partially dependent on the physiologic control mechanisms. In contrast, bariatric (weight-reducing) surgery readily achieves a sustained weight loss of 10–40%. Furthermore, surgery that bypasses the stomach and upper small intestine (but not simple restrictive banding) rapidly reverses some aspects of the metabolic syndrome even before significant weight is lost. However, even a 5–10% loss of weight is associated with a reduction in blood pressure and improved glycemic control.
PHARMACOTHERAPY: Orlistat is the only non-amphetamine drug currently approved in the United States for the treatment of obesity. Clinical trials and phase 4 reports suggest that orlistat is modestly effective for the duration of therapy (up to 1 year) and is probably safer than the amphetamine mimics. However, it does not produce more than a 5–10% loss of weight. Sibutramine was marketed for several years but was withdrawn because of increasing evidence of cardiovascular toxicity. Lorcaserin received intense study through 2010 and was submitted for approval to the FDA, but this was denied on the basis of considerations of inadequate safety and effectiveness.
Because of the redundancy of the physiologic mechanisms for control of body weight, it seems likely that polypharmacy targeting multiple pathways will be needed to achieve success.
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1. OBESITY
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