Pharmacological Approaches to Weight Reduction: Therapeutic Targets

Obesity is a chronic disease characterized by an accumulation of excess adipose tissue and associated with an increased risk of multiple morbidities and mortality. Weight loss prevents or tempers the severity of many obesity-related morbidities. Unfortunately, once adipose tissue accumulates, a system of overlapping neuroendocrine responses prevents it from diminishing. When food intake is limited, counterregulatory mechanisms cause an increase in appetite and a decrease in energy expenditure as protective measures against starvation, and make volitional weight loss by a hypocaloric diet difficult to achieve (1). Pharmacological intervention is, therefore, often necessary to aid in inducing weight loss and maintenance. This review summarizes the current pharmacotherapy for obesity and highlights how our understanding of the complex network of energy regulation may lead to more targeted and effective treatments. Current pharmacotherapy for weight loss Pharmacotherapy should be considered in overweight and obese patients with a body mass index greater than 27 kg/m 2 , particularly in the presence of comorbidites such as type 2 diabetes or hypertension or an increased waist circumference when conservative measures such as behavior therapy, diet, and exercise have not resulted in the desired weight loss (2). A realistic treatment goal is usually loss of 5–10% of initial body weight over a 6- to 12-month period, followed by longterm maintenance of reduced weight. Most cardiovascular risk factors are improved even at this level of modest weight reduction because of the predominant loss of visceral fat leading to disproportionate improvement in the risk of developing complications. The NIH guidelines recommend that if a chosen medication does not lead to a 2-kg weight loss in the first month of treatment, the dose should be adjusted or the medication discontinued. Only two drugs, sibutramine (Meridia, Abbott Laboratories, Abbott Park, IL) and orlistat (Xenical, Hoffman-LaRoche, Nutley, NJ), are approved by the Food and Drug Administration for long-term use. Sibutramine inhibits norepinephrine and serotonin reuptake. Although ineffective as an antidepressant, for which purpose it was originally developed, sibutramine was found to reduce body weight and appetite and increase satiety. More than 10 prospective, randomized, controlled trials of sibutramine have supported its efficacy (3). An analysis of three trials of at least 1-yr duration shows that patients on sibutramine lost 4.3 kg or 4.6% more weight than those taking