Pharmacologic options

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Patients with a BMI >30kg/m2 or with a BMI >27kg/m2 with concomitant obesity-related diseases should be considered for adjuvant pharmacologic therapy. Pharmacotherapy is appropriate in individuals who have not responded to previous weight loss attempts (diet, exercise and behavioral changes) or have been unsuccessful with sustaining previous weight loss attempts. The two medications approved by the FDA for long-term weight loss are sibutramine (Abbott laboratories, Abbott Park, IL; a norepinephrine and serotonin reuptake inhibitor that enhances satiety) and orlistat (Roche Pharmaceuticals, Nutley, NJ; a lipase inhibitor that reduces fat absorption). Both agents are approved for long-term use, have proven effective in large-scale multicenter trials and have side effects that may be easily monitored by the clinician.

Sibutramine produces a dose-dependent weight loss (available doses are 5, 10 and 15 mg capsules), with an average loss of about 8-10% of initial body weight at 6 months [28]. A greater proportion of participants achieve 5% and 10% weight loss on sibutramine than placebo in studies lasting 44 to 54 weeks [29-42]. Wadden et al. [32] demonstrated significantly greater weight reduction in patients combining pharmacotherapy with lifestyle modifications. Studies have demonstrated improvement in glycemic control in patients with type 2 diabetes [30, 33-35] and in cardiovascular risk factors [36-38]. Sibutramine can cause small increases in both blood pressure and pulse; however, studies have shown sibutramine to be safe in the treatment of obese patients with well-controlled hypertension [39, 40]. The most commonly reported side effects of sibutramine include headache, dry mouth, constipation and insomnia, all of which are generally mild and well tolerated. It is advisable to monitor blood pressure and heart rate monthly when starting patients on sibutramine. Contraindications to sibutramine use include uncontrolled hypertension, congestive heart failure, symptomatic coronary heart disease, arrhythmias or history of stroke.

Orlistat is a synthetic hydrogenated derivative of a naturally occurring lipase inhibitor, lipostatin, produced by the mold Strepto-myces toxytricini. Taken at a therapeutic dose of 120 mg tid, orlistat blocks the digestion and absorption of about 30% of dietary fat. Recently, the XENDOS trial randomized 3,305 obese subjects to lifestyle changes, plus either 120 mg of orlistat or placebo [41]. After 4 years, orlistat plus lifestyle changes led to a 37.3% (P = 0.0032) risk reduction in the development of diabetes and improved weight loss compared with placebo plus lifestyle changes. Multiple randomized, 1- to 2-year double-blind, placebo-controlled studies have shown that after 1 year, orlistat produces a weight loss of about 9-10% compared with a 4-6% weight loss in the placebo-treated groups [42,43]. Orlistat has been demonstrated to reduce the incidence of type 2 diabetes [41, 44], improve diabetic control and insulin sensitivity [45-47], and reduce cardiovascular risk factors [48, 49]. A pilot study by Beck-da-Silva et al. [50] demonstrated that orlistat can promote significant weight loss and symptoms of relief in obese patients with heart failure, as measured by 6-min walk test and functional capacity. The lipid profile in these patients also improved. Since orlistat is minimally (<1%) absorbed from the gastrointestinal tract, it has no systemic side effects. Tolerability to the drug is related to the malabsorption of dietary fat and subsequent passage of fat in the feces. Gastrointestinal tract side effects reported to occur in at least 10% of orlistat-treated patients include: oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation and increased defecation. The events are generally experienced early, diminish as patients control their dietary fat intake and infrequently cause patients to withdraw from clinical trials. Cavaliere et al. [51] demonstrated that psyllium mucilloid is helpful in controlling the orlistat-induced GI side effects when taken concomitantly with the medication. Due to potential deficiency of fat-soluble vitamins, a daily multivitamin is recommended.

Rimonabant (Sanofi-Aventis, Paris, France), an endocannabinoid receptor antagonist in clinical development, offers a unique approach to appetite control and weight reduction. Two randomized studies have demonstrated a reduction in body weight and waist circumference and an improvement in cardiovascular risk factors with rimonabant combined with a hypocaloric diet over 1 year [52, 53].

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