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Am Fam Physician. 2005;71(3):597-602

Weight loss can decrease the risk of obesity-related morbidities (see accompanying table), but voluntary weight loss through a reduction in caloric intake is difficult for most overweight persons because excess adipose tissue causes a series of neuroendocrine responses that prevent weight reduction. Decreased food intake generates increased appetite and decreased energy expenditure as a protection against starvation. Drug treatment may be necessary to induce weight loss and weight maintenance. Korner and Aronne reviewed current pharmacotherapeutic options for weight loss.

Efforts to reduce weight are appropriate in patients with a body mass index greater than 27 kg per m2, especially in patients with type 2 diabetes, hypertension, or increased waist circumference. When lifestyle modification does not induce weight loss, pharmacotherapy may be useful. A realistic and useful goal is a 5 to 10 percent loss of initial body weight within six to 12 months. Two medications currently are approved for long-term treatment: sibutramine and orlistat.

Abnormalities in health-related quality of life
Colon, rectal, prostate, endometrial, breast, and gallbladder cancer
Decreased life expectancy
Diabetes, insulin resistance, and metabolic syndrome
Greater risk of psychologic dysfunction
Heart disease
Increased all-cause mortality
Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Skin changes (e.g., stretch marks, acanthosis nigricans, hirsutism in women)
Sleep apnea

Sibutramine inhibits norepinephrine and serotonin reuptake, resulting in decreased appetite and increased satiety. Patients lose 4.6 percent more weight (4.3 kg [9 lb, 7 oz]) after at least one year of sibutramine treatment than patients taking placebo. Slight blood pressure and heart rate increases may occur; other adverse effects include dry mouth, constipation, and insomnia. The use of sibutramine is contraindicated in patients with uncontrolled hypertension or cardiovascular disease, as well as patients taking other serotonin reuptake inhibitors.

Orlistat is an inhibitor of pancreatic and gastrointestinal lipases and prevents the absorption of about 30 percent of dietary fat. Patients lost 2.9 percent more weight (2.7 kg [5 lb, 15 oz]) after one year of treatment than control patients. Low-density lipoprotein and total cholesterol levels decreased independent of weight loss. Glycemic control improved in diabetic patients taking orlistat. Possible side effects include oily spotting, liquid stools, fecal urgency, flatulence, and abdominal cramping. Because orlistat can impair absorption of fat-soluble vitamins, a multivitamin should be taken two hours before or after the medication is taken.

Phentermine, a noradrenergic agent, is approved for short-term use (up to three months). Users often lose 2 to 10 kg (4 lb, 6 oz to 22 lb) more weight than patients taking placebo. Reported side effects include insomnia, dry mouth, constipation, restlessness, euphoria, nervousness, increased pulse rate, and elevated blood pressure. Noradrenergic agents should not be used in patients with cardiovascular disease, hypertension, or a history of drug abuse. Like sibutramine, phentermine should not be used by persons taking monoamine oxidase inhibitors.

Clinical trials of leptin have been disappointing. Trials of ciliary neurotrophic factor and CB1 cannabinoid-receptor antagonists are in progress. The antiepileptic agents topirimate and zonisamide have some efficacy for weight loss, but adverse-effects analyses and further studies are necessary. Metformin is associated with weight loss and may be useful in persons at high risk for diabetes. Future studies will look at regulation of energy homeostasis in the hypothalamus, neurohormones secreted by the gastointestinal tract, ghrelin secreted by the stomach fundus cells, and mechanisms that affect substrate utilization rather than actual appetite and food intake.

The authors conclude that pharmacotherapy to decrease weight is a good option when conservative treatment fails. Eventually, multidrug regimens that target different regulatory mechanisms will provide the best long-term results.

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