Phentermine

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 [m.sup.2], 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.

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 cardio-vascular 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, hyper-tension, 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 pharmaco-therapy 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.

Korner J, Aronne LJ. Pharmacological approaches to weight reduction: therapeutic targets. J Clin Endocrinol Metab June 2004;89:6:2616-21.

EDITOR'S NOTE: Weight reduction is a recognized imperative for obese patients, but physicians often have little success encouraging them to make necessary lifestyle changes. Although encouraging increased exercise and diet modification often is disheartening to the patient and the physician, obesity management may be improved by reminder systems, brief training interventions, shared care, inpatient care and dietician-led treatments. (1) Efforts to develop management programs individualized to patient preferences and needs may be assisted by recent research (2) demonstrating that low-fat and low-carbohydrate diets probably are equally effective for weight loss and decreasing body fat in overweight and obese adults. Individualization choices based on comorbidities (e.g., a low-carbohydrate diet for a diabetic patient, or a low-fat diet for a patient with cardiovascular disease) might make lifestyle and dietary changes more palatable for patients and physicians alike. If lifestyle modifications fail, pharmaco-therapy is available. Sibutramine and orlistat have documented efficacy in promoting weight loss. (3)--R.S.

REFERENCES

(1.) Harvey EL, Glenny AM, Kirk SF, Summerbell CD. Improving health professionals' management and the organisation of care for overweight and obese people. Cochrane Database Syst Rev 2004;(3):CD000984.

(2.) Meckling KA, O'Sullivan C, Saari D. Comparison of a low-fat diet to a low-carbohydrate diet on weight loss, body composition, and risk factors for diabetes and cardiovascular disease in free-living, overweight men and women. J Clin Endocrinol Metab 2004;89:2717-23.

(3.) Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev 2004;(4):CD004094.

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