Orlistat inhibits the activity of pancreatic and gastric lipases, thus preventing the absorption of about 30 percent of dietary fat. Consultants from the Medical Letter on Drugs and Therapeutics reviewed the indications, clinical trials and safety profile of this new drug in the treatment of obesity. Although weight reduction is achieved by loss of calories, drug-induced adverse effects may also contribute to a decrease in food intake. Absorption of orlistat is minimal, and plasma concentrations are barely detectable eight hours after a radioactive-labeled dose.

Orlistat is indicated for use in patients with a body mass index of at least 30 kg per m² or 27 kg per m² in patients with hypertension, diabetes or dyslipidemia.

Two large placebo-controlled trials evaluated the effect of orlistat in a dosage of 120 mg three times daily or placebo in addition to a low-calorie diet for one year, followed by a second year of active drug or placebo and a weight-maintenance diet. Results of both studies showed that after one year, patients taking orlistat lost an average of 9 to 10 kg (19.9 to 22 lb) compared with a loss of 6 kg (13.2 lb) with placebo. In the second year, patients who continued to take orlistat regained 1.5 to 3 kg (3.3 to 6.6 lb) compared with a gain of 4 to 6 kg (8.8 to 13.2 lb) in patients who switched to placebo. Those taking orlistat showed significant but clinically trivial improvements in cardiovascular risk factors compared with those taking placebo. After one year, diastolic blood pressure in the orlistat group decreased by an average of 2 mm Hg; after two years, total cholesterol levels in this group decreased by 5 mg per dL (0.14 mmol per L).

In a double-blind trial using orlistat for weight maintenance in 729 patients who had lost about 10 kg (22 lb) by diet alone, patients taking 120 mg of orlistat three times daily for one year regained a mean weight of 2.6 kg (5.7 lb) compared with a gain of 4.4 kg (9.7 lb) in placebo-treated patients. Results indicated that about 24 percent of patients taking orlistat did not regain weight compared with 16 percent of those who were placebo-treated.

Obese patients with type 2 diabetes (formerly called non–insulin-dependent diabetes mellitus) who were treated with orlistat in a dosage of 120 mg three times daily in addition to diet for one year lost a mean weight of 1.9 kg (4.2 lb) more than those taking placebo plus diet. No study data are available comparing the use of orlistat with phentermine or sibutramine, the only drugs that are labeled by the U.S. Food and Drug Administration for long-term treatment of obesity.

A total of 20 to 40 percent of patients taking orlistat exhibited symptoms such as flatulence with discharge, oily spotting and fecal urgency. This percentage was twice that found in the placebo-treated group. It is presumed that these symptoms would be more severe in patients not adhering to a diet providing 30 percent or less of calories from fat. Decreases in mean serum concentrations of vitamins A, D and E and beta-carotene have been noted and, although taking fat-soluble vitamin supplements will correct the deficiency, it will not make up for the loss of fat-soluble carotenoids from fruits and vegetables. The long-term effects of chronic steatorrhea on neoplastic or inflammatory bowel disease are unknown. Orlistat is contraindicated in patients with chronic malabsorption syndrome or cholestasis.

Orlistat is supplied in 120-mg capsules. The recommended dosage is one capsule three times daily; the drug is to be taken with each main meal that contains fat. If the meal is fat-free, the dose can be omitted. Fat-soluble vitamin supplements should be taken at least two hours before or after taking orlistat. The wholesale cost of 90 120-mg capsules is about $118.80.

The consultants conclude that orlistat is modestly effective in assisting obese patients to lose weight. However, patients tend to regain at least some of the lost weight even if the drug is continued. Patients should understand that orlistat can produce uncomfortable and potentially embarrassing adverse effects. Interference of orlistat with absorption of fat-soluble vitamins, beta-carotene and other carotenoids makes vitamin supplementation necessary.

editor's note: Over the past year, the Medical Letter on Drugs and Therapeutics has reviewed data on phentermine, sibutramine and orlistat. Each new antiobesity drug offers promise to obese patients. However, as patients seek physicians' advice about the use of these agents, it is important to remind them that most of them will regain all or some of the weight after one year. Strict adherence to a weight-reduction diet and an exercise program offer the best hope for long-term successful weight reduction.—b.a.