Fat-Blocking Drug Is Helpful in Selected Obese Patients

The dropout rate was high, but for those who remained, lasting weight loss occurred.

A new drug that partially blocks fat absorption may help some obese patients retain weight loss and may reduce some cardiovascular risk factors as well. Orlistat (Xenical”), which structurally resembles a fatty acid, inhibits pancreatic and gastric lipase activity and blocks about 30% of ingested fat from being absorbed.

Large-scale study tests effectiveness, safety

In a 2-year randomized, double-blind, placebo-controlled study conducted at 18 U.S. research centers, 892 obese adults (BMI: 30-43 mg/kg2) were randomly assigned to treatment or placebo (JAMA 281:235, 1999). The study group included 223 placebo-treated subjects and 657 orlistat–treated subjects.

During a 4-week lead-in before the study, all subjects received placebo plus a controlled energy diet. Then, on study day 1, the diet was continued and subjects were randomized to receive placebo 3 times a day or orlistat, 120 mg 3 times a day, for 52 weeks. After 52 weeks, all subjects began a weight-maintenance diet and the placebo group (n=133) continued to receive placebo. Those receiving orlistat were re-randomized to placebo 3 times daily (n=138), or to 60 mg orlistat (n=152) or 120 mg orlistat (n=153) 3 times a day, for 52 weeks.

Greater weight loss but high dropout rates

During the first year, weight loss was greater among patients who received orlistat than among those in the placebo group (mean weight loss: 8.76 kg vs. 5.81 kg, respectively). In the first year of the study, 65.7% of the orlistat group lost more than 5% of their initial body weight, compared with 43.6% of placebo-treated subjects. In the second year, the group that received the 120-mg dose of orlistat kept their weight off better than those who received 60 mg (35% regain versus 51% regain, respectively). Subjects treated with orlistat maintained about two-thirds of their weight loss, while those who were originally on orlistat but switched to placebo regained most of the weight they had lost.

Blood pressure, cholesterol, and insulin levels

The orlistat group had a small but significantly greater fall in systolic blood pressure than the placebo group, and diastolic pressure also decreased more in the orlistat 120 mg group than in the placebo group. After 2 years, loss in mean waist circumference was significantly greater in the orlistat group compared with the placebo group (-4.52 cm vs. –2.38 cm, respectively).

Orlistat treatment led to improved fasting low-density lipoprotein cholesterol (LDL-C) and insulin levels, in association with weight loss and the low-fat diet that was prescribed. After 2 years of treatment with 120 mg of orlistat, LDL-C values were reduced significantly below initial values compared with placebo; the greater improvements in total and LDL-C levels were independent of the greater weight loss in the orlistat group. Serum insulin levels had fallen significantly in the orlistat group, but were unchanged in the placebo group (84.02 to 66.52 pmol/L vs. 86.37 to 86.32 pmol/L). These results echoed those reported in a recent study of orlistat among obese Americans with type 2 diabetes mellitus (Diabetes Care, August 3, 1998).

Adverse effects

During the first year, more subjects in the orlistat group than in the placebo group withdrew due to side effects (9.1% vs. 4%). The incidence of gastrointestinal effects was higher in the orlistat group. Most subjects withdrew because of steatorrhea (fatty stools), an effect that lessened with time. During the second year, withdrawal was similar among all treatment groups. The authors reported that orlistat acts on gastrointestinal lipases and is only minimally absorbed, so that systemic adverse effects were negligible.

Breast malignancies were reported by 3 women in the orlistat 120-mg group and by 1 woman treated with placebo. In all but one of these patients, there was strong evidence of preexisting disease (2 orlistat and 1 placebo). This, plus the lack of an estrogen-stimulating effect and minimal absorption led the authors to support the conclusion that there was no biological association between orlistat and breast cancer. Orlistat causes malabsorption of fat-soluble vitamins, so monitoring the status of these vitamins is advised.

Some questions remain

In an accompanying editorial, David F. Williamson, PhD, of the Centers for Disease Control and Prevention, poses several questions about orlistat and diet drugs in general. First, can weight-loss drugs such as orlistat lead to clinically meaningful changes in physiologic risk factors without lifestyle intervention? Second, will slight changes in physiologic risk factors translate into meaningful improvement in health? Third, will the yet-to-be-proven health benefits of weight-loss drugs (given the selection criteria and high dropout rates) be seen in other than a small group of these obese patients? Finally, he asks, is inordinate emphasis being placed on treating obesity rather than its primary prevention?

Dr. Williamson adds that despite some concerns about the side effects of diet drugs, drug therapy is often a reasonable option for some obese patients, particularly those who can tolerate the adverse gastrointestinal effects.