Orlistat as an Adjunct to Obesity Therapy in Primary Care

Source: Hauptman J, et al. Arch Fam Med 2000;9:160-167.

Obesity is a chronic medical condition associated with many deleterious health consequences in our society. Obesity affects approximately one-third of the U.S. population. Despite multiple approaches to treatment, physicians and patients alike may be dissatisfied with results of therapy. Some surgical and pharmacologic approaches to treatment have been accompanied by serious complications. Long-term outcomes of treatment are often disappointing, with initial weight loss followed by significant rebound or weight gain. This cycle is discouraging for physician and patient alike.

Orlistat (Xenical—Roche) is a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%. It is the first pharmacologic agent for the treatment of obesity in the United States and has been approved for use in type II diabetes mellitus. It is also the first anti-obesity agent that has been demonstrated to exert a direct salutary effect on blood lipids, with improvement in cholesterol and LDL levels and the HDL:LDL ratio. Orlistat is recommended in conjunction

with reduced calorie intake (but not extremely low calorie diets) and a total fat content of 30% of the diet. Its major side effects are gastrointestinal (GI), including fecal urgency, oily spotting, and increased defecation.

Two previous randomized, double-blind, placebo-controlled trials totaling more than 1600 patients were conducted by obesity treatment specialists in academic medical centers in the United States and Europe. Results from these trials indicated that orlistat could be used in conjunction with reduced calorie diets to achieve weight losses of 5-10% of initial body weight. Hauptman and colleagues conducted a randomized, double-blind, placebo-controlled study in 17 different primary care centers in the United States using orlistat as an adjunct to a reduced-calorie diet. Patients were instructed on a reduced calorie diet with approximately 30% fat, 50% carbohydrate, and 20% protein; dietary instruction was by the patient’s primary care physician or by their office staff, not by registered dieticians. No special nutrition training was provided to the physicians. A total of 635 patients were randomized to placebo, orlistat 60 mg tid, or orlistat 120 mg tid. Patients were encouraged to increase physical activity by walking 20 to 30 minutes three to five times per week, but were not required to keep a log. At the end of one year, patients were changed from a weight-loss to a weight-maintenance diet and continued on either orlistat or placebo. Regular measurements of patient weight, blood pressure, waist circumference, and fasting levels of blood lipids, serum glucose, and insulin levels were performed. Additional lab determinations included hematologic measurements, a urinalysis, 24-hour urine collection, vitamins A (retinol), D (25-hydroxy vitamin D), E (alpha-tocopherol), beta-carotene, stool for occult blood testing, and prothrombin time.

Data were analyzed in both the intention-to-treat group and the patients who completed the two-year study. Significantly more patients continued in the study in the 60 mg and 120 mg orlistat group than in the placebo group (72%, 72%, and 57% at 1 year, respectively, and 56%, 56%, and 43%, respectively, at 2 years). Discontinuance rates because of adverse effects were low: 11%, 6.6%, and 7.1% for orlistat 120 mg tid, orlistat 60 mg tid, and placebo. Adverse effects were most common in the early part of the study, and rare in the second year. Fecal incontinence, when experienced, was limited to one or two episodes (approximately 6% of orlistat-treated patients). Fat-soluble vitamins remained within reference ranges on all patients. Six percent or less of patients treated with orlistat required and received supplementation of fat-soluble vitamins. All patients receiving supplementation achieved normal levels by the end of the study.

Weight loss rates were consistent with previous studies. Approximately half of the orlistat-treated patients in the ITT population lost 5% or more of their initial body weight as compared to 30% of placebo-treated patients (P < 0.001 vs placebo). Patients who continued in the study demonstrated a similar pattern, but somewhat greater weight loss was seen for patients who completed the study. Ten percent or greater weight loss was achieved in 28.6% of the patients receiving 120 mg orlistat, 24.4% of the patients receiving 60 mg orlistat, and 11.3% of patients receiving placebo (P < 0.001). In patients who completed the study, orlistat-treated patients did not regain as much weight as those receiving placebo (P < 0.001). LDL cholesterol levels were lower in the orlistat-treated group at the end of the study (P = 0.03 for placebo vs 60 mg of orlistat and P = 0.1 for 120 mg of orlistat). Diastolic and systolic blood pressure decreased in the orlistat-treated groups (both 60 and 120 mg) as compared to placebo.

Comment by Ellen L. Sakornbut, MD

Obesity treatment is ineffective on a long-term basis unless patient commitment to lifestyle change is high. This population may represent a more motivated group of patients than a general population of obese individuals. However, it is notable that completion rates were higher in the drug-treated group than in the placebo group despite a frequent incidence of GI side effects upon initiation of orlistat. Patients want to see results, and results provide incentive.

Although Hauptman et al do not mention it, orlistat may provide a secondary effect in successful weight loss by providing a "negative feedback" experience for patients "cheating" on their diet. The successful reinforcement of a reduced fat diet is consistent with desired general preventive goals in the U.S. population.

No data exist on the safety of using orlistat for periods of time longer than two years. It requires both substantial lifestyle and, possibly, financial commitment on the part of the patient (since many insurance programs do not pay for this medication). There appears to be no reason why vitamin supplementation should not be provided prophylactically. This study would suggest that orlistat is a medication which is feasible and effective in a primary care setting.

Suggested Reading

1. Sjostrom L, et al. Lancet 1998;352(9123):167-172.

2. Davidson MH, et al. JAMA 1999;281(3):235-242.

Dr. Sakornbut is Associate Professor, University of Tennessee-Memphis, Memphis, TN.

Which one of the following statements is true?

a. Discontinuance rates of orlistat are high in randomized, controlled trials because of the frequency of GI side effects such as fecal urgency, oily spotting, and increased stool frequency.

b. The average weight loss of patients treated with orlistat in randomized, controlled trials was between 5% and 10% of initial body weight.

c. Orlistat should not be prescribed for patients without formal dietician counseling.

d. Vitamin D supplementation must be prescribed in conjunction with orlistat to prevent the development of coagulation defects.