Wirth A, Krause J. Long-term weight loss with sibutramine: a randomized controlled trial. JAMA 2001; 286:1331-39.

* BACKGROUND Obesity, defined as a body mass index (BMI) equal to or greater than 30 kg/[m.sup.2], is a common chronic disorder with a prevalence of 22.3% in American adults. (1) There is significant interest in pharmacologic interventions for this disorder because of the difficulty achieving and maintaining significant weight loss solely with lifestyle changes. Two drugs, sibutramine and orlistat (Xenical), have recently been approved by the Food and Drug Administration for long-term (greater than 12 weeks) management of obesity.

* POPULATION STUDIED The researchers enrolled 1102 obese (BMI = 3040 kg/[m.sup.2] adults from 111 private practices or outpatient clinics in Germany. Almost all subjects were white, and 75% were women aged between 18 and 65 years. After randomization, treatment groups were well matched demographically and had similar weights, BMI (mean = 34.8 kg/[m.sup.2], and waist circumference. Patients were excluded if they were pregnant or had serious cardiovascular or metabolic diseases, history of drug or alcohol abuse, depression, or treatment with antidepressants, [Beta]-blockers, or any drug influencing body weight.

* STUDY DESIGN AND VALIDITY This was a randomized (allocation assignment concealed) double-blind trial funded by the manufacturer of sibutramine. All patients were treated unblinded with 15 mg per day of sibutramine for 4 weeks. Patients with at least a 2% or 2 kg weight loss (responders) were then randomized to 1 of 3 treatment groups: 15 mg per day of sibutramine continuously during weeks 5 to 48; 15 mg per day of sibutramine intermittently during weeks 5 to 12, 19 to 30, and 37 to 48 and a placebo on all other days; or placebo once daily for weeks 5 to 48.

To mimic routine ambulatory practice in Germany, the study did not include formal dietary or behavior modification programs. Unfortunately, the use of potentially confounding variables, such as diet or exercise, were not reported. Differences in diet or levels of exercise between the 3 study groups could have had a significant impact on study results. Also, there was no testing of whether the side effects or weight loss produced by the medication allowed participants to identify the treatment group to which they were assigned. Correct identification of treatment group assignment by participants would suggest unsuccessful blinding, threatening the validity of study results. The results of this trial are only applicable to relatively healthy white persons.

* OUTCOMES MEASURED The primary outcome was weight loss during the 44-week randomized period. Secondary outcomes included waist circumference, heart rate, blood pressure, cholesterol levels, and side effects.

* RESULTS The average weight loss for the 1001 patients completing the 4-week nonblinded run-in period was 4.2 kg and was similar for patients going into each of the 3 treatment groups. Using intention-to-treat analysis, sustained mean weight loss during the 44-week randomized treatment period was 3.8 kg (4.0%) with continuous sibutramine therapy (95% confidence interval [CI], -4.42 to -3.20 kg) and 3.3 kg (3.5%) with intermittent therapy (95% CI, -3.96 to -2.66 kg). Mean weight gain in the placebo group was 0.2 kg (95% CI, -0.60 to 0.94 kg). Minimal decreases in low-density lipoprotein cholesterol (-5 mg/dL) occurred in both sibutramine treatment groups, but blood pressure was not affected. During the 4-week run-in period where everyone received sibutramine, 14% of the patients experienced drug-related adverse effects. During the 44-week double-blinded period, the proportion of withdrawals because of adverse events was similar across the 3 study groups. Twenty-one percent of the original subjects did not complete the entire 48-week study.

RECOMMENDATIONS FOR CLINICAL PRACTICE

Sibutramine 15 mg per day given continuously or intermittently for 44 weeks allows modest additional weight loss (3.55 kg, 7.8 lb) compared with placebo among initial sibutramine responders. This weight loss was achieved in a group of obese (mean BMI = 34.8 kg/[m.sup.2]), otherwise healthy women, most of whom were white. The same results may not occur in other races, and may not be applicable to many practices. Because truly long-term (beyond 1 year) safety, health, or mortality benefits have not been established for sibutramine, this drug should not be routinely used for treating obesity.

REFERENCE

(1.) Kuczmarski RJ, Carrol MD, Flegal KM, Troiano RP. Varying body mass index cut-off points to describe overweight prevalence among U.S. adults: NHANES III (1988 to 1994). Obesity Res 1997; 5:542-48.

J. Herbert Stevenson, MD
Thomas Trojian, MD, MS
Eric A. Jackson, PharmD
University of Connecticut School of Medicine
and Saint Francis Hospital and
Medical Center Hartford
E-mail: ejackson2@stfranciscare.org

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