Effectiveness of sibutramine - Letter to the Editor

Journal of Family Practice, Oct, 2002 by Joseph A. Lieberman, III

TO THE EDITOR:

In their commentary on the article by Wirth and Krause, (1) Drs Stevenson, Trojian, and Jackson (2) questioned the use of sibutramine in races other than whites and the use of the drug beyond 1 year because long-term health and mortality benefits have not been established.

Regarding the former point, McMahon and colleagues (3) showed that the mean percentage change in body weight among blacks receiving sibutramine (-4.0%) is comparable to that among whites (-4.9%). Studies by Fanghitnel and colleagues (4,5) and Cuellar and colleagues (6) showed that sibutramine given for at least 6 months can induce significant loss of body weight and waist circumference in obese Hispanic patients compared with patients receiving placebo. These studies confirm that data exist to support the efficacy and safety of sibutramine in obese populations of diverse ethnic backgrounds.

Regarding long term use, clinical studies that support the routine use and safety and efficacy of sibutramine administration for up to 1 year include those by Jones and colleagues (7) and Apfelbaum and colleagues. (8) The Sibutramine Trial of Obesity Reduction and Maintenance (STORM), (9) which was specifically designed to assess the safety and efficacy of sibutramine on maintenance of weight loss, showed that weight loss achieved with sibutramine can be maintained for up to 2 years and cause significant changes in high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, triglycerides, and uric acid exceeding those expected from weight loss alone. Adverse effects reported during the study were comparable to those seen with placebo. The small increases in blood pressure were counterbalanced by the beneficial effect on abnormal lipid levels and insulin resistance.

Although the long-term effect of sibutramine on obesity-associated mortality and morbidity has not been clearly established, the potential of developing coronary heart disease is directly related to the burden of risk factors present: Modest weight loss can affect this cluster of risk factors and thus may produce health benefits for certain patients with chronic obesity who are at risk for other diseases. With the use of risk equations based on the Framingham Heart Study, (11) analyses of metabolic and cardiovascular responses from a number of sibutramine trials suggested a decrease in the absolute risk of events of coronary heart disease; patients at the highest risk (those with hypertension, diabetes, or dyslipidemia) showed the greatest risk reduction. (9,12) Use of sibutramine as an adjunctive modality for obesity management undoubtedly requires a risk-versus-benefit analysis for each patient. However, the opportunity to ameliorate risk factors and prevent or delay catastrophic events logically would seem to prevail over potential small changes in other cardiovascular parameters, unless the individual patient proves unable to tolerate these problems, if they occur.

Joseph A. Lieberman III, MD, MPH
Jefferson Medical College
Philadelphia. Pennsylvania
E-mail: jlieberman@jalmd.com

DRS JACKSON, STEVENSON, AND TROJIAN RESPOND:

We appreciate Dr Lieberman's input on the appropriate role of sibutramine in the long-term management of obesity. We limited our comments in the Recommendations for Clinical Practice section of our POEM article to white Europeans because this was the patient population studied by Wirth and colleagues. (1) We hope that the sample sizes of the studies cited by Dr Lieberman in support of the drug's effectiveness in other ethnic groups (American blacks and Hispanics) were similar to that of Wirth et al, which included 1001 subjects, 800 of whom received sibutramine.

The STORM trial (9) cited by Dr Lieberman to support the long-term safety and efficacy of sibutramine provided 2-year data on only 204 sibutramine-treated patients who completed the study. The beneficial effects reported for sibutramine on serum lipids were included as secondary outcomes in that study of the drug's effect on weight maintenance after weight loss. The statement by Dr Lieberman that small increases in blood pressure caused by the drug were counterbalanced by its beneficial effects on lipids is conjecture. One can only guess how different effects on heart disease risk factors might affect final outcomes such as coronary events. Notwithstanding the 2-year study period, because of the small sample size composed of relatively low-risk patients, the STORM trial was not designed to provide meaningful conclusions about important clinical outcomes such as morbidity, mortality, and drug safety.

Using risk equations to estimate the effect of weight loss achieved with sibutramine on the risk of coronary heart disease events is not an acceptable substitute for well-designed, truly long-term controlled trials studying final, rather than intermediate, outcomes. These studies should include a significant number of patients with other heart disease risk factors to improve the generalizability of the results. This is especially important for drugs such as sibutramine that provide beneficial effects on some risk factors (lipids) and detrimental effects on others (blood pressure and heart rate).