Introduction

Metabolic syndrome is a common condition characterized by abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance, glucose intolerance, and prothrombotic and proinflammatory states.¹ The syndrome is associated with increased morbidity and mortality, including that associated with cardiovascular disease and type 2 diabetes mellitus.^2,3 Metabolic syndrome affects over 47 million adults in the United States, approximately one of every 5 individuals.⁴ Various definitions of the metabolic syndrome exist, one of the most commonly utilized was developed by the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)¹ (Table 1). Both genetic and lifestyle factors contribute to the development of metabolic syndrome; two of the primary causes being obesity and lack of physical exercise (sedentary lifestyle).

Results of a recent Finnish study (the Kuopio Ischaemic Heart Disease Risk Factor Study) demonstrated that men with metabolic syndrome (but no evidence of cardiovascular disease or diabetes at baseline) were up to 4.2 times more likely to die of coronary heart disease and up to 2.9 times more likely to die of cardiovascular disease than men without metabolic syndrome over the course of 11.6 years (median duration of follow-up).⁵

According to the NCEP ATP III Guidelines, treatment of the metabolic syndrome should include strategies to reduce weight and increase physical activity.¹ It has been proposed that the selective serotonin and norepinephrine reuptake inhibitor sibutramine (Meridia) could have beneficial effects in obese patients with metabolic syndrome, as it has been proven to help obese and overweight patients with comorbidities lose weight and maintain weight loss when used in conjunction with a reduced calorie diet. Several long-term studies of sibutramine have demonstrated a significant improvement in waist circumference, high-density lipoprotein (HDL)-cholesterol, triglycerides, fasting blood glucose and insulin resistance.^6-9 Data presented at the 2003 North American Association for the Study of Obesity (NAASO) Scientific Meeting support this proposed treatment, as they illustrate the beneficial effects of sibutramine in obese patients with metabolic syndrome.

Sibutramine Improves Risk Factors of Metabolic Syndrome

Results of a combined analysis that included data from 8 randomized, double-blind, placebo-controlled long-term trials of sibutramine in obese subjects with metabolic syndrome demonstrated that patients treated with sibutramine not only lose weight, but also experience significant reductions in metabolic risk factors.¹⁰ All patients who participated in these studies met at least 3 criteria for metabolic syndrome as defined by NCEP ATP III, including elevated triglycerides (≥150 mg/dL), reduced HDL-cholesterol (<50 mg/dL in women and <40 mg/dL in men); and abdominal obesity (waist circumference >88 cm (>35 inches) in women and >102 cm (>40 inches) in men). Additionally, one-half of each treatment arm (53% and 52% of the sibutramine and placebo treatment arms, respectively) had elevated blood pressure (BP) (≥130/85 mm Hg) and 15% and 17% had impaired fasting glucose (≥110 mg/dL) at baseline, respectively. Patients were randomized to treatment with a reduced calorie diet plus sibutramine 10 mg or 15 mg once daily (n = 397) or placebo (n = 200) for a duration of 6 to 12 months.

At endpoint, compared to patients treated with placebo, patients treated with sibutramine experienced significantly greater weight loss (-6.4 kg vs +0.2 kg; P<.001) (Figure 1A), reductions in waist circumference (-9.6 cm vs -3.9 cm; P<.001) (Figure 1B), increases in HDL-cholesterol (+19.1% vs +12.1%; P<.005) and reductions in triglycerides (-21% vs -8%; P<.001) (Figure 1C), and reductions in the triglyceride/HDL-cholesterol ratio (-2.4 vs -1.0; P<.001). Changes in BP and glucose were not significant and did not differ between treatment arms.

These findings suggest that obese patients with metabolic syndrome treated with sibutramine plus diet will experience benefits beyond weight loss, including reductions in abdominal obesity and improved lipid profiles. Therefore, sibutramine is an effective pharmacologic treatment option for obese metabolic syndrome patients.

Sibutramine: Impact on Blood Pressure is Equivalent to Placebo

Because sibutramine inhibits norepinephrine reuptake, it could theoretically increase BP in some patients. Small, clinically insignificant increases in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (1 to 3 mm Hg relative to placebo) were reported with sibutramine doses of 5 mg to 20 mg daily in initial clinical trials.¹¹ In one published study in patients with stabilized hypertension, sibutramine 10 mg plus diet resulted in mean reductions in BP of 4.0 mm Hg following 12 weeks of therapy.¹²

Retrospective analysis of data from obese subjects with normal BP or controlled hypertension who participated in any of 21 randomized, double-blind, placebo-controlled 12-week or longer trials of sibutramine (n = 1,898) or placebo (n = 1,521) demonstrated that sibutramine does not influence BP appreciably during the first 12 weeks of therapy in relation to placebo.¹³ Mean changes in SBP and DBP were similar in the sibutramine and placebo groups (mean changes (mm Hg) in SBP of -0.3 [±0.3] vs -1.2 [±0.4] and mean changes (mm Hg) in DBP of 0.5 [±0.2] vs -1.2 [±0.2] for sibutramine vs placebo, respectively). Similar proportions of sibutramine and placebo-treated patients experienced maximum increase or decreases of ≥10 mm Hg on 2 consecutive visits or on the last visit (Figure 2). These findings suggest that sibutramine is unlikely to have clinically significant impact on BP in patients with normal BP or controlled hypertension.

Early Efficacy Predicts Sibutramine Response in Nondiabetic and Diabetic Patients

Clinical evidence suggests weight loss between 5% and 10% of initial body weight can significantly reduce the health risks associated with obesity.¹ For clinicians, determining who is most likely to respond to sibutramine therapy can be a challenge. Retrospective analysis of data from all nondiabetic (n = 784) and diabetic (n = 158) subjects who participated in randomized, double-blind 12-month or longer trials of sibutramine 10 to 15 mg once daily demonstrated a relationship between response at 3 months and successful weight loss (≥5% of initial body weight) at 12 months.¹⁴ Several early weight loss targets were evaluated as predictors of response, including losses of ≥1 kg, ≥2 kg, ≥3 kg, and ≥4 kg at Months 1, 2, and 3. Of these, the >4 kg target at Month 3 was the best predictor of 12-month success. In other words, if a patient treated with sibutramine had achieved at least a 4 kg weight loss at Month 3, long-term successful weight loss (≥5% of initial body weight) was a high probability.

Approximately 85% of all patients who achieved this 3-month target (≥4 kg) experienced 12-month losses of at least 5% of their initial body weight. Conversely, nearly 71% of all patients who did not achieve this 3-month target did not experience successful weight loss at 12 months. Based on these data, patients need a minimum therapeutic trial of 3 months to appropriately evaluate the effects of sibutramine and the anticipated benefits of continued therapy.

Conclusion

Weight loss is one of the cornerstones of metabolic syndrome management. Results of recent analysis demonstrate that sibutramine plus diet and exercise leads to significant improvements in metabolic syndrome risk factors, including weight, waist circumference, and lipids without producing negative effects on blood pressure. Patients should be given a minimum three-month trial on sibutramine, when appropriate, to determine the likelihood of successful treatment.

References

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