Cardiovascular Risk-benefit Profile of Sibutramine
Posted: 12/03/2010; Am J Cardiovasc Drugs. 2010;10(5):321-334. © 2010 Adis Data Information BV
Sibutramine is a combined norepinephrine and serotonin reuptake inhibitor used as an antiobesity agent to reduce appetite and promote weight loss in combination with diet and exercise. At a daily dose of 10–20 mg, it was initially considered to have a good safety profile, as it does not induce primary pulmonary hypertension or adverse effects on cardiac valves, in contrast to previous reports relating to some other antiobesity agents. However, it exerts disparate effects on cardiovascular risk factors. On the one hand, sibutramine may have antiatherogenic activities, as it improves insulin resistance, glucose metabolism, dyslipidemia, and inflammatory markers, with most of these effects resulting from weight loss rather than from an intrinsic effect of the drug. On the other hand, because of its specific mode of action, sibutramine exerts a peripheral sympathomimetic effect, which induces a moderate increase in heart rate and attenuates the reduction in BP attributable to weight loss or even slightly increases BP. It may also prolong the QT interval, an effect that could induce arrhythmias. Because of these complex effects, it is difficult to conclude what the final impact of sibutramine on cardiovascular outcomes might be. Sibutramine has been shown to exert favorable effects on some surrogate cardiovascular endpoints such as reduction of left ventricular hypertrophy and improvement of endothelial dysfunction. A good cardiovascular safety profile was demonstrated in numerous 1- to 2-year controlled trials, in both diabetic and nondiabetic well selected patients, as well as in several observational studies. However, since 2002, several cardiovascular adverse events (hypertension, tachycardia, arrhythmias, and myocardial infarction) have been reported in sibutramine-treated patients. This led to a contraindication of the use of this antiobesity agent in patients with established coronary heart disease, previous stroke, heart failure, or cardiac arrhythmias. SCOUT (Sibutramine Cardiovascular and Diabetes Outcome Study) was designed to prospectively evaluate the efficacy/safety ratio of sibutramine in a high-risk population. The efficacy/safety results of the first 6-week lead-in open period of treatment with sibutramine 10 mg/day were reassuring in 10 742 overweight/obese high-risk subjects (97% had cardiovascular disease, 88%had hypertension, and 84%had type 2 diabetes mellitus). However, the final results of SCOUT showed that long-term (5 years') treatment with sibutramine (10–15 mg/day) exposed subjects with pre-existing cardiovascular disease to a significantly increased risk for nonfatal myocardial infarction and nonfatal stroke, but not cardiovascular death or all-cause mortality. Because the benefit of sibutramine as a weight-loss aid seems not to outweigh the cardiovascular risks, the European Medicines Agency recommended the suspension of marketing authorizations for sibutramine across the EU. The US FDA stated that the drug should carry a 'black box' warning due to an increased risk of stroke and heart attack in patients with a history of cardiovascular disease. In conclusion, concern still persists about the safety profile of sibutramine regarding cardiovascular outcomes, and the drug should not be prescribed for overweight/obese patients with a high cardiovascular risk profile.
Obesity is epidemic and considered a major health problem, as its prevalence continuously rises worldwide.Obesity is a major cause of morbidity and mortality, predominantly through cardiovascular disease (CVD).[2,3] The metabolic consequences of obesity, more particularly abdominal obesity associated with increased visceral adipose tissue, include atherogenic dyslipidemia, impaired glucose metabolism, hypertension, and silent inflammation, all of which are CVD risk factors.[8,9] Obesity has a major impact on CVD, such as heart failure, coronary heart disease, sudden cardiac death, and atrial fibrillation, and is associated with reduced overall survival.[2,3] Weight loss is considered to be the initial step that helps to prevent or to control the clinical consequences of obesity.[10,11] However, the current state of weight reduction in the prevention and treatment of CVD remains controversial.[10,12] One of the common health consequences of abdominal obesity is type 2 diabetes mellitus (T2DM), and antiobesity management is a prerequisite in preventing diabetes and treating diabetic patients.[5,13,14] Weight reduction in obese persons will improve hyperglycemia and will reduce all of the CVD risk factors associatedwithT2DM.However, no long-term, largescale study of intentional weight loss through medical means has been adequately powered to examine CVD endpoints in individuals with or without diabetes.
The initial clinical strategy for weight loss is lifestyle modification involving a combination of diet, exercise, and behavior change.[16,17] However, it is difficult for many individuals to achieve and maintain weight loss solely through this approach. Pharmacological therapy can be offered to obese patients who have failed to achieve their weight-loss goals through diet and exercise alone,[18–21] and should be considered for those with a body mass index (BMI) >30 kg/m2 or >27 kg/m2 in the presence of obesity-related risk factors or disease. Among the drugs still available to clinicians, only two agents, orlistat and sibutramine, have been approved to treat obesity over the long term. Although placebo-subtracted weight loss of >5% maintained over 1 year is the primary efficacy endpoint for antiobesity agents, an associated reduction in CVD risk factors is considered as an important secondary endpoint that may help in obtaining approval by the US FDA and European Medicines Agency.[23,24]Safety aspects are also critical in this indication, essentially because antiobesity agents are known to be associated with adverse events, and several of them have been withdrawn from the market because of serious safety problems.[25–28]
Sibutramine is one of the few established and well-proven agents for obesity and may be considered effective in the management of patients requiring pharmacotherapy as part of a multimodal approach to weight loss.[29–32]Although this norepinephrine-serotonin reuptake inhibitor was originally evaluated for possible use as an antidepressant, its research development was redirected to evaluate it as an anorexiant. The pharmacological mechanisms through which sibutramine exerts its weight-loss effect are likely to be due to a combination of reduced appetite, feelings of satiety, and possibly the induction of thermogenesis. Its efficacy for inducing initial weight loss and the subsequent maintenance of weight loss has been well proven in short- and long-term clinical trials of up to 2 years' duration.[34,35] Indirect comparisons suggest that sibutramine is slightly more effective than orlistat for promoting weight loss and weight maintenance, in both diabetic and nondiabetic patients.[35–37]Nevertheless, the mean weight loss achieved in many studies was only 5–10% of initial bodyweight, with large interindividual differences (good and poor responders). Sibutramine was also shown to improve atherogenic dyslipidemia, part of this effect possibly occurring independently of weight loss.[38,39] Several randomized clinical trials were performed in overweight/obese patients with T2DM and demonstrated the potential of sibutramine to improve glucose control.[36,40] In general, sibutramine has been well tolerated,[41,42] with no induction of primary pulmonary hypertension or adverse effects on cardiac valves,[44,45] in contrast to what was previously reported with fenfluramine and dexfenfluramine.[25,26] However, its action on the sympathetic nervous system has linked sibutramine to BP and heart rate (HR) elevations.[46,47] This raises the possibility of increased CVD risk, despite the favorable weight-reducing effect of the drug. For that reason, the use of sibutramine is contraindicated in patients with uncontrolled hypertension, coronary heart disease, cardiac dysrhythmias, congestive heart failure, or stroke.[41,42,49,50]