Abstract
Background/Objectives:The marketing authorization for the weight loss drug sibutramine was suspended in 2010 following a major trial that showed increased rates of non-fatal myocardial infarction and cerebrovascular events in patients with pre-existing cardiovascular disease. In routine clinical practice, sibutramine was already contraindicated in patients with cardiovascular disease and so the relevance of these influential clinical trial findings to the ‘real World' population of patients receiving or eligible for the drug is questionable. We assessed rates of myocardial infarction and cerebrovascular events in a cohort of patients prescribed sibutramine or orlistat in the United Kingdom.Subjects/Methods:A cohort of patients prescribed weight loss medication was identified within the Clinical Practice Research Datalink. Rates of myocardial infarction or cerebrovascular event, and all-cause mortality were compared between patients prescribed sibutramine and similar patients prescribed orlistat, using both a multivariable Cox proportional hazard model, and propensity score-adjusted model. Possible effect modification by pre-existing cardiovascular disease and cardiovascular risk factors was assessed.Results:Patients prescribed sibutramine (N=23 927) appeared to have an elevated rate of myocardial infarction or cerebrovascular events compared with those taking orlistat (N=77 047; hazard ratio 1.69, 95% confidence interval 1.12–2.56). However, subgroup analysis showed the elevated rate was larger in those with pre-existing cardiovascular disease (hazard ratio 4.37, 95% confidence interval 2.21–8.64), compared with those with no cardiovascular disease (hazard ratio 1.52, 95% confidence interval 0.92–2.48, P-interaction=0.0076). All-cause mortality was not increased in those prescribed sibutramine (hazard ratio 0.67, 95% confidence interval 0.34–1.32).Conclusions:Sibutramine was associated with increased rates of acute cardiovascular events in people with pre-existing cardiovascular disease, but there was a low absolute risk in those without. Sibutramine's marketing authorization may have, therefore, been inappropriately withdrawn for people without cardiovascular disease.
Highlights
Before 2010 sibutramine and orlistat were the two European Union approved pharmaceutical options for weight loss treatment for individuals with a body mass index (BMI) over 27 kg mÀ2.1 In January 2010, sibutramine was suspended following a review by the European Medicines Agency, who found an ‘increased risk of non-fatal myocardial infarction (MI) and stroke, which outweighed the possible benefits of medication through weight loss’.2 The United States Food and Drugs Administration followed suit later that year
There were 254 incident MI/cerebrovascular event (CVE) in the cohort; 34 in 0.126 per 100 000 person-years at risk (105 PYAR) in patients exposed to sibutramine and 220 in 1.092 per 105 PYAR in the orlistat group
In those exposed to sibutramine, the rate of MI or CVE (MI/CVE) was 269.39.12 per 105 PYAR
Summary
Before 2010 sibutramine and orlistat were the two European Union approved pharmaceutical options for weight loss treatment for individuals with a body mass index (BMI) over 27 kg mÀ2.1 In January 2010, sibutramine was suspended following a review by the European Medicines Agency, who found an ‘increased risk of non-fatal myocardial infarction (MI) and stroke, which outweighed the possible benefits of medication through weight loss’.2 The United States Food and Drugs Administration followed suit later that year. Concerns about sibutramine’s safety had been raised before, the risk was clarified by the Sibutramine Cardiovascular Outcomes Trial (SCOUT),[3] a randomized, placebo-controlled trial of over 10 000 patients with increased risk of cardiovascular events (that is, individuals with pre-existing cardiovascular disease or with type 2 diabetes mellitus (T2D) and cardiovascular risk factors). The aim of SCOUT was to clarify the cardiovascular and cerebrovascular side effect profile of sibutramine. The primary outcome was a composite of non-fatal MI, non-fatal cerebrovascular event (CVE), resuscitation after cardiac arrest, and cardiovascular death.[3] The rate was increased by 16% in the sibutramine group compared with placebo (hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.03–1.31, P = 0.02), with overall incidences of 11.4% and 10.0%, in the two groups, respectively
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