title: The effect of sibutramine prescribing in routine clinical practice on cardiovascular outcomes: a cohort study in the United Kingdom.
abstract: OBJECTIVE
  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.
  
  
  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 Sibutramine's marketing authorization may have, therefore, been inappropriately withdrawn for people without cardiovascular disease.
authors.affiliation: Division of Psychiatry, University College London, London, UK.
authors.forename: J F
authors.initials: JF
authors.lastname: Hayes
authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Bhaskaran
authors.affiliation: Department of Medicine, University College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Batterham
authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Smeeth
authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: I
authors.initials: I
authors.lastname: Douglas
mesh_terms: D019440:Anti-Obesity Agents / Q000009:adverse effects; D001067:Appetite Depressants / Q000009:adverse effects; D015331:Cohort Studies; D000075202:Contraindications; D003503:Cyclobutanes / Q000009:adverse effects; D005260:Female; D006801:Humans; D007783:Lactones / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000139:chemically induced / Q000453:epidemiology* / Q000401:mortality / Q000517:prevention & control; D009765:Obesity / Q000150:complications / Q000188:drug therapy*; D000077403:Orlistat; D061214:Patient Safety; D018579:Patient Selection; D010818:Practice Patterns, Physicians' / Q000706:statistics & numerical data*; D016016:Proportional Hazards Models; D012307:Risk Factors; D020521:Stroke / Q000139:chemically induced / Q000453:epidemiology* / Q000401:mortality / Q000517:prevention & control; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D003503:Cyclobutanes; D007783:Lactones; D000077403:Orlistat; C058254:sibutramine