Abstract
ObjectiveTo describe the likely extent of confounding in evaluating the risks of cardiovascular (CV) events and mortality in patients using diabetes medication.MethodsThe General Practice Research Database was used to identify inception cohorts of insulin and different oral antidiabetics. An analysis of bias and incidence of mortality, acute coronary syndrome, stroke and heart failure were analysed in GPRD, Hospital Episode Statistics and death certificates.Results206,940 patients were identified. The bias analysis showed that past thiazolidinedione users had a lower mortality risk compared to past metformin users. There were no differences between past users of rosiglitazone and pioglitazone (adjusted RR of 1.04; 95% CI 0.93–1.18). Current rosiglitazone users had an increased risk of death (adjusted RR 1.20; 95% CI 1.08–1.34) and of hospitalisation for heart failure (adjusted RR of 1.73; 95% CI 1.19–2.51) compared to current pioglitazone users. Risk of mortality was increased two-fold shortly after starting rosiglitazone. Excess risk of death over 3 years with rosiglitazone was 0.3 per 100 in those aged 50–64 years, 2.0 aged 65–74, 3.0 aged 75–84, and 7.0 aged 85+. The cause of death with rosiglitazone was more likely to be due to a disease of the circulatory system.ConclusionsHigher risks for death (overall and due to cardiovascular disease) and heart failure were found for rosiglitazone compared to pioglitazone. These excess risks were largest in patients aged 65 years or older. The European regulatory decision to suspend rosiglitazone is supported by this study.
Highlights
The thiazolidinediones - rosiglitazone and pioglitazone - have been widely used for the treatment of type 2 diabetes mellitus
Pioglitazone was reported to have a statistically significant lower risk in a composite endpoint of death, myocardial infarction (MI) and stroke from findings of another meta-analysis [3]. These reports were supported by a FDA meta-analysis of randomised controlled trials (RCTs), which found that the risk of all-cause and cardiovascular mortality and MI tended to be lower with pioglitazone and higher with rosiglitazone [4]
Each exposed patient was matched by age, sex and practice to one control patient, with the index date of the control being the same as that of the exposed patient. Within this overall exposed cohort, we identified inception cohorts for each class of diabetes medication
Summary
The thiazolidinediones - rosiglitazone and pioglitazone - have been widely used for the treatment of type 2 diabetes mellitus. Pioglitazone was reported to have a statistically significant lower risk in a composite endpoint of death, MI and stroke from findings of another meta-analysis [3] These reports were supported by a FDA meta-analysis of RCTs, which found that the risk of all-cause and cardiovascular mortality and MI tended to be lower with pioglitazone and higher with rosiglitazone ( most results did not reach statistical significance) [4]. This analysis highlighted that the risk of congestive heart failure was increased with both drugs [4]. The populations using the drugs and exposure characteristics in actual clinical practice may be different from those enrolled in RCTs [6]
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