Insulin sensitizers and heart failure: an engine flooded with fuel

Abstract

Rating: •Of Importance

Introduction: In 2007, a meta-analysis of 42 randomized controlled trials involving the thiazolidinedione (TZD) rosiglitazone reported a 1.4 fold increase in the risk of acute myocardial infarction (AMI) compared with non-TZD therapies. Subsequently, another meta-analysis of 19 randomized controlled trials involving the TZD pioglitazone found a significant reduction in the composite outcome of nonfatal AMI, stroke, and all-cause mortality, thereby suggesting a potential difference in cardiovascular risk between the two TZDs.

Aims: To determine if the risk of serious cardiovascular harm is increased by rosiglitazone compared with pioglitazone.

Methods: The study was designed as a nationwide observational, retrospective, inception cohort of 227,571 Medicare beneficiaries aged 65 years or older (mean age, 74.4 years) who initiated treatment with rosiglitazone or pioglitazone through a Medicare Part D prescription drug plan from July 2006-June 2009 and who underwent follow-up for up to three years after TZD initiation. Individual and composite end points of AMI, stroke, heart failure, and all-cause mortality were assessed using the following: incidence rates by TZD, attributable risk, number needed to harm, Kaplan-Meier plots of time to event, and Cox proportional hazard ratios for time to event. Data were adjusted for potential confounding factors, with pioglitazone as a reference.

Results: A total of 8,667 end points were observed during the study period. The adjusted hazard ratio for rosiglitazone compared with pioglitazone was 1.06 (95% CI, 0.96-1.18) for AMI; 1.27 (95% CI, 1.12-1.45) for stroke; 1.25 (95% CI, 1.16-1.34) for heart failure; 1.14 (95% CI, 1.05-1.24) for death; and 1.18 (95% CI, 1.12-1.23) for the composite of AMI, stroke, heart failure, or death. The attributable risk for this composite end point was 1.68 (95% CI, 1.27-2.08) excess events per 100 person-years of treatment with rosiglitazone compared with pioglitazone. The corresponding number needed to harm was 60 (95% CI, 48-79) treated for one year.

Discussion: This study contributes to the rising tide of retrospective analyses suggesting post-marketing cardiovascular complications from the insulin sensitizing group of agents known as TZDs, especially rosiglitazone. In this study, rosiglitazone was associated with an increased risk of stroke, heart failure, and death and the composite of AMI, stroke, heart failure, or death. Limitations of the present study include the absence of randomization, a potential for misclassification, and a potential for unmeasured confounding factors. Still, we consider this work important for the following reasons.