Rosiglitazone: Possible complications and treatment of non-alcoholic steatohepatitis (NASH)☆

Rosiglitazone evaluated for cardiovascular outcomes – an interim Analysis. Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ, RECORD Study Group.

Background

A recent meta-analysis raised concern regarding an increased risk of myocardial infarction and death from cardiovascular causes associated with rosiglitazone treatment of type 2 diabetes.

Methods

We conducted an unplanned interim analysis of a randomized, multicenter, open-label, noninferiority trial involving 4447 patients with type 2 diabetes who had inadequate glycemic control while receiving metformin or sulfonylurea, in which 2220 patients were assigned to receive add-on rosiglitazone (rosiglitazone group), and 2227 to receive a combination of metformin plus sulfonylurea (control group). The primary end point was hospitalization or death from cardiovascular causes.

Results

Because the mean follow-up was only 3.75 years, our interim analysis had limited statistical power to detect treatment differences. A total of 217 patients in the rosiglitazone group and 202 patients in the control group had the adjudicated primary end point (hazard ratio, 1.08; 95% confidence interval [CI], 0.89–1.31). After the inclusion of end points pending adjudication, the hazard ratio was 1.11 (95% CI, 0.93–1.32). There were no statistically significant differences between the rosiglitazone group and the control group regarding myocardial infarction and death from cardiovascular causes or any cause. There were more patients with heart failure in the rosiglitazone group than in the control group (hazard ratio, 2.15; 95% CI, 1.30–3.57).

Conclusions

Our interim findings from this ongoing study were inconclusive regarding the effect of rosiglitazone on the overall risk of hospitalization or death from cardiovascular causes. There was no evidence of any increase in death from either cardiovascular causes or all causes. Rosiglitazone was associated with an increased risk of heart failure. The data were insufficient to determine whether the drug was associated with an increase in the risk of myocardial infarction.

[Abstract reproduced by permission of N Engl J Med 2007;357:28–38]

Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. Nissen SE, Wolski K.

Background

Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus, but its effect on cardiovascular morbidity and mortality has not been determined.

Methods

We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarction and death from cardiovascular causes. Of116 potentially relevant studies, 42 trials met the inclusion criteria. We tabulated all occurrences of myocardial infarction and death from cardiovascular causes.

Results

Data were combined by means of a fixed-effects model. In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03–1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98–2.74; P=0.06).

Conclusions

Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.

[Abstract reproduced by permission of N Engl J Med 2007;356:2457–2471]