Rosiglitazone use may increase cardiovascular risk

Use of rosiglitazone for the treatment of type 2 diabetes appears to elevate the risk of cardiovascular (CV) events, particularly heart failure, according to the results of an individual patient level data (IPD) meta-analysis.

“However, clinical uncertainties about interpreting the CV risk of rosiglitazone might not be fully resolved because of different magnitudes of myocardial infarction (MI) risk that were attenuated when summary level data were used in addition to IPD,” the investigators said.

The following databases were searched to identify randomized controlled trials (phase II–IV) comparing rosiglitazone with any control for at least 24 weeks in adults: ClinicalStudyDataRequest.com for IPD and GSK Clinical Study Register, Medline, PubMed, Embase, Web of Science, Cochrane Central Registry of Controlled Trials, Scopus, and ClinicalTrials.gov from inception to January 2019 for summary level data.

Thirty-three trials with available IPD for a total of 21,156 patients were identified from ClinicalStudyDataRequest.com. In addition, 103 trials for which IPD were not available were included in the meta-analyses for MI (n=23,683 patients) and 103 trials for CV-related deaths (n=22,772 patients).

Twenty-nine trials with available IPD were included in previous meta-analyses using GSK’s summary level data, in which more MI events were identified by using IPD instead of summary level data for 26 trials and fewer CV-related deaths for five trials.

Analyses limited to trials with available IPD data, and applying a constant continuity correction of 0.5 as well as a random effects model to account for those with zero events in only one arm, revealed a 33-percent higher risk of a composite event (acute MI, heart failure, CV-related death and non-CV-related death) in patients receiving rosiglitazone vs controls (odds ratio [OR], 1.33, 95 percent confidence interval [CI], 1.09–1.61). [BMJ 2020;368:l7078]

Specifically, the ORs for individual outcomes were as follows: 1.17 (95 percent CI, 0.92–1.51) for MI, 1.54 (95 percent CI, 1.14–2.09) for heart failure, 1.15 (95 percent CI, 0.55–2.41) for CV-related death, and 1.18 (95 percent CI, 0.60–2.30) for non-CV-related death. ORs for MI (1,09, 95 percent CI, 0.88–1.35) and CV-related death (1.12, 95 percent CI, 0.72–1.74) were attenuated in analyses of trials for which IPD were not available.

Moreover, these results persisted when analyses were repeated using trials with zero events across both arms and either of the two continuity corrections was used.

“Although we observed that rosiglitazone use was associated with an increased CV risk of approximately 30 percent among trials for which IPD were available, this could partly be explained by a large increase in the number of heart failure events,” the investigators noted.

This finding supports a previous meta-analysis, which found a nearly 70-percent higher risk of heart failure among patients treated with rosiglitazone, and is consistent with warnings issued by the US Food and Drug Administration in 2001 and 2006. [Int J Cardiol 2010;143:135-140; BMJ 2010;341:c4848]