The association between rosiglitazone and increased cardiovascular (CV) risk, especially heart failure, was confirmed by the results of a systematic review and meta-analyses published in The BMJ.
Several meta-analyses have been published since 2007 with conflicting results about the CV risks linked to treatment with rosiglitazone. These studies have used various analytical approaches but were limited given a lack of access to individual patient-level data, which may identify adverse events on a more consistent basis. Using trials with and without patient-level data, researchers completed a systematic review and meta-analyses to examine the CV risks associated with this diabetes drug.
The systematic review included randomized controlled clinical trials (phases 2-4) that compared the effect of rosiglitazone with any control group in adults with a duration of ≥24 weeks.
In analyses of trials with available individual patient-level data, a composite outcome of acute myocardial infarction (MI), heart failure, CV-related death, and non-CV-related death was examined. In analyses that included trials for which patient-level data were not available, MI and CV-related death were examined, determined from summary-level data.
Of 59 trials requested from the GlaxoSmithKline clinical trial registry database, 33 with individual patient-level data were included, with a total of 21,156 patients; more than half received rosiglitazone (n=11,837; 56%). Among rosiglitazone-treated patients, there were 274 composite events (2.3%), 147 MIs (1.24%), 122 heart failures (1.03%), 15 CV-related deaths (0.13%), and 22 non-CV-related deaths (0.19%). Among 9319 patients who received comparator treatments, there were 219 composite events (2.4%), 133 MIs (1.4%), 80 heart failures (0.86%), 10 CV-related deaths (0.11%), and 13 non-CV-related deaths (0.14%).
The analyses for MI risk included 103 trials for which patient-level data were not available. Of 23,683 patients, 12,630 (53.3%) were randomly assigned to receive rosiglitazone. MI was documented in 43 patients (0.34%) treated with rosiglitazone and in 40 (0.36%) allocated to comparator treatments.
In analyses for CV mortality, 103 trials without patient-level data were included. Of 22,772 patients, 12,183 (53.5%) were randomly assigned to rosiglitazone treatment. There were 26 (0.21%) and 20 (0.19%) CV-related deaths in the rosiglitazone treatment group and the comparator treatment groups, respectively.
Of 29 trials with available individual patient-level data that were included in previous meta-analyses using GlaxoSmithKline’s summary-level data, 26 reported more MI events than those reported in summary-level data. Only 1 trial that had patient-level data reported fewer MIs.
As for CV-related mortality, there were more deaths in 1 trial that used individual patient-level data instead of summary-level data, whereas fewer CV-related deaths were reported in 5 studies that used patient- vs summary-level data.
When analyses were limited to trials that included patient-level data, there was a 33% increased risk for a composite event among rosiglitazone-treated patients vs comparator groups (odds ratio [OR], 1.33; 95% CI, 1.09-1.61; P =.005). When each outcome was examined independently, the ORs were 1.17 (95% CI, 0.92-1.51) for MI, 1.54 (95% CI, 1.14-2.09; P =.005) for heart failure, 1.15 (95% CI, 0.55-2.41) for CV-related death, and 1.18 (95% CI, 0.60-2.30) for non-CV-related death.
In analyses that included trials for which individual patient-level data were not available, ORs for MI and CV-related death were attenuated; treatment with rosiglitazone carried a 9% increased odds of MI (OR, 1.09; 95% CI, 0.88-1.35) and a 12% increased odds of CV-related deaths (OR, 1.12; 95% CI, 0.72-1.74).
The researchers acknowledged several study limitations, including analytical limitations, such as multiple testing and lower power, and data source limitations, such as the quality of the individual studies.
“When we limited our analysis to trials for which [individual patient-level data were] available, rosiglitazone use was associated with an increased cardiovascular risk, probably owing to heart failure events. However, clinical uncertainties about interpreting the cardiovascular risk of rosiglitazone might not be fully resolved because of different magnitudes of myocardial infarction risk that were attenuated when summary level data were used in addition to [individual patient-level data],” concluded the researchers, adding that this finding “suggests that [patient-level data] might be necessary to accurately classify all adverse events when performing meta-analyses focused on safety.”
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Wallach JD, Wang K, Zhang AD, et al. Updating insights into rosiglitazone and cardiovascular risk through shared data: individual patient and summary level meta-analyses. BMJ. 2020;368:l7078.