Updating Insights into Rosiglitazone and Cardiovascular Risk through Shared Data: Individual Patient- and Summary-Level Meta-Analyses

Abstract

Objective: To conduct a systematic review and meta-analysis of the effects of rosiglitazone therapy on cardiovascular risk and mortality using multiple data sources and varying analytical approaches. Design: Systematic review and meta-analysis of randomized controlled trials. Data sources: GlaxoSmithKline's (GSK) Clinical Study Data Request (CSDR) and Study Register platforms, MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Registry of Controlled Trials, Scopus, and ClinicalTrials.gov from inception to January 2019. Study selection criteria: Randomized, controlled, phase II-IV clinical trials comparing rosiglitazone with any control for at least 24 weeks in adults. Data extraction and synthesis: For analyses of trials for which individual patient-level data (IPD) were available, we examined a composite of the following events as our primary outcome: acute myocardial infarction, heart failure, cardiovascular-related deaths, and non-cardiovascular-related deaths. As secondary analyses, these four events were examined independently. When also including trials for which IPD were not available, we examined myocardial infarction and cardiovascular-related deaths, ascertained from summary-level data. Multiple meta-analyses were conducted, accounting for trials with zero events in one or all arms with two different continuity corrections (i.e., 0.5 constant and treatment arm comparator continuity correction), to calculate odds ratios and risk ratios with 95% confidence intervals. Results: There were 33 eligible trials for which IPD were available (21156 participants) through GSK's CSDR. We also identified 103 additional trials for which IPD were not available from which we ascertained myocardial infarctions (23683 patients) and 103 trials for cardiovascular-related deaths (22772 patients). Among trials for which IPD were available, we identified a greater number of myocardial infarctions and fewer cardiovascular-related deaths reported in the IPD as compared to the summary-level data. When limited to trials for which IPD were available and accounting for trials with zero-events in only one arm using a constant continuity correction of 0.5, patients treated with rosiglitazone had a 39% increased risk of a composite event compared with controls (Mantel-Haenszel odds ratio 1.39, 95% CI 1.15 to 1.68). When examined separately, the odds ratios for myocardial infarction, heart failure, cardiovascular-related death, and non-cardiovascular-related death were 1.25 (0.99 to 1.60), 1.60 (1.20 to 2.14), 1.18 (0.64 to 2.17), and 1.13 (0.58 to 2.20), respectively. When all trials for which IPD were and were not available were combined for myocardial infarction and cardiovascular-related deaths, the odds ratios were attenuated (1.13 (0.92 to 1.38) and 1.10 (0.73 to 1.65), respectively). Effect estimates and 95% confidence intervals were broadly consistent when analyses were repeated including trials with zero events across all arms using constant continuity corrections of 0.5 or treatment arm continuity corrections. Conclusions: Results of this comprehensive meta-analysis aggregating a multitude of trials and analyzed using a variety of statistical techniques suggest that rosiglitazone is consistently associated with an increased cardiovascular risk, likely driven by heart failure events, whose interpretation is complicated by varying magnitudes of myocardial infarction risk that were attenuated through aggregation of summary-level data in addition to IPD.

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

“…Rosiglitazone increases plasma LDL-C and HDL-C levels [ 161 ], whereas pioglitazone improves dyslipidemia by increasing plasma HDL-C levels and decreasing plasma TG levels without raising LDL-C [ 162 ] or increasing large, buoyant LDL [ 161 , 163 ]. While long-term rosiglitazone treatment of T2D patients may slightly increase the risk of myocardial infarction [ 164 ], pioglitazone somewhat decreases the risk of MACE (although the risk of heart failure increases with all glitazones) [ 165 , 166 ]. In biopsy-proven NASH patients, rosiglitazone treatment did not modify plasma TG or HDL-C levels but increased LDL-C [ 156 ].…”

Cardiovascular Safety of Biologics Targeting Interleukin (IL)-12 and/or IL-23: What Does the Evidence Say?

“…There are significant limitations to investigating MACE using meta-analyses of RCTs that are designed for efficacy. Serious adverse events may not be reported or measured systematically, as illustrated by the time it took to report the increased risk of MACE from rosiglitazone in type 2 diabetes mellitus [41]. Adjudication committees are often convened for predefined serious adverse events of special interest, which may not be the case if concern regarding MACE was not known prior to the initiation of the phase III RCTs.…”

Role of peroxisome proliferator‐activated receptors in stroke prevention and therapy—The best is yet to come?

“…Similar safety concerns resulted in some restrictions in the use of rosiglitazone; however, its use was not banned in United States (Cohen, 2010). Moreover, recent meta-analysis identified that rosiglitazone is associated with an increased cardiovascular risk, especially for heart failure events (Wallach et al, 2020). Another aspect of PPAR-γ biology that holds back their clinical use is that PPAR-γ receptors play role in bone homeostasis mechanisms, which is likely why they contribute to bone fractures seen in patients (Wei & Wan, 2011).…”