Yale study adds to evidence of diabetes drug’s link to heart risk

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Rosiglitazone was associated with a 33% increased risk of a composite cardiovascular event (heart attack, heart failure, cardiovascular and non-cardiovascular related death) compared with controls, found a Yale analysis of 130 trials involving 48,000 patients.

This study is the most comprehensive evaluation of the cardiovascular risk of rosiglitazone ever done. Rosiglitazone belongs to a class of drugs called thiazolidinediones. It helps control blood sugar levels in patients with type 2 diabetes, but it can also increase the risk of serious heart problems. This has led to suspension of the drug in Europe and previous restrictions on its use in the US.

However, since 2007, studies have reported conflicting findings about whether rosiglitazone increases the risk of heart attacks. But these studies didn’t have access to the raw data, also known as individual patient level data (IPD), from clinical trials and mostly relied on summary level data (results reported in publications and clinical trial registries), which are not as reliable when estimating the true safety profile of drugs.

Recent efforts by GlaxoSmithKline (GSK) – the maker of rosiglitazone – to make IPD available to external investigators, prompted a team of US researchers at Yale School of Public Health and the Yale-New Haven Health System, to re-analyse the data and clarify some of the uncertainties about rosiglitazone’s cardiovascular risk. They analysed the results of more than 130 trials involving over 48,000 adult patients that compared rosiglitazone with any control for at least 24 weeks. IPD were available for 33 trials, which included 21,156 patients; the remaining trials only had summary level data available.

When the researchers analysed the IPD from trials made available by GSK, they found rosiglitazone was associated with a 33% increased risk of a composite cardiovascular event (heart attack, heart failure, cardiovascular and non-cardiovascular related death) compared with controls. This was estimated from the 274 events among 11,837 rosiglitazone patients and 219 events among 9,319 control patients.

When examining cardiovascular events independently, the analyses of the 33 GSK trials with IPD resulted in higher estimates of the risk of heart attacks than the analyses of trials with IPD and summary level data.

These findings highlight the potential for different results derived from different data sources, and demonstrate the need for greater clinical trial transparency and data sharing to accurately assess the safety of drugs, say the researchers.

“Our study suggests that when evaluating drug safety and performing meta-analyses focused on safety, IPD might be necessary to accurately classify all adverse events,” they write. “By including these data in research, patients, clinicians, and researchers would be able to make more informed decisions about the safety of interventions.”

They add: “Our study highlights the need for independent evidence assessment to promote transparency and ensure confidence in approved therapeutics, and post-market surveillance that tracks known and unknown risks and benefits.”

Abstract
Objectives: To conduct a systematic review and meta-analysis of the effects of rosiglitazone treatment on cardiovascular risk and mortality using multiple data sources and varying analytical approaches with three aims in mind: to clarify uncertainties about the cardiovascular risk of rosiglitazone; to determine whether different analytical approaches are likely to alter the conclusions of adverse event meta-analyses; and to inform efforts to promote clinical trial transparency and data sharing.
Design: Systematic review and meta-analysis of randomized controlled trials.

Data sources: GlaxoSmithKline’s (GSK’s) ClinicalStudyDataRequest.com for individual patient level data (IPD) and GSK’s Study Register platforms, 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.
Eligibility criteria for selecting studies: Randomized, controlled, phase II-IV clinical trials that compared rosiglitazone with any control for at least 24 weeks in adults.

Data extraction and synthesis: For analyses of trials for which IPD were available, a composite outcome of acute myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death was examined. These four events were examined independently as secondary analyses. For analyses including trials for which IPD were not available, myocardial infarction and cardiovascular related death were examined, which were determined from summary level data. Multiple meta-analyses were conducted that accounted for trials with zero events in one or both arms with two different continuity corrections (0.5 constant and treatment arm) to calculate odds ratios and risk ratios with 95% confidence intervals.
Results: 33 eligible trials were identified from ClinicalStudyDataRequest.com for which IPD were available (21 156 patients). Additionally, 103 trials for which IPD were not available were included in the meta-analyses for myocardial infarction (23 683 patients), and 103 trials for which IPD were not available contributed to the meta-analyses for cardiovascular related death (22 772 patients). Among 29 trials for which IPD were available and that were included in previous meta-analyses using GSK’s summary level data, more myocardial infarction events were identified by using IPD instead of summary level data for 26 trials, and fewer cardiovascular related deaths for five trials. When analyses were limited to trials for which IPD were available, and a constant continuity correction of 0.5 and a random effects model were used to account for trials with zero events in only one arm, patients treated with rosiglitazone had a 33% increased risk of a composite event compared with controls (odds ratio 1.33, 95% confidence interval 1.09 to 1.61; rosiglitazone population: 274 events among 11 837 patients; control population: 219 events among 9319 patients). The odds ratios for myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death were 1.17 (0.92 to 1.51), 1.54 (1.14 to 2.09), 1.15 (0.55 to 2.41), and 1.18 (0.60 to 2.30), respectively. For analyses including trials for which IPD were not available, odds ratios for myocardial infarction and cardiovascular related death were attenuated (1.09, 0.88 to 1.35, and 1.12, 0.72 to 1.74, respectively). Results were broadly consistent when analyses were repeated using trials with zero events across both arms and either of the two continuity corrections was used.
Conclusions: The results suggest that rosiglitazone is associated with an increased cardiovascular risk, especially for heart failure events. Although increased risk of myocardial infarction was observed across analyses, the strength of the evidence varied and effect estimates were attenuated when summary level data were used in addition to IPD. Because more myocardial infarctions and fewer cardiovascular related deaths were reported in the IPD than in the summary level data, sharing IPD might be necessary when performing meta-analyses focused on safety.

Authors
Joshua D Wallach, Kun Wang, Audrey D Zhang, Deanna Cheng, Holly K Grossetta Nardini, Haiqun Lin, Michael B Bracken, Mayur Desai, Harlan M Krumholz, Joseph S Ross

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