Will the discovery of more adverse effects of rosiglitazone lead to its suspension in the US?
Rosiglitazone (Avandia) is an anti-diabetic agent that is associated with fluid retention and an increased risk of serious cardiovascular risks. Previous studies found that rosiglitazone increased heart failure events and supported the recommendation that the medication not be used in people who have symptomatic heart failure symptoms. Use is suspended in Europe and used only in special populations in the United States. Rosiglitazone, along with pioglitazone, is one of two currently marketed thiazolidinediones in the US. A recent meta-analysis of 16 observational studies found that rosiglitazone was associated with a higher risk of congestive heart failure, myocardial infarction, and death compared with pioglitazone. This study, conducted by GlaxoSmithKline (GSK), the maker of rosiglitazone, was undertaken to clarify uncertainties about its cardiovascular risk.
The original search for this meta-analysis obtained 130 trial matches containing 48,000 adult patients. Still, individual participant data was only found in 33 trials, which included 21,156 patients, over half of whom (11,837, 56.0%) received rosiglitazone. Most of the trials enrolled patients who had type 2 diabetes mellitus (25 of 33) but eight focused on other non-FDA approved (off label) indications including two psoriasis, one rheumatoid arthritis, one atherosclerosis, and four Alzheimer’s disease. The objective of this was to determine the effects of rosiglitazone treatment on cardiovascular risk and mortality. To be eligible, the study had to be randomized, controlled, phase two to four clinical trials that compared rosiglitazone with any control for at least 24 weeks in adults. The primary outcome of the trials was composed of four cardiovascular risk and mortality outcomes: acute myocardial infarction events, heart failure events, cardiovascular-related deaths, and non-cardiovascular related deaths.
The statistical analysis of this study included calculated trial specific odds ratios or relative risks, and their corresponding 95% confidence intervals. In the second stage, effect estimates from each trial were combined with fixed or random-effects meta-analysis models. Peto’s method was used to pool odds ratios because this was the method reported in the original rosiglitazone meta-analysis. Previous studies have noted that substantial imbalance exists in the number of patients in many of the rosiglitazone trials. The results were combined from each trial using conventional fixed (Mantel-Haenszel) or random (Dersimonian and Laird) effects methods. All analyses were redone by including single zero event trials and trials with zero events in both arms (total zero event trials), and the researchers applied two different continuity corrections: a constant continuity correction, which adds 0.5 to each cell in a 2×2 contingency table for the trials with at least one zero event; and a treatment arm continuity correction, when values proportionate to the reciprocal of the size of the opposite treatment group are added to each cell.
Results found a 33% increased risk of a composite cardiovascular event compared with controls (odds ratio 1.33, 95% confidence interval 1.09 to 1.61). Among 11,837 patients allocated to rosiglitazone treatment, there were 274 composite events (2.3%) and 147 myocardial infarctions (1.24%), 122 heart failures (1.03%), 15 cardiovascular related deaths (0.13%), and 22 non-cardiovascular related deaths (0.19%). Among 9,319 patients in the control group, there were 219 composite events (2.4%) and 133 myocardial infarctions (1.4%), 80 heart failures (0.86%), 10 cardiovascular related deaths (0.11%), and 13 non-cardiovascular related deaths (0.14%).
Among the 103 trials for which IPD were not available included in the meta-analyses for myocardial infarction, there were a total of 23,683 patients, of which 12,630 (53.3%) were randomized to rosiglitazone and 11,053 (46.7%) to comparator arms. Among the rosiglitazone and comparator arms, there were 26 (0.21%) and 20 (0.19%) cardiovascular–related deaths, respectively.
Across all data sources, rosiglitazone was associated with a 9% increased odds of myocardial infarction (odds ratio 1.09, 95% confidence interval 0.88 to 1.35, I2 =0; 60 single zero event trials. The association of heart failure with rosiglitazone complicates the findings of this article. A large number of heart failure events are similar to previous studies. Myocardial infarction has been the focus of prior studies. This study added to compiling evidence of increased risk of myocardial infarction proven by previous studies. Limitations of the study were the low numbers of events. Some studies had no outcomes but these did not have a significant effect on the study. Designs of the trials were focused on short term efficacy and not long term cardiovascular safety, and seemingly preferentially enrolled lower–risk patients. Short term monitoring makes it hard to evaluate cardiovascular risks.
- Rosiglitazone should be avoided in anyone who has symptomatic heart failure.
- The use of rosiglitazone should be carefully monitored and reserved as refractory therapy.
- The reporting of all adverse events during clinical trials, and post-marketing surveillance, are crucial to preventing adverse effects from drugs.
Wallach, Joshua D., et al. “Updating Insights into Rosiglitazone and Cardiovascular Risk through Shared Data: Individual Patient and Summary Level.” BMJ, vol. 368, 2020, p. l7078, doi:10.1136/bmj.l7078.
Wallach, Joshua D., et al. “Updating Insights into Rosiglitazone and Cardiovascular Risk through Shared Data: Individual Patient and Summary Level.” BMJ, vol. 368, British Medical Journal Publishing Group, Feb. 2020, p. l7078, doi:10.1136/bmj.l7078.
Antonio Bess, Florida Agricultural and Mechanical University College of Pharmacy