The diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) has already been suspended in Europe and is available in the U.S. and Canada on a restricted basis. A new study supports such actions as it has found the drug to be associated with significantly higher odds of congestive heart failure, heart attack and death compared with pioglitazone (Actos, Takeda Pharmaceuticals).
The meta-analysis, published March 17 in the British Medical Journal, analyzed the results of 16 studies involving 810,000 patients (429,000 on rosiglitazone and 381,000 on pioglitazone). Most patients were more than 60 years old.
Yoon Kong Loke, MD, senior lecturer in clinical pharmacology at the University of East Anglia in Norwich, England, and colleagues noted that both drugs, which help to control blood sugar levels in patients with type 2 diabetes, are known to increase the risk of heart failure. However, they said, "It is unclear whether there are clinically important differences in their cardiac safety."
Compared with pioglitazone, rosiglitazone was associated with a modest but statistically significant increased risk of heart attack (16 percent), congestive heart failure (23 percent) and mortality (14 percent).
In certain groups of patients with type 2 diabetes, this may lead to 170 excess heart attacks, 649 excess cases of heart failure and 431 excess deaths for every 100,000 patients who receive rosiglitazone rather than pioglitazone.
"The consistency in the magnitude of increased risk for the different cardiac outcomes, as well as mortality, indicates that this is unlikely to be a chance finding," the researchers concluded.
They also noted the large number of patients as a strength of the study and the "absence of substantial statistical heterogeneity, which suggests that the risk is maintained across most populations and is unaffected by geographical variations."
Loke and colleagues said their study has important implications especially since there are about 3.8 million prescriptions for rosiglitazone dispensed annually in the U.S.
The precise biological mechanisms responsible for the differences in cardiovascular risk and mortality between the two drugs are uncertain, according to the study.
However, it is known that rosiglitazone causes greater elevations of triglycerides and LDL-C levels than does pioglitazone. Pioglitazone also has shown some potential benefit in preventing progression of atherosclerosis, whereas rosiglitazone has not. In addition, rosiglitazone leads to more fluid retention, which may explain its greater risk of congestive heart failure.
In an accompanying BMJ editorial, Victor Montori, MD, and Nilay Shah, MD, from the Mayo Clinic in Rochester, Minn., argued that the rosiglitazone story "says much about how healthcare has become less about promoting patients' interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry."
When the FDA restricted the drug rather than suspend its use, the agency's explanation was that it "trusted clinicians and patients to balance the risks and benefits of this agent in the few patients for which the alternatives seemed less desirable or safe." Montori and Shah said that research should be undertaken to "understand what occurs when drugs are left on the market with strong warnings."
The two editorialists bemoaned that regulators and prescribers "have not learned from the rosiglitazone saga." They present the case of the newest diabetes agents, dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists. While these agents were approved relatively quickly—the FDA said it would trust the manufacturers to conduct cardiovascular safety trials—there are no studies to support their long-term efficacy in reducing diabetes complications or safety. These drugs already comprise 14 percent of the diabetes drug market in 2010, they said.
Montori and Shah suggested that clinicians can get unbiased information on antihyperglycaemic options here.