Canadian study raises more alarm bells about diabetes drug Avandia
A Canadian study is adding to concerns about the safety of a class of drugs for Type 2 diabetes after at least one of the medications appeared to raise the risk of heart failure, heart attack and death in older patients.
The study by the Institute for Clinical Evaluative Sciences (ICES) found that patients treated with glitazones, primarily Avandia (rosiglitazone), had a 60 per cent higher risk of heart failure requiring hospitalization compared to patients given another class of diabetes pill.
As well, those taking a glitazone had a 40 per cent increased risk of heart attack and a 30 per cent greater risk of dying compared to those on the other drugs, say ICES researchers, who conducted the study by analyzing records for 160,000 diabetics aged 65 and older from the Ontario Drug Benefit (ODB) database.
Dr. David Alter, co-author of the study published in Wednesday’s edition of the Journal of the American Medical Association, said those figures translate into three additional cases of heart failure, four more heart attacks and five extra premature deaths for every 100 patients taking the drugs over the four-year period covered by the study.
Among Ontario seniors prescribed a glitazone, most were taking Avandia, although some were on Actos (pioglitazone).
“What we don’t know and what this study was unfortunately not able to disentangle is whether this is a problem with the class of glitazones as a whole or whether the problem is restricted to only one type of drug, i.e., Avandia, within the glitazone family,” Alter said Tuesday. “We could not answer that question.”
The ICES study is the latest to raise red flags about Avandia.
Early last month, Health Canada withdrew approval of Avandia as a stand-alone therapy, except for patients who can’t tolerate older diabetes drugs. A week later the U.S. Food and Drug Administration slapped a black-box warning on Avandia, saying it might increase heart attack risk.
The regulators’ actions followed the May publication of a U.S. study – an analysis of pooled results involving 14,000 patients in 42 different studies that found Avandia users had a 43 per cent higher risk of heart attack than other diabetics.
Three other studies, which together tracked the same number of patients, could neither confirm nor refute the heart attack risk, perhaps leading to the ambivalent nature of the FDA warning.
Alter said evidence suggesting that glitazones might also cause heart failure, in which the lungs fill with fluid, led ICES scientists to conduct their own review of the drugs approved in Canada.
“What we didn’t know, and what prompted our study, was what sort of harm, what’s the magnitude of harm, and what does that lead to in terms of further adverse outcomes,” he said. “And in particular, what does that mean for a population of elderly folks who are at higher risk than younger patients and one of the most prevalent groups being treated with these drugs in the real world.
“Our findings clearly raise some alarm bells.”
While the findings suggest that Health Canada and the FDA need to further re-evaluate the safety of Avandia and similar drugs, Alter said diabetic patients on the medications and their doctors should also carefully reassess whether taking a glitazone is the right choice.
For some patients, there are few or no other options but glitazones, which work by increasing sensitivity to insulin by cells in the body. With Type 2 diabetes, cells become resistant to insulin and glucose can’t be properly metabolized. Uncontrolled, elevated blood sugar can lead to heart and kidney damage, blindness and other serious complications.
“One thing that’s very important is we shouldn’t be panicking with these results,” Alter stressed. “This is not a message for patients to stop taking their medication immediately without speaking to their doctors.”
“So each patient and each doctor need to reappraise what other options are available and weigh the risks and benefits of each of the options before making any changes to their medications.”
GlaxoSmithKline, maker of Avandia, released a statement Tuesday taking issue with the ICES conclusions.
“GSK believes that the ICES retrospective analysis of the Ontario Drug Benefit (ODB) database has significant limitations and generates misleading conclusions regarding acute myocardial infarction (heart attack) and death,” the company said. “These conclusions are inconsistent with a more robust body of evidence from large, long-term, prospective, well-designed clinical studies.”
“These long-term trials in diabetic patients comparing rosiglitazone to other oral anti-diabetic medicines show no increased risk for cardiovascular events compared to other commonly used medications, other than the well-known risk of congestive heart failure” with the drug class, GSK said.
Commenting on the research, diabetes expert Dr. Ehud Ur said the findings are consistent with other studies of the drugs, but all have limitations in their data collection or how they were analyzed and hence the strength of their conclusions.
“And so in terms of what I say to patients, we continue to use this drug with caution in appropriate patients and with appropriate warnings,” Ur, head of endocrinology at the University of British Columbia, said from Vancouver.
“But I don’t think that this study will really deliver the answer one way or the other in terms of safety in this class.”
He said a large randomized, controlled trial comparing diabetics on Avandia with those on other classes of drugs should have been undertaken when the medication was approved for widespread use nine years ago, a study that GSK has since agreed to under pressure from the FDA.
“The fact is they’re just starting this study and we won’t have an answer for five or six years and that’s not good news,” said Ur.
Dr. Lorraine Lipscombe, lead author of the ICES review, said it’s vital that the safety of the glitazone drugs be nailed down, particularly for seniors, who make up 40 per cent of those with Type 2 diabetes.
“We cannot be certain whether similar effects would be seen in younger patients,” Lipscombe said in a statement. “Our study represents a concern for older patients taking these drugs who are at higher risk for adverse cardiac outcomes.”
Although the study couldn’t look at younger diabetics because ODB data includes only those aged 65 and up, Alter believes a re-evaluation of the drug in patients under 65 is also warranted, based on a “signal” of possibly higher heart failure rates in earlier trials involving younger patients.
“I think there’s a signal, but the strength of the signal may be weaker in younger patients,” he said.
