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Wednesday, December 12, 2007

New Avandia Study finds higher risk of Heart Problems and Death

A new Canadian study on older patients who took diabetes medications known as thiazolidinediones (which include rosiglitazone or Avandia), concluded they ran a significantly higher risk of congestive heart failure, heart attack, and death compared with patients on other diabetes drugs.

The researchers said their study provides further evidence that thiazolidinediones (TZDs) do more harm than good. GlaxoSmithKline, who market Avandia said the study was misleading and conflicted with more robust clinical studies.

The study is published today, 12th December, in the early online issue of the Journal of the American Medical Association (JAMA) and is the work of Dr. Lorraine L. Lipscombe of the Institute for Clinical Evaluative Sciences, Toronto, Canada, and colleagues.

The TZDs rosiglitazone (brand name Avandia, marketed by Glaxosmithkline) and pioglitazone (brand name Actos, marketed by Takeda), are oral medications taken by patients with type 2 diabetes to help control blood sugar (glycemic control).

Lipscombe and colleagues wrote:

"While improved glycemic control has been linked to better clinical outcomes in diabetes and TZDs have been suggested as having potential cardiovascular benefits, recent concerns have arisen regarding adverse cardiac effects of these drugs."

Other studies have shown that both rosiglitazone and pioglitazone may raise the risk of congestive heart failure, and that rosiglitazone may be liked with an increased risk of acute myocardial infarction (heart attack) and death.

However, after reviewing the evidence on Avandia, the US Food and Drug Administration concluded last month that it was inconclusive, and allowed the drug to stay on the market. But the agency imposed the strongest warning, the so-called "black box" label, on the drug.

In this latest study, Lipscombe and colleagues evaluated the risk of congestive heart failure, heart attack and death from all causes linked to the use of TZDs compared with other oral hypoglycemic drugs among diabetic patients aged 66 years and above.

The authors said this group of older patients was often under-represented in TZD trials, despite having a higher rate of diabetes and being at higher risk of harm from medication.

The researchers used health care records from databases in Ontario, Canada, which covered 159,026 diabetics on oral oral hypoglycemic drugs who were monitored for a median period of 3.8 years, up to March 2006.

During the monitoring period, 7.9 per cent (12,491) of the patients visited the hospital for congestive heart failure, 7.9 per cent (12,578) for a heart attack, and 19 per cent (30,265) died.

After analyzing the records, the researchers showed that compared to patients on oral hypoglycemic agent combination treatments, the ones taking only a TZD had a 60 per cent higher risk of congestive heart failure, 40 per cent higher risk of heart attack, and 28 per cent higher risk of death. The increased risks appeared to be limited only to rosiglitazone (Avandia).

They concluded that:

"In this population-based study of older patients with diabetes, TZD treatment, primarily with rosiglitazone, was associated with an increased risk of congestive heart failure, acute myocardial infarction, and mortality when compared with other combination oral hypoglycemic agent treatments."

The authors were of the view that these findings argued against the current labeling policy of TZDs which warns against use only in patients at high risk of congestive heart failure. They said their study did not find any subgroup of older patients who were protected against the adverse effects of TZDs.

"These findings provide evidence from a real-world setting and support data from clinical trials that the harms of TZDs may outweigh their benefits, even in patients without obvious baseline cardiovascular disease," they added.

Until further studies quantify the risks versus the benefits of TZDs, and whether the hazards identified are restricted to rosiglitazone (Avandia), the authors recommended that treatment decisions be made on a patient by patient basis, with doctors weighing up the risk versus benefits according to the individual's situation, especially in the case of high risk elderly patients.

GlaxoSmithKline gave several examples of where the study was limited and misleading. For instance, the Ontario (ODB) database comprised a select group of patients:

"Rosiglitazone [Avandia] is only prescribed for those patients who fail treatment on metformin and sulfonylurea, or for whom sulfonylurea or metformin are contraindicated."

The patients on Avandia were therefore already at a higher baseline cardiovascular disease risk, said the drug company.

They also stressed another limitation of the study:

"Patients prescribed rosiglitazone alone suffered from more chronic diseases compared with those prescribed pioglitazone alone; therefore they were sicker patients."

GlaxoSmithKline said the authors did not correct for this in their analysis and that their conclusions were "inconsistent with a more robust body of evidence from large, long-term, prospective, well-designed clinical studies".

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