JAMA: Avandia linked with heart attacks and death, GSK responds

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Avandia. Source: GlaxoSmithKline

Thiazolidinediones (TZDs), primarily with rosiglitazone (Avandia), was associated with an increased risk of congestive heart failure, acute myocardial infarction (MI) and mortality when compared with other combination oral hypoglycemic agent treatments, according to a population-based study of older patients with diabetes published in the Dec. 12 issue of the Journal of the American Medical Association

The thiazolidinedione treatment's adverse effects were primarily with Avandia, said Lorraine I. Lipscombe, MD, of the University of Toronto, and colleagues. There was also a 60 percent rise in the relative risk of congestive heart failure associated with Avandia.

In response, GlaxoSmithKline (GSK) said that the “retrospective analysis of the Ontario Drug Benefit (ODB) database has significant limitations and generates misleading conclusions regarding acute myocardial infarction and death.” The London-based GSK added that the study’s “conclusions are inconsistent with a more robust body of evidence from large, long-term, prospective, well-designed clinical studies, including ADOPT and RECORD.”

The researchers undertook case-control analysis of a retrospective cohort study using healthcare databases in Ontario. They included diabetes patients aged 66 years or older treated with at least one oral hypoglycemic agent between 2002 and 2005, which left them with 159,026 patients and followed-up with them until March 31, 2006.

The primary outcome of the study consisted of an emergency department visit or hospitalization for congestive heart failure; and the secondary outcomes were an emergency department visit or hospitalization for acute myocardial infarction and all-cause mortality.

The risks of the events were then compared between persons treated with TZDs (Avandia and pioglitazone, or Actos) and other oral hypoglycemic agent combinations, after matching and adjusting for prognostic factors.

During a median follow-up of 3.8 years, 12,491 patients (7.9 percent) had a hospital visit for congestive heart failure, 12,578 (7.9 percent) had a visit for acute MI and 30,265 (19 percent) died. Current treatment with TZD monotherapy was associated with a significantly increased risk of congestive heart failure (78 cases), acute MI (65 cases) and death (102 cases). The findings compared with oral hypoglycemic agent combination therapies (3,478 congestive heart failure cases, 3,695 acute MI cases and 5,529 deaths).

Lipscombe and her colleagues found the increased risk of congestive heart failure, acute MI and mortality associated with TZD use appeared limited to Avandia.

GSK also said that “the authors of this retrospective analysis fail to acknowledge the findings of large epidemiological studies, encompassing over 1.3 million patients with type 2 diabetes, as well as other similar studies presented during the recent FDA Advisory Committee meeting.”

The authors wrote that the study was “to our knowledge the first study to evaluate thiazolidinedione-related outcomes among an entire population of older patients with diabetes.” They added that the study was the first to "document an increase in mortality among thiazolidinedione users. Although we could not determine the cause of death in our study, the fact that cardiovascular events were also increased with thiazolidinediones suggests a possible cardiovascular etiology in this older, high-risk population," they wrote.