WSJ Report Highlights GlaxoSmithKline Concerns With Rosiglitazone

January 14, 2009 (New York, New York) — Internal emails obtained by the Wall Street Journal (WSJ) reveal that GlaxoSmithKline had similar concerns about rosiglitazone (Avandia) as the researchers who first raised alarms about the diabetes drug [1].

"The numbers are the numbers, the analysis is very similar to our own," the Journal quotes a senior GlaxoSmithKline consultant writing days before results of a meta-analysis showed an increased cardiovascular risk with the drug. While GlaxoSmithKline couldn't "undermine" the data, it might be able to explain the results, the advisor notes.

The meta-analysis in question was led by Dr Steven Nissen (Cleveland Clinic, OH) and has been previously reported by heartwire [2]. In his analysis, which was published May 21, 2007 in the New England Journal of Medicine, Nissen, along with statistician Kathy Wolski (Cleveland Clinic), showed rosiglitazone significantly increased the risk of MI by 43% and increased the risk of cardiovascular death 64%, a finding of borderline statistical significance.

The findings led the US Congress to look into the role of the Food and Drug Administration in evaluating the safety of rosiglitazone, as well as led to congressional investigations into the company's marketing of the drug. The FDA eventually decided to allow rosiglitazone to stay on the market, but with increased warnings about the risk of cardiovascular events.

In the WSJ, GlaxoSmithKline says it did not attempt to conceal its own meta-analysis showing similar trends as the study by Nissen and Wolski. The company published a letter in the Lancet on May 30, 2007 by chief medical officer Ronald Krall stating it performed a similar meta-analysis in 2005 and 2006 and found hazard going in the same direction.

WSJ reporters Alicia Mundy and Jared Favole note that Sen Chuck Grassley (R-IA) is pushing the FDA to withdraw rosiglitazone and is writing a report containing excerpts of the GlaxoSmithKline documents and its efforts to defend the drug from the Nissen meta-analysis.

Leaked Documents

In a bizarre twist to the rosiglitazone backstory, it also came to light last year that Dr Steven Haffner (University of Texas Health Science Center at San Antonio), a peer reviewer for the New England Journal of Medicine meta-analysis, leaked the paper to GlaxoSmithKline weeks ahead of publication. Haffner, a GlaxoSmithKline consultant on rosiglitazone since 2000, had received more than $400 000 from the company over an eight-year period. He confirmed leaking the review to GlaxoSmithKline, saying he wasn't sure why he sent it and that he wasn't feeling well when he did. He also said sending it to GlaxoSmithKline was bad judgment.

According to the Journal, when GlaxoSmithKline obtained the draft of Nissen's meta-analysis from Haffner, it began its own review but found no statistical reason for disregarding the findings. In one May 8, 2007 email, Dr Moncef Slaoui, chair of research and development for GlaxoSmithKline, wrote that the "FDA, Nissen, and GlaxoSmithKline all come to comparable conclusions regarding increased risk for ischemic events, ranging from 30% to 43%!" GlaxoSmithKline spokesperson Nancy Pekarek told the paper that Slaoui used imprecise language in his internal email when he said that Nissen and GlaxoSmithKline came to comparable conclusions. In testimony to Congress last year, Slaoui defended the safety of rosiglitazone, saying it is comparable to that of the two most widely used oral antidiabetes medicines. The company also told the WSJ it didn't disagree with Nissen's data but with his decision to draw a conclusion from the meta-analysis.

Mundy and Favole also report that GlaxoSmithKline had strategic concerns about publishing the interim results of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study [3], a trial showing no statistically significant differences in the overall risk of hospitalization or death from cardiovascular causes. The company was worried the events in RECORD would be added to the meta-analysis and reinforce Nissen's findings.

Although it was eventually published in the New England Journal of Medicine in June last year, and GlaxoSmithKline called the study very reassuring to doctors and patients, others took a dimmer view, among them Dr David M Nathan (Massachusetts General Hospital, Boston), who wrote an editorial [4] accompanying the paper stating, "The jury may still be out with regard to the cardiotoxicity of rosiglitazone."

In their story, Mundy and Favole note the FDA is also under fire for its handling of rosiglitazone. Last June, the agency defended its decision to keep the drug on the market, stating that it was still doing an analysis of the data. However, according to documents obtained by the WSJ, the FDA received data from the company a year before Nissen's study was published.

1. Mundy A, Favole J. Glaxo's emails on Avandia reveal concern. Wall Street Journal, January 14, 2009. Available at www.wsj.com.

2. Nissen SE and Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 357: 100. 17517853

3. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med 2007; 357: 28-38. Abstract
   
   

4. Nathan DM. Rosiglitazone and cardiotoxicity: weighing the evidence. N Engl J Med 2007; 57: 64-6. Abstract

face="Verdana" size="1">The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Heartwire from Medscape © 2009  Medscape

Cite this: Michael O'Riordan . WSJ Report Highlights GlaxoSmithKline Concerns With Rosiglitazone - Medscape - Jan 14, 2009.