Rosiglitazone: Twists and Turns on the Road to Clarity Regarding Safety with Rosiglitazone. August 10, 2007

August 10, 2007 By Grendel Burrell [mailto:grendel.burrell@gmail.com]

Los Angeles CA: A new analysis of the data originally published June 14 in the [New England Journal of Medicine] finds no evidence of a significant excess risk of heart attack with rosiglitazone. In that publication, which has caused a media maelstrom, Dr. Steven E. Nissen, chairman of the Cleveland Clinic's department of cardiovascular medicine and Kathy Wolski, MPH, reported a significant 43% increased risk of heart attack and a 64% increase in CV death that did not achieve statistical significance among patients taking rosiglitazone (1). The authors stated in the conclusion that “Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.” And then the interviews, sound bites, congressional outcry for FDA reforms, and patient questions began.

The new analysis, based on the same trials but including trials without events in the analysis, employed several different statistical methods. Dr George Diamond, Leon Bax, MSc, and Dr. Sanjay Kaul, from Cedars-Sinai Medical Center, Los Angeles, found, in opposition to the findings of Nissen and Wolski, no significant increase in either end point. Published online August 6, 2007, in the Annals of Internal Medicine, the authors state that in reference to the Nissen/Wolski analysis “The meta-analysis was not based on a comprehensive search for all studies that might yield evidence about rosiglitazone’s cardiovascular effects. Studies were combined on the basis of a lack of statistical heterogeneity, despite substantial variability in study design and outcome assessment. The meta-analytic approach that was used required the exclusion of studies with zero events in the treatment and control groups.” (2)

After the publication of the Nissen/Wolski study, in July, the FDA convened an expert panel to consider the risk of myocardial infarction associated with rosiglitazone. While the panel recommended that the drug remain on the market, they requested that rosiglitazone’s maker, GlaxoSmithKline attach a warning to packaging that states that there may be an increased risk of heart attack. Drs. Diamond and Kaul presented their analysis at the July 30 FDA advisory panel hearing on rosiglitazone during the open public hearing. Also, during the open public hearing, data were presented from the Department of Defense TRICARE PRIME database, and a second study conducted by WellPoint, an American health insurance company. In these observational studies, no increased risk of cardiovascular events with rosiglitazone or with pioglitazone (Actos, Takeda Pharmaceuticals), the only other thiazolidinedione approved for sale in the US, as compared with other oral antidiabetic drugs was observed. Diamond et al found that Nissen's analysis excluded trials some trials in which there were no heart attacks in either the rosiglitazone or comparator group. They reexamined the same trials that Nissen and Wolski had used in their study with various modeling and weighting methods using a meta-analytic software package called MIX (Meta-analysis with Interactive eXplanations [Available at www.mix-for-meta-analysis.info]) (3) that allowed the studies with no events to be included. Regarding this analysis, the authors state, “Although the odds ratios from these analyses were elevated, the confidence intervals all contained an odds ratio of unity. Moreover, they suggest greater uncertainty than was reported in the original report but do not rule out the possibility that rosiglitazone increases risk for myocardial infarction or cardiovascular death.” (2)

In a “Perspective” piece released online August 8, 2007 by the New England Journal of Medicine and scheduled for publication in the journal's August 30 edition, Dr. Clifford Rosen, Maine Center for Osteoporosis, and chair of the recent FDA advisory committee panel that recommended rosiglitazone remain on the market, describing the FDA hearing wrote that “Presentations by FDA staff members suggested that a subgroup of patients with type 2 diabetes who are at higher risk for these events includes those with long-term nitrate use and those receiving concomitant insulin therapy. Still, there were several caveats inherent in the meta-analyses, including the facts that most of the clinical trials lasted only 6 months (although the two largest trials, which contributed most of the end points, were longer), that there were relatively few myocardial events overall, and that differences existed in adjudication of ischemic events.” (4) In this article, Rosen argues for a “change the regulatory pathway for drugs for the treatment of type 2 diabetes to make clinical outcomes, not surrogates, the primary end points. “ He cites the example of the FDA shift two decades ago from bone mineral density for osteoporosis drugs to fractures themselves. (4) He offers the following as “guiding principles for improving the process of approving new drugs: first, the pathogenesis of disorders that require intervention must be fully understood; second, treatment options for these diseases should be clarified through an evidence-based system; and third, a uniform approach should be used to determine the societal benefits and risks associated with a given intervention.” (4) It has been 80 years since insulin was discovered and 50 years since the introduction of sulfonylureas. Despite the tremendous strides have been made in understanding the origins and sequelae of diabetes mellitus, type 2 diabetes quadruples the risk of macrovascular disease and ischemic heart disease remains a major cause of death among patients with diabetes. GlaxoSmithKline said that it continues to support Avandia (rosigliltazone) as safe and effective when used appropriately (http://www.gsk.com/media/pressreleases.htm).

This discussion will, no doubt, continue in a variety of venues. An informal poll posted on www.theheart.org asks the question: Do you think the FDA advisory panels made the right decision to recommend keeping rosiglitazone on the market? To date (August 9, 2007), 63% of the respondents answered “yes” with 37% answering “no”. In 0.22 seconds, a Google search for rosiglitazone provided 1,080,000 references. And in just 0.04 seconds, 3,800,000 items on the Internet were located for Avandia (rosiglitazone, GlaxoSmithKline). Placing “rosiglitazone” in the PubMed “search for” window provides 2041 references. There will likely be more.


 * 1) ref1 pmid=17517853


 * 1) ref2 pmid=17679700


 * 1) ref3 pmid=17038197

http://content.nejm.org/cgi/content/full/NEJMp078167
 * 1) ref4 pmid=17687124

Resource: Rosiglitazone timeline: http://www.annals.org/content/vol0/issue2007/images/data/0000605-200710160-00182/DC1/rosiglitazone-timeline.shtml