BARI 2D Analysis Enters Rosiglitazone Debate, Finds No MI Hazard

June 29, 2010

June 29, 2010 (Orlando, Florida) — Amid the stormy debate over the safety of rosiglitazone (Avandia, GlaxoSmithKline), one that may reach a climax of sorts when the drug is scrutinized yet again by an FDA advisory panel in July, comes a new analysis that suggests the drug may not in fact pose a cardiovascular threat. Results of this latest study were released early as a result of an embargo break on Monday, the same day that two studies were released early by the JAMA/Archives publishing group, both of which showed rosiglitazone to be associated with increased cardiovascular risk.

Today, investigators from the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) presented this new analysis here at the American Diabetes Association 2010 Scientific Sessions suggesting that rosiglitazone therapy wasn't associated with an excess risk of MI or stroke in the trial, compared with no thiazolidinedione (TZD) therapy. Its researchers acknowledge it has substantial limitations but also some strengths, among them, they say, that the trial included a fairly high-CV–risk population, one with both diabetes and documented coronary disease, and still no excess risk was seen.

In addition to its randomization of 2368 such patients to intensive medical therapy with vs without coronary revascularization by either CABG or PCI, BARI 2D also assigned them to receive either insulin-sensitization therapy or insulin itself (or an insulin secretagogue).

Dr Richard G Bach

The current analysis covers 4.5 years of follow-up of the trial's patients who either received rosiglitazone at some point in their therapy or who hadn't received any TZDs, encompassing >2500 patient-years of treatment with the drug, BARI 2D investigator Dr Richard G Bach (Washington University School of Medicine, St Louis, MO) said at a briefing for the media.

After controlling for "a long list" of demographic and other baseline characteristics and for other medications received, he said, rosiglitazone was associated with a 28% drop in relative risk of death, MI, or stroke and a 64% decrease in risk of stroke. There was no significant difference between the rosiglitazone and no-TZD groups in risk of MI, heart failure, or death.

"And as has also been seen in previous studies of TZD drugs, patients in BARI 2D taking rosiglitazone experienced significantly higher rates of bone fractures, and this seemed more pronounced among women," according to Bach.

Relative Risk of Outcomes Over 4.5 Years, Rosiglitazone vs No TZD Therapy in BARI 2D: Post Hoc Analysis

Outcome RR* p
Death, MI, or stroke 0.72 0.01
Stroke 0.36 0.02
MI 0.77 0.15
Heart failure 1.17 0.35
Death 0.83 0.29
Bone fracture 1.62 0.03

*Relative risk, rosiglitazone recipients vs patients who received no TZDs

"Our observations from BARI 2D do not suggest a significant cardiovascular hazard and may suggest a potentially beneficial effect on ischemic cardiovascular events associated with treatment with rosiglitazone among patients with type 2 diabetes and established coronary artery disease like those treated in the trial," Bach said.

There are limitations to the analysis even beyond its post hoc nature. Bach noted that rosiglitazone was given to patients at physicians' discretion, and many recipients "were also taking multiple antidiabetic drugs, making isolation of the effects of any single agent difficult."

On the other hand, Bach sees strengths in the analysis as well. Clinical end points in the trial were prospectively collected and independently adjudicated, he said. There was a consistency in the population in that all patients were high risk for CV events based on their diabetes and established coronary artery disease.

There was evidence, Bach said, that rosiglitazone recipients may have been at even higher risk than others in the trial. "Patients treated with rosiglitazone in BARI 2D had an actually higher baseline hemoglobin A1c than patients who were not treated with rosiglitazone, a longer duration of diabetes, and more albuminuria." Such patients might be more likely to show adverse cardiovascular effects, he said, "if a drug were prone to cause those."

Dr Maria Brooks

Bach was somewhat coy in framing the BARI 2D post hoc analysis in context with the long history of allegations and accusations that rosiglitazone may promote MIs or other serious cardiovascular events and isn't as safe as another TZD, pioglitazone (Actos, Takeda Pharmaceuticals). To a great extent, he said, the data on which those allegations are based have "observational studies or meta-analyses as their foundation." Also, he said, much of it is apparently derived from "heterogeneous populations and relatively short-term trials in low-risk populations, making it difficult to arrive at certainty. I think the term uncertainty has been fairly applied to data regarding rosiglitazone."

Also at the press briefing, Dr Maria Brooks (University of Pittsburgh, PA) disclosed that she will be presenting the BARI 2D post hoc analysis at the upcoming FDA advisory panel hearing on the drug.

[ heartwire expects to update and expand this preliminary report, based entirely on a limited press conference, on the analysis after it is presented in more detail at the ADA sessions.]

BARI 2D was primarily funded by the US National Institutes of Health with "some support," Bach said, from GlaxoSmithKline. Bach discloses research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Merck/Schering Plough and committee activity for Hoffman-LaRoche, Forest Laboratories, and Wyeth.

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