FDA says again: Rosiglitazone does not up CV risk 

Miriam E Tucker

June 06, 2013

Silver Spring, MD - An extensive analysis by the US Food and Drug Administration (FDA) concludes that the much-discussed diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) does not increase the risk for adverse cardiovascular outcomes.

The data were discussed on the first day of a two-day joint meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, being held to determine the future of rosiglitazone in the US [1], and support the findings of a recent readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial.

Since September 2010, rosiglitazone's use there has been severely restricted due to cardiovascular safety concerns. At the time it imposed the restrictions, the FDA also called for an independent readjudication of GlaxoSmithKline's RECORD study, the only randomized trial of the drug to specifically examine CV outcomes.

Presentations yesterday were broadly supportive of the readjudication finding, although several concerns remain, many pertaining to the initial trial design. Today the two advisory committees will vote on what to do next with rosiglitazone.

DCRI accused of not being independent, mishandling data

The multicenter, open-label RECORD trial randomized 4447 patients with type 2 diabetes who were poorly controlled (HbA1c 7.9%), despite treatment with metformin or a sulfonylurea, to either rosiglitazone or a combination of metformin plus a sulfonylurea. The study met its primary end point, to show noninferiority with regard to composite end points of CV death and CV hospitalizations (hazard ratio 0.99, 95% CI 0.85-1.16) [2].

Presentations on the first day of the new hearing were given by the FDA, GlaxoSmithKline, and by the Duke Clinical Research Institute (DCRI), which conducted the RECORD readjudication with data provided by GlaxoSmithKline.

In the morning, Dr Thomas A Marciniak (FDA Division of Cardiovascular and Renal Products) delivered a personal critique of the RECORD readjudication, in which he stated that the DCRI's review was not independent because the institution was paid by GlaxoSmithKline. He also accused the DCRI of "extreme mishandling" of the data and cited methodological flaws of the original trial.

Marciniak, who had delivered a similar assessment of RECORD at a July 2010 FDA advisory committee hearing on the safety of rosiglitazone, when he was among the reviewers, was this time speaking only for himself and not on behalf of the FDA.

Irrespective of analysis, findings "reassuring"

Subsequent presenters yesterday included Dr Kenneth W Mahaffey, the DCRI's associate director, and Dr Robert Bigelow (DCRI), who summarized the readjudication, which involved 22 reviewers at eight organizations.

Readjudication of a total 2223 events revealed no significant event risks for the rosiglitazone group (2220 patients) compared with those receiving sulfonylureas and/or metformin (2227). The hazard ratios were 0.95 for the composite end point of CV death, MI, or stroke; 0.90 for CV death; 1.13 for MI; 0.79 for stroke; and 0.86 for all-cause death. None of those were statistically significant.

Numerous sensitivity analyses to account for missing data did not change the conclusion, that the results "were consistent with originally published RECORD results," said Mahaffey.

A series of detailed FDA presentations essentially backed up the DCRI's conclusion, despite numerous discrepancies between the original trial analysis and the readjudication in the attribution of causes of death.

"Irrespective of the specific analysis selected, the hazard ratio is in the favorable to neutral range, which seems reassuring," said Dr Ellis F Unger, director of the FDA's Office of Drug Evaluation 1.

However, several presenters and panel members expressed concern about one major limitation of RECORD that the readjudication could not address: it was an open-label trial, which introduces the potential for bias.

This was done out of necessity, because the "rescue medication," insulin, is contraindicated for use with rosiglitazone in Europe. It would have been impractical to blind the study subjects with multiple daily sham injections, noted Dr Karen Murry Mahoney (FDA Division of Metabolism and Endocrinology Products).

Another concern, raised by two panel members, related to the possible treatment effect of statins, which were used more often in the rosiglitazone patients. That topic will be discussed further today.

Panels will vote today on what to do with rosiglitazone

Rosiglitazone was pulled from the European market in 2010 at the same time the US imposed restrictions. In the US, it is available only under a risk evaluation and mitigation strategy (REMS), which limits its use to patients who were already taking it or to new patients for whom no other glucose-lowering agents are acceptable.

Since the REMS was imposed, the number of patients using rosiglitazone has dropped dramatically from 117 349 in 2009 to 3405 during 2011-2013.

Today, the two advisory panels will be asked to vote on whether to keep the current REMS program as is, modify it, remove it and allow freer use of rosiglitazone, or remove rosiglitazone from the US market.

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