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Senate report questions safety of rosiglitazone
FDA will present summary of new rosiglitazone safety data at advisory committee meeting in July.
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A new report released over the weekend by the United States Senate Committee on Finance brings more attention to the diabetes drug rosiglitazone.
The committee report, released by Sen. Max Baucus, D-Mont., chairman of the Committee on Finance, and Sen. Chuck Grassley, R-Iowa, is based on a two-year inquiry of rosiglitazone (Avandia, GlaxoSmithKline). The drug has received attention in recent years because of data linking it to an increased risk for CV events.
The 342-page report explores when GlaxoSmithKline became aware of MI risks associated with rosiglitazone, whether the company sufficiently warned patients and the FDA of the dangers, and steps it took to create doubt regarding the negative findings about the drug, according to a Senate press release.
“The totality of evidence suggests that GlaxoSmithKline was aware of the possible cardiac risks associated with Avandia years before such evidence became public,” the report said. “Based on this knowledge, GlaxoSmithKline had a duty to sufficiently warn patients and the FDA of its concerns in a timely manner.”
However, the report said GlaxoSmithKline executives instead “intimidated independent physicians, focused on strategies to minimize findings that Avandia may increase CV risk and sought ways to downplay findings that the rival drug Actos (pioglitazone, Takeda) might reduce CV risk.”
The report was developed over the past two years by committee investigators who reviewed more than 250,000 pages of documents provided by GlaxoSmithKline, the FDA and several research institutes, as well as interviews and phone calls with the company, agency and “anonymous whistleblowers.”
In a Feb. 18 letter addressed to FDA Commissioner Margaret A. Hamburg, MD, Baucus and Grassley asked the FDA to describe steps it has taken to protect patients in TIDE (Thiazolidinedione intervention with vitamin D evaluation), the cardiovascular safety trial the FDA asked GlaxoSmithKline to perform in 2007. Other requests in the letter include why the TIDE study is allowed to continue despite estimates by the FDA that rosiglitazone caused about 83,000 excess MIs between 1999 and 2007, according to the release.
GSK rejects Senate committee conclusions
GlaxoSmithKline issued a press release on Saturday stating that the report “draws conclusions on the safety of rosiglitazone that are based on analyses that are not consistent with the rigorous scientific evidence supporting the safety of the drug.”
Moreover, it states that “the report cherry-picks information from documents, which mischaracterizes GlaxoSmithKline’s comprehensive efforts to research Avandia and communicate those findings to regulators, physicians and patients.”
The company said safety and efficacy data are well characterized on the drug label approved by the FDA. Further, it added that scientific evidence to date does not establish an increased CV risk associated with rosiglitazone, and results of company-sponsored clinical trials and other meta-analyses and observational studies are available on the company Web site.
“In 2007, the FDA considered all the available scientific evidence on Avandia, including Dr. David Graham’s assertions of elevated heart attack risk and demands that the product be withdrawn. Based on the scientific evidence and a recommendation by an independent advisory committee of experts convened by the FDA, the agency has ruled that Avandia remain available to patients for the treatment of type 2 diabetes.”
GlaxoSmithKline also said seven large, prospective, randomized, clinical trials have reported results about the cardiovascular safety of rosiglitazone, including RECORD; none showed a statistically significant association between rosiglitazone and MI or other ischemic cardiovascular events.
“GlaxoSmithKline does not condone any effort to silence scientific debate,” GlaxoSmithKline officials said in the release. “When GlaxoSmithKline believes that statements made by others don’t accurately present information on its products or its actions, GlaxoSmithKline corrects inaccuracies and misstatements.”
Looking forward
An FDA statement released this afternoon indicated that the agency is currently conducting a review of data from the RECORD study that were submitted in 2009. The RECORD study was designed to evaluate the cardiovascular safety of rosiglitazone in 2,220 patients with type 2 diabetes taking rosiglitazone plus metformin or sulfonylurea compared with metformin or sulfonylurea alone. A mean 5.5-year follow-up revealed no difference in the occurrence of cardiovascular death or hospitalization in the rosiglitazone group vs. the metformin/sulfonylurea only group.
Primary data from the RECORD study to be reviewed will include follow-up audits and review of additional studies.
Once its review is completed, the FDA will present the totality of new and existing cardiovascular safety data on rosiglitazone at a joint public meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees in July. At that meeting, the advisory committee will provide an updated assessment of the risks and benefits of rosiglitazone for the treatment of type 2 diabetes.
“This work is ongoing and no new conclusions or recommendations about the use of rosiglitazone in the treatment of type 2 diabetes have been made at this time,” according to the FDA statement.
New AHA/ACC science advisory
The American Heart Association and American College of Cardiology Foundation released a joint science advisory stating that data are inconclusive on the CV risks associated with TZDs but the medications should be used with close monitoring for health care providers.
"Research is ongoing and more is needed to understand which agents, including TZDs, work best for diabetes control," AHA president Clyde Yancy, MD, said in a press release.
The advisory summarized currently available data concerning TZDs and CV risk and provided practical recommendations for health care workers seeking to minimize the burden of CVD and other complications for patients with type 2 diabetes.
According to the advisory, metformin should be the first-line therapy for glucose-lowering in diabetes. However, if a TZD is considered, it should not be used with an expectation of benefit in reducing the occurrence of MI or stroke. However, patients who have successfully achieved recommended HbA1c control with a TZD might considered remaining on the medication. If the treating physician and/or patient is uncomfortable with using a TZD, another medication could be substituted. It noted that there are currently not enough data to support the choice of a specific TZD. - by Katie Kalvaitis