[7] In 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of a 2009 trial which failed to show increased heart attack risk.

[8][9] In Europe, the European Medicines Agency (EMA) recommended in September 2010 that the drug be suspended because the benefits no longer outweighed the risks.

[13] Rosiglitazone was approved for glycemic control in people with type 2 diabetes, as measured by glycated haemoglobin A1c (HbA1c) as a surrogate endpoint, similar to that of other oral antidiabetic drugs.

[16] Published studies did not provide evidence that outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by rosiglitazone.

[18][19] Two meta-analyses of real life cohort studies found a higher risk of heart failure compared to pioglitazone.

[21][22] In 2005, at the insistence of the World Health Organization, GSK performed a meta-analysis of all 37 trials involving use of rosiglitazone, finding a hazard ratio of 1.29 (0.99 to 1.89).

FDA scientist Joy Mele presented a meta analysis examining the cardiovascular risk of rosiglitazone in completed clinical trials.

[28] Based on the 1.4 fold increased risk relative to control groups, FDA scientist David Graham presented an analysis suggesting that rosiglitazone had caused 83,000 excess heart attacks between 1999 and 2007.

European regulators concluded that due in part to design limitations, the results neither proved nor eliminated concerns of excess cardiovascular risk.

In June 2010, they published a retrospective study comparing roziglitazone to pioglitazone, the other thiazolidinedione marketed in the United States and concluded rosiglitazone was associated with "an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of AMI, stroke, heart failure, or all-cause mortality in patients 65 years or older".

[4] In 2012, the U.S. Justice Department announced GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for withholding the results of two studies of the cardiovascular safety of Avandia between 2001 and 2007.

[38] GlaxoSmithKline reported a greater incidence of fractures of the upper arms, hands and feet in female diabetics given rosiglitazone compared with those given metformin or glyburide.

It is also found in pancreatic beta cells, vascular endothelium, and macrophages[45] Rosiglitazone is a selective ligand of PPARγ and has no PPARα-binding action.

[51] Included among those suing: Santa Clara County, California, which claims to have spent $2 million on rosiglitazone between 1999 and 2007 at its public hospital and is asking for "triple damages".

[52] In May 2010, GlaxoSmithKline (GSK) reached settlement agreements for some of the cases against the company, agreeing to pay $60 million to resolve 700 suits.

[53] In July 2010, GSK reached settlement agreements to close another 10,000 of the lawsuits against it, agreeing to pay about $460 million to settle these suits.

[54][55] [56] In 2012, the U.S. Justice Department announced GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for withholding the results of two studies of the cardiovascular safety of Avandia between 2001 and 2007.

The settlement stems from claims made by four employees of GlaxoSmithKline, including a former senior marketing development manager for the company and a regional vice president, who tipped off the government about a range of improper practices from the late 1990s to the mid-2000s.

Senators Democrat Max Baucus and Republican Charles Grassley filed a report urging GSK to withdraw Avandia in 2008 due to the side effects.

[58] GSK defended itself by presenting data that its own tests found Avandia to be safe, although an FDA staff report showed the conclusions were flawed.

[60][61] The panel has come to some controversy, however; on July 20, 2010, one of the panelists was discovered to have been a paid speaker for GlaxoSmithKline, arousing questions of a conflict of interest.

The US label for rosiglitazone (Avandia, GlaxoSmithKline) and all rosiglitazone-containing medications (Avandamet and Avandaryl) now include the additional safety information and restrictions.

[67] Under the FDA's instruction, Avandia's maker, GlaxoSmithKline, had funded the Duke Clinical Research Institute to re-analyze the raw data from the study.

In their assessment, the European regulators acknowledged weaknesses of the study, such as an unexpectedly low rate of cardiovascular events and the open-label design, which may lead to reporting bias.

Additionally, the probe revealed that in 2000, members of the European panel in charge of reviewing Avandia prior to its approval had concerns about the long-term risks of the drug.

[69][70] Rosiglitazone was withdrawn from the New Zealand market April 2011 because Medsafe concluded the suspected cardiovascular risks of the medicine for patients with type 2 diabetes outweigh its benefits.

A 2010 article in Time uses the Avandia case as evidence of a broken FDA regulatory system that "may prove criminal as well as fatal".

It details the disclosure failures, adding, "Congressional reports revealed that GSK sat on early evidence of the heart risks of its drug, and that the FDA knew of the dangers months before it informed the public."

[75] In response to the rise in risk of heart attacks, the Indian government ordered GSK to suspend its research study, called TIDE, in 2010.

[79][80][81] The American Heart Association said in a statement in June 2010: " ...the reports deserves serious consideration, and patients with diabetes who are 65 years of age or older and being treated with rosiglitazone should discuss the findings with their prescribing physician....".