Rosiglitazone (trade name Avandia) is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or for use in combination with metformin or with glimepiride. First released in 1999, annual sales peaked at approximately $2.5 billion in 2006; however, following a meta-analysis in 2007 that linked the drug's use to an increased risk of heart attack, sales plummeted to just $9.5 million in 2012. The drug's patent expired in 2012.
It was patented in 1987 and approved for medical use in 1999. Despite rosiglitazone's effectiveness at decreasing blood sugar in type 2 diabetes mellitus, its use decreased dramatically as studies showed apparent associations with increased risks of heart attacks and death. Adverse effects alleged to be caused by rosiglitazone were the subject of over 13,000 lawsuits against GSK; as of July 2010, GSK had agreed to settlements on more than 11,500 of these suits.
Some reviewers recommended rosiglitazone be taken off the market, but an FDA panel disagreed, and it remains available in the US. From November 2011 until November 2013, the US federal government did not allow Avandia to be sold without a prescription from a certified doctor; moreover, patients were required to be informed of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies. 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.
In Europe, the European Medicines Agency (EMA) recommended in September 2010 that the drug be suspended because the benefits no longer outweighed the risks. It was withdrawn from the market in the UK, Spain and India in 2010, and in New Zealand and South Africa in 2011.
Medical uses 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. The controversy over adverse effects has dramatically reduced the use of rosiglitazone.
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.
Adverse effects
Heart failure One of the safety concerns identified before approval was fluid retention. Moreover, the combination of rosiglitazone with insulin resulted in a higher rate of congestive heart failure. In Europe there were contraindications for use in heart failure and combination with insulin.
A meta analysis of all trials from 2010 and 2019 confirmed a higher risk of heart failure and a double risk when rosiglitazone was administered as add-on therapy to insulin. Two meta-analyses of real life cohort studies found a higher risk of heart failure compared to pioglitazone. There were 649 excess cases of heart failure every 100,000 patients who received rosiglitazone rather than pioglitazone.
Heart attacks The relative risk of ischemic cardiac events seen in pre-approval trials of rosiglitazone was similar to that of comparable drugs, but there was increased LDL cholesterol, LDL/HDL cholesterol ratio, triglycerides and weight.
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). In 2006 the GSK updated the analysis, now including 42 trials and showing a hazard ratio of 1.31 (1.01 to 1.70). A large observational study comparing patients treated with rosiglitizone with patients treated with other diabetes therapies was performed at the same time and found a relative risk of 0.93 (95% C.I. 0.8 to 1.1) for those treated with rosiglitazone. The information was passed to the FDA and posted on the company website, but not otherwise published. GSK provided these analyses to the FDA, but neither the company nor the FDA warned prescribers or patients of the hazard. According to the FDA, the Agency did not issue a safety bulletin because the results of the meta analysis conflicted with those of the observational study and with the results of the ADOPT trial.
A meta-analysis in May 2007 reported the use of rosiglitazone was associated with a 1.4 fold increased risk of heart attack and a numerically higher (but non-significant) increase in risk of death from all cardiovascular diseases against control. It contained 42 trials of which 27 were unpublished. Another meta analysis of 4 trials with follow-up longer than 1 year found similar results. Nissen's meta analysis was criticized in a 2007 article by George Diamond et al. in the Annals of Internal Medicine. The authors concluded that Nissens' analysis had excluded trials with important data on the cardiovascular profile of rosiglitazone, had inappropriately combined trials of greatly differing design, and had inappropriately excluded trials with no cardiovascular events. The authors concluded that no firm conclusion could be drawn regarding whether rosiglitazone increased or decreased cardiovascular risk. Investigators from the Cochrane Collaboration published a meta-analysis of their own on the use of rosiglitazone in Type II diabetes, concluding there was not sufficient evidence to show any health benefit for rosiglitazone. Noting the recent publication by Nissen, they repeated their meta analysis including only the trials included in the Nissen study that dealt with Type II diabetics. (The Nissen study included some trials in people with other disorders.) They did not find a statistically significant increase in cardiovascular events, but noted that all of the cardiovascular endpoints they analyzed showed a non-significant trend toward worse outcomes in the rosiglitazone arms.
In July 2007 the FDA held a joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. FDA scientist Joy Mele presented a meta analysis examining the cardiovascular risk of rosiglitazone in completed clinical trials. The study found an overall 1.4 fold increase in risk of cardiovascular ischemic events relative to the control arms. The results were heterogenous, with clear evidence of increased risk relative to placebo but not relative to other diabetes treatments and higher risk associated with combinations of rosiglitazone with insulin or metformin. 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. The advisory panel voted 20 : 3 that the evidence available indicated that rosiglitazone increased the risk of cardiovascular events and 22 : 1 that the overall risk:benefit ratio of rosiglitazone justified its continued marketing in the United States. The FDA placed restrictions on the drug, including adding a boxed warning about heart attacks, but did not withdraw it.
In 2000 a study to address the concerns regarding cardiovascular safety was requested by the European Medicines Agency (EMA). GSK agreed to perform post-marketing a long-term cardiovascular morbidity/mortality study in patients on rosiglitazone in combination with a sulfonylurea or metformin: the RECORD study. The results as published in 2009 showed that rosiglitazone was non-inferior to treatment with metformin or a sulfonylurea with respect to the rate of cardiovascular events and cardiovascular death. European regulators concluded that due in part to design limitations, the results neither proved nor eliminated concerns of excess cardiovascular risk.
In February 2010, the FDA's associate director of drug safety, recommended rosiglitazone be taken off the market. 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". The number needed to harm with roziglitazone was sixty. Graham argued rosiglitazone caused 500 more heart attacks and 300 more heart failures than its main competitor.
Two meta analyses released in 2010, one incorporating 56 trials and a second incorporating 164 trials reached conflicting conclusions. Nissen et al. found again an increased risk for heart infarction against control, but no increased risk for cardiovascular death. Mannucci et al. found no statistically significant increase in cardiac events but a significant increase in heart failure. A 2011 drug class review found an increased risk of cardiovascular adverse events.
A meta-analysis of 16 observational studies released in March, 2011, compared rosiglitazone to pioglitazone, finding support for greater cardiovascular safety for pioglitazone. The meta-analysis involved 810 000 patients taking rosiglitazone or pioglitazone. The study suggests 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100 000 patients who receive rosiglitazone rather than pioglitazone. This was confirmed by another meta-analysis involving 945 286 patients in 8 retrospective cohort studies, most in the US.
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.
Death There was no difference in all cause and vascular death in a meta-analysis of 4 trials against controls. Two meta-analyses of cohort studies found excess deaths against pioglitazone.
Stroke A retrospective observational study performed using Medicare data found that patients treated with rosiglitazone had a 27% higher risk of stroke compared to those treated with pioglitazone.
Bone fractures 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.Cobitz, Alexander R (February 2007). . GlaxoSmithKline. Retrieved on 10 April 2007. The information was based on data from the ADOPT trial. The same increase has been found with pioglitazone (Actos), another thiazolidinedione.
A meta-analysis of 10 RCTs, involving 13,715 patients and including both rosiglitazone- and pioglitazone-treated patients, showed an overall 45% increased risk of fracture with thiazolidone use compared with placebo or active comparator. It doubled the risk of fractures among women with type 2 diabetes, without a significant increase in risk of fractures among men with type 2 diabetes.
Hypoglycaemia The risk of hypoglycaemia is reduced with thiazolidinediones when compared with sulfonylureas; the risk is similar to the risk with metformin (high strength of evidence).
Weight gain Both thiazolidinediones cause a similar degree of weight gain to that caused by sulfonylureas (moderate strength of evidence).
Eye damage Both rosiglitazone and pioglitazone have been suspected of causing macular edema, which damages the retina of the eye and causes partial blindness. Blindness is also a possible effect of diabetes, which rosiglitazone is intended to treat. One report documented several occurrences and recommended discontinuation at the first sign of vision problems. A retrospective cohort study showed an association between the use of thiazolidinediones and the incidence of diabetic macular edema (DME). Both use was associated with a 2,3 higher risk at 1 year and at 10 year follow-up, rising to 3 if associated with insulin.