|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||POM (UK) ℞-only (US)|
|Excretion||Renal (64%) and fecal (23%)|
|Mol. mass||357.428 g/mol|
|(what is this?)|
Rosiglitazone (trade name Avandia, GlaxoSmithKline) is an antidiabetic drug in the thiazolidinedione class of drugs. It works as an insulin sensitizer, by binding to the PPAR receptors 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 (trade name Avandamet) or with glimepiride (trade name Avandaryl). First released in 1999, annual sales peaked at approximately $2.5-billion in 2006; however, following a meta-analysis published in the New England Journal of Medicine 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.
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 U.S. From November 2011 until November 2013, the 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 November 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of the RECORD clinical trial (a six-year, randomized control trial), which failed to show any of the previously-suggested cardiac risks associated with the drug.
In Europe, the European Medicines Agency (EMA) recommended in September 2010 that the drug be suspended from the European market. However, patients currently taking rosiglitazone are advised to discuss alternative options during their next physician appointment. In New Zealand, rosiglitazone was withdrawn from the market in April 2011. It was banned in India in 2010.
- 1 Medical uses
- 2 Adverse effects
- 3 Pharmacology
- 4 Society and culture
- 5 Research
- 6 References
- 7 External links
Rosiglitazone appears to increase the risk of heart attacks and death. A meta-analysis in May 2007 reported the use of rosiglitazone was associated with an increased risk of heart attack (odds ratio = 1.43, 95% confidence interval, 1.03 to 1.98; P=0.03), and a higher (but non-significant) increase in risk of death from all cardiovascular diseases (odds ratio = 1.64, 95% confidence interval, 0.98 to 2.74; P=0.06). The U.S. Food and Drug Administration (FDA) issued an alert on May 21, 2007. On July 30, 2007, an Advisory Committee of the Food and Drug Administration concluded the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of myocardial ischemic events (including heart attacks) than a placebo, but data from several long term, prospective clinical trials showed when rosiglitazone was compared to metformin, or sulfonylurea, there was no difference in the risk of heart attack. These data, coupled with the meta-analysis, prompted the FDA to state the data on the association between rosiglitazone and myocardial ischemia were inconclusive. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate this, and several other reports have failed to resolve the controversy.
At the same time, a report by the Senate Finance Committee accused GlaxoSmithKline of knowing about the drug's risks well before they became public. The report also criticized the FDA for letting clinical trials continue, despite 83,000 heart attacks from 1999 to 2007 that the FDA linked to rosiglitazone. This Senate Committee report from November 2007 is entitled "The Intimidation of Dr. John Buse and the Diabetes Drug Avandia". The title refers to (temporarily successful) efforts made by GSK beginning in 1999 to intimidate an academic scientist from continuing to suggest Avandia had cardiovascular risk. The drug now bears a boxed warning about exactly this risk. GlaxoSmithKline maintains the drug is safe and the Senate report did not consider scientific evidence or the company's efforts to make known its concerns to the parties involved. However, the FDA still recommends patients continue taking it unless their doctors tell them otherwise.
In February 2010, David Graham, the FDA's associate director of drug safety, recommended rosiglitazone be taken off the market. In June 2010, Graham et al., published a retrospective study of 227,571 elderly American patients, comparing roziglitazone to pioglitazone, the other thiazolidinedione marketed in the United States. The authors 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.
Both TZDs are contraindicated in patients with NYHA Class III and IV heart failure.
The controversy over adverse effects has dramatically reduced the use of rosiglitazone. No studies have shown that rosiglitazone reduces the risk of stroke, amputation, heart attack, blindness, neuropathy or renal failure.
A meta-analysis of observational studies released in March, 2011, provides more evidence that rosiglitazone is associated with a higher risk of heart failure, myocardial infarction and death than a similar agent, pioglitazone. The meta-analysis had 16 observational studies involving 810 000 patients taking rosiglitazone or pioglitazone.
In June 2013 an FDA Advisory Committee reviewed all available data, including a re-adjudicated RECORD trial, found no evidence of increased cardiovascular risk with Avandia, and voted to remove the restrictions on Avandia marketing in the United States. In November 2013, the US FDA removed these marketing restrictions on the product.
Avandia has been linked to stroke. In a study led by FDA scientist David J. Graham, MD, MPH, by comparing the patient records of elderly patients using Avandia and alternative drug Actos, found Avandia increased the risk of stroke by over 27% relatively (for example, someone with a 1% risk of stroke taking Actos would have a 1.27% risk taking Avandia, on average).
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. The information was based on data from the ADOPT trial. The same increase has been found with pioglitazone (Actos), another TZD.
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.
Moderate to severe acute hepatitis has occurred in several adults who had been taking the drug at the recommended dose for two to four weeks. Plasma rosiglitazone concentrations may be significantly increased in patients with pre-existing hepatic impairment.
Rosiglitazone is a member of the thiazolidinedione class of drugs. Thiazolidinediones act as insulin sensitizers. They reduce glucose, fatty acid, and insulin blood concentrations. They work by binding to the peroxisome proliferator-activated receptors (PPARs). PPARs are receptors on the membrane of the cell nucleus. Thiazolidinediones enter the cell, bind to the nuclear receptors, and affect the expression of DNA. The several PPARs include PPARα, PPARβ/δ, and PPARγ. Thiazolidinediones bind to PPARγ.
PPARs are expressed in fat cells, cells of the liver, muscle, heart, and inner wall (endothelium) and smooth muscle of blood vessels. PPARγ is expressed mainly in fat tissue, where it regulates genes involved in fat cell (adipocyte) differentiation, fatty acid uptake and storage, and glucose uptake. It is also found in pancreatic beta cells, vascular endothelium, and macrophages. Rosiglitazone is a selective ligand of PPARγ and has no PPARα-binding action. Other drugs bind to PPARα.
Rosiglitazone also appears to have an anti-inflammatory effect in addition to its effect on insulin resistance. Nuclear factor kappa-B (NF-κB), a signaling molecule, stimulates the inflammatory pathways. NF-κB inhibitor (IκB) downregulates the inflammatory pathways. When patients take rosiglitazone, NF-κB levels fall and IκB levels increase.
Society and culture
Though sales have gone down since 2007 due to safety concerns, Avandia sales for 2009 totalled $1.2 billion worldwide.
The Guardian reported lawsuits over the drug could total from $1 billion to $6 billion, based on research by analysts for UBS, who say 13,000 suits have been filed. 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". 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. 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. In a statement, Michael Miller, the attorney representing 1,500 patients in the suit, said about the settlement, "It's a compromise that allows both sides to put this behind them and move on."
The drug has been under investigation in the US and in Europe. In September 2010, the U.S. Food and Drug Administration (FDA) decided rosiglitazone can remain available, but with certain restrictions. Also, the European Medicines Agency has decided to stop making all rosiglitazone-containing antidiabetes medication available in Europe. The FDA has decided on revising its prescribing information and medication guides for all rosilitazone containing medicines. The US label for rosiglitazone (Avandia, GlaxoSmithKline) and all rosiglitazone-containing medications (Avandamet and Avandaryl) now include the additional safety information and restrictions. The revised labels restrict use to patients already taking a rosiglitazone-containing medicine or to new patients who are unable to achieve adequate glycemic control on other diabetes medications and to those, who in consultation with their healthcare provider, have decided not to take Actos (pioglitazone) or other pioglitazone-containing medicines for medical reasons.
United States investigations
The FDA began investigating the drug in 2007 after reports it likely caused an increased risk in heart attacks, but following a 2007 study, an FDA advisory panel agreed Avandia did not cause a statistically significant increase in heart attacks. The FDA voted to keep the drug on the market; a few months later, however, the agency added a boxed warning about potential heart risks of Avandia. A study was conducted evaluating the geographic variation in the use of rosiglitazone following the boxed warning issued in 2007. Residual use varied by state, which may be explained by uncertainty regarding how to translate FDA warnings into practice, by differences in coverage policies among health plans and in formularies among states, and by regional differences in the distribution and influence of pharmaceutical marketing, specialists, and opinion leaders.
In 2007, a panel of independent researchers reported Avandia could, in fact, increase patients' risks of heart attack, but they recommended it remain on the market. An FDA oversight committee voted in 2007, eight to seven, to accept that advice and keep it on the market.
GlaxoSmithKline is currently being investigated by the FDA and the US Congress regarding Avandia.
Senators Democrat Max Baucus and Republican Charles Grassley filed a report urging GSK to withdraw Avandia in 2008 due to the side effects. The report noted the drug caused 500 avoidable heart attacks a month, and Glaxo officials sought to intimidate doctors who criticized the drug. It also said GSK continued to sell and promote the drug despite knowing the increased risk of heart attacks and stroke.
The Senate Finance Committee, in a panel investigation, revealed emails from GSK company officials that suggest the company downplayed scientific findings about safety risks dating back to 2000. It was also alleged by the committee that the company initiated a "ghostwriting campaign", whereby GSK sought outside companies to write positive articles about Avandia to submit to medical journals. 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. Many studies have found the drug to have serious safety concerns.[medical citation needed]
On July 14, 2010, after two days of extensive deliberations, the FDA panel investigating Avandia came to a mixed vote. Twelve members of the panel voted to take the drug off the market, 17 recommended to leave it on but with a more revised warning label, and three voted to keep it on the market with the current warning label. 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, arrousing questions of a conflict of interest. This panel member was one of the three who voted to keep Avandia on the market with no additional warning labels. The FDA is expected to vote soon on what to do next in regards to Avandia, though the FDA almost always agrees with its panel votes.[needs update]
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.
According to a probe by the British Medical Journal in September 2010, the United Kingdom's Commission on Human Medicines recommended to the Medicines and Healthcare Products Regulatory Agency (MHRA) back in July 2010, to withdraw Avandia sale because its "risks outweigh its benefits". 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. The European Medicines Agency recommended on 23 September 2010 that Avandia be suspended from the European market.
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 notice issued by the Medicines Control Council of South Africa on July 5, 2011 stated that it had resolved on July 3, 2011 to withdraw all rosiglitazone-containing medicines from the South African market due to safety risks. It disallowed all new prescriptions of Avandia.
Controversy and response
Following the reports in 2007 that Avandia can significantly increase the risk of heart attacks, the drug has been controversial. 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." It reports, "the FDA is investigating whether GSK broke the law by failing to fully inform the agency of Avandia's heart risks", according to deputy FDA commissioner Dr. Joshua Sharfstein. GSK threatened academics who reported adverse research results, and received multiple warning letters from the FDA for deceptive marketing and failure to report clinical data.
The maker of the drug, GlaxoSmithKline, has dealt with serious backlash against the company for the drug's controversy. Sales on the drug dropped significantly after the story first broke in 2007, dropping from $2.5 billion in 2006 to less than $408 million in 2009 in the US.
In response to the rise in risk of heart attacks, the Indian government ordered GSK to suspend its research study, called TIDE, in 2010. Takeda Pharmaceuticals responded to the controversy by running a large advertising campaign for its rival diabetes drug Actos, first in 2007 and again in 2010. The FDA also halted the TIDE study in the United States.
Three doctors' groups, the Endocrine Society, the American Diabetes Association and the American Association of Clinical Endocrinologists, urged patients to continue to take the drug as it would be much worse to stop all treatment, despite any associated risk, but that patients could consult their doctors and begin a switch to a different drug if they or their doctors find concern. 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....". "For patients with diabetes, the most serious consequences are heart disease and stroke, and the risk of suffering from them is significantly increased when diabetes is present. As in most situations, patients should not change or stop medications without consulting their healthcare provider."
Rosiglitazone was thought to be able to benefit patients with Alzheimer's disease who do not express the ApoE4 allele, but the phase III trial designed to test this showed that rosiglitazone was ineffective in all patients, including ApoE4-negative patients.
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