Rosiglitazone
Encyclopedia
Rosiglitazone 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 (Avandia) and in combination with metformin
(Avandamet) or with glimepiride
(Avandaryl). Annual sales peaked at approximately $2.5bn in 2006, but declined after reports of adverse effects. The drug's patent expires in 2012.
Some reports have found rosiglitazone is associated with an increased risk of heart attacks, but other reports have not found a statistically significant increase. Concern about adverse effects has reduced the use of rosiglitazone despite its sustained effects on glycemic control. The drug is currently the subject of over 13,000 lawsuits against GSK. As of July 2010, GSK has agreed to settlements on more than 11,500 of these suits.
The drug is controversial in the U.S. Some reviewers have concluded that rosiglitazone caused more deaths than pioglitazone
(Actos), and have recommended rosiglitazone be taken off the market, but an FDA Food and Drug Administration
panel disagreed, and it remains on the market in the U.S., subject to significant restrictions. From November 18, 2011 the federal government will not allow Avandia to be sold without a prescription from certified doctors. Patients will be required to be informed of the risks associated with the use of Avandia, and the drug will be required to be purchased by mail order through specified pharmacies.
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 the UK, Diabetes UK announced, "People currently taking all forms of the recently suspended drug Avandia (Rosiglitazone) have until 21 October to be reviewed and transferred onto an alternative treatment".
In New Zealand, rosiglitazone (Avandia) is to be withdrawn from the market before April 29, 2011 after concern about its make an elevated risk of cardiovascular events. Patients should discuss alternative treatments with their doctor as soon as possible, but to continue taking the drug in the meantime.
As reported by Medscape/Heartwire 23 September 2010,medscape the EMA has recommended the suspension of the marketing authorizations for all rosiglitazone-containing antidiabetes medications licensed in the EU—Avandia, Avandamet, and Avaglim.
A study in 2007 has been widely cited as finding that Avandia may increase the risk of heart attack by as much as 43%.
A meta-analysis
in May 2007 reported the use of rosiglitazone was associated with a significantly increased risk of heart attack
(odds ratio
=1.43, (95% confidence interval
, 1.03 to 1.98; P=0.03)), and an even higher risk of death from all cardiovascular diseases (odds ratio
=1.64).
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 conclude the controversy. Graham argued rosiglitazone caused 500 more heart attacks and 300 more heart failures than its main competitor.
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 trial
s 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 that Avandia had cardiovascular risk. The drug now bears a black box warning about exactly this risk. Further efforts by the vendors to protect their product are also described at Senate.gov, searchbox "Avandia". GlaxoSmithKline maintains the drug is safe and that 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 doctor tells them otherwise.
The 2009 RECORD study, an open label trial published in the Lancet, found there was no increase in cardiovascular hospitalisation or death with rosiglitazone compared to metformin
plus sulfonylurea
, but the rate of heart failure causing admission to a hospital or death was significantly increased.
Both TZDs are contraindicated in patients with NYHA Class III and IV heart failure.
In February 2010, David Graham, the FDA's associate director of drug safety, recommended rosiglitazone be taken off the market. Graham argued rosiglitazone caused 500 more heart attacks and 300 more heart failures than its main competitor.
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 that 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.
This weak evidence for adverse effects has dramatically reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control. 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
(MI) and death than a similar agent, pioglitazone. The meta-analysis had 16 observational studies involving 810 000 patients taking rosiglitazone or pioglitazone
.
s 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.
, 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.
s (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. There are several PPARs, including 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) is a signaling molecule which stimulates the inflammatory pathways. NF-κB inhibitor (IκB) is an inhibitor which downregulates the inflammatory pathways. When patients take rosiglitazone, NF-κB levels fall and IκB levels increase.
Rosiglitazone may also benefit patients with Alzheimer's disease
who do not express the ApoE4
allele
. This is the subject of a clinical trial currently underway.
Rosiglitazone may also treat mild to moderate ulcerative colitis
, due to its anti-inflammatory properties as a PPAR ligand.
A clinical trial has suggested these agents may be of use in treating malaria.
Though sales have gone down since 2007 due to safety concerns, Avandia sales for 2009 totalled $1.2 billion worldwide.
reported lawsuit
s over the drug could total anywhere from $1 billion to $6 billion. This is 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."
have decided that rosiglitazone can remain available, but with certain restrictions. Also, the European Medicines Agency
(EMA) 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 includes 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.
In 2007, a panel of independent researchers reported Avandia could, in fact, increase patients' risk 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 cited that the drug caused 500 avoidable heart attacks a month and that 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 Senate 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.
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.
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.
concluded that the suspected cardiovascular risks of the medicine for patients with type 2 diabetes outweigh its benefits. "Patients who are taking Avandia are advised to make an appointment to see their doctor to discuss alternative treatments as soon as possible," the agency's group manager, Stewart Jessamine, says in a media release.
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 raise 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 doctor 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."
Some doctors have been reported to have begun to stop prescribing Avandia.
(PCRM) announced they were suing the FDA for failing to notify patients of dietary substitutes for diabetes drugs. The lawsuit, filed in the U.S. District Court for the District of Columbia, is currently underway.
Thiazolidinedione
The thiazolidinediones , also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.- Mechanism of action :...
class of drugs. It works as an insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
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
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
(GSK) as a stand-alone drug (Avandia) and in combination with metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
(Avandamet) or with glimepiride
Glimepiride
Glimepiride is a medium-to-long acting sulfonylurea anti-diabetic drug. It is marketed as Amaryl by Sanofi-Aventis and GLIMY by Dr.Reddy's Labs...
(Avandaryl). Annual sales peaked at approximately $2.5bn in 2006, but declined after reports of adverse effects. The drug's patent expires in 2012.
Some reports have found rosiglitazone is associated with an increased risk of heart attacks, but other reports have not found a statistically significant increase. Concern about adverse effects has reduced the use of rosiglitazone despite its sustained effects on glycemic control. The drug is currently the subject of over 13,000 lawsuits against GSK. As of July 2010, GSK has agreed to settlements on more than 11,500 of these suits.
The drug is controversial in the U.S. Some reviewers have concluded that rosiglitazone caused more deaths than pioglitazone
Pioglitazone
Pioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic action.Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe,"Glizone" and "Pioz" in India by Zydus CND and USV respectively and Zactos in Mexico by Takeda...
(Actos), and have recommended rosiglitazone be taken off the market, but an FDA Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
panel disagreed, and it remains on the market in the U.S., subject to significant restrictions. From November 18, 2011 the federal government will not allow Avandia to be sold without a prescription from certified doctors. Patients will be required to be informed of the risks associated with the use of Avandia, and the drug will be required to be purchased by mail order through specified pharmacies.
In Europe, the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(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 the UK, Diabetes UK announced, "People currently taking all forms of the recently suspended drug Avandia (Rosiglitazone) have until 21 October to be reviewed and transferred onto an alternative treatment".
In New Zealand, rosiglitazone (Avandia) is to be withdrawn from the market before April 29, 2011 after concern about its make an elevated risk of cardiovascular events. Patients should discuss alternative treatments with their doctor as soon as possible, but to continue taking the drug in the meantime.
As reported by Medscape/Heartwire 23 September 2010,medscape the EMA has recommended the suspension of the marketing authorizations for all rosiglitazone-containing antidiabetes medications licensed in the EU—Avandia, Avandamet, and Avaglim.
Heart disease
Some studies conclude rosiglitazone increases fatalities from heart disease, but other studies do not.A study in 2007 has been widely cited as finding that Avandia may increase the risk of heart attack by as much as 43%.
A meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
in May 2007 reported the use of rosiglitazone was associated with a significantly increased risk of heart attack
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
(odds ratio
Odds ratio
The odds ratio is a measure of effect size, describing the strength of association or non-independence between two binary data values. It is used as a descriptive statistic, and plays an important role in logistic regression...
=1.43, (95% confidence interval
Confidence interval
In statistics, a confidence interval is a particular kind of interval estimate of a population parameter and is used to indicate the reliability of an estimate. It is an observed interval , in principle different from sample to sample, that frequently includes the parameter of interest, if the...
, 1.03 to 1.98; P=0.03)), and an even higher risk of death from all cardiovascular diseases (odds ratio
Odds ratio
The odds ratio is a measure of effect size, describing the strength of association or non-independence between two binary data values. It is used as a descriptive statistic, and plays an important role in logistic regression...
=1.64).
The U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) issued an alert on May 21, 2007. On July 30, 2007 an Advisory Committee of the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
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
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
, or sulfonylurea
Sulfonylurea
Sulfonylurea derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta cells in the pancreas.-First generation:* Carbutamide...
, 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 conclude the controversy. Graham argued rosiglitazone caused 500 more heart attacks and 300 more heart failures than its main competitor.
At the same time, a report by the Senate Finance Committee
United States Senate Committee on Finance
The U.S. Senate Committee on Finance is a standing committee of the United States Senate. The Committee concerns itself with matters relating to taxation and other revenue measures generally, and those relating to the insular possessions; bonded debt of the United States; customs, collection...
accused GlaxoSmithKline of knowing about the drug's risks well before they became public. The report also criticized the FDA for letting clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s 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 that Avandia had cardiovascular risk. The drug now bears a black box warning about exactly this risk. Further efforts by the vendors to protect their product are also described at Senate.gov, searchbox "Avandia". GlaxoSmithKline maintains the drug is safe and that 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 doctor tells them otherwise.
The 2009 RECORD study, an open label trial published in the Lancet, found there was no increase in cardiovascular hospitalisation or death with rosiglitazone compared to metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
plus sulfonylurea
Sulfonylurea
Sulfonylurea derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta cells in the pancreas.-First generation:* Carbutamide...
, but the rate of heart failure causing admission to a hospital or death was significantly increased.
Both TZDs are contraindicated in patients with NYHA Class III and IV heart failure.
In February 2010, David Graham, the FDA's associate director of drug safety, recommended rosiglitazone be taken off the market. Graham argued rosiglitazone caused 500 more heart attacks and 300 more heart failures than its main competitor.
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 that 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
Number needed to harm
The number needed to harm is an epidemiological measure that indicates how many patients need to be exposed to a risk-factor over a specific period to cause harm in one patient that would not otherwise have been harmed. It is defined as the inverse of the attributable risk...
with roziglitazone was sixty.
This weak evidence for adverse effects has dramatically reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control. 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
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
(MI) and death than a similar agent, pioglitazone. The meta-analysis had 16 observational studies involving 810 000 patients taking rosiglitazone or pioglitazone
Pioglitazone
Pioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic action.Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe,"Glizone" and "Pioz" in India by Zydus CND and USV respectively and Zactos in Mexico by Takeda...
.
Stroke
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 that Avandia increase the risk of stroke by over 27%..Bone fractures
GlaxoSmithKline reported a greater incidence of fractureFracture
A fracture is the separation of an object or material into two, or more, pieces under the action of stress.The word fracture is often applied to bones of living creatures , or to crystals or crystalline materials, such as gemstones or metal...
s 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.
Eye damage
Both rosiglitazone and pioglitazone have been suspected of causing macular edemaMacular edema
Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye and causes it to thicken and swell. The swelling may distort a person's central vision, as the macula is near the center of the retina at the back of the eyeball...
, 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.
Hepatotoxicity
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.Pharmacology
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 receptorPeroxisome proliferator-activated receptor
In the field of molecular biology, the peroxisome proliferator-activated receptors are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes...
s (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. There are several PPARs, including PPARα, PPARβ/δ, and PPARγ. Thiazolidinediones bind to PPARγ
Peroxisome proliferator-activated receptor gamma
Peroxisome proliferator-activated receptor gamma , also known as the glitazone receptor, or NR1C3 is a type II nuclear receptor that in humans is encoded by the PPARG gene.Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 and...
.
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
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
effect in addition to its effect on insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
. Nuclear factor kappa-B (NF-κB) is a signaling molecule which stimulates the inflammatory pathways. NF-κB inhibitor (IκB) is an inhibitor which downregulates the inflammatory pathways. When patients take rosiglitazone, NF-κB levels fall and IκB levels increase.
Rosiglitazone may also benefit patients with Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
who do not express the ApoE4
Apolipoprotein E
Apolipoprotein E is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.-Function:...
allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
. This is the subject of a clinical trial currently underway.
Rosiglitazone may also treat mild to moderate ulcerative colitis
Ulcerative colitis
Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
, due to its anti-inflammatory properties as a PPAR ligand.
A clinical trial has suggested these agents may be of use in treating malaria.
Sales
US sales of the drug were of $2.2 billion in 2006. Sales in 2Q 2007 down 22% compared to 2006. 4Q 2007 sales down to $252 million.Though sales have gone down since 2007 due to safety concerns, Avandia sales for 2009 totalled $1.2 billion worldwide.
Lawsuits
The GuardianThe Guardian
The Guardian, formerly known as The Manchester Guardian , is a British national daily newspaper in the Berliner format...
reported lawsuit
Lawsuit
A lawsuit or "suit in law" is a civil action brought in a court of law in which a plaintiff, a party who claims to have incurred loss as a result of a defendant's actions, demands a legal or equitable remedy. The defendant is required to respond to the plaintiff's complaint...
s over the drug could total anywhere from $1 billion to $6 billion. This is based on research by analysts for UBS
UBS AG
UBS AG is a Swiss global financial services company headquartered in Basel and Zürich, Switzerland, which provides investment banking, asset management, and wealth management services for private, corporate, and institutional clients worldwide, as well as retail clients in Switzerland...
, who say 13,000 suits have been filed. Included among those suing: Santa Clara County, California
Santa Clara County, California
Santa Clara County is a county located at the southern end of the San Francisco Bay Area in the U.S. state of California. As of 2010 it had a population of 1,781,642. The county seat is San Jose. The highly urbanized Santa Clara Valley within Santa Clara County is also known as Silicon Valley...
, 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."
Government investigations
The drug has been under investigation in the US and in Europe. In September 2010, the U.S. Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
have decided that rosiglitazone can remain available, but with certain restrictions. Also, the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(EMA) 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
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
) and all rosiglitazone-containing medications (Avandamet and Avandaryl) now includes 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
Pioglitazone
Pioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic action.Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe,"Glizone" and "Pioz" in India by Zydus CND and USV respectively and Zactos in Mexico by Takeda...
) or other pioglitazone-containing medicines for medical reasons.
United States investigations
The U.S. 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 black-box warning about potential heart risks of Avandia. A study was conducted evaluating the geographic variation in the use of rosiglitazone following the black box warning issued in 2007. Residual rosiglitazone 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' risk 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
Max Baucus
Max Sieben Baucus is the senior United States Senator from Montana and a member of the Democratic Party. First elected to the Senate in 1978, as of 2010 he is the longest-serving Senator from Montana, and the fifth longest-serving U.S...
and Republican Charles Grassley filed a report urging GSK to withdraw Avandia in 2008 due to the side effects. The report cited that the drug caused 500 avoidable heart attacks a month and that 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 Senate 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.
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.
European investigations
According to a probe by the British Medical JournalBritish Medical Journal
BMJ is a partially open-access peer-reviewed medical journal. Originally called the British Medical Journal, the title was officially shortened to BMJ in 1988. The journal is published by the BMJ Group, a wholly owned subsidiary of the British Medical Association...
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.
New Zealand
Rosiglitazone was withdrawn from the New Zealand market April 2011 because MedsafeMedsafe
Medsafe is the medical regulatory body run by the New Zealand Ministry of Health, administering the Medicines Act 1981 and Medicines Regulations 1984. Medsafe employs approximately 60 staff members in two offices...
concluded that the suspected cardiovascular risks of the medicine for patients with type 2 diabetes outweigh its benefits. "Patients who are taking Avandia are advised to make an appointment to see their doctor to discuss alternative treatments as soon as possible," the agency's group manager, Stewart Jessamine, says in a media release.
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 raise 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
American Diabetes Association
The American Diabetes Association is a United States-based association working to fight the consequences of diabetes, and to help those affected by diabetes...
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 doctor find concern. The American Heart Association
American Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
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."
Some doctors have been reported to have begun to stop prescribing Avandia.
PCRM lawsuit
On July 19, 2010 the nonprofit group Physicians Committee for Responsible MedicinePhysicians Committee for Responsible Medicine
The Physicians Committee for Responsible Medicine is a non-profit organization based in Washington, D.C., which promotes a vegan diet, preventive medicine, alternatives to animal research, and encourages what it describes as "higher standards of ethics and effectiveness in research." Its primary...
(PCRM) announced they were suing the FDA for failing to notify patients of dietary substitutes for diabetes drugs. The lawsuit, filed in the U.S. District Court for the District of Columbia, is currently underway.