Avandia helps Type 2 diabetes patients control their blood sugar by making them more sensitive to insulin, but the drug has been linked to several serious and even potentially fatal side effects, including heart attacks.
Approved in 1999, Avandia is used along with diet and exercise and sometimes other medications to treat Type 2 diabetes. Through the years, Avandia has gone from being a top-seller to a disgraced diabetes drug.
The impetus for Avandia’s abrupt fall was a 2007 study by cardiologist Steven Nissen that exposed the drug’s association with heart risks — risks its manufacturer GlaxoSmithKline has been accused of hiding from the public.
But heart failure is just one of several risks tied to use of the drug. Avandia is also linked to bone fractures, liver failure and even a risk of increased pregnancy.
The U.S. Food and Drug Administration (FDA) and Avandia maker GlaxoSmithKline (GSK) have long recognized that rosiglitazone, the active ingredient in Avandia, may be associated with certain heart problems.
The prescribing information for all rosiglitazone-containing products has addressed the risk since 2001, but the FDA has significantly strengthened the warnings over the years, including requiring a black box warning, the agency’s strongest warning, about congestive heart failure.
The black box warning added in 2007 notifies consumers that Avandia can cause or exacerbate congestive heart failure in some patients. It also warns against use of the drug in patients with symptomatic heart failure and in patients with established New York Heart Association (NYHA) Class III or IV heart failure.
The FDA released a safety alert about the heart risks in 2007 and sought advice from experts at a joint meeting of the FDA Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees. Studies, including one that used GSK’s own data, showed increases in heart risks as high as 43 percent in people taking Avandia. Several organizations agreed that the risk deserved “serious attention and follow-up,” according to the FDA.
The FDA as well as outside experts have continued to study the effects of Avandia on heart health. In 2010, the FDA announced that it was significantly restricting the use of Avandia to patients with Type 2 diabetes who cannot control their diabetes on other medications.
“These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia,” the agency said.
For three years, the drug was considered all but banned in the U.S. and became known as a last resort for diabetic people who were so sick that they were willing to risk having a heart attack.
Consumers concerned about the heart risks associated with the drug questioned why it had not been recalled in the U.S. (The European Medicines Agency removed the drug from the market in Europe), and people began filing lawsuits against GSK, claiming the company hid the heart risks and marketed an unsafe drug.
The FDA has since lifted the restrictions on Avandia use, but the heart failure and heart problem warnings, including the black box warning, remain in the drug’s prescribing information.
Avandia’s black box warning says patients should be observed carefully after starting Avandia and after dose increases for signs and symptoms of heart failure.
“If these signs and symptoms develop, the heart failure should be managed according to current standards of care,” the black box reads. “Furthermore, discontinuation or dose reduction of Avandia must be considered.”
Avandia’s label has been repeatedly updated to include new information about bone fracture risk. In 2007 — eight years after Avandia hit the market — a new drug label featured information about increased incidence of bone fractures in women taking Avandia. By October 2008, the label cautioned that the bone fracture risk may also apply to men.
The labeling changes were the result of several studies that found a link between Avandia use and bone fractures. Drugs like Avandia are said to cause slower bone formation and faster bone loss. Researchers believe the drugs trigger the body to reabsorb bone, making bones more likely to break.
Long-term trials RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) and ADOPT (active-controlled trials in patients with diabetes) were among the studies with findings that support the bone fracture warnings. An increased incidence of bone fractures “was noted after the first year of treatment and persisted during the course of the trial,” according to the drug’s label.
Most fractures in the women who received Avandia happened in areas not usually associated with postmenopausal osteoporosis. Bone fractures in the Avandia users were in the upper arm, hand and foot; postmenopausal osteoporosis is associated with fractures in the hip or spine.
A Swiss analysis of the records of British diabetic patients with fractures found patients on Avandia or Actos had double or triple the odds of fractures in sites other than the spine. Patients who took the drugs for about 12 to 18 months had an even higher chance of bone fracture. The highest risk was for those with two or more years of Avandia or Actos use.
The research published in the journal Archives of Internal Medicine compared the records of 1,020 diabetic patients with fractures diagnosed by British doctors between 1994 and 2005 against a control group of diabetics who did not have fractures.
“Fractures of the hip and wrist were most notable,” the study’s authors wrote.
A study published in 2010 in Diabetes Obesity and Metabolism found the use of drugs like Avandia is associated with an increased risk of fractures in both women and men.
The study was the first to provide evidence that men might be subjected to similar bone risks as those previously described in women, Reuters reported. It found a significant decrease in bone mineral density in those taking Avandia. It also demonstrated that the risk of bone fracture is increased even in younger women.
Use of drugs like Avandia “was associated with a higher fracture risk in women aged above and below 50 years and in men aged above 50 years,” the study’s authors wrote.
A different study published in Acta Diabetologica in 2015 found results consistent with the findings of previous trials that Avandia is associated with an increased risk of bone fractures in women and probably men, too.
Before Avandia gained FDA approval in 1999, the biggest concern surrounding the drug was whether it would cause liver toxicity. A similar drug Rezulin was linked to scores of confirmed cases of liver failure and was ultimately pulled from the market.
Records show SmithKline Beecham representatives repeatedly assured the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee that their drug will not damage the liver. The committee ultimately endorsed the drug, unanimously recommending FDA approval.
However, within a year of entering the market, Avandia was linked to two cases of liver failure. In one case, the patient had also taken Rezulin. One of the patients died and the other recovered without needing a liver transplant
Since then, studies have implicated Avandia in liver failure. One case series published in 2009 in Pharmacoepidemiology Drug Safety showed evidence that drugs like Avandia can cause liver problems. It found 11 cases of liver failure associated with rosiglitazone (Avandia) and with pioglitazone (Actos) among all cases of liver failure reported between 1997 and 2006.
Today, the drug’s label warns doctors to measure their patients’ liver enzymes before starting Avandia and periodically throughout treatment. Patients with abnormally high liver enzyme levels should not start taking Avandia.
“Do not initiate Avandia if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels,” the drug’s label states.
Doctors should be cautious about continuing treatment with Avandia in patients with mild liver enzyme elevations. These patients require “close clinical follow-up, including liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worse,” according to the drug’s label.
Patients should get their liver enzymes checked if they experience any symptoms that suggest liver problems. The decision whether to continue taking Avandia is one that patients should make with their doctors. Do not stop taking Avandia without consulting a doctor who can make a clinical judgement based on laboratory evaluations.
Unfortunately when liver function is severely diminished, a liver transplant may be the only option. People who undergo a liver transplant have an operation to remove the liver and replace it with a healthy, donated liver. This surgery, like all surgeries, carries significant risks.
Although heart failure, bone fractures and liver toxicity are the more well-known side effects of Avandia. The drug is also linked to other life-altering effects, including swelling, weight gain, vision problems, blood and blood sugar effects and an increased risk of pregnancy.
Diabetic people treated with Avandia during controlled clinical trials reported mild to moderate edema, or swelling. Edema occurs when fluid becomes trapped in the body’s tissues. Avandia can cause fluid retention, which can worsen or lead to congestive heart failure.
“In a clinical trial in healthy volunteers who received 8 mg of Avandia daily for 8 weeks, there was a statistically significant increase in median plasma volume compared with placebo,” the drug’s label states.
Increased plasma volume is necessary for edema to develop, according to a study published in American Journal of Physiology. Edema can become increasingly painful and uncomfortable. Sometimes, the swelling causes stiffness, decreases blood circulation and makes it difficult to walk.
Edema in Avandia users may be dose related, and the drug should be used with caution in people with edema. People with ongoing edema who take both insulin and Avandia have a greater chance of experiencing adverse events associated with edema, studies show.
People who took Avandia by itself and in combination with other diabetes drugs experienced unusually rapid weight gain. It’s unclear exactly how the drug caused users to gain weight, though it “probably involves a combination of fluid retention and fat accumulation,” according to the drug’s label.
One trial looked at Type 2 diabetes patients not previously treated with antidiabetic medication. Those who began taking Avandia gained an average of nearly 8 pounds. By comparison, patients who began taking the anti-diabetic medication glyburide gained an average of 4 pounds.
Avandia users who experience increases in their weight should be assessed for fluid accumulation as well as edema and congestive heart failure.
Some diabetic patients who were taking Avandia reported experiencing macular edema. The American Academy of Ophthalmology defines macular edema as swelling or thickening of the part of the eye responsible for detailed, central vision, known as the macula. Macular edema is the result of fluids leaking from blood vessels in the retina.
The macula allows a person to do things like read, sew or recognize a face. When the macula is swollen it does not function properly. As a result, Avandia users who developed macular edema reported blurred vision and decreased visual activity. Vision improved for some patients after they stopped taking Avandia.
Adults treated with Avandia showed decreases in average hemoglobin, the protein found in red blood cells that carries oxygen throughout the body, and hematocrit, the number of red blood cells in the blood. The decreases varied based on the amount of drug patients took. These blood effects could be related to the increase in plasma volume that results from Avandia use.
Avandia users should undergo periodic fasting blood glucose and HbA1c tests to monitor their response to the drug. People who take Avandia and other anti-diabetic medications simultaneously may be at risk for hypoglycemia. A doctor may instruct you to reduce the dose of the other diabetes drug.
Some premenopausal anovulatory women may experience ovulation while taking Avandia. This could put Avandia users at an increased risk for pregnancy while taking the drug. The drug’s label advises doctors to recommend adequate contraception in premenopausal women using Avandia. The FDA cautions women to avoid using the drug while pregnant.
“This possible effect has not been specifically investigated in clinical trials; therefore, the frequency of this occurrence is not known,” the drug’s label states.
Preclinical studies showed hormonal imbalance. Women should review the benefits of continuing Avandia treatment with their doctors if unexpected menstrual dysfunction occurs.
Please seek the advice of a medical professional before making health care decisions.
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