Congestive Heart Failure
Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk.
Hypoglycemia (Low Blood Sugar)
When used with insulin or other diabetes drugs, a lower dose of the insulin or the other diabetes drugs may be needed to reduce the risk of hypoglycemia.
Increased incidence of bone fractures seen in long-term trials.
Bladder Cancer (pioglitazone only)
May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer.
The use of Avandia in combination with insulin may increase the risk of myocardial infarction.
Do Not Use: These drugs may be less effective than other drugs for diabetes and may cause liver damage, weight gain, anemia and heart failure.
Rosiglitazone (AVANDIA) and pioglitazone (ACTOS) are members of the thiazolidinedione (or glitazone) family of type 2 diabetes drugs, which are thought to work by increasing the body’s sensitivity to insulin. This family of drugs has been wracked with serious problems. In fact, the first glitazone to reach the market, troglitazone (REZULIN), was banned in the U.S. in March 2000 because of liver toxicity and deaths caused by its use.
Further, clinical trials show that many patients who previously had used nonglitazone antidiabetic therapy did not respond to glitazones as well as they did to nonglitazones. Moreover, in nine out of the 10 head-to-head trials comparing glitazones with other antidiabetic drugs, the glitazone tested was considered the inferior drug.
In research conducted before the approval of rosiglitazone and pioglitazone, a significant number of trial subjects experienced early signs of possible liver damage. Furthermore, cases of liver failure associated with both rosiglitazone and pioglitazone have been reported in the medical literature, indicating that these drugs are also capable of inflicting clinically significant liver damage.,,,
Heart failure and heart attack are two different but related conditions.
Heart failure occurs when the heart can no longer pump enough blood to the other organs in the body. It can have a variety of causes, including high blood pressure, the narrowing of the arteries that supply blood to the heart muscle, primary disease of the heart muscle itself, infection of the heart valves or heart muscle, or a past heart attack. Symptoms can include exercise intolerance, difficulty breathing and swelling of the legs.
A heart attack, on the other hand, is the death of heart muscle due to the sudden blockage of a coronary artery that supplies that muscle with blood and oxygen. Heart muscle death is irreversible, and the dead heart muscle is replaced by scar tissue. If this damage is severe enough, heart failure also can ensue.
Heart problems are a very consistent adverse effect of both rosiglitazone and pioglitazone. Rosiglitazone attracted a great deal of attention after a May 2007 New England Journal of Medicine (NEJM) meta-analysis study pooling data from multiple comparable clinical trials testing rosiglitazone found a 43% increase in heart attacks in people using the drug. Within the first six years of rosiglitazone’s approval, there had been 689 cases of heart failure reported to the Food and Drug Administration (FDA) in patients using the drug. In addition, there have been reports of anemia (low red blood cell count), which, along with heart failure, increases the risk of a heart attack.
In May 2007, shortly after the release of this NEJM study, the FDA warned that patients using rosiglitazone are at an increased risk of adverse cardiovascular events (including heart attack and other heart-related adverse events, some fatal) relative to other drugs used to treat diabetes.
The increased risk of heart attacks with use of rosiglitazone has not been observed in patients taking pioglitazone, but pioglitazone is associated with other serious heart safety concerns. A 24-week safety study conducted after the approval of pioglitazone found overnight hospitalization for heart failure was reported in almost 10% of patients taking pioglitazone and only about 5% of patients taking glyburide (DIABETA, GLYNASE).
The authors of a study evaluating the risk of heart-related adverse effects in patients treated with rosiglitazone and pioglitazone and published in The British Medical Journal concluded the following:
Among older patients with diabetes, pioglitazone is associated with a significantly lower risk of heart failure and death than is rosiglitazone. Given that rosiglitazone lacks a distinct clinical advantage over pioglitazone, continued use of rosiglitazone may not be justified.
In 2011, another article published in The British Medical Journal also compared the cardiovascular effects of rosiglitazone and pioglitazone in patients treated for type 2 diabetes. The results of this study also found that rosiglitazone use is associated with a higher risk of cardiovascular effects than is pioglitazone use. The cardiovascular events in this study included congestive heart failure, myocardial infarction and death.
The product labels for both of these drugs now include a black-box warning about the risk of worsening heart failure.
Weight gain and fluid retention
Another consistent finding with all glitazones is weight gain. This occurs for two reasons. First, these drugs promote the conversion of sugar to fat and cause the production of new fat cells in the body.,
Second, glitazones can cause fluid accumulation in the legs, ankles and lungs., Fluid accumulation may lead to difficulty breathing and heart failure, especially in patients with a history of cardiovascular disease. It is not known how much weight gain can be expected with long-term use of these drugs or if the negative effects of weight gain are outbalanced by the decrease in blood sugar levels.
The FDA has warned of the possibility of visual impairment due to swelling of part of the retina (macular edema) with the use of pioglitazone,  rosiglitazone and the combination of rosiglitazone and another diabetes drug, metformin (AVANDAMET). Vision loss from macular edema can progress over a period of months.
The FDA warning concluded that in the majority of reported cases of macular edema, the patients also reported concurrent peripheral edema, such as swollen legs, which occurred at the same time as the macular edema. In some cases, the macular edema resolved or improved following discontinuation of therapy, and in one case, macular edema resolved after dose reduction.
Anemia (low red blood cell levels that may result in weakness and fatigue) is associated with glitazone use. It appears to be more pronounced when using a glitazone with another diabetes drug, metformin (GLUCOPHAGE), or when using a combination pill including metformin and a glitazone, such as AVANDAMET or ACTOPLUS MET. Glitazone-induced anemia is thought to be caused by fat cells accumulating in the bone marrow, thus limiting blood cell production.
In 2005, rosiglitazone's product label was revised to reflect post-marketing reports of allergic reactions causing swelling around the face and mouth (angioedema) and hives on the skin (urticaria).
In 2007, the FDA notified health care professionals of safety data concerning pioglitazone- and rosiglitazone-containing products. The warning included reports of fractures in female patients taking these products. The majority of fractures observed in female patients were in the forearm, hand and wrist, or foot and ankle.,
A large randomized controlled clinical trial published in 2016 that compared pioglitazone with a placebo in non-diabetic patients who had suffered a stroke found that pioglitazone increased the risk of fractures in both men and women. 
Studies show …
Rosiglitazone is not approved for use in children ages 10-17 with type 2 diabetes. The product label has been revised to describe the results of a study comparing the effects of rosiglitazone with those of metformin in this age group.
In November 2007, Health Canada, the Canadian drug regulatory agency, issued new restrictions on the use of rosiglitazone products due to cardiac concerns. Rosiglitazone is no longer approved in Canada as monotherapy for type 2 diabetes, except when metformin use is contraindicated or not tolerated. Rosiglitazone is also no longer approved in Canada for use in combination with a sulfonylurea, except when metformin is contraindicated or not tolerated. Treatment with all rosiglitazone products is no longer recommended in patients with any stage of heart failure.
In 2009, Public Citizen presented information in a published article on liver failure associated with rosiglitazone and pioglitazone use. Case reports of liver failure reported to the FDA Adverse Event Reporting System (FAERS) from 1997 to 2006 were evaluated to determine the number of cases of liver failure that were associated with rosiglitazone and pioglitazone use. Based on the information from that study, Public Citizen concluded that the use of rosiglitazone and pioglitazone can cause severe liver toxicity.
In 2010, Health Canada informed the public that restrictions on the use of rosiglitazone had been enacted based on a review of data implicating that there may be an increased risk of cardiovascular events, such as heart attack and stroke, associated with the use of rosiglitazone.
Unlike the FDA, which responded inadequately, the European Medicines Agency, an agency similar to the FDA in the European Union, recommended the suspension of marketing authorizations for rosiglitazone-containing antidiabetic medications in September 2010. As a result, the medications are no longer available in Europe.
In 2012, The British Medical Journal (BMJ) published the results of a trial on the risk of bladder cancer associated with the use of pioglitazone in patients with type 2 diabetes. The data showed that there was an increased risk of bladder cancer in patients taking pioglitazone. The risk was also found to be higher in patients taking the drug for more than 24 months. Another study published in the BMJ in 2016 also found that pioglitazone use was associated with an increased risk of bladder cancer.
In 2020, BMJ published a meta-analysis of data from randomized clinical trials showing that rosiglitazone was associated with an increased risk of heart disease, particularly heart failure.
Regulatory actions surrounding glitazones
2000: Public Citizen petitioned the FDA to add warnings to the product labels of rosiglitazone and other glitazones because of safety concerns about heart function, fluid retention, weight gain, anemia and liver toxicity.
2007: In May, the FDA warned that patients using rosiglitazone are at an increased risk of cardiovascular events (including heart attack or heart-related adverse events, some fatal) relative to patients who take other drugs used to treat diabetes.
In October, the Department of Veterans Affairs, after conducting its own review, removed rosiglitazone from the list of drugs its doctors may prescribe, concluding that “for some patients, rosiglitazone may not afford the same margin of safety as alternative drug therapies.”
In November, the FDA modified its black-box warning for rosiglitazone to include information about a potentially increased risk of heart attack. The FDA warning is confusing, however, and provides no useful guidance to patients or their physicians. The new warning should be revised to clearly note that using rosiglitazone carries serious risks.
2008: Public Citizen formally petitioned the FDA to immediately ban the dangerous diabetes drug rosiglitazone after its researchers found that the drug causes liver failure in addition to many other previously known kinds of serious toxicity.
Public Citizen researchers identified 14 cases of liver failure — including 12 deaths — in the FAERS database.
The petition was released just as an unprecedented announcement by both the American Diabetes Association and the European Association for the Study of Diabetes appeared in a prepublication consensus article on the treatment of diabetes. The two groups concluded that for the treatment of diabetes, “given that other [treatment] options are now recommended, the consensus group members unanimously advised against using rosiglitazone"[emphasis added]. 
2009: The FDA required the manufacturer of pioglitazone-containing products to distribute a Medication Guide to patients being treated with these products. This decision was made based on information the FDA reviewed from clinical trials and post-marketing reports concerning congestive heart failure in patients being treated with these products.
2010: In February, the FDA notified the public that it was conducting an ongoing review of data from a large, long-term clinical study concerning possible cardiovascular risks associated with the use of rosiglitazone.
In September, the FDA stated, based on a review of data, that there may be an increased risk of cardiovascular events, such as heart attack and stroke, associated with the use of rosiglitazone. The FDA stated that it would significantly restrict the use of rosiglitazone. Further, rosiglitazone use would be confined to patients who cannot control their type 2 diabetes with other medications. The agency required the manufacturer of rosiglitazone to develop a restricted-access program for the drug.
Also in September, the FDA stated that it was conducting an ongoing review of data evaluating whether there may be an increased risk of bladder cancer associated with pioglitazone use.
2011: In May, the FDA issued the following statement on rosiglitazone-containing products (AVANDIA, AVANDAMET, AVANDARYL) to the public and health care professionals:
Because of the potential increased risk of myocardial infarction, AVANDIA is available only through a restricted distribution program called the AVANDIA-Rosiglitazone Medicines Access Program. Both prescribers and patients must enroll in the program to be able to prescribe or receive AVANDIA, respectively. AVANDIA will be available only from specially certified pharmacies participating in the program. As part of the program, prescribers will be educated about the potential increased risk of myocardial infarction and the need to limit the use of AVANDIA to eligible patients. Prescribers will need to discuss with patients the risks and benefits of taking AVANDIA. To enroll, call 1-800-AVANDIA or visit www.AVANDIA.com.
In June, the FDA issued a safety update stating that a review of information in ongoing studies had found that using pioglitazone for more than one year may be associated with an increased risk of bladder cancer.
The FDA update also stated that France had suspended the use of pioglitazone and that Germany had recommended against starting pioglitazone in new patients.
In August, the FDA approved updated information on the pioglitazone-containing medicines' drug labels to warn that using pioglitazone for more than one year may be associated with an increased risk of bladder cancer.
In a Nov. 21 letter, the FDA rejected an Oct. 30, 2008, Public Citizen petition in which we asked the FDA to ban rosiglitazone because its benefits were greatly outweighed by its multiple risks, including increased heart attacks, heart failure, fractures, vision-threatening macular edema and other serious problems.
The FDA’s decision not to ban the drug but to limit prescriptions for rosiglitazone — so that patients will have theoretically tried other treatments first — was a dangerous and reckless refutation of the precautionary principle that is supposed to guide decisions involving public health. The evidence shows the drug has no unique clinical benefits but has unique risks. Unless the FDA can provide evidence that Americans are more resistant to the life-threatening adverse effects of rosiglitazone than are people in Europe and the other countries that have banned the drug, this decision cannot be described as science-based or rational.
2013: The FDA announced that it is requiring changes to the current restrictions on rosiglitazone products due to the risk of heart attacks. This action involves the removal of most of the prescribing and dispensing restrictions for rosiglitazone medicines that were put in place in 2010.
At an FDA hearing in June, the agency signaled a willingness to relax most of the restrictions it had previously placed on rosiglitazone. The drug was banned in Europe in 2010 due to its serious cardiovascular risks. But that same year, using the same safety studies that prompted the European ban, the FDA decided to leave rosiglitazone on the market, restricting its use through a program designed to make the drug available to those who might benefit from it, even though there was no evidence that such a group exists.
Three years later, no evidence indicates that the drug’s benefits outweigh its risks for any group of patients, and the European ban remains in place. At the 2013 hearing, the FDA and drug company GlaxoSmithKline helped persuade a majority of the advisory committee to vote in favor of relaxing the previous restrictions. This move to loosen restrictions comes despite a lack of any new evidence lessening safety concerns.
2016: In December, the FDA announced that it had concluded that use of pioglitazone may be linked to an increased risk of bladder cancer. The agency required that the drug label for pioglitazone be revised to include information from the results of new studies about this risk.