Drug Profile

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 United States in March 2000 because of liver toxicity and deaths caused by its use.[1]

Further, clinical trials show that many patients who previously had used non-glitazone antidiabetic therapy did not respond to glitazones as well as they did to non-glitazones. 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.[2]

Adverse effects

Liver damage

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.[3],[4],[5],[6]

Heart problems

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.[7]

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.[8]

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.[9]

The product labels for both of these drugs now include a boxed 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.[10],[11] Second, glitazones can cause fluid accumulation in the legs, ankles and lungs.[12],[13] 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 whether the negative effects of weight gain are outbalanced by the decrease in blood sugar levels.

Vision problems

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, [14] rosiglitazone, and the combination of rosiglitazone and another diabetes drug, metformin (AVANDAMET).[15] 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.[15]

Anemia

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.[10] Glitazone-induced anemia is thought to be caused by fat cells accumulating in the bone marrow, thus limiting blood cell production.[16]

Hives

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).[17]

Bone fractures

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 in the foot and ankle.[18],[19]

A large randomized controlled clinical trial published in 2016 that compared pioglitazone with a placebo in nondiabetic patients who had suffered a stroke found that pioglitazone increased the risk of fractures in both men and women. [20]

Studies show...

Rosiglitazone is not approved for use in children ages 10-17 years 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.[21]

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.[22]

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.[23]

In 2010 Health Canada informed the public that restrictions on the use of rosiglitazone had been enacted based on a review of data indicating that there may be an increased risk of cardiovascular events, such as heart attack and stroke, associated with the use of rosiglitazone.[24]

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.[25]

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.[26] 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.[27]

In 2024 Journal of Diabetes and Its Complications published an article showing that patients with type 2 diabetes mellitus whose diabetes was not controlled with metformin had an increased risk of ischemic heart disease when pioglitazone and insulin were added.[28]

In 2024 Journal of Diabetes and Its Complications published an article showing that patients with type 2 diabetes mellitus whose diabetes was not controlled with metformin had an increased risk of ischemic heart disease when pioglitazone and insulin were added .[28]