New Findings: AVANDIA Poses Risks of Heart Attacks, Heart Failure

The widely prescribed type-2 diabetes drug AVANDIA (rosiglitazone) has been linked with heart attacks and heart-related death, according to a study published in the May 2007 New England Journal of Medicine (NEJM), a prominent medical journal. 

“These new findings linking AVANDIA to heart attacks strengthen the case that the drug should not be on the market,” said Dr. Sidney Wolfe, director of the Health Research Group at Public Citizen.

ACTOS (pioglitazone), a closely related drug also used to treat type-2 diabetes, was not included in the NEJM study. Although at least one study has suggested ACTOS may be less detrimental to heart health, these findings have since been contradicted.

The NEJM study

The recent NEJM article, co-authored by a physician and a public health expert, analyzed 42 clinical trials of patients who took AVANDIA to treat type-2 diabetes. In these trials, 15,560 patients had been randomly assigned to take AVANDIA, and 12,283 had been assigned to groups in which they were not taking AVANDIA. In some of these 42 studies patients were taking placebos, in others, alternative diabetes drugs. The average age of patients in these trials was 56.

Overall, of those who had been assigned to the AVANDIA group, 86 patients suffered heart attacks, compared to 72 patients taking other drugs or a placebo. In addition, there were 39 deaths from heart-related causes in those taking AVANDIA, compared with 22 in the other drugs/placebo group. The study’s authors concluded that:

Rosiglitazone [AVANDIA] was associated with a significant increase in the risk of myocardial infarction [heart attack] and with an increase in the risk of death from cardiovascular causes that had borderline significance. ... [P]atients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type-2 diabetes.

AVANDIA, manufactured by GlaxoSmithKline, was approved to treat type-2 diabetes in 1999. Last year, according to the pharmacy magazine Drug Topics, more than 11.3 million prescriptions were dispensed in US pharmacies, at an estimated retail cost to consumers of over $1.6 billion. 

Heart attack vs. heart failure

The Food and Drug Administration (FDA) has known for several years that both ACTOS and AVANDIA can cause heart failure. The NEJM’s analysis brings forth the new finding of heart attacks linked to AVANDIA.

Heart failure and heart attacks 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, narrowed arteries that supply blood to the heart muscle, primary disease of the heart muscle itself, infection of the heart valves and/or heart muscle, or a past heart attack. Symptoms can include exercise intolerance 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 can also ensue.

While the percentages of heart attacks and deaths found in the journal analysis are small, millions of people are prescribed AVANDIA each year to control the symptoms of type-2 diabetes. In addition to the risk of heart attack and death, the fact that AVANDIA has not been shown to benefit the health of diabetes patients in a clinically meaningful way should be examined when considering this drug. 

Lab test measurements vs. real results

AVANDIA lowers both blood sugar and a laboratory measurement called HbA1c levels (which is a measure of blood sugar control over time). But there is no evidence that this drug will reduce the serious complications associated with type-2 diabetes such as heart risk, kidney problems and blindness. Instead, as many studies discussed here note, certain heart risks are elevated by using this drug.

The FDA allows the approval of diabetes drugs based on short-term clinical trials using these so-called surrogates (lab test results) as outcomes. Unfortunately for patients, many doctors and other health professionals believe it is common sense that if blood sugar and HbA1c are reduced, a meaningful health benefit will automatically ensue. But, as the AVANDIA case illustrates, assumptions based on common sense can be mistaken in medical matters. Rigorous testing based on the longer-term benefits and toxicities of such drugs should be undertaken.

Even if there was evidence that lowering HbA1c levels could have a meaningful health benefit, AVANDIA and ACTOS are not as effective (and appear to be less safe) than the older sulfonylurea class of drugs such as glyburide (DIABETA, GLYNASE, MICRONASE) in reducing blood sugar and HbA1c, which has been shown in head-to-head comparisons.

Background

Damage to the heart was one of the most consistent findings in animal studies done prior to AVANDIA’s approval in May 1999, and postmarketing reports have strongly reflected a heart risk for patients taking both AVANDIA and ACTOS.
In 2000 Public Citizen petitioned the FDA to add warnings to the professional product labels (or package inserts) of AVANDIA, ACTOS and REZULIN (troglitazone), another drug in the same family that has since been pulled from the market. This petition cited concerns about heart failure, fluid retention, weight gain, anemia and liver toxicity. 

In a May 22, 2007, letter to FDA Commissioner Andrew von Eschenbach, Public Citizen revealed that it had received a 2002 internal memo from the FDA’s Division of Drug Risk Evaluation that analyzed the reported cases of people who were hospitalized because of heart failure resulting from the use of AVANDIA or ACTOS. 

The division’s analysis found 25 cases in which the use of AVANDIA resulted in hospitalization for heart failure, as well as 22 comparable cases for ACTOS. As of last year, those numbers had increased to 415 for AVANDIA and 388 for ACTOS. This is certainly not the total number of cases of heart failure related to the drug because physicians are not required to report such reactions to the government: the FDA conservatively estimates that for every report of an adverse drug reaction, 10 go unreported.

In the memo, FDA staff made a specific recommendation to include postmarketing reports of heart failure resulting in hospitalization in the drug’s label. The FDA updated the warnings to include information about heart failure, but failed to include the specific numbers of these serious episodes of heart failure. When patients stopped taking the drugs, the heart failure improved in many of them, the memo said.

By omitting this information, the FDA denied the public important information that could have an impact on type-2 diabetics’ treatment decisions. The incident underscores the widespread concern that the FDA favors drug company interests over patients’ interests. 

Because of the risks of side effects and the drugs’ marginal effectiveness at controlling type-2 diabetes, Public Citizen has listed both AVANDIA and ACTOS as “Do Not Use” drugs since 2004.

What You Can Do

If you are now taking either AVANDIA or ACTOS, you should discuss other possible options to treat type-2 diabetes with your health care professional.