Dangerous, Inappropriate Prescribing Of Diabetes Drugs Metformin (GLUCOPHAGE), Rosiglitazone (AVANDIA), And Pioglitazone (ACTOS) To Patients With Heart Failure

Government-sponsored research published in the July 2, 2003 Journal of the American Medical Association found that the diabetes drugs metformin (GLUCOPHAGE), rosiglitazone (AVANDIA), and pioglitazone (ACTOS) were being prescribed inappropriately to patients with heart failure and that the inappropriate prescribing of these drugs has been increasing over time.

Metformin is a close chemical relative of phenformin, a diabetes drug the Health Research Group helped to remove from the market in the mid 1970s because of an adverse effect known as lactic acidosis. Rosiglitazone and pioglitazone belong to a family of diabetes drugs known as “glitazones.” The first member of the glitazone family, troglitazone (REZULIN), was banned in March 2000 due to liver toxicity. The Health Research Group was also instrumental in getting this dangerous drug off the market (see Worst Pills, Best Pills News May 2000).

The research was done by the National Heart Care Project, an initiative of the Centers for Medicare and Medicaid Services (formerly the Health Care Financing Administration), to improve the quality of care for Medicare recipients hospitalized with heart failure. The study was designed to determine the extent of use of metformin or a glitazone in patients hospitalized with heart failure who also had a diagnosis of diabetes.

The researchers looked at the records for Medicare fee-for-service beneficiaries during two time periods. Ultimately, the records of 12,505 patients hospitalized during 1998 to 1999, and 13,158 patients hospitalized in the period 2000 to 2001, were examined.

The researchers found that in the group hospitalized for heart failure during 1998 to 1999, 7.1 percent were discharged with a prescription for metformin and 7.2 percent with a prescription for a glitazone. In the group of 13,158 patients hospitalized between 2000 and 2001, they found that prescriptions for metformin had increased to 11.2 percent and glitazone use had jumped to 16.1 percent. The differences between the two time periods were statistically significant, and similar increases were found when the data was analyzed to take into account age, race, and sex.

The table below summarizes the results of study.

The FDA professional product labeling, or package inserts, for these drugs are very clear about their dangers when used in patients with heart failure. The professional product labeling for metformin unequivocally states that the drug should not be used in patients with “congestive heart failure requiring pharmacologic treatment.”

The reason for this warning is that the risk of lactic acidosis, an adverse reaction that can be fatal, is increased when metformin is given to patients with heart failure. The signs of lactic acidosis are: feeling very weak, tired, or uncomfortable; unusual muscle pain; trouble breathing; unusual or unexpected stomach discomfort; feeling cold; feeling dizzy or lightheaded; or suddenly developing a slow or irregular heartbeat. If these signs develop, contact the prescribing physician immediately.

The FDA also requires a black box warning in the professional product labeling for metformin. Black box warnings are the strongest type of warning that the FDA can require and are generally reserved for drugs associated with or causing serious adverse drug reactions involving patients, but can be required on the basis of animal data. The black box warning for metformin contains the following language regarding heart failure:

Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion [poor blood flow as a result of congestive heart failure]   and hypoxemia [poor oxygenation of the blood] , are at increased risk of lactic acidosis.

The professional product labeling for rosiglitazone warns that this glitazone may lead to heart failure or make it worse:

Cardiac Failure and Other Cardiac Effects: AVANDIA, like other thiazolidinediones [long name for glitazones], alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate [make worse] or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. In combination with insulin, thiazolidinediones may also increase the risk of other cardiovascular adverse events. AVANDIA should be discontinued if any deterioration in cardiac status occurs.

The rosiglitazone labeling also instructs physicians to tell patients to watch for the symptoms of heart failure and to report these symptoms to the physician should they appear:

Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on AVANDIA should immediately report these symptoms to their physician.

The professional product labeling for pioglitazone carries similar warnings to that of rosiglitazone.

The authors of the study concluded:

... this study demonstrates that elderly, diabetic patients hospitalized with heart failure are commonly treated with antihyperglycemic [blood sugar lowering] drugs that are not recommended for patients with moderate-to-severe heart failure.

The conclusion of the study, from the public perspective, should have been that FDA safety labeling warnings are ignored by too many physicians and pharmacists and too often needlessly place patients at risk of preventable adverse drug reactions. We have written several times about the failure of FDA-required safety labeling changes, including the failure of black box warnings, to change inappropriate prescribing and dispensing (see Worst Pills, Best Pills News October and December 2001).

The results of this study are just one more example of the failure of the “system” to adequately protect the public from needless harm.

What You Can Do

If you or a family member are taking metformin, rosiglitazone, or pioglitazone for diabetes and have heart failure that requires a drug, you should talk to the physician as soon as possible.