Warning — proceed with caution: Rezulin can cause liver failure
Chances of complications can be reduced with monitoring
Physicians have been warned to monitor liver functions of Type II diabetics using Rezulin (troglitazone), easing the alarm over liver failure and even death among patients using the anti-insulin-resistance drug.
Richard Kahn, PhD, chief scientific and medical officer of the American Diabetic Association in Alexandria, VA, says new labeling included with the drug since July by its manufacturer, Parke-Davis, a division of Warner-Lambert Co. in Morris Plains, NJ, "minimizes the likelihood of adverse side effects and liver disease" from troglitazone. (See box on manufacturer’s warning label, p. 3.)
"We think the benefits outweigh the risk, if the recommended testing is followed," Kahn says, echoing a statement issued by the U.S. Food and Drug Administration (FDA) in early December. He dismisses a Dec. 7 Los Angeles Times report highly critical of Rezulin, the approval and marketing tactics used for the drug, and the "potential conflict of interest" on the part of Richard C. Eastman, MD, the National Institutes of Health’s top diabetes researcher. Kahn says, "It didn’t raise anything we didn’t know already."
Rezulin is currently being used by approximately 1 million Type II diabetics, with sales for Warner-Lambert approaching $1 billion, according to the Los Angeles Times article.
Troglitazone was hailed as a great new drug of our time when it first came on the market in March 1997. By December of that year, deaths began to be reported among troglitazone users in Great Britain, and Glaxo-Wellcome withdrew its application for European approval of the drug. Shortly thereafter, the U.S. FDA issued a warning about potential liver dysfunction among patients using the drug and recommended liver monitoring five times a year.
In June, the National Institutes of Health (NIH) removed troglitazone from a study of non-diabetics after the death of a patient who needed a liver transplant.
In July, the U.S. consumer advocacy group Public Citizen petitioned the FDA to withdraw troglitazone from the market after 26 deaths from liver failure and three reported liver transplants among troglitazone users. The same month, Parke-Davis issued a "Dear Health Care Professional" letter urging frequent liver monitoring for patients using the drug.
Parke-Davis now says serum transaminase levels should be checked before a patient begins taking Rezulin, and levels should be re-checked "monthly for the first eight months of therapy, every two months for the remainder of the first year, and periodically thereafter."
The manufacturer also states, "Rezulin should be added to, not substituted for," sulfonylureas or insulin or as an adjunct to diet and exercise control.
Parke-Davis: Data show it is safe’
The company’s studies showed a 600 mg daily dosage of Rezulin plus glyburide was most effective in long-term glycemic control.
"Liver disease is not a problem from our perspective. The clinical data show it is safe," says Howard Foyt, MD, PhD, director of clinical research, diabetes, and metabolic disorders at Parke-Davis in Ann Arbor, MI. "We don’t anticipate major future problems with liver dysfunction. We think the labeling took care of it."
In response to the withdrawal of troglitazone from the NIH study, Foyt says Parke-Davis is currently conducting a study of the same questions. "The NIH shut down our arm of the study because they questioned the risk in non-diabetic patients," he says. "To counteract that, we have instituted appropriate monitoring with the approval of the FDA."
Researchers hope that new insulin sensitizers currently under study may also target the underlying cause of diabetes without the risk present in troglitazone. SmithKline Beecham, the Philadelphia-based manufacturer of rosiglitazone, a TZD class drug, submitted the drug for FDA approval in late November. (See definitions, above.)
"It’s an exciting future" for new drugs to treat Type II diabetics, says Jerry P. Palmer, MD, chief of endocrinology, metabolism, and nutrition at the Department of Veterans Affairs, Puget Sound Health Care System in Seattle, and director of diabetic and endocrinology research at the University of Washington, also in Seattle.
He says newer classes of drugs "will change how we treat the disease and identify people at risk earlier." Palmer, who is a diabetic, says he takes Rezulin and metformin. "I feel [Rezulin] is pretty safe. There are concerns, but if you do the safety checks, including liver function studies, I wouldn’t worry too much. The instance of severe liver function problems is one in 60,000. There is no perfectly safe medication. It is a wonderful medication and works well."
Insulin resistance is spreading like wildfire with 2,000 new cases being diagnosed daily, according to Kathy Mulcahy, CDE, RN, president of the American Association of Diabetes Educators and director of the INOVA Diabetes Center in Fairfax, VA.
While Mulcahy confirms the cost of the newer drugs is high, she adds, "The therapy to achieve near-normal blood glucose levels is cost-effective in comparison to the cost of complications at about $20 billion a year."
For further information, contact Howard Foyt, MD, PhD, Director of Clinical Research, Diabetes, and Metabolic Disorders, Parke-Davis, Ann Arbor, MI. Telephone: (734) 622-3618.
How the Drugs Work
Sulfonylureas.
These drugs stimulate the pancreas to produce insulin. Long-term result may be pancreatic fatigue and increased insulin resistance.
Metformin.
Drug decreases sugar levels in the liver without increasing insulin demands.
Troglitazone.
In a class of drugs called thiazolidinediones, or TZDs, this drug turns insulin-resistant cells into insulin-sensitive cells, allowing more efficient use of the body’s naturally produced insulin, sparing the pancreas from overwork.
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