FDA moves on drugs that attack insulin resistance

Rezulin under fire again; Avandia on fast track

While the rosy glow around Warner-Lambert Parke-Davis’s Rezulin (troglitazone) has somewhat dimmed after reports of liver damage and deaths from the use of the drug that targets insulin resistance, a new generation of thiazolidinediones is on the federal Food and Drug Administration’s (FDA) fast track for approval.

The FDA’s advisory committee on Endocrin ologic and Metabolic Drugs will meet March 26 to consider "adverse events" associated with Rezulin according to a spokeswoman for the FDA.

At about the same time, the FDA gave a six-month priority review to SmithKline Beecham’s Avandia (rosiglitazone).

The post-approval review of troglitazone is unusual, says Richard Kahn, PhD, chief scientific and medical officer of the American Diabetic Association in Alexandria, VA. But, he says, "It’s premature to think this is the end of Rezulin. I don’t think we have the data or anything that shows an increase in the numbers of deaths. What the FDA has, no one else knows."

Rosiglitazone may have been put on the fast track, Kahn says, because "at the very least, it’s being considered as a substitute when there are two drugs in the same class." So if troglitazone is pulled, rosiglitazone may be available as a substitute.

Reports of deaths from liver failure began to emerge shortly after Rezulin was approved in March 1997.

In July 1998, 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 FDA responded by issuing a "Dear Health Care Professional" letter recommending vigilance and monitoring liver functions of patients on Rezulin. Warner-Lambert Parke-Davis also issued new labeling.

In response to the Public Citizen’s petition, the manufacturer issued a statement and presented data supporting the benefits of Rezulin. The company said the report "offers statistics that verify an overall decline in the rate of severe liver events possibly associated with the therapy that is related to labeling revisions and increased patient monitoring."

In a letter to the Annals of Internal Medicine on Feb. 16, two physicians and a pharmacist said the reports on troglitazone are "worrisome."

Risk too high?

One of the writers, William L. Isley, MD, is an endocrinologist, and an associate professor of medicine at the University of Missouri in Kansas City, and director of the dyslipidemia clinic at the Lipid and Diabetes Research Center at St. Luke’s Hospital also in Kansas City.

"The risk/benefit ratio is too high," he says, for troglitazone and, while he has had "miraculous" responses in lowering glucose in some patients who did not respond to other therapies, he says those gains may be temporary.

"Many of them gained 20 to 30 pounds, their low-density lipoprotein (LDL) cholesterols went up in the space of a year to 18 months," Isley says. "After that, I found myself scratching my head and wondering if I did anything for this patient."

He says he "won’t be disappointed if Rezulin is taken off the market," and adds he thinks the indications for troglitazone should be "reduced to patients poorly controlled on insulin" and the monotherapy indications for Rezulin should be eliminated.

The March 26 FDA advisory committee meeting was open to the public. Kahn says the ADA will make a statement, but the content of that statement had not yet been determined at press time.

Rezulin is currently being used by about 1 million Type 2 diabetics, with sales for Warner-Lambert approaching $1 billion, according to a Dec. 7 article in the Los Angeles Times.

[Richard Kahn can be reached at (703) 549-1500. Contact William Isley at (816) 932-3100.]