Actos

SAN ANTONIO -- Neither Avandia nor Actos, the two insulin-sensitizing diabetes drugs on the U.S. market, appear to share the liver toxicity problems of Rezulin, based on the results of two industry-sponsored studies presented at the annual scientific session of the American Diabetes Association.

Since Rezulin (troglitazone) was pulled from the U.S. market in March 2000 because of excess hepatotoxicity, there has been lingering concern that the problem could be a class effect common to all thiazolidinedione (TZD) agents or to other drugs that target the peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]).

The issue is complicated by the fact that a small proportion of diabetics would be expected to develop some sort of liver disorder no matter what treatment they were on, said Dr. Harold E. Lebovitz, director of the diabetes diagnostic and treatment center at the State University of New York, Brooklyn.

In a recent study done in the United Kingdom, 1.5% of 40,190 type 2 diabetics who were taking non-TZD oral antidiabetic agents experienced elevated liver enzymes. Of those, 41% had preexisting liver abnormalities, 31% had only transient elevations, 19% had a specific nondrug cause (such as hepatitis), and only 10% of patients had a possible drug-induced elevation. "Postmarketing surveillance of any drug will find about a 5 per 1,000 rate of liver disease," said Dr. Lebovitz, who is a consultant for SmithKline Beecham Pharmaceuticals, Philadelphia.

As of November 1999, the rate of ALT levels that were three or more times the upper limit of normal has been 2.9 per 1,000 patient-years for rosiglitazone (Avandia), compared with 5.9 per 1,000 for placebo and 7.3 per 1,000 with suifonylureas or metformin. The difference is not statistically significant. Troglitazone's equivalent rate of liver enzyme elevation was three times greater.

Moreover, the Food and Drug Administration found that the rates of liver failure with troglitazone rose the longer it was on the market, from 16 cases by the end of the third quarter to 40 cases by the fifth. In contrast, there have only been two cases of liver failure among the more than one million people who have taken rosiglitazone, and the rate isn't increasing with time. Both of those patients were found to have other conditions predisposing them to liver failure, he noted.

"I think we can conclude that the hepatotoxicity with troglitazone is unique and is not a class effect of the TZDs or PPAR-[gamma]. These data should give us more confidence as we move ahead with the two drugs on the market and new drug development," Dr. Lebovitz remarked at the session.

The data for Actos (pioglitazone), presented in a poster by Dr. Cindy J. Rubin and Dr. Roberta L. Schneider of Takeda America Research and Development Center Inc., Princeton, N.J., were similarly reassuring.

During placebo-controlled U.S. trials, ALT levels of three or more times the upper limit of normal occurred in 4 of 1,526 patients on the drug and in 2 of 793 placebo-treated patients, a nearly identical result. Among all 2,561 patients in controlled and open-label U.S. trials of pioglitazone, 0.43% have experienced that degree of liver enzyme elevation. Of those, seven patients had elevated ALT levels prior to starting the drug treatment, two had other predisposing conditions, and one had no clearly associated event.

The elevated ALT levels were reversible in all of the patients for whom follow-up values were obtained, and none of the elevations was considered serious, Dr. Rubin and Dr. Schneider said.

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