Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials: Evidence That Rosiglitazone Does Not Cause Hepatic Dysfunction

Harold E. Lebovitz, MD, Margaret Kreider, PHD, Martin I. Freed, MD

Disclosures

Diabetes Care. 2002;25(5) 

In This Article

Abstract and Introduction

Objective. Troglitazone treatment has been associated with idiosyncratic hepatic reaction leading to hepatic failure and death in some patients. This raises questions regarding whether all thiazolidinediones or peroxisomal proliferator–activated receptor-gamma (PPAR-gamma) agonists are hepatotoxic and whether data from clinical trials are adequate to detect a signal of potentially serious drug-related hepatotoxicity. The purpose of this study was to assess whether the idiosyncratic liver toxicity reported with troglitazone is molecule-specific or a thiazolidinedione class effect, based on liver enzyme data collected prospectively during phase 2/3 clinical trials with rosiglitazone, a new, potent, and specific member of the thiazolidinedione class.
Research Design and Methods. This is an analysis of liver function in type 2 diabetic patients at baseline and serially in 13 double-blind, 2 open-label active-controlled, and 7 open-label extension studies of rosiglitazone treatment conducted in outpatient centers throughout North America and Europe. The study comprised >6,000 patients aged 30–80 years with type 2 diabetes. Patients underwent baseline liver function studies and were excluded from clinical trials if they had an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase value 2.5 times greater than the upper limit of the reference range. The main outcome measures were liver enzyme levels, which were assessed at screening, at baseline, and every 4 weeks for the first 3 months of treatment and at 6- to 12-week intervals thereafter. Patients with at least one on-therapy ALT value >3 times the upper limit of the reference range were identified, and their case records examined in detail.
Results. At baseline, 5.6% of the patients with type 2 diabetes (mean HbA1c 8.5–9.0%) had serum ALT values between 1.0 and 2.5 times the upper limit of the reference range. On antidiabetic therapy, most of those patients (~83%) had a decrease in ALT values, many into the normal range. The percentages of all patients with an on-therapy ALT value >3 times the upper limit of the reference range during double-blind and open-label treatment were as follows: rosiglitazone-treated 0.32%, placebo-treated 0.17%, and sulfonylurea-, metformin-, or insulin-treated 0.40%. The respective rates of ALT values >3 times the upper limit of the reference range per 100 person-years of exposure were 0.29, 0.59, and 0.64.
Conclusions. No evidence of hepatotoxic effects was observed in studies that involved 5,006 patients taking rosiglitazone as monotherapy or combination therapy for 5,508 person-years. This is in keeping with hepatic data from clinical trials of another member of the class, pioglitazone, and in contrast to the clear evidence of hepatotoxic effects observed during the troglitazone clinical trial program. These findings suggest that the idiosyncratic liver toxicity observed with troglitazone is unlikely to be a thiazolidinedione or a PPAR-gamma agonist class effect. Poorly controlled patients with type 2 diabetes may have moderate elevations of serum ALT that will decrease with improved glycemic control during treatment with rosiglitazone or other antihyperglycemic agents.

In recent years, increasing recognition of the role of insulin resistance in the pathogenesis of type 2 diabetes [1,2,3] has heightened interest in therapeutic strategies that target insulin sensitivity rather than insulin secretion [4,5,6,7]. The discovery of the selective peroxisomal proliferator–activated receptor-gamma (PPAR-gamma) agonist thiazolidinediones and the introduction of the first approved thiazolidinedione, troglitazone, were significant advances in the search for effective insulin-sensitizing agents [6,8–10]. However, postmarketing reports of serious hepatic reactions to troglitazone, including fatal fulminant hepatitis [11,12,13,14,15,16], raised concerns about the safety of troglitazone and other members of this class. In the U.K., troglitazone was voluntarily withdrawn from the market, and in the U.S., the Food and Drug Administration (FDA) requested removal of the drug after prescribing information had been revised several times to include stronger warnings and guidelines for extensive monitoring of hepatic function in patients taking troglitazone [6,17,18].

Rosiglitazone is a new thiazolidinedione that has been shown to be highly effective in reducing insulin resistance and improving glycemic control in both animal models of diabetes and human type 2 diabetes [19,20]. Although rosiglitazone and troglitazone are both members of the thiazolidinedione class, there are a number of biochemical and metabolic features that distinguish them with respect to their potential for hepatotoxicity.

As a PPAR-gamma agonist, rosiglitazone is 100 times more potent than troglitazone [21]; this difference in potency has translated into a clinical dose that is approximately one-hundredth that of troglitazone (4–8 vs. 400–600 mg). Although the two compounds share a common thiazolidinedione core, troglitazone is characterized by an alpha-tocopherol moiety, which may contribute to the formation of quinone metabolites [8,9,22], whereas rosiglitazone has an amino pyridyl side chain and no such metabolite [21]. Troglitazone has been shown to be directly toxic to cultured rat hepatocytes at concentrations as low as 20 µmol/l [23,24], whereas rosiglitazone shows no toxicity at concentrations up to 100 µmol/l (limit of solubility) [23]. Rosiglitazone and troglitazone also differ in their propensity to cause hepatotoxicity in preclinical species; troglitazone shows toxicity in all species tested (mouse, rat, and dog) [25]. In contrast, rosiglitazone has produced elevation of alanine aminotransferase (ALT) only in dogs at concentrations four times greater than those found in humans at recommended doses. Finally, troglitazone undergoes significant enterohepatic circulation and is excreted primarily through the liver [26,27]. Rosiglitazone is renally excreted and does not undergo enterohepatic recirculation [28]. These preclinical data suggested that rosiglitazone may have little or no potential to cause hepatotoxicity during clinical use.

We describe in this communication the results of prospectively monitoring hepatic function in all patients who participated in randomized, controlled trials or in long-term extension studies of rosiglitazone through November 1999.

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