Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials
Evidence that rosiglitazone does not cause hepatic dysfunction
- 1State University of New York, Brooklyn, New York
- 2SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania
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-γ (PPAR-γ) 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-γ 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.
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- FDA, Food and Drug Administration
- PPAR-γ, peroxisomal proliferator–activated receptor-γ
Address correspondence and reprint requests to Harold E. Lebovitz, MD, SUNY Health Science Center at Brooklyn, Department of Medicine, Division of Endocrinology, 450 Clarkson Ave., Box 50, Brooklyn, NY 11203. E-mail:.
Received for publication 21 November 2000 and accepted in revised form 17 January 2002.
Harold E. Lebovitz is a major stock shareholder of Bayer, Bristol-Myers Squibb, and SmithKline Beecham; is a paid consultant of Amylin (Advisory Board), Bayer (Advisory Board), Bristol-Myers Squibb (Advisory Board), Knoll, Novartis, Novo-Nordisk (Advisory Board), Pfizer, SmithKline Beecham (Advisory Board), and Merck-Lipha; has received grants and research support from Bristol-Myers Squibb, SmithKline Beecham, and Novo-Nordisk; and is on the Speaker’s Bureau of all of these companies. M.K. and M.I.F. are employees and active shareholders of GlaxoSmithKline Pharmaceuticals.
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