Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials

Abstract

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-␥ (PPAR-␥) 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 Ͼ6,000 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 Ͼ3 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 HbA 1c 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 (ϳ83%) had a decrease in ALT values, many into the normal range. The percentages of all patients with an on-therapy ALT value Ͼ3 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 insulintreated 0.40%. The respective rates of ALT values Ͼ3 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 personyears. 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-␥ agonist class effect. Poorly controlled patients with type 2 diabetes may ...

Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice†

“…However, although treated animals gain more weight than untreated mice, this increase did not correlate with triglyceride levels in liver tissue. Even though data from clinical trials indicate that RGZ does not appear to cause liver injury, 31 some NASH patients treated with RGZ developed abrupt rises in ALT levels likely related to therapy. Moreover, several case reports of liver injury in association with RGZ 32 or pioglitazone use have been published in the last years.…”

Drug Interactions of Medications Commonly Used in Diabetes

“…32,33 Unlike troglitazone, no data link pioglitazone or rosiglitazone to drug-induced hepatotoxicity. 34,35 Nevertheless, it is recommended that drug therapy not be started if the alanine aminotransferase (ALT) is > 2.5 times the upper limit of normal and stopped if the ALT is > 3 times the upper limit of normal (Table 1). Prudent clinical judgment is needed for TZD drug-disease interactions, but a full discussion is beyond the scope of this review.…”

Current Therapeutic Options in Type 2 Diabetes Mellitus: A Practical Approach

“…Despite the removal of troglitazone from the market in 2000 because of liver toxicity, two newer agents, rosiglitazone and pioglitazone (approved in 1999), continue in widespread use without evidence of similar problems. 31 However, the edema and weight gain seen with the TZDs can be limiting in some patients. These agents bind to peroxisome proliferator activator receptor-gamma nuclear receptors affecting gene regulation in target cells.…”