REPLY
Troglitazone-Associated Hepatic Failure
Brent A. Neuschwander-Tetri, MD;
William L. Isley, MD; and
Julie C. Oki, PharmD
16 February 1999 | Volume 130 Issue 4 Part 1 | Page 330
IN RESPONSE:
Dr. Misbin's update on troglitazone hepatotoxicity based on reports to the FDA is indeed worrisome. It would appear that some patients can experience an unpredictable yet fatal progression of liver disease well into the course of treatment. Delayed elevation of liver enzyme levels was noted in the initial published review of the clinical trials data (1), yet the analysis of this relatively small and well-controlled initial experience led to the conclusion that the enzyme changes were uniformly reversible (2). If minor elevations in ALT levels (<3 times the upper limit of normal) can be a harbinger of liver failure in some patients, as suggested by the experience reported by Dr. Misbin, then a little more fear and attentiveness are needed on the part of all prescribers than was suggested by the early conclusions (2). The erratic progression of liver disease documented by this case and the observation that continued hepatocellular injury can progress even weeks after discontinuation of troglitazone therapy only re-emphasizes the need to closely follow all patients treated with this drug for the development of any liver enzyme abnormalities well into the course of treatment.
Furthermore, in light of the recent publication of the UK Prospective Diabetes Study showing reduction in microvascular disease and no increase in macrovascular disease with sulfonylurea or insulin therapy (3), one must question the utility of monotherapy with a drug (troglitazone) that induces less improvement in glycemia than these established therapies (4) and seems to have a problematic risk–benefit ratio and a high cost (drug acquisition and liver test monitoring)-benefit ratio. We believe that troglitazone's major clinical utility is in combination with insulin (5) in patients whose diabetes is poorly controlled by other therapies.
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Author and Article Information
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St. Louis University School of Medicine; St. Louis, MO 63110 (Neuschwander-Tetri)
St. Lukes Hospital; Kansas City, MO 64111 (Isley)
University of Missouri-Kansas City School of Medicine; Kansas City, MO 64108 (Oki)
1. Watkins PB, Whitcomb RW. Hepatic dysfunction associated with troglitazone [Letter] N Engl J Med. 1998;338:916-7.
2. Imura H. A novel antidiabetic drug, troglitazone—reason for hope and concern [Editorial] N Engl J Med. 1998;338:908-9.
3. Intensive bloo D-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study Group. Lancet. 1998; 352:837-53.
4. Riddle MC. Learning to use troglitazone [Editorial] Diabetes Care. 1998;21:1389-90.
5. Schwartz S, Raskin P, Fonseca V, Graveline JF. Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. Troglitazone and Exogenous Insulin Study Group N Engl J Med. 1998;338:861-6.
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