Current issues of ACP Journal Club are published in Annals of Internal Medicine


Troglitazone improved glycemic control in insulin-treated patients with type 2 diabetes mellitus

ACP J Club. 1998 Sep-Oct;129:40. doi:10.7326/ACPJC-1998-129-2-040

Source Citation

Schwartz S, Raskin P, Fonseca V, Graveline JF, for the Troglitazone and Exogenous Insulin Study Group. Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. N Engl J Med. 1998 Mar 26;338:861-6.



In insulin-treated patients with poorly controlled type 2 diabetes mellitus, does troglitazone improve glycemic control?


Randomized, double-blind, placebo-controlled trial.


22 U.S. centers.


350 patients who had type 2 diabetes for < 20 years (mean age 56 y, 52% women); received ≥ 30 U of insulin/d; and had fasting serum glucose levels > 7.8 mmol/L, glycosylated hemoglobin (HbA1c) values between 8% and 12%, and fasting serum C-peptide levels ≥ 0.3 nmol/L. Follow-up was 90%.


After a 2-week screening period and an 8-week placebo baseline period, patients were allocated to troglitazone, 200 mg once daily (n = 116); troglitazone, 600 mg once daily (n = 116); or placebo (n = 118). Insulin doses were not changed unless the fasting serum glucose level was < 5.0 mmol/L at 1 visit, between 5.0 and 6.1 mmol/L on 2 consecutive visits, or < 5.6 mmol/L on 2 consecutive days during self-monitoring at home.

Main outcome measures

Changes in HbA1c values and levels of fasting serum glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride.

Main results

A dose-related improvement in glycemic control occurred in patients who received troglitazone. HbA1c values decreased by 0.8 and 1.4 percentage points in patients who received 200 mg and 600 mg of troglitazone, respectively, compared with a decrease of 0.1 percentage points in patients who received placebo (P < 0.001). Daily insulin doses decreased by 11% and 29% with 200 mg and 600 mg of troglitazone, respectively, compared with a 1% increase with placebo (P < 0.001). Fasting serum glucose levels decreased by 1.96 mmol/L and 2.74 mmol/L with 200 mg and 600 mg of troglitazone, respectively, and increased by 0.04 mmol/L with placebo (P < 0.001). Slight increases from baseline occurred in patients receiving troglitazone at both doses for total cholesterol levels (increases of 0.18 mmol/L at 200 mg and 0.31 mmol/L at 600 mg, P < 0.05 for both), LDL cholesterol levels (increases of 0.23 mmol/L at 200 mg and 0.36 mmol/L at 600 mg, P < 0.05 for both), and HDL cholesterol levels (increases of 0.05 mmol/L at 200 mg and 0.08 mmol/L at 600 mg, P < 0.001 for 600 mg). A slight decrease was seen in serum triglyceride levels (0.14 and 0.4 mmol/L for the 200-mg and 600-mg groups, respectively). Average weight gain during the study was 1.5, 1.9, and 3.6 kg for placebo, 200-mg, and 600-mg groups, respectively (P < 0.001 for troglitazone vs placebo groups). The groups did not differ in the proportion of patients having > 1 adverse event; 1 patient in the troglitazone 600-mg group discontinued therapy because of hepatic dysfunction.


Troglitazone led to a dose-related improvement in glycemic control when used in conjunction with insulin in patients with poorly controlled type 2 diabetes mellitus.

Sources of funding: Sankyo USA Corporation and Parke-Davis Pharmaceutical Research.

For correspondence: Ms. J.F. Graveline, Sankyo USA, 780 Third Avenue, Suite 4700, New York, NY 10017, USA. FAX 212-308-2513.


Type 2 diabetes mellitus is characterized by defects in insulin secretion, insulin action, and glucose effectiveness. For many years, insulin secretagogues (the sulfonylureas) have been the mainstay of pharmacologic therapy. Recently, drugs that improve insulin action have become available. Among these agents are the thiazolidinedione drugs, which mediate their effects by binding to the peroxisome proliferator-activated γ-nuclear receptor.

The study by Schwartz and colleagues documents the ability of troglitazone, the first marketed thiazolidinedione, to decrease insulin requirements in patients receiving exogenous insulin. However, a reduction in insulin dose is not a major goal of therapy. Rather, the ability of the drug to achieve and maintain optimal glycemic control in patients with poorly controlled disease is what matters. The results of this study show a clinically significant decrease in fasting glucose and HbAlc levels that are maintained over a 26-week period. Other components of the metabolic syndrome, including hypertriglyceridemia and low HDL cholesterol levels, also seem to improve. The dose-related weight gain seen in this study is a concern. The authors do not comment on the degree of compliance with a weight-maintenance diet.

The indications for troglitazone have expanded to include monotherapy and concomitant use with a sulfonylurea. Troglitazone clearly adds to the metabolic effects of the biguanide metformin (1). The drug is currently being evaluated in some diabetes prevention trials. However, the enthusiasm for troglitazone needs to be tempered by recent reports that it has caused liver failure and death on rare occasions (2, 3). Therefore, prescribers must adhere to the recommendations of the Food and Drug Administration and the manufacturer about performing liver function tests. It is hoped that such testing will ensure a favorable risk-benefit ratio for this potentially important new agent.

Sean F. Dinneen, MD
Mayo Clinic and FoundationRochester, Minnesota, USA

Sean F. Dinneen, MD
Mayo Clinic and Foundation
Rochester, Minnesota, USA


1. Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med. 1998;338:867-72.

2. Neuschwander-Tetri B, Isley WL, Oki JC, et al. Roglitazone-induced hepatic failure leading to liver transplantation. A case report. Ann Intern Med. 1998;129:38-41.

3. Vella A, de Groen P, Dinneen SF. Fatal hepatotoxicity associated with troglitazone. Ann Intern Med. 1998;129:1080.