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Metabolic Effects of Troglitazone Monotherapy in Type 2 Diabetes Mellitus: A Randomized, Double-Blind, Placebo-Controlled Trial

David G. Maggs, MD; Thomas A. Buchanan, MD; Charles F. Burant, MD, PhD; Gary Cline, PhD; Barry Gumbiner, MD; Willa A. Hsueh, MD; Silvio Inzucchi, MD; David Kelley, MD; John Nolan, MD; Jerrold M. Olefsky, MD; Kenneth S. Polonsky, MD; David Silver, MEd; Thomas R. Valiquett, MS; and Gerald I. Shulman, MD, PhD
[+] Article, Author, and Disclosure Information

For author affiliations and current author addresses, see end of text. Acknowledgments: The authors thank Veronica Walton and Parvccn Vohra for assistance with the stable isotope analyses. Grant Support: By grants from the U.S. Public Health Service; grants RO1-DK 49230 and RO1-DK 33649; GCRC grants MO1-RR00827, MO1-RR00125, and MO1-RR00043; and Warner Lambert Co. Dr. Shulman is an investigator of the Howard Hughes Medical Institute. Requests for Reprints: David G. Maggs, MD, Yale University School of Medicine, Box 208020, New Haven, CT 06520-8020. Current Author Addresses: Drs. Maggs, Cline, Inzucchi, Silver, and Shulman: Yale University School of Medicine, Box 208020, New Haven, CT 06520-8020.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1998;128(3):176-185. doi:10.7326/0003-4819-128-3-199802010-00002
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Background: Troglitazone is a new insulin-sensitizing agent used to treat type 2 diabetes mellitus. The mechanism by which troglitazone exerts its effect on systemic glucose metabolism is unknown.

Objective: To determine the effects of 6 months of troglitazone monotherapy on glucose metabolism in patients with type 2 diabetes mellitus.

Design: Randomized, double-blind, placebo-controlled trial.

Setting: Six general clinical research centers at university hospitals.

Patients: 93 patients (mean age, 52 years) with type 2 diabetes mellitus (mean fasting plasma glucose level, 11.2 mmol/L) who were being treated with diet alone or who had discontinued oral antidiabetic medication therapy.

Intervention: Patients were randomly assigned to one of five treatment groups (100, 200, 400, or 600 mg of troglitazone daily or placebo) and had metabolic assessment before and after 6 months of treatment.

Measurements: Plasma glucose and insulin profiles during a meal tolerance test; basal hepatic glucose production and insulin-stimulated glucose disposal rate during a hyperinsulinemic-euglycemic clamp procedure.

Results: Troglitazone at 400 and 600 mg/d decreased both fasting (P < 0.001) and postprandial (P = 0.016) plasma glucose levels by approximately 20%. All four troglitazone dosages also decreased fasting (P = 0.012) and postprandial (P < 0.001) triglyceride levels; 600 mg of the drug per day decreased fasting free fatty acid levels (P = 0.018). Plasma insulin levels decreased in the 200-, 400-, and 600-mg/d groups (P < 0.001), and C-peptide levels decreased in all five study groups (P < 0.001). Basal hepatic glucose production was suppressed in the 600-mg/d group compared with the placebo group (P = 0.02). Troglitazone at 400 and 600 mg/d increased glucose disposal rate by approximately 45% above pretreatment levels (P = 0.003). Stepwise regression analysis showed that troglitazone therapy was the strongest predictor of a decrease in fasting (P < 0.001) or postprandial (P = 0.01) glucose levels. Fasting C-peptide level was the next strongest predictor (higher C-peptide level equaled greater glucose-lowering effect).

Conclusion: Troglitazone monotherapy decreased fasting and postprandial glucose levels in patients with type 2 diabetes, primarily by augmenting insulin-mediated glucose disposal.


Grahic Jump Location
Figure 1.
Plasma glucose profiles during meal tolerance test before treatment (top) and after treatment (bottom).

To convert glucose values to SI units (mmol/L), multiply by 0.05551.

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Figure 2.
Mean changes in fasting (black ovals) and postprandial (white ovals) plasma levels of glucose (top), free fatty acid (top middle), triglyceride (bottom middle), and C-peptide (bottom).

Changes are given as the level after treatment minus the level before treatment. Vertical bars represent 95% CIs. To convert glucose, triglyceride, and C-peptide values to SI units (mmol/L for glucose and triglyceride; nmol/L for C-peptide), multiply by 0.05551, 0.01129, and 0.331, respectively.

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Grahic Jump Location
Figure 3.
Plot of basal hepatic glucose production against fasting plasma glucose levels in 93 patients with type 2 diabetes mellitus (black squares) and 8 controls without diabetes (white squares).

To convert glucose values to SI units (mmol/L), multiply by 0.05551.

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Grahic Jump Location
Figure 4.
Mean changes in glucose disposal rate measured during the clamp procedure.P

Changes are given as the rate after treatment minus the rate before treatment. Steady-state glucose disposal rates increased in all troglitazone groups compared with placebo ( < 0.005). Vertical bars represent 95% CIs.

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