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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 and Author 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.

Figures

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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Grahic Jump Location
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.

Grahic Jump Location
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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