Metabolic Effects of Troglitazone Monotherapy in Type 2 Diabetes Mellitus

A Randomized, Double-Blind, Placebo-Controlled Trial

  1. David G. Maggs, MD;
  2. Thomas A. Buchanan, MD;
  3. Charles F. Burant, MD, PhD;
  4. Gary Cline, PhD;
  5. Barry Gumbiner, MD;
  6. Willa A. Hsueh, MD;
  7. Silvio Inzucchi, MD;
  8. David Kelley, MD;
  9. John Nolan, MD;
  10. Jerrold M. Olefsky, MD;
  11. Kenneth S. Polonsky, MD;
  12. David Silver, MEd;
  13. Thomas R. Valiquett, MS; and
  14. Gerald I. Shulman, MD, PhD
  1. 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.

    Abstract

    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.

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    1. Ann Intern Med February 1, 1998 vol. 128 no. 3 176-185
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