The Effect of a Thiazolidinedione Drug, Troglitazone, on Glycemia in Patients with Type 2 Diabetes Mellitus Poorly Controlled with Sulfonylurea and Metformin: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

The Effect of a Thiazolidinedione Drug, Troglitazone, on Glycemia in Patients with Type 2 Diabetes Mellitus Poorly Controlled with Sulfonylurea and Metformin: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Jean-François Yale, MD;
Thomas R. Valiquett, MS;
Mahmoud N. Ghazzi, MD, PhD;
Janet K. Owens-Grillo, PhD;
Randall W. Whitcomb, MD;
Howard L. Foyt, MD, PhD; and
for the Troglitazone Triple-Therapy Study Group*

From McGill University, Montreal, Quebec, Canada; and Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan.

Abstract

Background: The thiazolidinediones are a new class of antidiabetes medication that enhances the actions of insulin in muscle, liver, and adipose tissue. Data have been lacking on their use in combination with both sulfonylurea and metformin among patients for whom insulin is the usual therapeutic alternative for improved glycemic control.

Objective: To determine the effects of troglitazone on hemoglobin A_1c level in patients treated with maximum tolerated doses of sulfonylurea and metformin who have hemoglobin A_1c levels of at least 0.085 (8.5%). This trial was completed before troglitazone was taken off the U.S. market.

Design: Randomized, double-blind, placebo-controlled trial, followed by an open-label extension during which all patients received troglitazone.

Setting: 16 outpatient clinics in Canada.

Patients: 200 patients (mean age, 59 years) with type 2 diabetes mellitus and hemoglobin A_1c levels at least 0.085 (8.5%) (mean hemoglobin A_1c level, 0.097 [9.7%] and mean fasting plasma glucose level, 12.9 mmol/L [233 mg/dL]) while receiving maximum doses of sulfonylurea and metformin.

Measurements: Levels of hemoglobin A_1c, fasting plasma glucose, total insulin, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol.

Results: Troglitazone, 400 mg/d, when added to sulfonylurea and metformin, significantly decreased hemoglobin A_1c level by 0.014 ± 0.002 (95% CI, 0.0167 to 0.0109; P < 0.001) (1.4% ± 0.2% [CI, 1.67% to 1.09%]) and insulin by 19 ± 4 pmol/L (CI, 30 to 10 pmol/L; P < 0.001). At 6 months, 43% of troglitazone-treated patients achieved hemoglobin A_1c levels of 0.08 (8%) or lower compared with 6% of placebo recipients. Efficacy was maintained at 12 months.

Conclusions: The thiazolidinedione troglitazone, at a dosage of 400 mg/d, is effective when used in combination with sulfonylurea and metformin. Thiazolidinediones may therefore offer an effective alternative to insulin for patients treated with sulfonylurea and metformin who do not achieve adequate glycemic control.

*For members of the Troglitazone Triple-Therapy Study Group, see Appendix.

Article and Author Information

Note: Portions of these data were present at the 59th Annual Meeting of the American Diabetes Association, June 1999.
Acknowledgments: The authors thank Miggi Tomovici, Nadia Romano, Daniel Strieter, Sandra Vermeulen, and Barbara Faja for their assistance with summarizing data.
Grant Support: By Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company.
Requests for Single Reprints: Jean-François Yale, MD, McGill University Health Centre, 687 Pine Avenue West, Room H685, Montreal, Quebec H3A 1A1, Canada.
Current Author Addresses: Dr. Yale: McGill University Health Centre, 687 Pine Avenue West, Room H685, Montreal, Quebec H3A 1A1, Canada.
Mr. Valiquett and Drs. Ghazzi, Owens-Grillo, Whitcomb, and Foyt: Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105.
Author Contributions: Conception and design: J.F. Yale, T.R. Valiquett, M.N. Ghazzi, R.W. Whitcomb, H.L. Foyt.
Analysis and interpretation of the data: J.F. Yale, T.R. Valiquett, J.K. Owens-Grillo, R.W. Whitcomb, H.L. Foyt.
Drafting of the article: J.F. Yale, T.R. Valiquett.
Critical revision of the article for important intellectual content: T.R. Valiquett, J.K. Owens-Grillo, R.W. Whitcomb, H.L. Foyt.
Final approval of the article: J.F. Yale, R.W. Whitcomb, H.L. Foyt.
Provision of study materials or patients: J.F. Yale.
Administrative, technical, or logistic support: J.K. Owens-Grillo.
Collection and assembly of data: T.R. Valiquett, J.K. Owens-Grillo.