Efficacy and Safety of Troglitazone in the Treatment of Lipodystrophy Syndromes

  1. Elif Arioglu, MD;
  2. Jennifer Duncan-Morin, RN;
  3. Nancy Sebring, RD;
  4. Kristina I. Rother, MD;
  5. Nicole Gottlieb, BA;
  6. Jay Lieberman, BS;
  7. David Herion, MD;
  8. David E. Kleiner, MD, PhD;
  9. James Reynolds, MD;
  10. Ahalya Premkumar, MD;
  11. Anne E. Sumner, MD;
  12. Jay Hoofnagle, MD;
  13. Marc L. Reitman, MD, PhD; and
  14. Simeon I. Taylor, MD, PhD
  1. From National Institute of Diabetes and Digestive and Kidney Diseases and Clinical Center, National Institutes of Health, and National Cancer Institute, Bethesda, Maryland.

    Abstract

    Background: Troglitazone promotes adipocyte differentiation in vitro and increases insulin sensitivity in vivo. Therefore, troglitazone may have therapeutic benefit in lipoatrophic diabetes.

    Objective: To determine whether troglitazone ameliorates hyperglycemia and hypertriglyceridemia or increases fat mass in lipoatrophic patients.

    Design: Open-labeled prospective study.

    Setting: United States and Canada.

    Patients: 20 patients with various syndromes associated with lipoatrophy or lipodystrophy.

    Intervention: 6 months of therapy with troglitazone, 200 to 600 mg/d.

    Measurements: Levels of hemoglobin A1c, triglycerides, free fatty acids, and insulin; respiratory quotient; percentage of body fat; liver volume; and regional fat mass.

    Results: In the 13 patients with diabetes who completed 6 months of troglitazone therapy, hemoglobin A1c levels decreased by a mean of 2.8% (95% CI, 1.9% to 3.7%; P < 0.001). In all 19 study patients, fasting triglyceride levels decreased by 2.6 mmol/L (230 mg/dL) (CI, 0.7 to 4.5 mmol/L [62 to 398 mg/dL]; P = 0.019) and free fatty acid levels decreased by 325 µmol/L (CI, 135 to 515 µmol/L; P = 0.035). The respiratory quotient decreased by a mean of 0.12 (CI, 0.08 to 0.16; P < 0.001), suggesting that troglitazone promoted oxidation of fat. Body fat increased by a mean of 2.4 percentage points (CI, 1.3 to 4.5 percentage points; P = 0.044). Magnetic resonance imaging showed an increase in subcutaneous adipose tissue but not in visceral fat. In one patient, the serum alanine aminotransferase level increased eightfold during the 10th months of troglitazone treatment but normalized 3 months after discontinuation of treatment. Liver biopsy revealed an eosinophilic infiltrate, suggesting hypersensitivity reaction as a cause of hepatotoxicity.

    Conclusion: Troglitazone therapy improved metabolic control and increased body fat in patients with lipoatrophic diabetes. The substantial benefits of troglitazone must be balanced against the risk for hepatotoxicity, which can occur relatively late in the treatment course.

    Article and Author Information

    • Acknowledgments: The authors thank Dr. Phillip Gorden for advice, encouragement, and support and Drs. Oksana Gavrilova, Monica Skarulis, Susan Phillips, and Karim Calis for valuable discussion. They also thank Craig Cochran, RN; Joy Jones, RN; Kathy O'Bunse, RN; Kathleen Beville, RN; and Delores Medina, RN, for excellent nursing support and the Fellows of the National Institutes of Health Inter-Institute Endocrine Training Program for their contribution in the care of the patients. The Respiratory Care Department at the Clinical Center performed the indirect calorimetry studies, and Bernice Marcus-Samuels performed the leptin assays. Finally, the authors thank Dr. Harvey Kushner for statistical advice and Ms. Esther Bergman for assistance in the coordination of the research trial.

    • Requests for Single Reprints: Elif Arioglu, MD, National Institutes of Health, Building 10, Room 9S213, Bethesda, MD 20892; e-mail, elif_arioglu@nih.gov.

    • Requests To Purchase Bulk Reprints (minimum, 100 copies): the Reprints Coordinator; phone, 215-351-2657; e-mail, reprints{at}mail.acponline.org.

    • Current Author Addresses: Drs. Arioglu, Rother, Sumner, and Taylor, Ms. Duncan-Morin, Ms. Gottlieb, and Mr. Lieberman: Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9S213, Bethesda, MD 20892.

    • Ms. Sebring: National Institutes of Health, Clinical Center, Room B15234, Bethesda, MD 20892.

    • Dr. Herion: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B16, 10 Center Drive, MSC1800, Bethesda, MD 20892.

    • Dr. Kleiner: Laboratory of Pathology, National Cancer Institute, Building 10, Room 2N212, Bethesda, MD 20892.

    • Dr. Reynolds: National Institutes of Health, Clinical Center, Building 10, Room 1C401, Bethesda, MD 20892.

    • Dr. Premkumar: National Institutes of Health, Clinical Center, Building 10, Room IC660, Bethesda, MD 20892.

    • Dr. Hoofnagle: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 31, Room 9A23, Bethesda, MD 20892.

    • Dr. Reitman: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 8N250, Bethesda, MD 20892.

    • Author Contributions: Conception and design: E. Arioglu, K.I. Rother, J. Reynolds, A. Premkumar, M.L. Reitman, S.I. Taylor.

    • Analysis and interpretation of the data: E. Arioglu, J. Duncan-Morin, N. Sebring, N. Gottlieb, J. Lieberman, D. Herion, D.E. Kleiner, A.E. Sumner, A. Premkumar, J. Hoofnagle, S.I. Taylor.

    • Drafting of the article: E. Arioglu, S.I. Taylor.

    • Critical revision of the article for important intellectual content: E. Arioglu, J. Duncan-Morin, N. Sebring, K.I. Rother, N. Gottlieb, J. Lieberman, D. Herion, D.E. Kleiner, A. Premkumar, A.E. Sumner, J. Hoofnagle, M.L. Reitman, S.I. Taylor.

    • Final approval of the article: E. Arioglu, J. Duncan-Morin, N. Sebring, N. Gottlieb, J. Lieberman, D. Herion, D.E. Kleiner, J. Reynolds, A. Premkumar, A.E. Sumner, J. Hoofnagle, M.L. Reitman, S.I. Taylor.

    • Provision of study materials or patients: E. Arioglu, K.I. Rother, D. Herion, D.E. Kleiner, J. Reynolds, A. Premkumar, S.I. Taylor.

    • Obtaining of funding: S.I. Taylor.

    • Administrative, technical, or logistic support: J. Duncan-Morin, N. Sebring, N. Gottlieb, S.I. Taylor.

    • Collection and assembly of data: E. Arioglu, J. Duncan-Morin, N. Sebring, K.I. Rother, N. Gottlieb, J. Lieberman, D. Herion, J. Reynolds, A. Premkumar.

    Summary for Patients

    • Summaries for Patients:Using Troglitazone To Treat People with Lipoatrophy Syndromes Ann Intern Med August 15, 2000 133:263
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    1. Ann Intern Med August 15, 2000 vol. 133 no. 4 263-274
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