Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes

Background: Troglitazone promotes adipocyte differentiation in vitro and in creases insulin sensitivity in vivo. Therefore, troglitazone may have thera peutic 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 A(1c), triglycerides, free fatty acids, and insulin; respiratory quotient; percentage of body fat; liver volume; an d regional fat mass. Results: In the 13 patients with diabetes who completed 6 months of troglit azone therapy, hemoglobin A(1c) 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 l evels 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 mu mol/L (CI , 135 to 515 mu mol/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 pr omoted oxidation of fat. Body fat increased by a mean of 2.4 percentage poi nts (CI, 1.3 to 4.5 percentage points; P = 0.044). Magnetic resonance imagi ng showed an increase in subcutaneous adipose tissue but not in visceral fa t. In one patient, the serum alanine aminotransferase level increased eight fold during the 10th months of troglitazone treatment but normalized 3 mont hs after discontinuation of treatment. Liver biopsy revealed an eosinophili c infiltrate, suggesting hypersensitivity reaction as a cause of hepatotoxi city. Conclusion: Troglitazone therapy improved metabolic control and increased b ody fat in patients with lipoatrophic diabetes. The substantial benefits of troglitazone must be balanced against the risk for hepatotoxicity, which c an occur relatively late in the treatment course.