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Efficacy and Safety of Troglitazone in the Treatment of Lipodystrophy Syndromes

Elif Arioglu, MD; Jennifer Duncan-Morin, RN; Nancy Sebring, RD; Kristina I. Rother, MD; Nicole Gottlieb, BA; Jay Lieberman, BS; David Herion, MD; David E. Kleiner, MD, PhD; James Reynolds, MD; Ahalya Premkumar, MD; Anne E. Sumner, MD; Jay Hoofnagle, MD; Marc L. Reitman, MD, PhD; and Simeon I. Taylor, MD, PhD
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Copyright ©2004 by the American College of Physicians


Ann Intern Med. 2000;133(4):263-274. doi:10.7326/0003-4819-133-4-200008150-00009
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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.

Figures

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Figure 1.
Decrease in mean hemoglobin A 1c values in 13 diabetic (white bars) and 6 nondiabetic (gray bars) patients after 6 months of therapy with troglitazone.

Error bars represent 95% CIs. Baseline hemoglobin A values were 10.5% ± 2.7% in diabetic patients and 5.9% ± 0.6% in nondiabetic patients (normal range, 4.2% to 6.6%). Baseline data differ slightly from the data presented in the Results section because the figures exclude data from patient A2, in whom troglitazone therapy was discontinued before 6 months of treatment was completed. * < 0.002; † < 0.001.

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Figure 2.
Decreases in mean levels of triglycerides and free fatty acids in 19 patients after 6 months of therapy with troglitazone.

Decrease in mean levels of triglycerides. The mean triglyceride level at baseline was 6.0 ± 5.7 mmol/L (530 ± 504 mg/dL) (normal value, 0.4 to 1.7 mmol/L [35 to 150 mg/dL]). Decrease in mean levels of free fatty acids in the fasting state ( ) and 2 hours after oral administration of glucose, 75 g ( ). Mean levels at baseline were 899 µmol/L ± 338 µmol/L and 566 µmol/L ± 377 µmol/L, respectively (normal range, 350 to 500 µmol/L and <50 µmol/L). Error bars represent 95% CIs. * < 0.05; † < 0.02. To convert triglyceride values to mmol/L, multiply by 0.0113.

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Figure 3.
Decrease in mean respiratory quotient after 6 months of therapy with troglitazone.

At each time point, the percentage contribution of fat oxidation to total-body nonprotein oxygen consumption is indicated. In the calculation of fractional oxidation of carbohydrate and fat, the contribution of fatty acid biosynthesis to the measured value of respiratory quotient was not included. However, because the process of lipogenesis is associated with an estimated respiratory quotient of 1.48 to 9.6 (whereas oxidation of carbohydrate and fat yield respiratory quotients of 1.0 and 0.7, respectively), an increased rate of fatty acid biosynthesis may have contributed to the elevated respiratory quotient. The values on the y-axis begin at 0.7 because this is the lowest observable value for the respiratory quotient. Error bars represent 95% CIs. * < 0.002; † < 0.001.

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Figure 4.
Increase in mean body fat values after 6 months of troglitazone therapy.

Dual-energy x-ray absorptiometry was used to measure body fat. Mean values at baseline were 19.2% ± 12.8% for right-arm fat ( ) and 24.4% ± 10.1% for total-body fat ( ). Error bars represent 95% CIs. * < 0.05; † < 0.02.

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Figure 5.
Liver biopsy specimen showing hepatotoxicity due to troglitazone therapy.

Liver biopsy was performed 4 days after the patient discontinued troglitazone therapy (6 days after the maximum alanine aminotransferase concentration was observed). A 40× magnification of the liver specimen obtained by percutaneous liver biopsy and stained with hematoxylin–eosin. Hepatic architecture is preserved, and no steatosis is present. However, a chronic inflammatory infiltrate containing many eosinophils associated with moderate piecemeal necrosis along the edge of the portal area can be seen. The hepatic parenchyma contains numerous small foci of lobular inflammation and hepatocellular apoptosis. There are no areas of confluent necrosis or fibrosis. A 60× magnification showing the predominance of eosinophils in the infiltrate. Electron microscopy did not reveal abnormalities in mitochondria or peroxisomes (data not shown).

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Summary for Patients

Using Troglitazone To Treat People with Lipoatrophy Syndromes

Copyright ©2004 by the American College of Physicians

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