Context: Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin.
Objective: Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin.
Design: Prospective, single-arm, open-label studies with continuous enrollment since 2000.
Setting: National Institutes of Health, Bethesda, Maryland.
Patients: Fifty-three patients aged 6 months to <18 years with lipodystrophy, leptin level <8 ng/mL (male patients) or <12 ng/mL (female patients), and ≥1 metabolic abnormality (diabetes, insulin resistance, or hypertriglyceridemia).
Intervention: Subcutaneous metreleptin injections (0.04 to 0.19 mg/kg/d).
Main Outcome Measures: Change in A1c, lipid, and transaminase levels after a mean ± standard deviation (SD) of 12 ± 0.2 months and 61 ± 39 months. Changes in liver histology, growth, and pubertal development throughout treatment.
Results: After 12 months, the A1c level (mean ± SD) decreased from 8.3% ± 2.4% to 6.5% ± 1.8%, and median triglyceride level decreased from 374 mg/dL [geometric mean (25th,75th percentile), 190, 1065] to 189 mg/dL (112, 334; P < 0.0001), despite decreased glucose- and lipid-lowering medications. The median [geometric mean (25th,75th percentile)] alanine aminotransferase level decreased from 73 U/L (45, 126) to 41 U/L (25, 59; P = 0.001), and that of aspartate aminotransferase decreased from 51 U/L (29, 90) to 26 U/L (18, 42; P = 0.0002). These improvements were maintained over long-term treatment. In 17 patients who underwent paired biopsies, the NAFLD activity score (mean ± SD) decreased from 4.5 ± 2.0 to 3.4 ± 2.0 after 3.3 ± 3.2 years of metreleptin therapy (P = 0.03). There were no clinically significant changes in growth or puberty.
Conclusion: Metreleptin lowered A1c and triglyceride levels, and improved biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443330 | PMC |
| http://dx.doi.org/10.1210/jc.2016-3628 | DOI Listing |
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Article Synopsis
- * A study involved 33 physicians from six countries who shared their experiences with diagnosing and managing lipodystrophy, highlighting themes like diagnostic challenges, impact on patient quality of life, treatment approaches, and barriers to accessing certain therapies.
- * The findings revealed that lipodystrophy cases are often misdiagnosed or overlooked, delaying treatment; physicians recommended early referrals to specialist teams, acknowledging the significant effects on patients' mental health and self-image.
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Inserm U938, Centre de recherche Saint-Antoine, Institut de cardiométabolisme et nutrition (ICAN), Sorbonne université, Paris, France; Service d'endocrinologie, hôpital Saint-Antoine, Centre de référence des maladies rares de l'insulino-sécrétion et de l'insulino-sensibilité (PRISIS), Assistance publique-Hôpitaux de Paris (AP-HP), Paris, France.
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- - Lipodystrophic syndromes are rare diseases, either acquired or genetic, that cause a significant lack of fat tissue, leading to severe metabolic issues like insulin resistance and high triglycerides.
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- * Leptin production is significantly reduced in individuals with generalized lipodystrophy, where fat is nearly absent, compared to partial forms where some fat is present but can be unevenly distributed.
- * Leptin replacement therapy, specifically with metreleptin, has shown promise in treating metabolic complications linked to lipodystrophy, and newer treatments involving monoclonal antibodies targeting leptin receptors are currently being explored.
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