Effects of Metreleptin in Pediatric Patients With Lipodystrophy

J Clin Endocrinol Metab. 2017 May 1;102(5):1511-1519. doi: 10.1210/jc.2016-3628.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00005905 NCT00025883 NCT01778556 NCT02262832 NCT02262806.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Alanine Transaminase / blood
  • Aspartate Aminotransferases / blood
  • Blood Glucose / metabolism
  • Body Height
  • Child
  • Child, Preschool
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism*
  • Female
  • Glycated Hemoglobin / metabolism
  • Humans
  • Hyperlipidemias / blood*
  • Hyperlipidemias / drug therapy
  • Hypoglycemic Agents / therapeutic use
  • Hypolipidemic Agents / therapeutic use
  • Infant
  • Insulin Resistance*
  • Leptin / analogs & derivatives*
  • Leptin / blood
  • Leptin / therapeutic use
  • Lipodystrophy / blood
  • Lipodystrophy / drug therapy*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Non-alcoholic Fatty Liver Disease / blood*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Prospective Studies
  • Puberty
  • Triglycerides / blood

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Hypolipidemic Agents
  • Leptin
  • Triglycerides
  • hemoglobin A1c protein, human
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • metreleptin

Associated data

  • ClinicalTrials.gov/NCT00005905
  • ClinicalTrials.gov/NCT00025883
  • ClinicalTrials.gov/NCT01778556
  • ClinicalTrials.gov/NCT02262832
  • ClinicalTrials.gov/NCT02262806