Effects of Metreleptin in Pediatric Patients With Lipodystrophy

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.

Copyright © 2017 by the Endocrine Society

Figures

Figure 1.

Mean ± standard error of the mean for (a) glucose, (b) hemoglobin A1c, and (c) C-peptide levels at baseline (black bars) and after 1 year (white bars) and ∼5 years (gray bars) of metreleptin treatment. Normal ranges are indicated by dashed lines (glucose, 70–100 mg/dL; hemoglobin A1c, 4%–5.7%; C-peptide, 0.5–3 mg/dL). *Statistically significant changes relative to baseline.

Figure 2.

Mean ± standard error of the mean of lipid levels (geometric mean and 95% confidence intervals for triglyceride levels) at baseline (black bars) and after 1 year (white bars) and ~5 years (gray bars) of metreleptin treatment. (a) Triglyceride, (b) total cholesterol, (c) HDL, and (d) LDL levels. Upper limits for low cardiovascular risk in children for levels of triglycerides (150 mg/dL), total cholesterol (170 mg/dL), and LDL (110 mg/dL), and the lower limit for low cardiovascular risk for HDL level (35 mg/dL) are indicated by dashed lines. *, statistically significant changes relative to baseline.

Figure 3.

Representative liver histology micrographs from an 11-year-old patient with CGL due to AGPAT2 mutation. The micrographs were taken before and after 1 year of metreleptin treatment, respectively. (a) Micrograph of pretreatment biopsy specimen showing steatohepatitis with ballooning (arrows) and moderate steatosis. (b) Micrograph of posttreatment biopsy specimen with reduction in steatosis and no ballooning. Scale bar = 50 μm.

Figure 4.

NASs before and after a mean of 3.3 ± 3.2 years of metreleptin treatment in 17 patients who underwent liver biopsies. The NAS is a combination of scoring for steatosis, inflammation, and ballooning, and ranges from 0 to 8. Mean NAS ± SD (gray bars) decreased from 4.5 ± 2.0 before to 3.4 ± 2.0 after metreleptin therapy (P = 0.03).