Effects of Metreleptin in Pediatric Patients With Lipodystrophy.
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.



Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin.



Prospective, single-arm, open-label studies with continuous enrollment since 2000.



National Institutes of Health, Bethesda, Maryland.



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).



Subcutaneous metreleptin injections (0.04 to 0.19 mg/kg/d).



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.



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.



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.
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.
Rebecca J
RJ
Brown
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.
Cristina Adelia
CA
Meehan
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.
Elaine
E
Cochran
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.
Kristina I
KI
Rother
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
David E
DE
Kleiner
Clinical Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Mary
M
Walter
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.
Phillip
P
Gorden
D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001827:Body Height; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood* / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007223:Infant; D007333:Insulin Resistance; D020738:Leptin / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D008060:Lipodystrophy / Q000097:blood / Q000188:drug therapy*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000473:pathology; D011446:Prospective Studies; D011627:Puberty; D014280:Triglycerides / Q000097:blood
D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D020738:Leptin; D014280:Triglycerides; C517652:hemoglobin A1c protein, human; C415771:metreleptin