Children, Lipodystrophy and Leptin

Lipodystrophy (LD) could be familial or acquired, partial or generalized. This original NIH study shows that metreleptin, a leptin analog, can nicely improve LD metabolic anomalies; such as high glucose, triglycerides and liver enzymes. These benefits are expected to decrease long-term lipodystrophy complications in young individuals.


Also see:

Other lipodystrophy related posts

Leptin related posts


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Prospective Study

May 2017

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: 53 patients aged 6 months – 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 – 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.


After 12 months, the A1c level decreased from 8.3% to 6.5%, and median triglyceride level decreased from 374 mg/dL to 189 mg/dL, despite decreased glucose- and lipid-lowering medications.

The median ALT level decreased from 73 U/L to 41 U/L, and that of AST decreased from 51 U/L to 26 U/L. These improvements were maintained over long-term treatment.

In 17 patients who underwent paired biopsies, the NAFLD activity score decreased from 4.5 to 3.4 after 3.3 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 ALT/AST biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease.



More from the Publication:

Lipodystrophy syndromes comprise a rare, heterogeneous group of disorders characterized by generalized or partial lack of adipose tissue and deficiency of leptin, an adipocyte-secreted hormone. Lipodystrophy syndromes are inherited or acquired, and are classified into 4 major subtypes: acquired or congenital vs. generalized or partial (2 x 2). An additional subtype is progeroid disorders, which are associated with either generalized or partial lipodystrophy.

Most pediatric patients with congenital generalized lipodystrophy (CGL) present at birth or within the first year of life,

whereas patients with acquired generalized and partial lipodystrophies may not present until early childhood or adolescence, or even in adulthood.

Patients with lipodystrophy have metabolic disturbances, including severe insulin resistance, diabetes, hypertriglyceridemia, and NASH. These often lead to morbidity and increased mortality risk, even with use of conventional lipid-lowering or antihyperglycemic agents. Metreleptin, a recombinant analog of leptin, has been shown to improve metabolic abnormalities in patients with generalized lipodystrophy and in selected patients with partial lipodystrophy, leading to FDA approval in 2014 of metreleptin for generalized lipodystrophy.

In this study, we analyzed effects of 1 year and long-term metreleptin therapy on key metabolic comorbidities, including dysglycemia and dyslipidemia. Because metabolic complications of lipodystrophy often present or worsen during puberty, we compared metreleptin’s efficacy in younger children (<12 years old) vs adolescents (12 -18 years old). In addition, because NASH can lead to cirrhosis and liver failure at young ages in patients with lipodystrophy, we sought to understand whether metreleptin can prevent advancement of liver disease, thus preventing late complications (e.g., portal hypertension, transplant, or death). We assessed this by studying effects of metreleptin on biomarkers of liver disease, including transaminases and pathologic markers of NASH. Finally, because leptin is permissive for puberty, we studied growth and pubertal development.

This is, to our knowledge, the largest report of the efficacy of metreleptin in pediatric patients with lipodystrophy. Metreleptin treatment was effective at improving metabolic abnormalities associated with lipodystrophy and low baseline leptin levels, both in the short term (1 year) and long term (mean, 5 years). Many of these changes have the potential to substantially improve patients’ quality of life:

Mean A1c level at 1 year was <7%, thus reducing risk of microvascular complications in patients facing a lifetime with diabetes. Moreover, half of patients who required insulin before metreleptin therapy discontinued insulin entirely at 1 year, thus dramatically reducing the burdens of diabetes management. These glycemic improvements with minimal changes in C-peptide level are consistent with prior studies demonstrating that metreleptin improves insulin sensitivity. More than one-quarter of patients had severe elevation of triglyceride levels (>1000 mg/dL) at baseline sufficient to place them at risk for pancreatitis, whereas only 4 patients (7.5%) had triglyceride levels >1000 mg/dL after 1 year.

Patients with lipodystrophy typically have NAFLD/NASH before leptin replacement, and those with AGL may have concomitant autoimmune hepatitis. Particularly in patients with BSCL2 mutations, NAFLD can lead to cirrhosis, portal hypertension, and early death or need for transplantation. In the current study, ALT and AST levels decreased with metreleptin, suggesting decreased hepatocellular injury. The improvement in liver enzyme levels mirrors findings from a cohort of adult and pediatric patients from our group.

Metreleptin also improved biopsy-specimen measures of NAFLD, as shown by reductions in the NAS. Statistically significant reductions in ballooning injury were observed, with nonsignificant reductions in steatosis and portal inflammation. Similar to a prior analysis by our group (including adults and children), no change in fibrosis score was seen.

Although histologic improvements observed with metreleptin may have limited generalizability due to differences between the biopsy and nonbiopsy cohorts, our findings support a beneficial effect of metreleptin on NAFLD histology in pediatric patients with more severe baseline liver disease. Further investigation is needed to determine if metreleptin treatment in pediatric patients with lipodystrophy will alter the natural history of NAFLD, reducing the incidence of cirrhosis and its complications.

Given the role of leptin in reproduction and puberty, our data are reassuring in demonstrating that metreleptin treatment may help normalize delayed pubertal progression but does not cause precocious puberty. Most patients had advanced bone age before initiating metreleptin treatment, but bone age progression was normal during treatment, further supporting the idea that metreleptin did not accelerate or trigger puberty. 

We previously demonstrated that patients with CGL are tall, with advanced bone age. The current study showed growth deceleration during metreleptin treatment. This likely represents partial normalization of rapid growth before initiating metreleptin therapy, because mean height remained within the upper part of the normal range. However, growth deceleration could occur for other reasons, including earlier than average puberty leading to earlier growth spurt and, hence, crossing of growth percentiles downward at the typical age of puberty; improvement in insulin resistance leading to less hyperinsulinemia driving excessive growth; or metreleptin-induced weight loss causing growth failure, which did not appear to be the case for most patients.

In conclusion, metreleptin was effective in treating metabolic abnormalities in pediatric patients with lipodystrophy, including diabetes and hypertriglyceridemia, and improved biomarkers of NAFLD. The observed improvements are likely to lead to improved quality of life with reduced burden of disease. Longer follow-up is needed to determine the impact of metreleptin on life expectancy.