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WASHINGTON -- Adolescent patients with lipodystrophy saw metabolic abnormalities improve during 12 months of treatment with metreleptin, a researcher said here.
Among patients ages 12 to 18, there was a 2.3% decrease in hemoglobin (Hb) A1c and a 44% decrease in triglycerides after 1 year on the investigational recombinant analog of the hormone leptin, according to Rebecca J. Brown, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., and colleagues.
"The lipodystrophy syndromes are a heterogeneous group of disorders characterized by selective loss of adipose tissue, which may be partial or generalized," Brown said at the annual meeting of the Pediatric Endocrine Society.
This loss of adipose tissue leads to a deficiency of adipocyte-derived hormones, particularly leptin, which is a major regulator of appetite and energy regulation. In turn, leptin deficiency results in hyperphagia and excess calories being stored in ectopic locations rather than in adipose tissue.
"The consequences are analogous to those seen in extreme obesity, including severe insulin resistance and diabetes, hypertriglyceridemia, and steatohepatitis that can cause fibrosis and cirrhosis even in very young children," Brown explained.
Since 2000, 39 patients younger than 18 have been receiving metreleptin for lipodystrophy at the National Institutes of Health.
Inclusion criteria for the study, in addition to lipodystrophy, were low leptin levels, age older than 6 months, and metabolic abnormalities such as diabetes, insulin resistance, and hypertriglyceridemia.
Two-thirds of the patients had congenital generalized lipodystrophy, about one-quarter had acquired generalized lipodystrophy, and small subsets had familial or acquired partial lipodystrophy.
The doses of metreleptin used were based on weight and adjusted for metabolic response, with the average daily dose being 0.09 mg/kg given by subcutaneous injection.
Mean exposure to the drug was 46 months, while the maximum was 11 years.
For this analysis, patients were divided according to age, with 17 being age 12 and under at enrollment, and 22 being ages 12 to 18.
Mean age in the younger and older groups were 7.6 and 15.2 years, respectively.
More of the patients were female, reflecting the observation that girls seem to be more metabolically affected than boys with the condition, Brown noted.
Fasting leptin levels were "extremely low" in both groups, being 1 ng/mL in the younger group and 2.1 ng/mL in the older group.
In the children younger than 12 group, the mean HbA1c was just under the upper limit of the normal range, but among the older group the mean HbA1c was almost 10% at baseline, according to the researcher.
A similar pattern was seen for triglycerides, with children under 12 having a median level around 250 mg/dL.
In contrast, the adolescents had triglyceride levels above 1,000 mg/dL, with some having extremely high levels up to almost 8,000 mg/dL.
Liver enzymes were mildly elevated in both age groups, with a mean alanine aminotransferase (ALT) level of 100 to 200 U/L and levels just under 100 U/L for aspartate aminotransferase (AST).
"This was used as a marker of steatohepatitis," Brown noted.
The analysis of metabolic responses to metreleptin included participants who completed at least 12 months of therapy.
Unlike in the adolescents, changes in HbA1c and triglycerides in the younger group were small and nonsignificant. In this group, frank diabetes and severe hypertriglyceridemia had been unusual at baseline, she pointed out.
In general, improvements started within the first 4 months of treatment, and continued throughout.
Adverse events included clinically significant weight loss in three patients, hypoglycemia in three patients who were also being given insulin, and nausea and fatigue in two patients each.
Serious adverse events judged by the investigators to be unrelated to treatment included worsening of kidney disease, exacerbation of autoimmune hepatitis, and T-cell lymphoma, each occurring in one patient. In addition, one patient died from pancreatitis. All these serious events were considered to have resulted from the underlying disease, according to Brown.
While the changes in ALT and AST were not statistically significant, possibly because of inadequate statistical power, they suggest improvements in steatohepatitis. However, these markers are insensitive for measuring steatohepatic disease activity, so the researchers also obtained biopsies in many patients that showed improvements in pathologic scores with treatment.
Metreleptin is currently under review by the FDA for use in these lipodystrophy syndromes.
Brown reported no disclosures, but some co-authors were employees of Bristol-Myers Squibb.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Pediatric Endocrine SocietySource Reference: Brown R, et al "Clinical effects of metreleptin treatment in pediatric patients with lipodystrophy" PES 2013; Abstract 3490.3.