High-Dose Regimen Fixes Severe Obesity From Mutated Leptin
TOPLINE:
Researchers have successfully treated two unrelated children with characteristics of leptin dysfunction — including intense hyperphagia, impaired satiety, and severe, early onset obesity — only after raising the usual dose of a recombinant leptin analog (metreleptin, Myalept) by 5- to 23-fold.
METHODOLOGY:
Researchers found that each child was homozygous for one of two variant leptin genes that each produced leptin that worked as a competitive antagonist to wild-type leptin, making both children resistant to usual metreleptin doses.
High-dose treatment produced steep rises in circulating leptin (both endogenous and exogenous) that eventually produced a therapeutic response, with normalization of food intake, satiety, and weight loss, and over time both patients achieved near-normal weight.
Both patients developed anti-metreleptin antibodies, but no loss of metreleptin efficacy occurred in either patient at any time, suggesting no development of clinical leptin resistance.
TAKEAWAYS:
Biologically inactive leptin variants can cause hormone dysfunction due to aberrant receptor binding.
The reported observations change the diagnostic strategy for patients with severe, early onset obesity from just leptin assessment in a patient’s circulation to additional determination of leptin’s receptor-binding capacity in affected individuals.
Although patients with biologically inactive leptin variants have a good response to low metreleptin doses that mimic the response in patients with classic leptin deficiency, higher-than-usual doses are necessary to produce a good treatment response in the former individuals.
The authors report in vitro and in vivo evidence for leptin variants that bind to, but do not fully activate, the leptin receptor, and hence, act as competitive antagonists to nonvariant leptin and to metreleptin.
IN PRACTICE:
“Correct diagnosis of classical leptin deficiency or leptin dysfunction with inactive or antagonistic variants is a requisite for the personalized treatment of affected patients,” say the authors in their report.
STUDY DETAILS:
The authors, primarily based at Ulm University Medical Center, Germany, published their findings in the New England Journal of Medicine.
LIMITATIONS:
The authors did not cite any limitations; the study is a report of only two case studies.
DISCLOSURES:
The study received no commercial funding. Most authors reported no relevant financial relationships. One author is an employee of Sidra Medicine.
Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler
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