Metreleptin for metabolic disorders associated with generalized or partial lipodystrophy

Abstract

Lipodystrophy is a group of acquired and inherited disorders characterized by selective loss of adipose tissue. Despite wide genotypic and phenotypic variety, many patients with lipodystrophy have similar metabolic complications including insulin resistance, diabetes mellitus, hypertriglyceridemia and hepatic steatosis. Often, these metabolic abnormalities are severe and difficult to treat with conventional glucose and lipid-lowering therapies. Lack of adipose tissue also results in marked hypoleptinemia, and there has recently been much interest in using leptin-replacement therapy to treat the metabolic complications of lipodystrophy. Administration of metreleptin, the human recombinant leptin analogue, has been shown in prospective, open-label studies to improve glucose control, dyslipidemia and steatohepatitis. This article summarizes the current evidence for the safety and efficacy of leptin-replacement therapy in patients with lipodystrophy.

Keywords::

• diabetes mellitus
• hypertriglyceridemia
• insulin resistance
• leptin therapy
• lipodystrophy
• metreleptin
• steatohepatitis

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Erratum

Disclaimer

This article has been amended to reflect the recent FDA approval of metreleptin.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Lipodystrophies are a group of heterogeneous acquired and inherited disorders characterized by selective loss of adipose tissue.

• Patients with lipodystrophy have common metabolic abnormalities related to insulin resistance such as diabetes mellitus, hypertriglyceridemia and steatohepatitis, which are sometimes difficult to treat with conventional glucose and lipid-lowering therapies.

• Metreleptin, a human recombinant leptin analog, has been shown in open-label trials to cause significant reduction in glucose and lipid levels, besides histological improvement in non-alcoholic steatohepatitis, in patients with lipodystrophy and hypoleptinemia.

• Patients with generalized lipodystrophy and those with severe metabolic abnormalities show more robust response to leptin replacement therapy.

• There is concern about development of leptin antibodies in those treated with metreleptin, which can potentially limit long-term efficacy. Development of hematological malignancies such as T-cell lymphoma has been noted in three patients on metreleptin therapy.

• The benefit of leptin therapy in patients with HIV-associated lipodystrophy is not clearly established.

• Metreleptin therapy was approved for clinical use by the US FDA in February 2014.