Rationale for leptin-replacement therapy for severe lipodystrophy.

Objective: To review evidence supporting the hypothesis that metabolic manifestations of lipodystrophy result from leptin deficiency and that leptin replacement may be a viable treatment for generalized lipodystrophy.

Methods: This review results from the authors' collective clinical experience and a comprehensive MEDLINE search of the English-language literature (1998 to 2009) on "leptin and lipodystrophy."

Results: Severe lipodystrophy syndromes are characterized by loss of subcutaneous adipose tissue and thus a relative deficiency of the adipocyte-secreted hormone leptin. Several small, nonrandomized, open-label trials in a composite total of more than 100 patients with severe lipodystrophy not related to human immunodeficiency virus infection have evaluated the efficacy and safety of recombinant human methionyl leptin (metreleptin) therapy. Variables observed to improve after treatment with metreleptin include glycemic control, insulin sensitivity, plasma triglycerides, caloric intake, liver volume and lipid content, intramyocellular lipid content, and neuroendocrine and immunologic end points. In these studies, metreleptin treatment was well tolerated. Typical daily replacement doses for metreleptin were 0.06 to 0.08 mg/kg for female patients and 0.04 mg/kg for male patients, administered by subcutaneous injection twice daily. Although metreleptin is not yet approved for routine clinical use, it is available by means of expanded access provisions for patients with severe lipodystrophy and associated metabolic abnormalities.

Conclusion: Evidence published in the medical literature indicates that treating severe lipodystrophy as a leptin deficiency syndrome can improve the metabolic outcomes in affected patients.