SUN-666 - Effectiveness and Safety of Metreleptin Therapy in Patients with Partial Lipodystrophy: A Systematic Review

Background:
Partial lipodystrophy (PL) is a rare, heterogeneous disorder characterized by selective loss of adipose tissue and a wide spectrum of metabolic complications. Overall, responses to metreleptin in patients with PL are moderate with greater improvements reported in some patient subgroups. To better characterize the effectiveness and safety of metreleptin in PL, we conducted a systematic review of the available literature.

Methods:
Literature searches were conducted in Medline and Embase (from database inception to February 2026). Only original published data from clinical and real-world studies (including case series/reports, congress abstracts) describing metreleptin use in PL were eligible for inclusion. Baseline and post-treatment data were extracted from the final analysis set (FAS) followed by manual inspection for quality control purposes. Due to the lack of standardization across the studies in the FAS, results are presented descriptively, focusing on directional trends, clinically relevant thresholds, and subgroup response patterns rather than pooled effect estimates.

Results:
Our initial search identified 825 publications of which 65 comprised the FAS after exclusion of duplicate records and publications describing non-original data. In general, metreleptin was associated with improvements in glycemic control and triglyceride (TG) levels. Although responses to metreleptin were heterogeneous, mean or median reductions from baseline up to 12 months generally ranged between –0.4% and –1.0% for HbA1c and between –15% and –60% for TG. Clinical improvements were more prominent in some PL subgroups with more severe baseline metabolic disease. A trend between lower leptin levels and more pronounced responses to metreleptin was also reported; however, this observation was not confirmed across all studies, and no reliable leptin level cut‑off to predict treatment response was identified. Broader clinical effects of metreleptin in PL were seen in a subset of studies, including improvements in liver histopathology, hyperphagia, episodes of pancreatitis, physical appearance, and quality of life parameters. Metreleptin was well tolerated across all PL populations examined with no new safety signals detected; lymphoma cases were not documented in any patients in the FAS. The development of neutralizing antibodies to metreleptin, resulting in loss of efficacy, was reported in one patient.

Conclusions:
To our knowledge, this is the first comprehensive review evaluating the effectiveness and safety of metreleptin in PL. Evidence suggests that metreleptin is associated with modest but clinically meaningful metabolic improvements with more marked improvements in patients with severe baseline disease. Safety signals were consistent with the established profile of metreleptin.

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