Long-Term Efficacy, Safety of Metreleptin for Generalized Lipodystrophy

Fat cells
Fat cells
Investigators examined the safety and efficacy of metreleptin in patients with congenital or acquired generalized lipodystrophy.

Long-term metreleptin treatment for generalized lipodystrophy is generally well-tolerated and produces significant, sustained improvements in glycemic control, hypertriglyceridemia, and liver volume, according to a study published in Endocrine.

The study examined the efficacy and safety of metreleptin treatment for generalized lipodystrophy in a combined analysis of 2 investigator-sponsored, open-label trials (1 pilot study and 1 long-term extension study), which had similar protocols and the same set of study participants.

The primary end points for the study were the percent change in fasting triglycerides and actual change in glycated hemoglobin (HbA1c) from baseline to month 12.

Additional secondary end points included fasting plasma glucose over time, serum leptin concentration measurements, and changes and/or discontinuations in [generalized lipodystrophy]-related medications. Safety end points for the study included metreleptin duration and dose, and incidence of severe adverse effects (SAE) and treatment-emergent adverse effects (TEAE).

The current study included 66 participants with generalized lipodystrophy, 21 with acquired generalized lipodystrophy and 45 with congenital generalized lipodystrophy. Most were female (77.3%), with a median age of 15, and had been diagnosed with diabetes (74%). By month 12, participants showed significant improvements in hypertriglyceridemia and glycemic control, with substantial reductions in fasting concentrations of triglycerides (14.7 to 4.5 mmol/L; and mean patient level change –32.1%, =.001) and in mean HbA1c (from 8.6 to 6.4%; –2.2%, <.001).

Clinically meaningful reductions were also found in fasting plasma glucose levels (10.2 to 7.0 mmol/L; <.001), especially in female participants (–3.4; <.001, compared with –1.6; =.191 in males), possibly due to higher levels at baseline. Of the participants who were receiving insulin at baseline (n=39), 41% (n=16) successfully discontinued insulin during the study. Eleven of these were within the first year of treatment. Seven of the 32 participants (21.9%) taking oral antidiabetic medications and 8 of 34 (23.5%) taking lipid-lowering medications were able to discontinue those drugs.

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The majority of participants (89.4%) experienced at least 1 TEAE, mostly mild to moderate, and 35% experienced a SAE, but only 48.5% of TEAEs and 4.5% of SAEs were drug-related. The most prevalent TEAEs were weight decrease, decreased appetite, and hypoglycemia.

Study investigators conclude that “this trial showed that HbA1c, fasting [triglycerides], and [fasting plasma glucose] levels decreased, along with liver volume and enzymes, during treatment with metreleptin for [generalized lipodystrophy]. Results from this trial further support the recommendation of metreleptin as first-line treatment (with diet) for patients with [generalized lipodystrophy], including children.”

This study was sponsored by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases.


Brown RJ, Oral EA, Cochran E, et al. Long-term effectiveness and safety of metreleptin in the treatment of patients with generalized lipodystrophyEndocrine. 2018; 60(3):479-489.