Efficacy of Metreleptin Treatment in Familial Partial Lipodystrophy Due to PPARG vs LMNA Pathogenic Variants

Abstract

Context: Familial partial lipodystrophy (FPLD) is most commonly caused by pathogenic variants in LMNA and PPARG. Leptin replacement with metreleptin has largely been studied in the LMNA group.

Objective: To understand the efficacy of metreleptin in PPARG vs LMNA pathogenic variants and investigate predictors of metreleptin responsiveness.

Design: Subgroup analysis of a prospective open-label study of metreleptin in lipodystrophy.

Setting: National Institutes of Health, Bethesda, Maryland.

Participants: Patients with LMNA (n = 22) or PPARG pathogenic variants (n = 7), leptin <12 ng/mL, and diabetes, insulin resistance, or high triglycerides.

Intervention: Metreleptin (0.08 to 0.16 mg/kg) for 12 months.

Outcome: Hemoglobin A1c (HbA1c), lipids, and medication use at baseline and after 12 months.

Results: Baseline characteristics were comparable in patients with PPARG and LMNA: HbA1c, 9.2 ± 2.3 vs 7.8 ± 2.1%; median [25th, 75th percentile] triglycerides, 1377 [278, 5577] vs 332 [198, 562] mg/dL; leptin, 6.3 ± 3.8 vs 5.5 ± 2.5 ng/mL (P > 0.05). After 12 months of metreleptin, HbA1c declined to 7.7 ± 2.4 in PPARG and 7.3 ± 1.7% in LMNA; insulin requirement decreased from 3.8 [2.7, 4.3] to 2.1 [1.6, 3.0] U/kg/d in PPARG and from 1.7 [1.3, 4.4] to 1.2 [1.0, 2.3] U/kg/d in LMNA (P < 0.05). Triglycerides decreased to 293 [148, 406] mg/dL in LMNA (P < 0.05), but changes were not significant in PPARG: 680 [296, 783] mg/dL at 12 months (P = 0.2). Both groups were more likely to experience clinically relevant triglyceride (≥30%) or HbA1c (≥1%) reduction with metreleptin if they had baseline triglycerides ≥500 mg/dL or HbA1c >8%.

Conclusion: Metreleptin resulted in similar metabolic improvements in patients with LMNA and PPARG pathogenic variants. Our findings support the efficacy of metreleptin in patients with the two most common genetic causes of FPLD.

Trial registration: ClinicalTrials.gov NCT00005905 NCT00025883 NCT01778556 NCT02262806.

Published by Oxford University Press on behalf of the Endocrine Society 2019.

Figures

Figure 1.

Changes in (A) HbA1c and (B) serum triglyceride levels in patients with familial partial lipodystrophy due to pathogenic variants in PPARG and LMNA at month 0 (M0) prior to metreleptin and month 12 (M12) after metreleptin treatment. The mean reduction in HbA1c value was 1.5% in the PPARG variant group (P = 0.02) and 0.6% in the LMNA variant group (P = 0.01). The median reduction in triglyceride level was 2170 mg/dL in the PPARG variant group (P = 0.2) and 560 mg/dL in the LMNA variant group (P = 0.001).