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

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.