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

• Published in: The journal of clinical endocrinology and metabolism 2019-08, Vol.104 (8), p.3068-3076
• Main Authors: Sekizkardes, Hilal, Cochran, Elaine, Malandrino, Noemi, Garg, Abhimanyu, Brown, Rebecca J
• Format: Article
• Language: English
• Subjects: Adult; Alanine Transaminase - blood; Aspartate Aminotransferases - blood; Clinical s; Diabetes mellitus; Female; Genetic aspects; Glycosylated hemoglobin; Hemoglobin; Humans; Insulin; Insulin resistance; Lamin Type A - genetics; Leptin; Leptin - adverse effects; Leptin - analogs & derivatives; Leptin - therapeutic use; Lipids; Lipodystrophy; Lipodystrophy, Familial Partial - drug therapy; Lipodystrophy, Familial Partial - genetics; Peroxisome proliferator-activated receptors; PPAR gamma - genetics; Prospective Studies; Triglycerides
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2018-02787

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 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. Metreleptin treatment of 12 months led to similar improvements in HbA1c, insulin dose, and triglycerides in patients with familial partial lipodystrophy due to PPARG vs LMNA pathogenic variants.