SUN-645 Leptin- And Incretin-based Combination Therapy In Lipodystrophy: A Promising Metabolic Strategy?

Abstract Disclosure: M. Celik Guler: None. R. Meral: None. M. Lightbourne: None. O. Besci: None. A. Neidert: None. M.C. Foss de Freitas: None. R.J. Brown: Pfizer, Inc., Regeneron Pharmaceuticals, Chiesi Farmaceutici, Marea Therapeutics. E.A. Oral: Ionis Pharmaceuticals Inc., Novo Nordisk, Chiesi Farmaceutici, Rhythm Pharmaceuticals, Marea Therapeutics, Rejuvenate Bio, Fractyl, Morphic Medical, Regeneron Pharmaceuticals. Lipodystrophy syndromes (LD) are rare disorders characterized by partial or generalized loss of adipose tissue and significant metabolic disturbances. Metreleptin (ML) remains the cornerstone of treatment for generalized lipodystrophy (GL); however, its efficacy in partial lipodystrophy (PL) can be limited, highlighting the need for alternative or incremental therapies to achieve optimal metabolic control. We hypothesize that combining leptin-based therapies, such as ML or leptin receptor agonists like mibavademab (investigational product), with incretin-based agents may offer a promising therapeutic strategy to enhance metabolic outcomes in this population. We report 6 patients taking ML or mibavademab for clinical or compassionate use in whom incretin-based therapies were added to enhance metabolic control, with outcomes prospectively followed. P1 (25-year-old, congenital generalized lipodystrophy (CGL) type 1, treated with metreleptin for 2.5 years): following the addition of semaglutide for 8 months, HbA1c reduced from 8.7% to 5.6%, BMI from 24.7 to 21.9 kg/m², and triglycerides (TG) from 2261 to 33 mg/dL. P2 (36-year-old, acquired GL, treated with metreleptin for 18 years): after 9 months of tirzepatide treatment, HbA1c reduced from 9.1% to 6.5%, BMI from 19.5 to 17.6 kg/m², and TG from 1240 to 100 mg/dL. P3 (25-year-old, LMNA related GL (with T10I variant), treated with mibavademab for 4 years): after adding dulaglutide for 5 months, HbA1c reduced from 8.9% to 7.3%, with stable BMI (14.4 kg/m²) and no change in TG (265 to 273 mg/dL). P4 (44-year-old, familial partial lipodystrophy type 2 (FPLD2), treated with metreleptin for 3.5 years): after 17 months of tirzepatide therapy, HbA1c reduced from 6.6% to 5.1%, BMI from 18.2 to 16.2 kg/m², and TG from 298 to 104 mg/dL. P5 (23-year-old, atypical PL, previously treated with mibavademab for 5 years and 10 months): Following initiation of tirzepatide for 4 months, there was no change in HbA1c (10.1% to 10.5%) or BMI (27.1 to 27.3 kg/m²) but a 49% reduction in TG (1764 to 895 mg/dL) was observed. P6 (52-year-old, FPLD2, treated with metreleptin for 10 years): initiation of tirzepatide for 5 months led to reductions in HbA1c (6.8% to 5.7%), BMI (26.0 to 21.8 kg/m²), and TG (279 to 127 mg/dL). There were no unexpected adverse events with combination therapy, but patient P5 had an episode of pancreatitis at month 5 due to running out of her insulin and worsening glucose control. In summary, combined leptin-based and incretin-based therapies may enhance metabolic outcomes in lipodystrophy. Future randomized controlled trials are needed to evaluate the efficacy of incretin-based therapies either with or without leptin pathway treatments to confidently determine the extent of benefit of combination therapy in lipodystrophy. Presentation: Sunday, July 13, 2025