RARE DISEASE
Acquired partial lipodystrophy
Acquired partial lipodystrophy
Acquired partial lipodystrophy
Synonyms: Barraquer-Simons syndrome, Progressive cephalothoracic lipodystrophy
Synonyms: Barraquer-Simons syndrome, Progressive cephalothoracic lipodystrophy
Synonyms: Barraquer-Simons syndrome, Progressive cephalothoracic lipodystrophy
Drug discovery
1
drug
With orphan designation
Overview
Acquired partial lipodystrophy (APL) is a rare adipose tissue disorder characterized by progressive, symmetric fat loss in the face, neck, arms, and upper trunk, often with lower-body sparing or lipohypertrophy. It typically emerges in childhood/adolescence, shows female predominance (4:1 ratio), and associates with C3 hypocomplementemia, C3-nephritic factor, and renal complications like C3 glomerulopathy [1][6][12]. Metabolic disturbances (insulin resistance, dyslipidemia) occur less frequently than in other lipodystrophies [1][4].
Therapies
Metabolic management: Insulin sensitizers (metformin), lipid-lowering agents (statins), and dietary modification [8][17]
Targeted therapies: Anti-complement agents (e.g., eculizumab) for C3 glomerulopathy; experimental adipose transplantation [6][12]
Adjunctive care: Psychological support and cosmetic interventions (fat grafting) [8][16]
Categories: rare endocrine diseases, rare skin diseases
Research Papers
167 drug discovery papers about Acquired partial lipodystrophy, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
167 drug discovery papers about Acquired partial lipodystrophy, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-09 | Case Report: Dramatic metabolic improvement with tirzepatide in a patient with acquired partial lipodystrophy following hematopoietic stem cell transplantation.
Acquired lipodystrophy is a rare disorder characterized by adipose tissue loss or dysfunction and is frequently associated with severe insulin resistance and metabolic complications. Metabolic complications of lipodystrophy have occasionally been reported after hematopoietic stem cell transplantation (HSCT), but their clinical features and optimal treatment strategies remain poorly defined. Tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has recently emerged as a novel therapy for type 2 diabetes. We report a 37-year-old woman who underwent allogeneic HSCT at 12 years of age for relapsed acute lymphoblastic leukemia after a conditioning regimen including total body irradiation (TBI), high-dose cytarabine, and melphalan. She subsequently developed diabetes mellitus and fatty liver disease at 17 years of age. Although no apparent fat loss was initially recognized, lipodystrophy was clinically suspected based on severe insulin resistance and metabolic abnormalities disproportionate to her body habitus. Computed tomography at 37 years of age revealed region-specific fat loss extending from the lower back to the gluteal region. Glycemic control remained inadequate despite high-dose insulin therapy and sequential treatment with several GLP-1 receptor agonists. After initiation of tirzepatide, glycemic control improved dramatically, allowing complete discontinuation of insulin therapy. Body weight decreased modestly and hepatic steatosis improved. The high-molecular-weight (HMW)/total adiponectin ratio after treatment was elevated (64.0%), suggesting possible improvement in adipocyte secretory function. This case highlights acquired partial lipodystrophy developing after HSCT, supported by region-specific fat loss and characteristic metabolic abnormalities, and demonstrates a marked therapeutic response to tirzepatide. Dual incretin receptor agonism may represent a promising therapeutic strategy for severe insulin resistance associated with adipose tissue dysfunction, potentially through both weight-dependent and weight-independent mechanisms.
2026-02-17 | Lipodystrophies in Clinical Practice: A Case Series From a Local Health Unit in Portugal
Background Lipodystrophies are rare disorders characterized by loss of adipose tissue, leading to severe metabolic and multisystem complications. Data on real-world management remain limited, particularly in Portugal. Objectives The objective of this study is to describe the clinical, metabolic, genetic, and therapeutic characteristics of patients with confirmed or suspected lipodystrophy followed at a Portuguese Endocrinology Outpatient Clinic. Methods We conducted a retrospective observational study including 21 patients with clinical suspicion or diagnosis of lipodystrophy. Demographic, clinical, laboratory, imaging, and genetic data were collected. Results The cohort was predominantly female (90.5%) with a median age at diagnosis of 49 years. Sixteen patients (76.2%) had familial partial lipodystrophy (FPLD), two (9.5%) had congenital generalized lipodystrophy, two (9.5%) had acquired generalized lipodystrophy, and one presented a complex syndromic form. Diabetes mellitus was present in 71.4% of patients and hypertriglyceridemia in 52.4%. Metabolic liver disease occurred in both generalized and partial forms. Autoimmune disorders affected 31.6% of patients, and cardiac involvement was observed in 23.8%. Genetic testing identified pathogenic or likely pathogenic variants in BSCL2 and PPARG in three patients, while most FPLD cases remained genetically unexplained. Metreleptin therapy in three patients with generalized lipodystrophy improved glycemic control, triglycerides, liver enzymes, and proteinuria. Dual-energy X-ray absorptiometry imaging supported the phenotypic characterization of adipose tissue loss. Conclusions Detailed physical examination, genetic testing, imaging, and early therapeutic interventions are critical for management. These findings align with European registry data and highlight the need for increased awareness and systematic evaluation in real-world clinical practice.
2026-01-01 | O-30 AUTOSOMAL RECESSIVE LIPE PATHOGENIC VARIANT-ASSOCIATED FAMILIAL PARTIAL LIPODYSTROPHY TYPE 6
Abstract Introduction Lipodystrophy is a rare and heterogeneous disorder characterized by selective loss or abnormal redistribution of adipose tissue, leading to metabolic complications such as insulin resistance, diabetes mellitus, hepatic steatosis, and dyslipidemia. Lipodystrophy is divided into 4 main groups: congenital generalized lipodystrophy (CGL), familial partial lipodystrophy (FPLD), acquired generalized lipodystrophy (AGL), and acquired partial lipodystrophy (APL). FPLD is caused by mutations is genes regulating adipocyte function and lipid metabolism, with six subtypes identified to date. Among these, type 6 (FPLD6) results from inactivating mutation in the LIPE gene, which encodes hormone-sensitive lipase (HSL). Here, we present a very rare case of autosomal recessive familial partial lipodystrophy type 6. Clinical Case A 34-year-old female was referred for evaluation of suspected Cushing’s syndrome. She was receiving hormone replacement therapy for primary ovarian insufficiency and had no other known medical conditions. She had gestational diabetes during her second pregnancy, managed with diet alone. Over three years she gained 29 kg (BMI 35.2 kg/m²). Family history revealed parental consanguinity. Physical examination revealed characteristic cushingoid features including a prominent buffalo hump, supraclavicular fat pads, and centripetal obesity. She had fat accumulation in the upper body while subcutaneous fat was markedly reduced in the extremities and breasts (Figure 1). Acanthosis nigricans was noted in the axillary and cervical regions. Additionally, she had undergone a cosmetic liposuction procedure targeting the deltoid and occipital regions. Low-dose dexamethasone testing excluded Cushing’s syndrome. Oral glucose tolerance test indicated insulin resistance; triglycerides were elevated, while leptin was normal. Laboratory results are summarized in Table 1. Whole-body DXA demonstrated markedly reduced fat mass in the upper and lower extremities, with central fat accumulation. This distribution was compatible with partial lipodystrophy. FibroScan revealed advanced hepatic steatosis (S3) without fibrosis (F0), consistent with nonalcoholic fatty liver disease (NAFLD). Genetic analysis identified a homozygous pathogenic LIPE gene variant (c.2182G>A), confirming the diagnosis of autosomal recessive familial partial lipodystrophy type 6. Treatment with metformin, SGLT-2 inhibitor, and fenofibrate was initiated, alongside lifestyle modification and genetic counseling. Conclusion FPLD6 is a very rare subtype of familial partial lipodystrophy. Unlike other subtypes, it is caused by LIPE mutations leading to defective lipolysis, and typically presents in adulthood rather than early life. It is further characterized by severe insulin resistance, dyslipidemia, and hepatic steatosis. In addition, the presence of subcutaneous lipomas distinguishes FPLD6 from other many forms and may lead to diagnostic confusion with multiple lipomatosis.Figure 1:a.Sagittal magnetic resonance imaging (MRI) of the neck and cervical spine region demonstrating abnormal fat distribution consistent with partial lipodystrophy b.Dual-energy X-ray absorptiometry (DEXA) scan demonstrating body composition c.Posterior view of the trunk showing loss of peripheral fat and abnormal fat deposition in the upper body Table 1:Biochemical parameters of the patientIR: insulin resistance
2025-10-01 | SUN-646 Immune Landscape and Clinical Characteristics of Patients with Acquired Partial and Generalized Lipodystrophy Syndromes
Abstract Disclosure: O. Besci: None. C.D. Uwandu: None. U. Cavdar: None. B. Akinci: None. D. Gilio: None. M.C. Foss de Freitas: None. K. Walkovich: None. E.A. Oral: Regeneron Pharmaceuticals, Rhythm Pharmaceuticals, Novo Nordisk, Amryt Pharmaceuticals, Ionis Pharmaceuticals Inc., Morphic Medical, Rejuvenate Bio, Fractyl Laboratories. Introduction: Acquired lipodystrophy syndromes (ALS) are characterized by loss of adipose tissue and associated metabolic abnormalities, manifesting in either partial (APL) or generalized forms (AGL). Increasing evidence of ALS links to autoimmunity, infections, malignancies, and associated treatments highlights the need for an understanding of the associated immune-mediated mechanisms. Objective: We sought to provide immune-related insights on ALS by correlating coexisting disorders with their underlying immune mechanisms and identifying patterns of phenotypic presentations via comprehensive case review and literature analysis. Methods: We retrospectively reviewed all cases from the University of Michigan (n = 30) and published cases (n = 462). We systematically searched PubMed for ALS studies published in English with full-text availability from 2004 to the present (last accessed: December, 2024) and reviewed references from comprehensive studies (1919-2004) to identify phenotypical descriptions matching the published diagnostic criteria for AGL and APL1,2. Barraquer-Simons syndrome and phenotypes resembling Dunnigan syndrome, with lipoatrophy in the extremities and fat retention in the face, neck, and abdomen, were classified as APL. Cases were categorized based on immune mechanisms and presenting phenotypes. Results: In our analysis of 492 patients with ALS, 32% (n=159) had AGL and 68% (n=333) had APL. ALS with autoimmune disorders was significantly more common in AGL compared to APL (39% vs 26%, p=0.004), as was ALS with regulatory T cell defects (7% vs. 1%, p<0.001), colitis (7% vs. 2%, p=0.01) and panniculitis (26% vs. 1%, p<0.001). ALS associated with malignancy, involving immune checkpoint inhibitors (7% vs. 1%, p<0.001), lymphoma (6% vs. <1%, p<0.001), and paraneoplastic syndromes (2% vs. <1%, p=0.04) predominantly exhibited the AGL phenotype, whereas prior exposure to HSCT/TBI was significantly associated with the APL phenotype (5% vs. <1%, p=0.01). While C3 deficiency was significantly more common in APL compared to AGL (39% vs 4%, p<0.001), C4 deficiency was more frequently observed in AGL than in APL (5% vs 1%, p=0.02). Conclusion: Our study highlights the diverse clinical manifestations of patients with APL and AGL, emphasizing ALS with autoimmune disorders, regulatory T-cell defects, lymphoma, panniculitis and colitis are predominantly linked to the AGL, while complement deficiencies and prior HSCT/TBI exposure are more frequently associated with APL. References: 1. Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore). 2003. 2. Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore). 2004. Presentation: Sunday, July 13, 2025
2025-10-01 | 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
2026-07-09 | Case Report: Dramatic metabolic improvement with tirzepatide in a patient with acquired partial lipodystrophy following hematopoietic stem cell transplantation.
Acquired lipodystrophy is a rare disorder characterized by adipose tissue loss or dysfunction and is frequently associated with severe insulin resistance and metabolic complications. Metabolic complications of lipodystrophy have occasionally been reported after hematopoietic stem cell transplantation (HSCT), but their clinical features and optimal treatment strategies remain poorly defined. Tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has recently emerged as a novel therapy for type 2 diabetes. We report a 37-year-old woman who underwent allogeneic HSCT at 12 years of age for relapsed acute lymphoblastic leukemia after a conditioning regimen including total body irradiation (TBI), high-dose cytarabine, and melphalan. She subsequently developed diabetes mellitus and fatty liver disease at 17 years of age. Although no apparent fat loss was initially recognized, lipodystrophy was clinically suspected based on severe insulin resistance and metabolic abnormalities disproportionate to her body habitus. Computed tomography at 37 years of age revealed region-specific fat loss extending from the lower back to the gluteal region. Glycemic control remained inadequate despite high-dose insulin therapy and sequential treatment with several GLP-1 receptor agonists. After initiation of tirzepatide, glycemic control improved dramatically, allowing complete discontinuation of insulin therapy. Body weight decreased modestly and hepatic steatosis improved. The high-molecular-weight (HMW)/total adiponectin ratio after treatment was elevated (64.0%), suggesting possible improvement in adipocyte secretory function. This case highlights acquired partial lipodystrophy developing after HSCT, supported by region-specific fat loss and characteristic metabolic abnormalities, and demonstrates a marked therapeutic response to tirzepatide. Dual incretin receptor agonism may represent a promising therapeutic strategy for severe insulin resistance associated with adipose tissue dysfunction, potentially through both weight-dependent and weight-independent mechanisms.
2026-02-17 | Lipodystrophies in Clinical Practice: A Case Series From a Local Health Unit in Portugal
Background Lipodystrophies are rare disorders characterized by loss of adipose tissue, leading to severe metabolic and multisystem complications. Data on real-world management remain limited, particularly in Portugal. Objectives The objective of this study is to describe the clinical, metabolic, genetic, and therapeutic characteristics of patients with confirmed or suspected lipodystrophy followed at a Portuguese Endocrinology Outpatient Clinic. Methods We conducted a retrospective observational study including 21 patients with clinical suspicion or diagnosis of lipodystrophy. Demographic, clinical, laboratory, imaging, and genetic data were collected. Results The cohort was predominantly female (90.5%) with a median age at diagnosis of 49 years. Sixteen patients (76.2%) had familial partial lipodystrophy (FPLD), two (9.5%) had congenital generalized lipodystrophy, two (9.5%) had acquired generalized lipodystrophy, and one presented a complex syndromic form. Diabetes mellitus was present in 71.4% of patients and hypertriglyceridemia in 52.4%. Metabolic liver disease occurred in both generalized and partial forms. Autoimmune disorders affected 31.6% of patients, and cardiac involvement was observed in 23.8%. Genetic testing identified pathogenic or likely pathogenic variants in BSCL2 and PPARG in three patients, while most FPLD cases remained genetically unexplained. Metreleptin therapy in three patients with generalized lipodystrophy improved glycemic control, triglycerides, liver enzymes, and proteinuria. Dual-energy X-ray absorptiometry imaging supported the phenotypic characterization of adipose tissue loss. Conclusions Detailed physical examination, genetic testing, imaging, and early therapeutic interventions are critical for management. These findings align with European registry data and highlight the need for increased awareness and systematic evaluation in real-world clinical practice.
2026-01-01 | O-30 AUTOSOMAL RECESSIVE LIPE PATHOGENIC VARIANT-ASSOCIATED FAMILIAL PARTIAL LIPODYSTROPHY TYPE 6
Abstract Introduction Lipodystrophy is a rare and heterogeneous disorder characterized by selective loss or abnormal redistribution of adipose tissue, leading to metabolic complications such as insulin resistance, diabetes mellitus, hepatic steatosis, and dyslipidemia. Lipodystrophy is divided into 4 main groups: congenital generalized lipodystrophy (CGL), familial partial lipodystrophy (FPLD), acquired generalized lipodystrophy (AGL), and acquired partial lipodystrophy (APL). FPLD is caused by mutations is genes regulating adipocyte function and lipid metabolism, with six subtypes identified to date. Among these, type 6 (FPLD6) results from inactivating mutation in the LIPE gene, which encodes hormone-sensitive lipase (HSL). Here, we present a very rare case of autosomal recessive familial partial lipodystrophy type 6. Clinical Case A 34-year-old female was referred for evaluation of suspected Cushing’s syndrome. She was receiving hormone replacement therapy for primary ovarian insufficiency and had no other known medical conditions. She had gestational diabetes during her second pregnancy, managed with diet alone. Over three years she gained 29 kg (BMI 35.2 kg/m²). Family history revealed parental consanguinity. Physical examination revealed characteristic cushingoid features including a prominent buffalo hump, supraclavicular fat pads, and centripetal obesity. She had fat accumulation in the upper body while subcutaneous fat was markedly reduced in the extremities and breasts (Figure 1). Acanthosis nigricans was noted in the axillary and cervical regions. Additionally, she had undergone a cosmetic liposuction procedure targeting the deltoid and occipital regions. Low-dose dexamethasone testing excluded Cushing’s syndrome. Oral glucose tolerance test indicated insulin resistance; triglycerides were elevated, while leptin was normal. Laboratory results are summarized in Table 1. Whole-body DXA demonstrated markedly reduced fat mass in the upper and lower extremities, with central fat accumulation. This distribution was compatible with partial lipodystrophy. FibroScan revealed advanced hepatic steatosis (S3) without fibrosis (F0), consistent with nonalcoholic fatty liver disease (NAFLD). Genetic analysis identified a homozygous pathogenic LIPE gene variant (c.2182G>A), confirming the diagnosis of autosomal recessive familial partial lipodystrophy type 6. Treatment with metformin, SGLT-2 inhibitor, and fenofibrate was initiated, alongside lifestyle modification and genetic counseling. Conclusion FPLD6 is a very rare subtype of familial partial lipodystrophy. Unlike other subtypes, it is caused by LIPE mutations leading to defective lipolysis, and typically presents in adulthood rather than early life. It is further characterized by severe insulin resistance, dyslipidemia, and hepatic steatosis. In addition, the presence of subcutaneous lipomas distinguishes FPLD6 from other many forms and may lead to diagnostic confusion with multiple lipomatosis.Figure 1:a.Sagittal magnetic resonance imaging (MRI) of the neck and cervical spine region demonstrating abnormal fat distribution consistent with partial lipodystrophy b.Dual-energy X-ray absorptiometry (DEXA) scan demonstrating body composition c.Posterior view of the trunk showing loss of peripheral fat and abnormal fat deposition in the upper body Table 1:Biochemical parameters of the patientIR: insulin resistance
2025-10-01 | SUN-646 Immune Landscape and Clinical Characteristics of Patients with Acquired Partial and Generalized Lipodystrophy Syndromes
Abstract Disclosure: O. Besci: None. C.D. Uwandu: None. U. Cavdar: None. B. Akinci: None. D. Gilio: None. M.C. Foss de Freitas: None. K. Walkovich: None. E.A. Oral: Regeneron Pharmaceuticals, Rhythm Pharmaceuticals, Novo Nordisk, Amryt Pharmaceuticals, Ionis Pharmaceuticals Inc., Morphic Medical, Rejuvenate Bio, Fractyl Laboratories. Introduction: Acquired lipodystrophy syndromes (ALS) are characterized by loss of adipose tissue and associated metabolic abnormalities, manifesting in either partial (APL) or generalized forms (AGL). Increasing evidence of ALS links to autoimmunity, infections, malignancies, and associated treatments highlights the need for an understanding of the associated immune-mediated mechanisms. Objective: We sought to provide immune-related insights on ALS by correlating coexisting disorders with their underlying immune mechanisms and identifying patterns of phenotypic presentations via comprehensive case review and literature analysis. Methods: We retrospectively reviewed all cases from the University of Michigan (n = 30) and published cases (n = 462). We systematically searched PubMed for ALS studies published in English with full-text availability from 2004 to the present (last accessed: December, 2024) and reviewed references from comprehensive studies (1919-2004) to identify phenotypical descriptions matching the published diagnostic criteria for AGL and APL1,2. Barraquer-Simons syndrome and phenotypes resembling Dunnigan syndrome, with lipoatrophy in the extremities and fat retention in the face, neck, and abdomen, were classified as APL. Cases were categorized based on immune mechanisms and presenting phenotypes. Results: In our analysis of 492 patients with ALS, 32% (n=159) had AGL and 68% (n=333) had APL. ALS with autoimmune disorders was significantly more common in AGL compared to APL (39% vs 26%, p=0.004), as was ALS with regulatory T cell defects (7% vs. 1%, p<0.001), colitis (7% vs. 2%, p=0.01) and panniculitis (26% vs. 1%, p<0.001). ALS associated with malignancy, involving immune checkpoint inhibitors (7% vs. 1%, p<0.001), lymphoma (6% vs. <1%, p<0.001), and paraneoplastic syndromes (2% vs. <1%, p=0.04) predominantly exhibited the AGL phenotype, whereas prior exposure to HSCT/TBI was significantly associated with the APL phenotype (5% vs. <1%, p=0.01). While C3 deficiency was significantly more common in APL compared to AGL (39% vs 4%, p<0.001), C4 deficiency was more frequently observed in AGL than in APL (5% vs 1%, p=0.02). Conclusion: Our study highlights the diverse clinical manifestations of patients with APL and AGL, emphasizing ALS with autoimmune disorders, regulatory T-cell defects, lymphoma, panniculitis and colitis are predominantly linked to the AGL, while complement deficiencies and prior HSCT/TBI exposure are more frequently associated with APL. References: 1. Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore). 2003. 2. Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore). 2004. Presentation: Sunday, July 13, 2025
2025-10-01 | 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
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Acquired partial lipodystrophy, including 1 approved therapy.
1 orphan drug designation for Acquired partial lipodystrophy, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Metreleptin [Myalepta] | proteins | EMA | 2012-07-17 | 2018-08-01 | Chiesi Farmaceutici S.p.A. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.