To describe the effects of Glucagon-like peptide-1 receptor agonists (GLP-1RA) in patients with familial partial lipodystrophy (FPLD) assessed in a real-life setting in a national reference network. We retrospectively collected clinical and metabolic parameters in patients with FPLD in the French lipodystrophy reference network, who initiated GLP-1RA. Data were recorded before, at one-year (12 ± 6 months) and at the latest follow-up on GLP-1RA therapy (≥18 months). Seventy-six patients (89.4% of women), diagnosed with LMNA-related FPLD2 (n = 57), PPARG-related FPLD3 (n = 4), PLIN1-related FPLD4 (n = 5) or FPLD1 (n = 10) initiated GLP-1RA therapy between 2008 and 2024. Patients were aged a median (IQR) 48 years (34.5-57), body mass index (BMI) was 26.0 kg/m2 (23.9-29.5), HbA1c 8.3% (7.5-9.3), triglycerides 2.31 mmol/L (1.62-3.88). GLP-1RA were used in addition to previously used antidiabetics, 50% of patients being insulin-treated. After one year with GLP-1RA therapy, BMI, HbA1c and triglycerides significantly decreased to 25.6 kg/m2 (22.7-29.1), 7.3% (6.6-8.3) and 1.97 mmol/L (1.5-3.2) respectively (p < 0.001, p < 0.001 and p < 0.01, respectively), without significant changes in other antidiabetic and lipid-lowering drugs. Gamma-glutamyl-transferase and alanine-aminotransferase levels also significantly decreased. Effects on HbA1c, BMI and triglycerides persisted in the long term. One case of acute pancreatitis occurred during follow-up, associated with severe hypertriglyceridemia in a non-observant patient. Gastrointestinal symptoms affected 34% of patients, leading to GLP-1RA withdrawal in six patients. GLP-1RA significantly improved BMI, HbA1c and triglycerides in a large majority of patients with FPLD. Larger and prospective controlled studies are warranted for identification of predictive factors and safety.

Pathogenic variants in PLIN1-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1-related FPL. We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1-mutated FPL and 3 controls. Patients with PLIN1-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P<0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P=0.006). Compared with controls, patients with PLIN1-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P=0.005). VLDL-apoB100 production was not different between patients with PLIN1-related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (P=0.031) and IDL-apoB100 (P=0.031). Plasma LPL mass was significantly lower in patients with PLIN1-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P<0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass. We show that hypertriglyceridemia associated with PLIN1-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.