DUAL GIP/GLP-1Ra reduces residual proteinuria in non-diabetic fabry disease.

BACKGROUND: Residual proteinuria remains a major determinant of renal disease progression in Fabry disease (FD) despite optimized enzyme replacement or chaperone therapy and maximal renin-angiotensin system (RAS) blockade. Dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonists exert anti-inflammatory, natriuretic, and antifibrotic effects beyond metabolic control. We evaluated the impact of add-on tirzepatide on residual proteinuria in overweight, non-diabetic Fabry patients receiving optimized background therapy. METHODS: In this prospective, proof-of-concept observational study, 15 FD patients with persistent proteinuria ≥ 0.5 g/24 h despite stable disease-specific therapy and maximal tolerated RAS blockade were treated with tirzepatide for 6 months. The primary endpoint was change in 24-hour proteinuria. Secondary endpoints included change in estimated glomerular filtration rate (eGFR), body mass index (BMI), cardiac biomarkers (NT-proBNP, high-sensitivity troponin T), and safety. RESULTS: Tirzepatide is associated with a progressive reduction in proteinuria, which became statistically significant at Month 1 and continued through Month 6 (1.11 ± 0.23 g/24 h at baseline to 0.35 ± 0.19 g/24 h at 6 months; 68.9% reduction; P < 0.001). Two-thirds of patients (66.7%) achieved proteinuria < 0.5 g/24 h. eGFR remained stable throughout the treatment period (P = 0.87). Tirzepatide induced significant weight loss, with BMI decreasing from 29.0 (27.1-29.3) kg/m² at baseline to 24.2 (23.4-25.1) kg/m² at Month 6 (P < 0.001). Beyond the renal effects, cardiac biomarkers also showed significant reductions, with NT-proBNP and high-sensitivity troponin T decreasing by 33.3% (P < 0.01) and 14.3% (P < 0.05), respectively, in the absence of structural echocardiographic changes, that may reflect early modulation of myocardial stress. The drug was well tolerated, with mild gastrointestinal symptoms during initial dose titration and no treatment discontinuations. CONCLUSIONS: Add-on dual GIP/GLP-1 receptor agonism is associated with a reduction in residual proteinuria and showed improvements in cardiac biomarkers in overweight Fabry patients receiving optimized therapy, without affecting eGFR. These findings support a multi-pathway nephroprotective strategy beyond substrate reduction and RAS inhibition.