{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:52:02Z","timestamp":1781862722869,"version":"3.54.5"},"reference-count":31,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Residual proteinuria remains a major determinant of renal disease progression in Fabry disease (FD) despite optimized enzyme replacement or chaperone therapy and maximal renin\u2013angiotensin 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this prospective, proof-of-concept observational study, 15 FD patients with persistent proteinuria \u22650.5\u00a0g\/24\u00a0h despite stable disease-specific therapy and maximal tolerated RAS blockade were treated with tirzepatide for 6 months. The primary endpoint was change in 24-h 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Tirzepatide is associated with a progressive reduction in proteinuria, which became statistically significant at Month 1 and continued through Month 6 (1.11\u00a0\u00b1\u00a00.23\u00a0g\/24\u00a0h at baseline to 0.35\u00a0\u00b1\u00a00.19\u00a0g\/24\u00a0h at 6 months; 68.9% reduction; P\u00a0&amp;lt;\u00a0.001). Two-thirds of patients (66.7%) achieved proteinuria &amp;lt;0.5\u00a0g\/24\u00a0h. eGFR remained stable throughout the treatment period (P\u00a0=\u00a0.87). Tirzepatide induced significant weight loss, with BMI decreasing from 29.0 (27.1\u201329.3) kg\/m\u00b2 at baseline to 24.2 (23.4\u201325.1) kg\/m\u00b2 at Month 6 (P\u00a0&amp;lt;\u00a0.001). Beyond the renal effects, cardiac biomarkers also showed significant reductions, with NT-proBNP and high-sensitivity troponin T decreasing by 33.3% (P\u00a0&amp;lt;\u00a0.01) and 14.3% (P\u00a0&amp;lt;\u00a0.05), 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ndt\/gfag115","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:39:08Z","timestamp":1779190748000},"source":"Crossref","is-referenced-by-count":0,"title":["DUAL GIP\/GLP-1Ra reduces residual proteinuria in non-diabetic Fabry disease"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5379-1104","authenticated-orcid":false,"given":"Eleonora","family":"Riccio","sequence":"first","affiliation":[{"name":"Chair of Nephrology, Federico II University Department of Public Health, , Naples ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Cuomo","sequence":"additional","affiliation":[{"name":"Federico II University Department of Clinical Medicine and Surgery, , Naples ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6559-196X","authenticated-orcid":false,"given":"Ivana","family":"Capuano","sequence":"additional","affiliation":[{"name":"Chair of Nephrology, Federico II University Department of Public Health, , Naples ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia","family":"Spinelli","sequence":"additional","affiliation":[{"name":"Federico II University Department of Clinical Medicine and Surgery, , Naples ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Iaccarino","sequence":"additional","affiliation":[{"name":"Federico II University Department of Clinical Medicine and Surgery, , Naples ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8299-7160","authenticated-orcid":false,"given":"Oriana","family":"De\u00a0Marco","sequence":"additional","affiliation":[{"name":"University of Campania \u201cLuigi Vanvitelli\u201d Department of Mental and Physical Health and Preventive Medicine, , Naples ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Pisani","sequence":"additional","affiliation":[{"name":"Chair of Nephrology, Federico II University Department of Public Health, , Naples ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"2026061905020431200_bib1","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/1750-1172-5-30","article-title":"Fabry disease","volume":"5","author":"Germain","year":"2010","journal-title":"Orphanet J Rare Dis"},{"key":"2026061905020431200_bib2","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1111\/cge.12386","article-title":"The kidney in Fabry\u2019s disease","volume":"86","author":"Pisani","year":"2014","journal-title":"Clin Genet"},{"key":"2026061905020431200_bib3","doi-asserted-by":"publisher","first-page":"2220","DOI":"10.2215\/CJN.04340510","article-title":"Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry","volume":"5","author":"Wanner","year":"2010","journal-title":"Clin J Am Soc Nephrol"},{"key":"2026061905020431200_bib4","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.ymgme.2012.08.003","article-title":"Enzyme replacement therapy in patients with Fabry disease: state of the art and review of the literature","volume":"107","author":"Pisani","year":"2012","journal-title":"Mol Genet Metab"},{"key":"2026061905020431200_bib5","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.ymgme.2019.10.010","article-title":"Pathogenesis of Fabry nephropathy: the pathways leading to fibrosis","volume":"129","author":"Rozenfeld","year":"2020","journal-title":"Mol Genet Metab"},{"key":"2026061905020431200_bib6","doi-asserted-by":"publisher","first-page":"2609","DOI":"10.1681\/ASN.2006121400","article-title":"Antiproteinuric therapy and Fabry nephropathy: sustained reduction of proteinuria in patients receiving enzyme replacement therapy with agalsidase-beta","volume":"18","author":"Tahir","year":"2007","journal-title":"J Am Soc Nephrol"},{"key":"2026061905020431200_bib7","doi-asserted-by":"publisher","first-page":"107558","DOI":"10.18632\/oncotarget.22505","article-title":"Genetic variants associated with Fabry disease progression despite enzyme replacement therapy","volume":"8","author":"Scionti","year":"2017","journal-title":"Oncotarget"},{"key":"2026061905020431200_bib8","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1136\/jmedgenet-2015-103471","article-title":"Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy","volume":"52","author":"Warnock","year":"2015","journal-title":"J Med Genet"},{"key":"2026061905020431200_bib9","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1093\/ndt\/gfu273","article-title":"Antiproteinuric effect of add-on paricalcitol in Fabry disease patients: a prospective observational study","volume":"30","author":"Pisani","year":"2015","journal-title":"Nephrol Dial Transplant"},{"key":"2026061905020431200_bib10","doi-asserted-by":"publisher","first-page":"103742","DOI":"10.1016\/j.ekir.2025.103742","article-title":"Dapagliflozin in patients with CKD with Fabry disease","volume":"11","author":"Battaglia","year":"2025","journal-title":"Kidney Int Rep"},{"key":"2026061905020431200_bib11","doi-asserted-by":"publisher","first-page":"1989","DOI":"10.1093\/ndt\/gfaf088","article-title":"Semaglutide in non-diabetic patients with Fabry disease","volume":"40","author":"Riccio","year":"2025","journal-title":"Nephrol Dial Transplant"},{"key":"2026061905020431200_bib12","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1056\/NEJMoa2403347","article-title":"Effects of semaglutide on chronic kidney disease in patients with Type 2 diabetes","volume":"391","author":"Perkovic","year":"2024","journal-title":"N Engl J Med"},{"key":"2026061905020431200_bib13","first-page":"278","article-title":"Semaglutide in patients with overweight or obesity and chronic kidney disease without diabetes: a randomized double-blind placebo-controlled clinical trial","volume":"1","author":"Apperloo","year":"2024","journal-title":"Nat Med"},{"key":"2026061905020431200_bib14","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1056\/NEJMoa2307563","article-title":"Semaglutide and cardiovascular outcomes in obesity without diabetes","volume":"389","author":"Lincoff","year":"2023","journal-title":"N Engl J Med"},{"key":"2026061905020431200_bib15","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1007\/s11154-023-09825-1","article-title":"Beyond glycemia: comparing tirzepatide to glp-1 analogues","volume":"24","author":"Andraos","year":"2023","journal-title":"Rev Endocr Metab Disord"},{"key":"2026061905020431200_bib16","doi-asserted-by":"publisher","first-page":"101641","DOI":"10.1016\/j.diabet.2025.101641","article-title":"Renoprotective mechanisms of glucagon-like peptide-1 receptor agonists","volume":"51","author":"Chen","year":"2025","journal-title":"Diabetes Metab"},{"key":"2026061905020431200_bib17","doi-asserted-by":"publisher","first-page":"F355","DOI":"10.1152\/ajprenal.00729.2010","article-title":"Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1","volume":"301","author":"Crajoinas","year":"2011","journal-title":"Am J Physiol Renal Physiol"},{"key":"2026061905020431200_bib18","doi-asserted-by":"publisher","first-page":"113877","DOI":"10.1016\/j.intimp.2024.113877","article-title":"GLP-1\/GIP dual agonist tirzepatide normalizes diabetic nephropathy via PI3K\/AKT mediated suppression of oxidative stress","volume":"146","author":"Tian","year":"2025","journal-title":"Int Immunopharmacol"},{"key":"2026061905020431200_bib19","doi-asserted-by":"publisher","first-page":"20420188231222367","DOI":"10.1177\/20420188231222367","article-title":"Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications","volume":"15","author":"Alharbi","year":"2024","journal-title":"Therapeutic Adv Endocrinol"},{"key":"2026061905020431200_bib20","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.3390\/biom15101403","article-title":"GLP-1 receptor agonists in heart failure","volume":"15","author":"Rahmani","year":"2025","journal-title":"Biomolecules"},{"key":"2026061905020431200_bib21","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3389\/fcell.2020.00123","article-title":"Diverse role of TGF-\u03b2 in kidney disease","volume":"8","author":"Gu","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"2026061905020431200_bib22","doi-asserted-by":"publisher","first-page":"1669685","DOI":"10.3389\/fmed.2025.1669685","article-title":"Glucagon-like peptide-1 receptor agonists and the endothelium: molecular and clinical insights into cardiovascular protection","volume":"12","author":"Battistoni","year":"2025","journal-title":"Front Med"},{"key":"2026061905020431200_bib23","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.2215\/CJN.02480221","article-title":"Clinical implications of an acute dip in eGFR after SGLT2 inhibitor initiation","volume":"16","author":"Heerspink","year":"2021","journal-title":"Clin J Am Soc Nephrol"},{"key":"2026061905020431200_bib24","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1093\/ndt\/gfad164","article-title":"Interpretation of GFR slope in untreated and treated adult Fabry patients","volume":"39","author":"Pisani","year":"2023","journal-title":"Nephrol Dial Transplant"},{"key":"2026061905020431200_bib25","doi-asserted-by":"publisher","first-page":"1440636","DOI":"10.3389\/fcvm.2024.1440636","article-title":"Cardiac involvement in Anderson-Fabry disease. The role of advanced echocardiography","volume":"11","author":"Spinelli","year":"2024","journal-title":"Front Cardiovasc Med"},{"key":"2026061905020431200_bib26","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.semarthrit.2020.10.016","article-title":"Are troponin and B-type natriuretic peptides useful biomarkers for the diagnosis of systemic sclerosis heart involvement? A systematic literature review","volume":"51","author":"Ross","year":"2021","journal-title":"Semin Arthritis Rheum"},{"key":"2026061905020431200_bib27","first-page":"123","article-title":"The effect of GLP-1 receptor agonists on N-terminal pro-brain natriuretic peptide. A scoping review and metanalysis","volume":"357","author":"Avogaro","year":"2022","journal-title":"J Cardiol"},{"key":"2026061905020431200_bib28","doi-asserted-by":"publisher","first-page":"e007019","DOI":"10.1161\/CIRCIMAGING.117.007019","article-title":"Early cardiac involvement affects left ventricular longitudinal function in females carrying \u03b1-galactosidase a mutation: role of hybrid positron emission tomography and magnetic resonance imaging and speckle-tracking echocardiography","volume":"11","author":"Spinelli","year":"2018","journal-title":"Circ Cardiovasc Imaging"},{"key":"2026061905020431200_bib29","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s11547-011-0710-9","article-title":"Role of cardiac MRI in evaluating patients with Anderson-Fabry disease: assessing cardiac effects of long-term enzyme replacement therapy","volume":"117","author":"Messalli","year":"2012","journal-title":"Radiol Med"},{"key":"2026061905020431200_bib30","doi-asserted-by":"publisher","first-page":"27333","DOI":"10.18632\/oncotarget.25542","volume":"9","author":"Cammarata","year":"2018","journal-title":"Oncotarget"},{"key":"2026061905020431200_bib31","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1111\/dom.70322","article-title":"GLP-1 receptor agonists for treating obesity without diabetes: a systematic review and meta-analysis of economic evaluations","volume":"28","author":"Dhippayom","year":"2026","journal-title":"Diabetes Obesity Metab"}],"container-title":["Nephrology Dialysis Transplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ndt\/advance-article-pdf\/doi\/10.1093\/ndt\/gfag115\/68344957\/gfag115.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ndt\/advance-article-pdf\/doi\/10.1093\/ndt\/gfag115\/68344957\/gfag115.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:02:11Z","timestamp":1781859731000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ndt\/advance-article\/doi\/10.1093\/ndt\/gfag115\/8688100"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,20]]},"references-count":31,"URL":"https:\/\/doi.org\/10.1093\/ndt\/gfag115","relation":{},"ISSN":["0931-0509","1460-2385"],"issn-type":[{"value":"0931-0509","type":"print"},{"value":"1460-2385","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,20]]},"article-number":"gfag115"}}