Cardio-kidney-metabolic protective effects of semaglutide across the spectrum of chronic kidney disease

doi:10.5527/wjn.v14.i4.109457

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World Journal of Nephrology

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World J Nephrol. Dec 25, 2025; 14(4): 109457
Published online Dec 25, 2025. doi: 10.5527/wjn.v14.i4.109457

Cardio-kidney-metabolic protective effects of semaglutide across the spectrum of chronic kidney disease

Harry Economos, Richard J MacIsaac

Harry Economos, Richard J MacIsaac, Department of Endocrinology and Diabetes, St Vincent’s Hospital Melbourne, Melbourne 3065, Victoria, Australia

Richard J MacIsaac, Department of Medicine, The University of Melbourne, Melbourne 3010, Australia

Richard J MacIsaac, Australian Centre for Accelerating Diabetes Innovations, The University of Melbourne, Victoria, Melbourne 3010, Australia

Author contributions: Economos H was the first author and was responsible for the majority of the review’s literature review, writing and drafting; MacIsaac RJ provided the conceptualisation, supervision, contributed substantially to writing and critical revisions, and assisted in finalising the manuscript.

Conflict-of-interest statement: Economos H had no conflicts to declare. MacIsaac RJ has received research grants from Novo Nordisk, Servier, Medtronic, The Rebecca Cooper Medical Research Foundation, St Vincent’s Research Foundation, The Juvenile Diabetes Research Foundation, Grey Innovations, The Diabetes Australia Research Trust/Program and The National Health and Medical Research Council of Australia. Also received honoraria for lectures from Eli Lilly, Novo Nordisk, Sanofi Aventis, Astra Zeneca, Merck Sharp & Dohme, Norvartis, and Boehringer Ingelheim, and has been or is on the advisory boards for Novo Nordisk, Boehringer Ingelheim-Eli Lilly Diabetes Alliance, Astra Zeneca, and Merck Shape and Dohme. Travel support has been supplied by Novo Nordisk, Sanofi, Boehringer Ingelheim and Astra Zeneca. Has been a principal investigator for industry-sponsored clinical trials run by Novo Nordisk, Sanofi, Bayer, Johnson-Cilag and Abbive. He has been an investigator on industry-sponsored trials involving liraglutide, semaglutide, canagliflozin, sotagliflozin, and finerenone.

Corresponding author: Richard J MacIsaac, Director, Professor, Department of Endocrinology and Diabetes, St Vincent’s Hospital Melbourne, 4^th Floor, Daly Wing, 35 Victoria Parade, PO Box 2900, Fitzroy 3065, Victoria, Australia. r.macisaac@unimelb.edu.au

Received: May 12, 2025
Revised: June 23, 2025
Accepted: September 26, 2025
Published online: December 25, 2025
Processing time: 225 Days and 20.5 Hours

Abstract

There is growing evidence suggesting that semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is effective in preventing and treating chronic kidney disease (CKD) in patients with type 2 diabetes mellitus (T2D). The Evaluate Renal Function with Semaglutide Once Weekly trial demonstrated that semaglutide significantly reduced the risk of major kidney outcomes, including kidney failure, death from kidney or cardiovascular causes, reduced albuminuria and major cardiovascular events. Emerging evidence also suggests a potential kidney-protective effect of GLP-RAs in people without diabetes. Based on this data, contemporary guidelines now support GLP-1RA use, notably semaglutide, as the fourth pillar of diabetic kidney disease (DKD) management in T2D, alongside existing cardio-kidney protective agents (the other 3 pillars of DKD therapy) sodium glucose co-transporter-2 inhibitors, non-steroidal mineralocorticoid receptor antagonists and renin-angiotensin-aldosterone-system blockers. Semaglutide offers complementary and synchronous benefits through distinct mechanisms, underscoring its role in the comprehensive management of patients with T2D. Furthermore, GLP-1RA use in people with T2D and CKD improves metabolic parameters not achievable with the other DKD therapies. This review summarises the clinical evidence for semaglutide’s kidney-protective effects in individuals with and without T2D, and highlights recent trial data supporting its broader metabolic effects in CKD. Together these findings position semaglutide as a key agent in modern CKD management.

Keywords: Semaglutide; Glucagon-like peptide-1 receptor agonist; Chronic kidney disease; Diabetes; Albuminuria

Core Tip: In people with type 2 diabetes and chronic kidney disease, semaglutide, saves kidneys, hearts and lives. The glucagon-like peptide-1 receptor agonist (GLP-1RA) class of medications are now being proposed as the fourth pillar of diabetic kidney disease therapy, along with renin-angiotensin-aldosterone system blocking agents, sodium glucose co-transporter-2 inhibitors, and finerenone. We await definitive evidence to support a kidney protective effect of GLP-1RAs outside of the setting of diabetes.