GLP-1 Receptor Agonists Reduce Kidney Disease Risk: What Clinical Trials Show

Introduction How GLP-1 RAs protect the kidneys Reducing albuminuria and assessing kidney risk Kidney outcomes: Assessing GLP-1 RAs across randomized trials Kidney benefits in people without diabetes Investigating combination therapies and dual agonists Challenges and clinical limitations References Further reading From urinary protein loss to declining filtration, clinical trials are testing where GLP-1 therapies fit in kidney care and which patients might benefit.

Image Credit: Toey Andante / Shutterstock.com Introduction Chronic kidney disease (CKD) refers to abnormalities in kidney structure or function that last at least three months. A global estimate for 2017 indicated that 9.1% of the world’s population was affected by CKD, a condition associated with increased risks of kidney failure and cardiovascular mortality.

1 Since their approval, glucagon -like peptide-1 (GLP-1) receptor agonists (RAs) have revolutionized the management of type 2 diabetes mellitus (T2DM) and obesity, both of which are prevalent risk factors for CKD. Clinical trials have demonstrated kidney benefits with several GLP-1 RAs, with the strongest dedicated kidney outcome evidence coming from semaglutide in patients with T2DM and CKD.

1,4 How GLP-1 RAs protect the kidneys CKD can involve the progressive loss of functional nephrons and is frequently associated with underlying chronic conditions like T2DM, obesity, and atherosclerotic cardiovascular disease (ASCVD). 4 Blood pressure control and renin-angiotensin system blockade remain established components of treatment, though residual kidney and cardiovascular risks persist.

1,2 Researchers are evaluating GLP-1 RAs as complementary therapies alongside these treatments and sodium-glucose cotransporter 2 (SGLT2) inhibitors. 4 Initially developed for glycemic management, GLP-1 RAs are increasingly being studied for their effects on kidney and cardiovascular outcomes beyond glucose lowering.

1,3 Proposed mechanisms include improvements in body weight, blood pressure, and glycemic control, together with possible direct effects on kidney inflammation and hemodynamics. 1,4 Experimental studies suggest that GLP-1 signaling can suppress inflammatory pathways involving advanced glycation end products and their receptor, reducing endothelial adhesion molecule expression and inflammatory signaling in mesangial cells, which support the kidney’s filtering structures.

4 These studies also describe a shift toward anti-inflammatory macrophage phenotypes in the kidney microenvironment. 4 Nevertheless, the contribution of these experimental mechanisms to clinical kidney protection remains uncertain. 1,4 GLP-1 RAs may promote natriuresis, the process by which kidneys excrete sodium into urine, partly through inhibition of sodium-hydrogen exchanger 3 in renal proximal tubular cells.

Increased sodium delivery to the macula densa, a group of sodium-sensing cells, could alter tubuloglomerular feedback, which regulates filtration, and reduce intraglomerular pressure. 1 GLP-1 RAs also lower mean systolic blood pressure by approximately 3-5 mmHg, which may contribute to their cardiorenal benefits.

3 Reducing albuminuria and assessing kidney risk Albuminuria, increased urinary albumin excretion, marks kidney injury and independently predicts kidney disease progression and cardiovascular risk. 2 Meta-analyses report that GLP-1 RAs reduce albuminuria, including reductions in the urinary albumin-to-creatinine ratio (UACR).

1,2 One meta-analysis reported larger UACR reductions in a subgroup classified as CKD stages 1 and 2 than in stages 3 through 5. This comparison involved only three studies with different populations and treatments. Albuminuria reduction and preservation of kidney filtration are related but distinct outcomes; lower UACR alone does not establish prevention of kidney failure.

1,2 Semaglutide, Chronic Kidney Disease, and Diabetes | NEJM Kidney outcomes: Assessing GLP-1 RAs across randomized trials Early evidence of kidney benefits emerged from large cardiovascular outcome trials, such as the SUSTAIN-6 trial with semaglutide, which revealed a 36% relative risk reduction in new or worsening nephropathy.

4 This composite included persistent macroalbuminuria, doubling of serum creatinine, kidney replacement therapy, or death from kidney disease. 4 The REWIND trial evaluating dulaglutide reported a 15% reduction in a composite kidney endpoint over a median follow-up of 5.4 years. The REWIND benefit was driven mainly by fewer cases of new macroalbuminuria.

4 FLOW, a dedicated double-blind kidney outcome trial in patients with T2DM and albuminuric CKD, found that once-weekly semaglutide reduced the relative risk of a primary composite of kidney failure, a sustained decline of at least 50% in estimated glomerular filtration rate (eGFR), or death from kidney or cardiovascular causes by 24%.

Kidney failure in FLOW meant sustained eGFR below 15 mL/min/1.73 m2 or long-term kidney replacement therapy. 4 A meta-analysis of nine randomized controlled trials (RCTs) with 21,717 participants, predominantly with T2DM, reported relative reductions of 16% in major adverse kidney events and 17% in all-cause mortality compared with placebo or standard care.

A separate meta-analysis reported a 12% reduction in the risk of substantial kidney function decline across nine trials involving 34,100 participants. Its analysis of eGFR slope, the rate of change in estimated kidney filtration over time, included 16 trials and 30,538 participants and found an average slowing of annual eGFR loss by 0.45 mL/min/1.73 m2 versus comparators, with substantial variation between studies.

1 Kidney benefits in people without diabetes Several GLP-1 RAs have shown kidney benefits; however, evidence strength varies by drug, population, and outcome. Findings from individual agents should not be assumed to establish identical effects throughout the class. 1,4 Emerging data extend these therapeutic benefits to selected populations without diabetes, suggesting that glucose lowering does not fully explain the observed kidney effects.

1,4 In the SELECT trial, semaglutide produced a 22% relative reduction in a prespecified composite kidney endpoint in individuals with overweight or obesity and established cardiovascular disease without diabetes. 4 The composite included persistent macroalbuminuria; therefore, it should not be interpreted as a 22% reduction in kidney failure alone.

4 Among patients with a baseline eGFR under 60 mL/min/1.73 m2, the difference in eGFR change favored semaglutide over placebo by 2.19 mL/min/1.73 m2 at 104 weeks. 4 A separate randomized trial in people with overweight or obesity and CKD without diabetes found that semaglutide reduced UACR by 52.1% versus placebo at 24 weeks.

This short-term result supports an albuminuria-lowering effect but does not establish prevention of kidney failure. 4 Image Credit: Edugrafo / Shutterstock.com Investigating combination therapies and dual agonists A post hoc analysis of the EXSCEL trial associated exenatide plus an SGLT2 inhibitor with a slower annual eGFR decline, with a between-group difference of 1.94 mL/min/1.73 m2 versus placebo.

SGLT2 inhibitor use was not randomized, limiting causal interpretation. No increase in hypoglycemia or kidney adverse events was observed, though reductions in kidney composite outcomes were not statistically significant. 4 Observational comparisons of liraglutide and dulaglutide suggest differences in some metabolic and kidney measures, but residual confounding and comparable major outcomes prevent firm conclusions about one agent’s superiority.

4 In a post hoc kidney analysis of the SURPASS-4 trial, the dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide significantly slowed eGFR decline compared with insulin glargine, with an annual eGFR slope difference of 2.2 mL/min/1.73 m2.

4 Pooled analyses of SURPASS trials reported dose-dependent UACR reductions with tirzepatide, reaching 47.3% at the highest dose among participants with baseline UACR of at least 30 mg/g. These findings support further investigation, but do not yet establish tirzepatide’s effects on kidney failure.

4 Challenges and clinical limitations High-certainty randomized evidence remains limited in advanced CKD, particularly stage 5 and dialysis populations. Some trials included stage 4 CKD; however, representation and outcome reporting remain incomplete. 4 Thus, longer trials are needed to clarify kidney failure outcomes in people without diabetes, particularly those without obesity, and dedicated trials should test tirzepatide and combination regimens.

1,4 Tolerability remains a major barrier to treatment persistence, as GLP-1 RAs increase gastrointestinal adverse events, which can lead to premature treatment discontinuation. 1,4 References Sasaki, T., Giang, S. M., Wu, J., et al . (2025).

The effect of GLP-1 receptor agonists on renal outcomes: a systematic review and meta-analysis. Nephrology Dialysis Transplantation 41 (4); 681-691. DOI : 10.1093/ndt/gfaf193. https://academic.oup.com/ndt/article/41/4/681/8261545 Wang, Y., Feng, L., Wang, Y., et al. (2026).

Cardiorenal protective effects of glucagon-like peptide-1 receptor agonists in chronic kidney disease: a systematic review and meta-analysis. Renal Failure 48 (1). DOI : 10.1080/0886022x.2026.2620155. https://www.tandfonline.com/doi/full/10.1080/0886022X.2026.2620155 Kong, F., Zhao, Y., Zhang, W., et al . (2026).

Comprehensive evaluation of GLP-1 receptor agonists: an umbrella review of clinical outcomes across multiple diseases. Nature Communications 17 (1). DOI : 10.1038/s41467-025-67701-9. https://www.nature.com/articles/s41467-025-67701-9 Rico-Fontalvo, J., Daza-Arnedo, R., Elbert, A., et al . (2026).

Renal Outcomes of GLP-1 Receptor Agonists and Tirzepatide Across CKD Stages and Metabolic Phenotypes (Type 2 Diabetes and/or Overweight/Obesity): A Scoping Review. Diabetes Therapy 17 (4); 499-528. DOI : 10.1007/s13300-026-01854-8. https://link.springer.com/article/10.1007/s13300-026-01854-8 Further Reading All Chronic Kidney Disease Content Chronic Kidney Disease (CKD) Living with Chronic Kidney Disease Chronic Kidney Disease Symptoms Chronic Kidney Disease Causes Last Updated: Oct 27, 2026