Genetic Evidence Supports GLP-1 Drugs for Kidney Disease Protection, Especially IgA Nephropathy | Research

The takeaway

Mendelian randomization provides genetic evidence that GLP-1 receptor activation reduces chronic kidney disease risk by 17% and IgA nephropathy risk by 30%, primarily through FGF23 suppression rather than blood sugar control alone.

30% lower IgA nephropathy risk
Genetically predicted GLP-1 receptor activation reduces IgA nephropathy risk (OR 0.70), with FGF23 suppression identified as a key mediating pathway

What the researchers found

Genetically predicted GLP-1R activation significantly reduced risks of CKD (OR 0.83, p=9.22E-9), IgA nephropathy (OR 0.70, p=2.11E-3), and preserved kidney function (eGFR β=0.01, p=9.11E-3). Effects on other CKD subtypes (membranous nephropathy, nephrotic syndrome, chronic glomerulonephritis) were null.

Mediation analysis revealed FGF23 suppression as the dominant pathway, mediating 26.57% of the eGFR effect and 13.50% of CKD protection. Metabolic mediators contributed modestly: BMI (2.08% for CKD, 5.51% for eGFR), HDL (0.79% for CKD), and HbA1c (8.25% for eGFR). For IgA nephropathy specifically, only BMI showed a mediation effect.

Why it matters

Chronic kidney disease affects over 800 million people globally and IgA nephropathy is the most common primary glomerular disease worldwide with limited treatment options. Genetic evidence for GLP-1 drugs' kidney benefits — especially through a novel FGF23 pathway rather than just glucose control — could accelerate clinical trials for these kidney diseases and expand the therapeutic scope of an already widely used drug class.

How the study worked

Two-sample Mendelian randomization using large-scale GWAS data to estimate causal effects of GLP-1R activation on kidney outcomes. Positive control analyses validated instruments using HbA1c, blood glucose, T2DM, and diabetic nephropathy. Mediation MR assessed pathways through BMI, lipids, glycemic markers, and inflammatory proteins. Data from MRC IEU OpenGWAS, FinnGen, GWAS Catalogue, and cohort studies.

What this study cannot tell us

Mendelian randomization assumes genetic variants only affect outcomes through the proposed pathway, which may not always hold. Data were primarily from European ancestry populations, limiting generalizability. This is genetic evidence for causality, not clinical trial evidence. The null results for some CKD subtypes suggest the kidney protection is not universal across all kidney diseases. FGF23 mediation, while significant, leaves most of the protective mechanism unexplained.

How to read the evidence

Mendelian randomization provides stronger causal evidence than observational studies by using genetic variants as natural experiments. The highly significant p-values and validated positive controls strengthen confidence. However, this remains genetic evidence rather than direct clinical trial data.

When this study was published

Published in 2025, this study uses the latest large-scale GWAS data to provide timely genetic support for repurposing GLP-1 drugs in kidney disease.

The bigger picture

GLP-1 drugs keep revealing benefits beyond diabetes — cardiovascular, neurological, liver, and now compelling genetic evidence for kidney protection. The identification of FGF23 as a key mediator is particularly exciting because FGF23 is itself a therapeutic target in kidney disease. This suggests GLP-1 drugs may work through anti-inflammatory pathways distinct from their metabolic effects, opening new research directions.

Questions still open

Should clinical trials of GLP-1 drugs specifically for IgA nephropathy be prioritized given this genetic evidence?
Could combining GLP-1 drugs with FGF23-targeting therapies provide synergistic kidney protection?
Do these genetic findings hold in non-European populations where both CKD and GLP-1 drug use patterns differ?

Common questions

What is Mendelian randomization and why does it matter here?

It's a research method that uses natural genetic differences between people as a kind of natural experiment. People with certain gene variants naturally have more GLP-1 receptor activity. By studying their kidney health, researchers can estimate what GLP-1 drugs would do — without the biases of observational studies. It's stronger evidence than typical associations.

What is FGF23 and why is it important for kidneys?

FGF23 (fibroblast growth factor 23) is a protein that rises in kidney disease and contributes to inflammation and cardiovascular problems. This study found that GLP-1 drugs may protect kidneys partly by lowering FGF23 levels — a completely different mechanism from their blood sugar effects. This could explain kidney benefits in non-diabetic patients too.

Read the original research

Genetic evidence for repurposing GLP-1 receptor agonists in chronic kidney disease and IgA nephropathy: Metabolic and anti-inflammatory pathways beyond glycaemic control.

Diabetes, obesity & metabolism, 27(12), 7395-7407

View on PubMed ↗Publisher’s paper ↗

Citation

Yang, Xueying; Tang, Wenhao; Chan, Han; Wang, Mo; Yang, Haiping; Li, Qiu. (2025). Genetic evidence for repurposing GLP-1 receptor agonists in chronic kidney disease and IgA nephropathy: Metabolic and anti-inflammatory pathways beyond glycaemic control.. Diabetes, obesity & metabolism, 27(12), 7395-7407. https://doi.org/10.1111/dom.70144