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

Sep 25, 2025Diabetes, obesity & metabolism

Genetic support for using GLP-1 receptor drugs to treat chronic kidney disease and IgA nephropathy through metabolism and inflammation pathways beyond blood sugar control

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Abstract

Genetic proxies for GLP-1R activation are associated with a lower risk of chronic kidney disease (CKD) (odds ratio = 0.83, p = 9.22E-9).

GLP-1R activation is linked to reduced levels of glycated hemoglobin (HbA1c) and blood glucose, indicating potential benefits for glycemic control.
There is a decreased risk of type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) associated with GLP-1R activation.
Genetic factors related to GLP-1R activation lower the risk of immunoglobulin A nephropathy (IgAN) (odds ratio = 0.70, p = 2.11E-3) and contribute to the preservation of kidney function.
Mediation analyses suggest that suppression of fibroblast growth factor 23 (FGF23) accounts for a significant portion of the protective effects on kidney function and CKD.
Metabolic traits, including body mass index and high-density lipoprotein levels, partially mediate the benefits of GLP-1R activation on CKD and estimated glomerular filtration rate (eGFR).

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AIMS: Despite observational links between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and kidney benefits, causal mechanisms remain unclear. This study aims to dissect genetic causality and mediation pathways underlying the effects of GLP-1RAs on chronic kidney disease (CKD) and related renal outcomes.

MATERIALS AND METHODS: Using large-scale Genome - Wide Association Study (GWAS) data, we applied two-sample Mendelian randomisation (MR) to estimate the causal effects of GLP-1RAs on CKD, estimated glomerular filtration rate (eGFR) and subtypes (IgA nephropathy, membranous nephropathy, nephrotic syndrome and chronic glomerulonephritis), with sensitivity analyses. The glycaemic markers (glycated haemoglobin [HbA1c] and blood glucose), type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) served as positive controls. Mediation MR assessed body mass index (BMI), lipids, glycaemic markers and inflammatory proteins. Data were sourced from MRC Integrative Epidemiology Unit Open Genome - Wide Association Studies OpenGWAS, FinnGen, GWAS Catalogue and cohort-specific studies.

RESULTS: Positive control analyses revealed that genetically predicted GLP-1R activation was associated with reduced levels of HbA1c (p = 4.93E-15) and blood glucose (p = 9.73E-5), as well as a decreased risk of T2DM (p = 2.45E-4) and DN (p = 6.35E-4), fully validating the reliability of the genetic instruments. Genetic proxies for GLP-1R activation lowered risks of CKD (odds ratio [OR] = 0.83, p = 9.22E-9), immunoglobulin A nephropathy (IgAN) (OR = 0.70, p = 2.11E-3) and kidney function preservation (β = 0.01, p = 9.11E-3), but showed null effects on other CKD subtypes. Mediation analyses indicated that fibroblast growth factor 23 (FGF23) suppression mediated 26.57% of the effect on eGFR and 13.50% of CKD protection, whereas metabolic traits (BMI: 2.08% for CKD, 5.51% for eGFR; high-density lipoprotein: 0.79% for CKD, 2.34% for eGFR; HbA1c: 8.25% for eGFR) partially explained the benefits on CKD and eGFR. Only BMI exhibited a mediation effect on IgAN. Sensitivity analyses confirmed minimal pleiotropy.

CONCLUSIONS: This study provides robust genetic evidence for repurposing GLP-1RAs in CKD and IgAN through anti-inflammatory (FGF23) and metabolic pathways, extending their utility beyond glucose control. While European ancestry data limit generalisability, our framework prioritises FGF23 and metabolic modulation as key targets for clinical trials in renal protection.

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

Abstract

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