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Heterogeneous treatment effects of GLP-1RA on kidney outcomes in patients with type 2 diabetes

Yang Xu1, Carolien C H M Maas2, Tao Huang3

  • 1Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Kidney International
|July 24, 2026
PubMed
Abstract

Insights

Glucagon-like peptide-1 receptor agonists (GLP-1RA) offer kidney benefits for type 2 diabetes patients, particularly those at high risk. Personalized prescribing based on kidney function and risk stratification maximizes treatment effectiveness.

Area of Science:

  • Nephrology
  • Endocrinology
  • Pharmacology

Background:

  • Glucagon-like peptide-1 receptor agonists (GLP-1RA) are known to reduce kidney outcome risks in type 2 diabetes.
  • Individual patient responses to GLP-1RA therapy for kidney protection vary significantly.
  • Identifying subgroups that benefit most from GLP-1RA is crucial for personalized treatment.

Purpose of the Study:

  • To identify patient subgroups within type 2 diabetes who are more likely to experience kidney benefits from GLP-1RA therapy.
  • To investigate the heterogeneity of treatment effects of GLP-1RA on kidney outcomes compared to dipeptidyl peptidase-4 inhibitors (DPP-4i).

Main Methods:

  • A target trial emulation framework was used for a new-user, active comparator cohort study.
  • Over 28,000 individuals with type 2 diabetes initiating GLP-1RA or DPP-4i were analyzed.
  • Heterogeneous treatment effects were estimated using risk modeling (KFRE) and causal survival forests, with Shapley Additive Explanations for feature importance.

Main Results:

  • GLP-1RA initiation was associated with a reduced five-year risk of kidney outcomes compared to DPP-4i (HR 0.84).
  • Significant heterogeneity was observed: highest KFRE-risk patients showed substantial benefit (HR 0.70), while lowest-risk patients showed none (HR 1.06).
  • Predictors of benefit included lower eGFR, faster eGFR decline, higher albuminuria, higher HbA1c, and greater prior healthcare utilization.

Conclusions:

  • GLP-1RA therapy provides heterogeneous kidney benefits in type 2 diabetes, with highest-risk subgroups deriving the most significant risk reduction.
  • Personalized GLP-1RA prescribing, guided by kidney function, eGFR decline trajectory, and KFRE risk stratification, is supported by these findings.
Keywords:
glucagon-like peptide-1 receptor agonistsheterogeneous treatment effectkidney

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