Large Comparative Study Addresses Evidence Gap
INITIATING treatment with sodium–glucose cotransporter-2 inhibitors (SGLT2i) is associated with improved kidney outcomes compared with glucagon-like peptide-1 receptor agonists (GLP-1RA) in individuals with Type 2 diabetes, according to a nationwide comparative effectiveness study.
While both drug classes are widely recommended for cardiometabolic risk reduction in Type 2 diabetes, no randomised clinical trials have directly compared their effects on kidney outcomes. This study sought to address that gap using a target trial emulation approach based on population-level data from Denmark.
Study Design and Population
The investigators analysed nationwide registry data from individuals with metformin-treated Type 2 diabetes who initiated either an SGLT2i or a GLP-1RA between January 2014 and November 2020, with follow-up through October 2024. The final cohort included 36,279 SGLT2i initiators and 18,782 GLP-1RA initiators, with comparable baseline kidney function, diabetes duration, and albuminuria levels.
The two coprimary outcomes were chronic kidney disease (CKD), defined by a ≥40% decline in estimated glomerular filtration rate, severe albuminuria, or kidney failure, and acute kidney injury (AKI). Intention-to-treat analyses were performed using inverse probability weighting.
SGLT2 Inhibitors Reduce CKD and AKI Risk
Over five years, initiation of SGLT2i therapy was associated with a significantly lower risk of CKD compared with GLP-1RA initiation (6.7% vs 8.2%), corresponding to a 19% relative risk reduction. SGLT2i initiation was also associated with a lower burden of AKI events, with a mean cumulative count of 25.2 vs 28.7 AKI events per 100 individuals over five years.
These benefits were consistent across most subgroups and were most pronounced among individuals without pre-existing kidney disease, suggesting a role for SGLT2 inhibitors in primary prevention of diabetic kidney disease.
Secondary Outcomes and Clinical Implications
In contrast, secondary outcomes showed slightly lower risks of albuminuria progression and mortality among GLP-1RA initiators, highlighting potential trade-offs between the two drug classes. The authors emphasise that treatment decisions should remain individualised, particularly in patients with competing renal and cardiovascular priorities.
Implications for Clinical Practice
The findings strengthen evidence supporting SGLT2 inhibitors as a preferred option for kidney protection in people with Type 2 diabetes. In the absence of direct randomised comparisons, this large real-world analysis provides clinically relevant data to guide therapeutic selection and kidney disease prevention strategies.
Reference
Jensen SK et al. SGLT2 inhibitors vs GLP-1 receptor agonists for kidney outcomes in individuals with Type 2 diabetes. JAMA Intern Med. 2026;doi: 10.1001/jamainternmed.2025.7409
