SGLT2 Inhibitors Linked to Lower Risk of CKD, AKI Than GLP-1 RAs

Although both sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used in type 2 diabetes, their comparative effects on kidney outcomes have remained uncertain.¹

Initiation of SGLT2is was associated with a significantly lower risk of chronic kidney disease (CKD) and fewer acute kidney injury (AKI) events over 5 years compared with GLP-1 RAs, according to new research.

This comparative effectiveness analysis is published in JAMA Internal Medicine.

“To our knowledge, no head-to-head randomized clinical trials have directly compared the effectiveness of SGLT2is vs. GLP-1RAs in reducing CKD and AKI,” wrote the researchers of the study. “Network meta-analyses of randomized trials comparing SGLT2i and GLP-1RA treatment have reported mixed results.”

SGLT2is are a class of oral medications for type 2 diabetes that work by blocking the sodium‑glucose cotransporter‑2 protein in the kidneys, which reduces glucose reabsorption and increases its excretion in the urine, lowering blood sugar and modestly reducing blood pressure and weight.² They are also used to manage heart failure and CKD, helping to lower the risk of hospitalizations and slow kidney disease progression in individuals with or without diabetes.

This study analyzed nationwide, population-based registry data from Denmark to compare kidney outcomes among individuals with metformin-treated type 2 diabetes who initiated an SGLT2i or a GLP-1 RA between January 2014 and November 2020, with follow-up through October 2024.¹ Patients were included regardless of comorbidities, and treatment groups were balanced to account for baseline differences. Intention-to-treat analyses were performed, with CKD risk and AKI burden assessed.

Among 55,061 participants, 36,279 initiated an SGLT2i and 18,782 initiated a GLP-1RA, with similar baseline diabetes duration, kidney function, and albuminuria. Over 5 years, the weighted risk of CKD was lower among SGLT2i initiators than GLP-1 RA initiators (6.7% [95% CI, 6.4%-7.0%] vs 8.2% [95% CI, 7.8%-8.6%]; risk ratio, 0.81 [95% CI, 0.76-0.87]; risk difference, −1.5% [95% CI, −2.0% to −1.0%]).

The 5-year mean cumulative count of AKI per 100 individuals was also lower with SGLT2is (25.2; 95% CI, 24.4-26.1) compared with GLP-1 RAs (28.7; 95% CI, 27.4-30.0), corresponding to a mean cumulative count (MCC) ratio of 0.88 (95% CI, 0.83-0.93) and an MCC difference of −3.5 events (95% CI, −5.0 to −2.0).

In contrast, secondary outcomes showed modest reductions in albuminuria and mortality among GLP-1 RA initiators. Results were consistent across subgroups, with the largest reductions in CKD and AKI observed among individuals without preexisting kidney disease.

However, the researchers noted several limitations. Because treatment was not randomly assigned, residual confounding may have been present. Body mass index data were also unavailable, although sensitivity analyses among individuals with obesity showed similar results. Additionally, reliance on registry data carried a risk of misclassification, though validated algorithms and laboratory-based outcome definitions were used to minimize this risk. Finally, generalizability may have been limited, as the findings were based on a Nordic population and may not extend to other ethnic or health care settings.

Despite these limitations, the researchers believe the study found that initiation of SGLT2is in individuals with type 2 diabetes was associated with a lower 5-year risk of CKD and fewer AKI events compared with GLP-1 RAs.

“Notably, the differences in kidney outcomes were consistent across subgroups and most pronounced among individuals without preexisting kidney disease, which underscores a potential for primary prevention,” wrote the researchers. “Importantly, the divergent outcomes of eGFR [estimated glomerular filtration rate] and albuminuria suggest that combined treatment may offer additive benefits, which should be explored in future studies.”

References

1. Jensen SK, Heide-Jørgensen U, Andersen IT, et al. SGLT2 inhibitors vs GLP-1 receptor agonists for kidney outcomes in individuals with type 2 diabetes.  JAMA Intern Med.  Published online January 20, 2026. doi:10.1001/jamainternmed.2025.7409

2. Learning about SGLT2 inhibitors. Kaiser Permanente. Current as of October 2, 2025. Accessed January 21, 2026. https://healthy.kaiserpermanente.org/health-wellness/health-encyclopedia/he.learning-about-sglt2-inhibitors.aco0117