Comparative Effectiveness of SGLT2 Inhibitor and GLP-1 Receptor Agonist on Kidney and Cardiovascular Outcomes by Kidney Failure Risk
Related Experiment Video
Updated: Jan 22, 2026
Robot-Assisted Kidney Transplantation
Published on: July 19, 2021
Sydney E Hartsell1,2,3,4, Guo Wei1,2,3, Ravinder Singh1,3,5
1Cardiovascular, Renal and Metabolism Center, Spencer Fox Eccles School of Medicine, Salt Lake City, Utah.
Key Points:
In veterans with type 2 diabetes and low kidney failure risk, sodium-glucose cotransporter 2 inhibitors (SGLT2is) were more kidney protective while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were more cardioprotective. For cardiovascular-kidney-metabolic outcomes, GLP-1 RAs were more protective at moderate kidney failure risk and SGLT2is were more protective at high kidney failure risk. The kidney failure risk equation might be a clinically useful tool to guide therapy in type 2 diabetes.
Background:
Head-to-head comparisons of non-exendin glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) on kidney failure or cardiovascular-kidney-metabolic (CKM) composite end points are lacking. Whether kidney failure risk modifies the comparative effectiveness of GLP-1 RA versus SGLT2i is clinically relevant.
Methods:
We defined a national veterans cohort with type 2 diabetes who initiated an SGLT2i, non-exendin GLP-1 RA, or insulin glargine between January 1, 2018, and December 31, 2021. After applying inverse probability of treatment weighting to balance baseline characteristics, outcomes were compared across new-user groups through March 31, 2023. Outcomes included kidney failure (stage 5 CKD or long-term KRT), major adverse cardiovascular events (MACEs: heart failure, myocardial infarction, or stroke), CKM composite (kidney failure or MACE), all-cause death, and composites of outcomes with death. We tested for effect modification by the kidney failure risk equation (KFRE) score on comparative pairwise drug effectiveness.
Results:
Out of 160,428 veterans, 53%, 14%, and 34% were new users of SGLT2i, GLP-1 RA, and insulin glargine, respectively. Relative to GLP-1 RA new-users, SGLT2i new-users had similar mortality risk, a trend toward lower kidney failure risk (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.74 to 1.06), but higher risk of MACE (HR, 1.14; 95% CI, 1.09 to 1.20) and CKM composite (HR, 1.13; 95% CI, 1.08 to 1.19). The effect of SGLT2i versus GLP-1 RA differed significantly between moderate-risk (2%-6%) and high-risk (≥6%) KFRE subgroups for all outcomes except all-cause death. In those with moderate-risk KFRE, GLP-1 RA seemed more protective for kidney failure, MACE, and CKM composite, while SGLT2i appeared more protective in those with high-risk KFRE.
Conclusions:
Compared with GLP-1 RA, SGLT2i had comparable risks of mortality, perhaps a lower risk of kidney failure, but modestly higher risk of cardiovascular events in the entire cohort. However, GLP-1 RA were more beneficial in those with moderate kidney failure risk and SGLT2i more beneficial in those with high kidney failure risk.
Podcast:
This article contains a podcast at https://dts.podtrac.com/redirect.mp3//www.asn-online.org/media/podcast/JASN/2026_07_29_KTS_July2026.mp3.
Insights
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and non-exendin glucagon-like peptide-1 receptor agonists (GLP-1 RA) show differing benefits for type 2 diabetes patients based on kidney failure risk. GLP-1 RAs are more protective for moderate risk, while SGLT2i are more beneficial for high risk.
Area of Science:
- Endocrinology
- Nephrology
- Cardiology
Background:
- Direct comparisons between non-exendin glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) for kidney failure or cardiovascular-kidney-metabolic (CKM) composite endpoints are limited.
- Understanding if baseline kidney failure risk influences the comparative effectiveness of GLP-1 RA versus SGLT2i is crucial for clinical decision-making in type 2 diabetes management.
Purpose of the Study:
- To compare the effectiveness of SGLT2 inhibitors and non-exendin GLP-1 receptor agonists in a large cohort of veterans with type 2 diabetes.
- To investigate whether the Kidney Failure Risk Equation (KFRE) score modifies the comparative effectiveness of these drug classes on kidney and cardiovascular outcomes.
Main Methods:
- A national veterans cohort with type 2 diabetes initiating SGLT2i, non-exendin GLP-1 RA, or insulin glargine was established.
- Inverse probability of treatment weighting was used to balance baseline characteristics before comparing outcomes including kidney failure, major adverse cardiac events (MACE), and CKM composite endpoints.
- Effect modification by KFRE score was tested for comparative drug effectiveness.
Main Results:
- Compared to GLP-1 RA, SGLT2i users showed a trend toward lower kidney failure risk but a higher risk of MACE and the CKM composite.
- The comparative effectiveness of SGLT2i versus GLP-1 RA significantly differed between moderate-risk (2-6% KFRE) and high-risk (≥6% KFRE) subgroups for most outcomes.
- GLP-1 RA demonstrated greater protection for kidney failure, MACE, and CKM composite in the moderate-risk KFRE group, whereas SGLT2i showed greater benefit in the high-risk KFRE group.
Conclusions:
- SGLT2i and GLP-1 RA have comparable mortality risks, with SGLT2i potentially offering a lower kidney failure risk but a modestly higher cardiovascular event risk than GLP-1 RA.
- The choice between SGLT2i and GLP-1 RA should consider individual patient's kidney failure risk, as GLP-1 RA appears more beneficial for moderate risk and SGLT2i for high risk.
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