Comparative Effectiveness of SGLT2 Inhibitor and GLP-1 Receptor Agonist on Kidney and Cardiovascular Outcomes by Kidney Failure Risk.
SGLT2 inhibitors may be more kidney protective, while GLP-1 receptor agonists offer better cardiovascular protection, with effectiveness varying by kidney failure risk in veterans with type 2 diabetes.
Where it sits
this study against the rest of the lixisenatide corpusSummary and findings
The study assessed the comparative effectiveness of SGLT2 inhibitors and GLP-1 receptor agonists on kidney and cardiovascular outcomes in veterans with type 2 diabetes. It found that SGLT2 inhibitors were more protective for kidneys, while GLP-1 receptor agonists were more cardioprotective, with variations based on kidney failure risk. The study involved 160,428 veterans and used inverse probability of treatment weighting to balance baseline characteristics.
Abstract
<h4>Key points</h4>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.<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.<h4>Podcast</h4>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.
Background
This study addresses the comparative effectiveness of SGLT2 inhibitors and GLP-1 receptor agonists on kidney and cardiovascular outcomes in type 2 diabetes patients. Prior research has not extensively compared these two classes of drugs head-to-head, particularly in relation to kidney failure risk. Understanding these differences is clinically relevant for optimizing treatment strategies in patients with varying risks of kidney failure.
Methods
The study utilized a national cohort of veterans with type 2 diabetes who initiated treatment with SGLT2 inhibitors, GLP-1 receptor agonists, or insulin glargine between January 1, 2018, and December 31, 2021. Inverse probability of treatment weighting was applied to balance baseline characteristics among the groups. Outcomes assessed included kidney failure, major adverse cardiovascular events, a composite of kidney and cardiovascular outcomes, all-cause death, and composites of outcomes with death. The study also examined effect modification by the kidney failure risk equation score.
Results
Among 160,428 veterans, 53% were new users of SGLT2 inhibitors, 14% of GLP-1 receptor agonists, and 34% of insulin glargine. SGLT2i users had a hazard ratio of 0.89 for kidney failure risk compared to GLP-1 RA users, indicating a trend toward lower risk. However, they had a higher risk of major adverse cardiovascular events (HR, 1.14) and the composite cardiovascular-kidney-metabolic outcome (HR, 1.13). The effectiveness of these drugs differed significantly between moderate-risk and high-risk kidney failure subgroups, with GLP-1 RA being more protective in moderate-risk and SGLT2i in high-risk groups.
Interpretation
The study suggests that while SGLT2 inhibitors may offer better kidney protection, GLP-1 receptor agonists provide superior cardiovascular protection, particularly in patients with moderate kidney failure risk. The findings align with existing literature on the differential effects of these drug classes but highlight the importance of considering kidney failure risk when choosing treatment. The observational nature of the study and its focus on a veteran population may limit the generalizability of the results.
Key findings
- 53% of veterans were new users of SGLT2 inhibitors.
- 14% of veterans were new users of GLP-1 receptor agonists.
- SGLT2i users had a hazard ratio of 0.89 for kidney failure risk compared to GLP-1 RA users.
- SGLT2i users had a hazard ratio of 1.14 for major adverse cardiovascular events compared to GLP-1 RA users.
- The effect of SGLT2i vs GLP-1 RA differed significantly between moderate-risk (2%-6%) and high-risk (≥6%) KFRE subgroups.
Limitations
- Observational study design
- Specific to veteran population
- Potential confounding despite weighting
- No randomization
- Results may not generalize to non-veteran populations