Clinical Research: Diabetes and the Kidney

Head-to-head comparisons of non-exendin glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) on kidney failure or cardiovascular-kidney-metabolic (CKM) composite endpoints 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 1/1/2018 and 12/31/2021. After applying inverse probability of treatment weighting to balance baseline characteristics, outcomes were compared across new-user groups through 3/31/2023. Outcomes included kidney failure (stage 5 chronic kidney disease or long-term renal replacement therapy), major adverse cardiac events (MACE: 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 (HR 0.89, 95% CI 0.74-1.06), but higher risk of MACE (HR 1.14, 95% CI 1.09-1.20) and CKM composite (HR 1.13, 95% CI 1.08-1.19). The effect of SGLT2i versus GLP-1 RA differed significantly between moderate-risk (2 to 6%) and high-risk (≥6%) KFRE subgroups for all outcomes except all-cause death. In those with moderate-risk KFRE, GLP-1 RA appeared more protective for kidney failure, MACE, and CKM composite, while SGLT2i appeared more protective in those with high-risk KFRE.

Conclusions: 

Compared to 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.