SGLT2 Inhibitors Show Superior Kidney Protection Over GLP-1RAs in Type 2 Diabetes
Real-world study finds SGLT2 inhibitors reduce chronic kidney disease and acute kidney injury risk more effectively than GLP-1 receptor agonists in patients with type 2 diabetes, with greatest benefits in those without preexisting kidney disease.
Initiation of sodium-glucose co-transporter 2 inhibitors (SGLT2is), compared with glucagon-like peptide-1 receptor agonists (GLP-1RAs), is associated with lower 5-year chronic kidney disease (CKD) risk and acute kidney injury (AKI) incidence among individuals with type 2 diabetes (T2D), according to study findings published in JAMA.
In real-world clinical practice, SGLT2is and GLP-1RAs are commonly prescribed to individuals with T2D who tend to be younger and have fewer comorbid conditions than patients enrolled in clinical trials. To date, no randomized controlled trial (RCT) has directly evaluated the comparative effectiveness of SGLT2is vs GLP-1RAs in preventing acute or chronic kidney outcomes.
Researchers aimed to compare the relative effectiveness of SGLT2i therapy with GLP-1RA therapy in reducing AKI and CKD outcomes among patients with T2D. Population-level data were sourced from Denmark between January 2014 to November 2020, with follow-up conducted through October 2024. Individuals with a prior dispensing of either medication were excluded from the study.
Using inverse probability of treatment weights to compare CKD risk assessment via the Aalen-Johansen estimator, the researchers estimated the intention-to-treat (ITT) effect. Subgroup analyses included stratification by kidney or preexisting cardiovascular disease.
The study enrolled 18,782 participants who initiated a GLP-1RA (median age, 63 years) and 36,279 participants who initiated a SGLT2i (median age, 61 years) with comparable estimated glomerular filtration rate (eGFR), diabetes duration, and urine albumin-creatinine ratios (UACR).
At 5 years, initiation of SGLT2 inhibitors vs GLP-1RAs was associated with a lower adjusted risk for CKD (6.7% vs 8.2%; risk ratio, 0.81; absolute risk difference, -1.5%). Similarly, the mean cumulative count (MCC) of AKI events per 100 individuals over 5 years was lower among SGLT2i initiators than GLP-1RA initiators (25.2 vs 28.7; MCC ratio, 0.88; MCC difference, -3.5).
In contrast, initiation of GLP-1RA therapy was associated with modestly lower rates of albuminuria and mortality. These findings were consistent across subgroups; the greatest reductions in CKD and AKI were observed with SGLT2i use among individuals without preexisting kidney disease.
Analysis of individual CKD components showed that SGLT2i vs GLP-1RA initiation was associated with a reduced risk for sustained eGFR decline (risk ratio, 0.75; risk difference, -1.4%) and kidney failure (risk ratio, 0.77; risk difference, −0.1%), whereas the risk for severe albuminuria was comparable between treatment groups (risk ratio, 0.98; risk difference, -0.1%).
The co–primary outcomes were AKI and CKD (defined as a 40% decline in eGFR, severe albuminuria, or kidney failure), while secondary outcomes included albuminuria, all-cause mortality, and the individual CKD components.
Study limitations include nonrandomized treatment assignment with potential residual confounding despite extensive adjustment, missing body mass index (BMI) data, possible misclassification from registry-based data despite validated definitions, and limited generalizability beyond Nordic populations.
Semaglutide, a GLP-1RA, has shown renoprotective benefits, particularly through reducing albuminuria in patients with microalbuminuria and macroalbuminuria compared with placebo. Both drug classes have demonstrated cardiovascular and renal protection in major clinical outcome trials, with reductions in hospitalization for heart failure and all-cause mortality.
Dapagliflozin, an SGLT-2 inhibitor, has consistently been associated with reductions in body weight and systolic blood pressure, while maintaining a favorable safety profile. The Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial demonstrated a 17% reduction in the composite outcome of cardiovascular death or hospitalization for heart failure with dapagliflozin.
The findings underscore the potential of SGLT2i treatment for primary prevention of kidney disease in individuals with type 2 diabetes.