Effects of RAS and SGLT2 inhibitors alone or in combination on end-stage kidney disease and/or all-cause death in patients with both diabetes and hypertension: a nationwide cohort study

Abstract

Background: Renin-angiotensin-aldosterone system (RAS) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors are key treatments for diabetic kidney disease. However, their independent and combined effects on end-stage kidney disease (ESKD) and mortality remain unclear. This study evaluates their impact, alone or in combination, on ESKD and all-cause mortality in patients with diabetes and hypertension. Methods: A nationwide cohort study using the Korean National Health Database included 261,783 individuals with type 2 diabetes and hypertension (2015-2017). Participants were grouped into (1) no RAS or SGLT2 inhibitors (reference), (2) SGLT2 inhibitors alone, (3) RAS inhibitors alone, and (4) combination therapy. Cox regression models were used to estimate hazard ratios (HRs) for ESKD, mortality, and their composite. Results: Over 5.38 years, 2,674 (1.02%) developed ESKD and 20,866 (7.97%) died. Combination therapy showed the greatest risk reduction for composite outcomes [HR 0.68, 95% confidence interval (CI) 0.56-0.82] and mortality (HR 0.68, 95% CI 0.56-0.83). SGLT2 inhibitors alone reduced composite risk (HR 0.71, 95% CI 0.61-0.84) and mortality (HR 0.68, 95% CI 0.57-0.81). RAS inhibitors alone had modest effects (HR 0.96, 95% CI 0.93-0.98) on composite outcomes and mortality (HR 0.94, 95% CI 0.91-0.97). Notably, only combination therapy was associated with lower ESKD risk (HR 0.63, 95% CI 0.37-1.07), but this was not statistically significant. SGLT2 inhibitors consistently reduced ESKD and mortality, while RAS inhibitors were beneficial mainly in non-SGLT2 inhibitor users. Conclusion: Combination therapy may provide the greatest renal and survival benefit for diabetic patients with hypertension. SGLT2 inhibitors alone significantly reduced mortality, while RAS inhibitors alone had a modest impact.