Dose and Time Effects of Renin–Angiotensin Inhibitors on Patients With Advanced Stages 4 to 5 of Diabetic Kidney Disease

Abstract

Abstract Context Limited evidence exists regarding the cumulative dosing and duration impact of renin–angiotensin system inhibitors (RASis) on cardiorenal and mortality outcomes in patients with advanced stages (predominantly in stage 5 and a minority in stage 4) of diabetic kidney disease (DKD). Objective To retrospectively investigate whether there are dose- and time-dependent relationships between RASis and cardiorenal and mortality outcomes in this population. Methods Using Taiwan's national health insurance data in 2000-2017, we analyzed 2196 RASi users and 2196 propensity-matched nonusers among 8738 patients living with diabetes and newly diagnosed with advanced chronic kidney disease (23% stage 4, 77% stage 5). Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHRs) and 95% CI. Results RASi use was significantly associated with reduced risks of all-cause mortality (aHR, 0.53; 95% CI 0.47-0.60) and cardiovascular mortality (0.68; 0.56-0.83) with the degree of benefit depending on therapeutic dosage and duration, despite a nonsignificant increase in acute kidney injury risk (1.16; 0.98-1.38) and a significant increase in hyperkalemia risk (1.45; 1.19-1.77). Significant differences in proteinuria risk (1.32; 1.21-1.43) were observed, while there were no significant differences in end-stage renal disease risk (1.01; 0.88-1.15) and no dose– or time–response relationships for either end-stage renal disease or proteinuria risks. Sensitivity analyses confirmed cardiovascular and survival benefits, even in patients with stage 5 DKD. Conclusion This real-world study suggests that RASi use in advanced stages 4 to 5 DKD may provide dose- and time-dependent cardioprotection and improved survival, without excess renal harms.