Renoprotective Effects of RAAS Inhibitors in Patients with Diabetic Nephropathy: A Comprehensive Meta-Analysis of Randomized Controlled Trials

Abstract

Background: Diabetic nephropathy (DN) is a major driver of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide. A pivotal contributor to DN progression is the overactivation of the renin-angiotensin-aldosterone system (RAAS). Pharmacologic blockade of this pathway has become foundational in DN management. Recently, interest has grown in combining RAAS inhibitors with novel agents—such as non-steroidal mineralocorticoid receptor antagonists (MRAs, e.g., finerenone) and sodium-glucose cotransporter 2 (SGLT2) inhibitors—to enhance renoprotective outcomes while assessing associated risks. Objectives: This meta-analysis synthesizes current randomized controlled trial (RCT) evidence to evaluate the efficacy and safety of RAAS inhibitors, alone and in combination, in preserving renal function, reducing proteinuria, and limiting progression to ESRD in patients with DN. Methodology: Databases including PubMed, Scopus, and the Cochrane Library were systematically searched through May 2025. Only RCTs evaluating ACE inhibitors, ARBs, or MRAs either as monotherapy or in combination with other renoprotective agents were included. Primary outcomes were changes in estimated glomerular filtration rate (eGFR), proteinuria/albuminuria, ESRD incidence, and adverse events such as hyperkalemia. Data were synthesized using a random-effects model, and study quality was assessed using the Cochrane RoB 2.0 tool. Results: Seven RCTs encompassing 10,500 participants were included. RAAS inhibitors significantly reduced albuminuria (18–30%) and slowed the annual decline in eGFR. Finerenone, as an adjunct to RAAS blockade, further improved composite renal outcomes and reduced albuminuria. Combination therapies (RAASi + SGLT2i or MRA) were more effective than monotherapy but were associated with a modestly elevated risk of hyperkalemia (1.5–2 times increase). No significant heterogeneity or publication bias was detected. Conclusion: RAAS inhibition remains a cornerstone in DN treatment, offering substantial renoprotective benefits. The addition of agents like finerenone or SGLT2 inhibitors enhances therapeutic outcomes, supporting their integration into combination strategies—albeit with careful monitoring for adverse effects. The renoprotective benefits of RAAS inhibitors in diabetic nephropathy have remained of great importance in terms of preventing proteinuria and retarded decline of renal functions. Incremental benefits are seen with newer agents such as finerenone that, when added to baseline RAAS blockade, are associated with close attention to adverse effects. The results prove the further application of RAAS inhibitors and underline the importance of combination therapy in the maximization of the renal outcomes of diabetic patients.