Sodium-Glucose Co-Transporter 2 Inhibitors and Hyperkalemia-Related Discontinuation of Renin-Angiotensin-Aldosterone System Inhibitors During Mineralocorticoid Receptor Antagonist Therapy: A Real-World Cohort Study.

Background: Hyperkalemia (HK) is a common complication of renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, and the risk is often increased by concomitant use of a mineralocorticoid receptor antagonist (MRA). The effect of SGLT2i co-prescription on this risk in routine clinical practice remains incompletely understood. Methods: This is a secondary analysis of a published retrospective cohort of 905 adult RAASi users attending outpatient clinics at King Abdulaziz Medical City, Jeddah, Saudi Arabia (IRB: NRJ22J/279/11), followed for a median of 28 months. Patients were classified as RAASi alone (n = 723) or RAASi plus MRA (n = 182). Beta-blockers and digoxin were excluded from the exposure definition. Effect modification by SGLT2i was assessed using logistic regression with a multiplicative interaction term. Results: MRA addition was associated with significantly higher rates of any HK (48.4% vs. 28.9%; RR 1.67, 95% CI 1.38-2.02, p < 0.001) and moderate-to-severe HK (13.7% vs. 6.9%; RR 1.99, 95% CI 1.26-3.12, p = 0.003). Overall, RAASi discontinuation rates were similar between groups. SGLT2i co-prescription significantly modified the association between MRA use and HK-driven RAASi discontinuation (interaction p = 0.004): among patients without SGLT2i, MRA addition was associated with a more than 5-fold increase in HK-driven discontinuation (21.1% vs. 4.1%; RR 5.11, p = 0.001), whereas no significant excess risk was observed among SGLT2i users (1.8% vs. 4.2%; RR 0.44, 95% CI 0.12-1.57, p = 0.190), although this subgroup estimate was imprecise. CKD (aOR 2.16, 95% CI 1.56-2.99) and age ≥ 75 years (aOR 1.64, 95% CI 1.04-2.58) were the strongest independent predictors of HK. Conclusions: MRA addition to RAASi substantially increases HK burden, and SGLT2i co-prescription appears to protect against HK-driven RAASi discontinuation in combined RAASi-MRA-treated patients. In patients with established indications for SGLT2i, co-prescription may confer the additional benefit of preserving RAASi continuity in the setting of MRA combination therapy.