Perioperative empagliflozin and risk of acute kidney injury after cardiac surgery: a systematic review and meta-analysis

Introduction Hypertension is the leading modifiable risk factor for cardiovascular disease globally, driven by a sodium-rich, potassium-poor dietary phenotype. Whilst potassium-enriched salt substitutes (PESS) demonstrate hypotensive potential, widespread clinical implementation is hindered by theoretical concerns regarding fatal hyperkalaemia, particularly in vulnerable populations. Purpose To evaluate the efficacy of PESS in reducing Systolic Blood Pressure (SBP) and Major Adverse Cardiovascular Events (MACE), whilst assessing safety regarding hyperkalaemia and sudden death. Methods We conducted a systematic review following PRISMA guidelines, searching PubMed and Embase databases without date restrictions. Eligibility criteria included RCTs involving adults with hypertension or high cardiovascular risk, comparing PESS (specifically 75% NaCl / 25% KCl formulations) against regular salt. Outcomes included SBP, MACE, 24-hour urinary Na/K excretion, hyperkalaemia, and sudden death. Statistical analysis utilised RStudio with a random-effects model to account for clinical heterogeneity. Effect measures included Mean Difference (MD) and Hazard Ratio (HR) or Risk Ratio (RR) with 95% Confidence Intervals (CI) and I2 statistic for heterogeneity. Results The search identified 104 records; following screening, four RCTs were included (N=24,998), comprising the SSaSS, DECIDE-Salt, Bernabe-Ortiz (Peru), and Barros (Brazil) trials. Efficacy analysis demonstrated robust SBP reduction, with MDs ranging from -1.29 mmHg in the Peruvian cohort to -7.10 mmHg in DECIDE (Pooled MD: -4.51 mmHg; 95% CI -6.10 to -2.92; I2=91%). Significant protection against MACE was observed with high consistency (I2<25%) in large trials (SSaSS: HR 0.86 [95% CI 0.77-0.96]; DECIDE: HR 0.60 [95% CI 0.38-0.96]). The mechanism was validated by urinary excretion changes: sodium reduction (-15.2 to -55.5 mmol/day) and potassium increase (+16.1 to +20.6 mmol/day). Regarding safety, whilst biochemical hyperkalaemia events increased significantly (RR 2.10; 95% CI 1.35-3.26; I2=0%), the meta-analysis of Sudden Death demonstrated no significant difference between groups (RR 1.05; 95% CI 0.82-1.34; I2=0%), indicating a dissociation between laboratory markers and fatal clinical endpoints. Conclusion Replacing regular salt with potassium-enriched formulations (75/25) is an efficacious strategy for BP reduction and MACE prevention. The biochemical risk of hyperkalaemia did not translate into increased sudden mortality in large-scale trials. Future studies should focus on Western populations to address dietary heterogeneity and consolidate generalisability.Risk of AKI: Empagliflozin vs. Control.Risk of POAF: Empagliflozin vs. Control.