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Meta-Analysis Evaluating Risk of Hyperkalemia Stratified by Baseline MRA Usage in Patients with Heart Failure Receiving SGLT2 Inhibitors

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Both mineralocorticoid receptor antagonists (MRAs) and sodium-glucose co-transporter type 2 inhibitors (SGLT2is) have demonstrated beneficial reductions in cardiovascular outcomes. However, the risk of precipitating hyperkalemia with their concomitant usage remains unclear.


MEDLINE and Cochrane were searched from inception through March 2022. Randomized controlled trials on patients with heart failure (HF) evaluating the effect of SGLT2is on clinical outcomes between MRA users and non-users were considered for inclusion. Outcomes of interest were mild and moderate/severe hyperkalemia, for which hazard ratios (HR) were pooled using a random effects model.


From the 972 articles retrieved from the initial search, three RCTs (n = 14,462 patients) were included in our meta-analysis. Pooled analysis demonstrated no significant difference in the incidence of mild hyperkalemia between MRA users (HR 0.82 [0.70–0.97]) and non-users (HR 0.95 [0.77–1.17]) (P-interaction = 0.28). The risk of severe hyperkalemia was significantly decreased in MRA users (HR 0.59 [0.44–0.78]; p = 0.0002; I2 = 0%) but not in non-users (HR 0.76 [0.56–1.02]; p = 0.07; I2 = 0%) (P-interaction = 0.22). Sensitivity analysis including patients with HF with reduced ejection fraction (HFrEF) revealed similar results across all subgroups, but no significant reduction in the incidence of mild hyperkalemia (HR 0.89 [0.76–1.04] was noted in MRA users with HFrEF.


MRAs reduced the risk of mild or moderate/severe hyperkalemia, when added to SGLT2is. Future clinical trials should target scrupulous assessment of the risk of mild and moderate/severe hyperkalemia when used concomitantly with MRAs.

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Fig. 1

Data Availability

All raw data used for our meta-analysis has been sourced from already published papers referenced in our manuscript.

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Authors and Affiliations



AA conceived the idea of this study and performed the meta-analysis. WA majorly contributed to the writing of the manuscript. MSA, AS, and EA helped in data collection and writing of the manuscript. IS and MMM supervised all stages of data collection, analysis, and manuscript writing.

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Correspondence to Muhammad Sameer Arshad.

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Data used in this meta-analysis was publicly available hence ethical approval was not required.

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All authors declare that they have no conflicts of interest.

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Ahmed, A., Ahmed, W., Arshad, M.S. et al. Meta-Analysis Evaluating Risk of Hyperkalemia Stratified by Baseline MRA Usage in Patients with Heart Failure Receiving SGLT2 Inhibitors. Cardiovasc Drugs Ther (2023).

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