Serum potassium changes due to concomitant ACEI/ARB and spironolactone therapy: A systematic review and meta-analysis

Am J Health Syst Pharm. 2021 Dec 9;78(24):2245-2255. doi: 10.1093/ajhp/zxab215.


Purpose: To provide evidence of serum potassium changes in individuals taking angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) concomitantly with spironolactone compared to ACEI/ARB therapy alone.

Methods: PubMed, Embase, Scopus, and Web of Science were searched for studies including exposure to both spironolactone and ACEI/ARB therapy compared to ACEI/ARB therapy alone. The primary outcome was serum potassium change over time. Main effects were calculated to estimate average treatment effect using random effects models. Heterogeneity was assessed using Cochran's Q and I2. Risk of bias was assessed using the revised Cochrane risk of bias tool.

Results: From the total of 1,225 articles identified, 20 randomized controlled studies were included in the meta-analysis. The spironolactone plus ACEI/ARB group included 570 patients, while the ACEI/ARB group included 547 patients. Treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L), with intermediate heterogeneity across studies (Q statistic = 46.5, P = 0.004; I2 = 59). Sensitivity analyses showed that the direction and magnitude of this outcome did not change with the exclusion of individual studies, indicating a high level of reliability. Reporting risk of bias was low for 16 studies (80%), unclear for 3 studies (15%) and high for 1 study (5%).

Conclusion: Treatment with spironolactone in combination with ACEI/ARB therapy increases the mean serum potassium concentration by less than 0.20 mEq/L compared to ACEI/ARB therapy alone. However, serum potassium and renal function must be monitored in patients starting combination therapy to avoid changes in serum potassium that could lead to hyperkalemia.

Keywords: angiotensin receptor blockers; angiotensin-converting enzyme inhibitors; hyperkalemia; spironolactone.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Angiotensin Receptor Antagonists*
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects
  • Humans
  • Potassium
  • Reproducibility of Results
  • Spironolactone* / adverse effects


  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Spironolactone
  • Potassium