Among the drug combinations that may increase serum potassium in patients with diabetic kidney disease, those that include a mineralocorticoid receptor antagonist (MRA) carry the highest risk for hyperkalemia, investigators report. Use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) may decrease hyperkalemia risk.

Investigators led by Zhiguo Mao, MD, of Changzheng Hospital, Second Military Medical University in Shanghai, China, conducted a network meta-analysis of drug combinations involving renin-angiotensin-aldosterone-system inhibitors (RAASi). The analysis was based on 27 studies involving 43,589 adults with diabetic kidney disease.

Angiotensin receptor blockers (ARB) significantly increased the odds of hyperkalemia 2.4-fold compared with placebo and 3.8-fold compared with angiotensin-converting enzyme inhibitors (ACEi). Renin inhibitors combined with ACEI or ARB were significantly associated with 2.7-fold increased odds of hyperkalemia.

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An MRA added to ACEi or ARB significantly increased the odds of hyperkalemia 6.1-fold compared with placebo, Dr Mao’s team reported in the Clinical Journal of the American Society of Nephrology. MRA added to ACEi or ARB increased the odds of hyperkalemia by 3.1-, 2.6-, and 9.2-fold, respectively, compared with ACEi, ARB, or SGLT2i monotherapy, respectively. MRA combined with ACEi/ARB was significantly associated with 2.2-fold increased odds of hyperkalemia a compared with a renin inhibitor and ACEi/ARB. MRA plus ACEi/ARB was significantly associated with 4.1-fold increased odds of hyperkalemia compared with SGLT2i and ACEi/ARB.

The likelihood of hyperkalemia was highest with the steroidal MRA spironolactone followed by the nonsteroidal MRAs esaxerenone and finerenone in combination with ACEI/ARB: 9.5-, 6.3-, and 3.4-fold increased odds, respectively. Data on eplerenone were unclear.

SGLT2i significantly lowered the odds of hyperkalemia by 67%, 72%, 83%, 89%, and 76% compared with ACEi, ARB, ACEi plus ARB, MRA (finerenone or esaxerenone) plus ACEi/ARB, and renin inhibitors combined with ACEi/ARB, respectively.

Adding SGLT2i to the combination of MRA (finerenone or esaxerenone) and ACEi/ARB, significantly reduced the odds of hyperkalemia by 69% compared with MRA plus ACEi/ARB alone.

“Our study provided additional rationales for the combined use of SGLT2i, MRA, and ACEI/ARB in diabetic kidney disease,” Dr Mao’s team wrote.

The investigators could not rule out the influence of background medications.


Luo X, Jing Xu M, Zhou S, Cheng Xue M, Chen Z, Zhiguo Mao M. Influence of SGLT2i and RAASi and their combination on risk of hyperkalemia in DKD: a network meta-analysis. Clin J Am Soc Nephrol. Published online May 31, 2023. doi:10.2215/CJN.0000000000000205