Hyperkalemia raises the risk of cardiac arrhythmias and mortality and restricts the use of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptors antagonists, which improve clinical outcomes in persons with chronic kidney disease or systolic heart failure. In persons with type 2 diabetes at high cardiovascular risk or who have chronic kidney disease, sodium-glucose cotransporter 2 (SGLT2) inhibitors minimize the risk of cardiorenal events. However, their impact on hyperkalemia has not been well studied.

Individual participant data from randomized, double-blind, placebo-controlled clinical outcome studies with SGLT2 inhibitors in persons with type 2 diabetes at high cardiovascular risk or chronic renal disease were included in a meta-analysis. The major objective was time to significant hyperkalemia, defined as blood potassium 6.0 mmol/L measured by a central laboratory, with other outcomes including investigator-reported hyperkalemia episodes and hypokalemia (serum potassium ≤3.5 mmol/L). Cox regression analyses estimated treatment effects from each trial, with hazard ratios and matching 95% CIs combined using random-effects models to generate overall and key subgroup summary treatment effects.

About 6 studies with a total of 49,875 people evaluating four SGLT2 inhibitors were included in the study. A total of 1,754 patients experienced severe hyperkalemia, and 1,119 investigator-reported hyperkalemia incidents were documented. SGLT2 inhibitors decreased the risk of severe hyperkalemia (hazard ratio, 0.84 [95% CI, 0.76–0.93]), a result that was consistent across trials (Pheterogeneity=0.71). With SGLT2 inhibitors, the incidence of investigator-reported hyperkalemia was similarly decreased (hazard ratio, 0.80 [95% CI, 0.68–0.93]; Pheterogeneity=0.21). Serious hyperkalemia was reduced in a variety of categories, including those with impaired kidney function, a history of heart failure, and use of renin-angiotensin-aldosterone system inhibitors, diuretics, and mineralocorticoid receptor antagonists. Hypokalemia was not increased by SGLT2 inhibitors (hazard ratio, 1.04 [95% CI, 0.94–1.15]; Pheterogeneity=0.42).

SGLT2 inhibitors lowered the risk of severe hyperkalemia in persons with type 2 diabetes who are at high cardiovascular risk or who have chronic renal disease without increasing the risk of hypokalemia.