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

Abstract

Mineralocorticoid receptor antagonists (MRAs) are guideline-recommended medications for patients with heart failure (HF) that reduce the risk of cardiovascular death and hospitalization, and improve survival. Evidence from recent clinical trials has indicated that the use of SGLT2is reduces the risk of HF hospitalization in HF patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). The clinical benefit of these two drugs is based on highest level of clinical trial evidence. However, the risk of hyperkalemia limits the usage of MRAs (1). Considering this risk, both the current European Society of Cardiology (ESC) and American Heart Association/ American College of Cardiology (AHA/ACC) guidelines practice caution and recommend halving the dose and cessation of MRA therapy at serum potassium levels of >5.5 mmol/L and >6.0 mmol/L, respectively (2 – 4). SGLT2is exert diuretic effects and initially impair kidney function in patients. The combination of these two drugs is therefore expected to cause severe exacerbation in hyperkalemia. However, evidence from recent clinical trials has demonstrated that the use of SGLT2i may potentially reduce the rate of hyperkalemia when added to MRA therapy, and thus, can be used to optimize guideline-recommended MRA usage among patients with HF (5 – 7). Data regarding whether the concomitant use of both therapies reduces the risk of precipitating hyperkalemia among patients with HF is unclear. Therefore, we conducted a meta-analysis to evaluate the effect of baseline MRA therapy on the incidence of hyperkalemia in patients taking SGLT2is.

Combination therapy with kidney protective therapies: optimizing the benefits?

“…The ROTATE-3 study showed that the incidence of hyperkalemia was significantly lower in the combination arm compared with the eplerenone arm, suggesting that using SGLT-2 inhibitors together with MRAs could mitigate the risk of hyperkalemia. A meta-analysis using participant individual participant data from randomized, double-blind, placebo-controlled clinical outcome trials with SGLT-2 inhibitors in people with type 2 diabetes showed that SGLT-2 inhibitors reduce the risk of serious hyperkalemia, further confirmed by a meta-analysis that analyzed three RCTs (14 462 patients) in people with heart failure, when added to MRA suggesting that combining SGLT-2 inhibitors with MRA's especially the newer nonsteroidal MRAs, which are less likely to cause hyperkalemia might further mitigate the risk [35,36]. The sodium retention and risk of edema with ERAs could also perhaps be mitigated by combining their use with SGLT-2 inhibitors.…”