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.
MEDLINE and Cochrane were systematically searched from inception through March 2022, without any time or language restrictions. Studies were included if they: (a) were published randomized controlled trials or their post-hoc analyses; (b) included patients with HF randomized to SGLT2is therapy versus placebo; (c) compared the effect of SGLT2is on clinical outcomes between MRA users and non-users. Outcomes of interest included mild hyperkalemia (serum K+ > 5.5mmol/L), and moderate/severe hyperkalemia (serum K+ > 6.0 mmol/L). For each outcome, hazard ratios (HR) with 95% confidence intervals (CI) were extracted and pooled using a random-effects model for both MRA users and non-users. Given the well-established differences between etiology of patients with HFrEF and HFpEF, a sensitivity analysis was conducted by excluding the EMPEROR-Preserved trial. A p-value of < 0.05 was considered significant and I2 statistic was used to evaluate heterogeneity. All statistical analyses were conducted on Review Manager (Version 5.5; Cochrane Collaboration, Oxford, UK).
Initial search yielded 972 potential studies, of which 3 trials involving 14,462 patients with HF were included in this meta-analysis (5 – 7). Study and baseline characteristics of the included trials are provided in Table 1. Pooled analysis demonstrated no significant difference in the incidence of mild hyperkalemia between MRA users (HR: 0.82 [0.70-0.97]; p=0.02; I2=34%) and non-users (HR: 0.95 [0.77-1.17]; p=0.63; I2=23%) taking SGLT2is (P-interaction=0.28). (Figure 1A)., A significant reduction in the incidence of severe hyperkalemia was observed 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) (Figure 1B). Patients intaking concomitant therapy of MRA and SGLT2i showed reduction in the risk of mild and moderate/severe hyperkalemia by 13% and 17% respectively, when compared to patients intaking only SGLT2i. Sensitivity analysis revealed MRA use at baseline to be associated with no significant reduction in the incidence of mild hyperkalemia (HR: 0.89 [0.76-1.04]; p=0.14; I2=0%) while yielding otherwise consistent results for outcomes across both subgroups.
The results of this meta-analysis demonstrate that SGLT2is significantly reduce the risk of severe hyperkalemia in both MRA users and nonusers, while demonstrating similar reduction in the risk of mild hyperkalemia for either subgroup, when compared to placebo. Importantly, a marked 65% reduction in the risk of moderate/severe hyperkalemia in MRA users versus non-users suggests that harnessing SGLT2is may enable up titration and continuation of guideline-recommended MRA therapy in HFrEF patients. Although subgroup interactions failed to achieve significance, it is noteworthy to observe the beneficial effect exerted by concomitant SGLT2is and MRA therapy in reducing severe hyperkalemia, a major safety concern for currently recommending MRAs. It is to be noted, however, that in all included trials, patients were assigned to subgroups on the basis of baseline MRA therapy, and not MRA therapy initiated later during the trial. In addition, the use of SGLT2is in alleviating the risk of severe hyperkalemia may be due to the higher rates of discontinuation of MRA therapy during follow-up (8), a possibility that should be investigated in future. Moreover, the possibility of residual confounding cannot be eliminated since MRA use at baseline was not used as a stratification variable in any of the three trials. These inherent flaws in the included studies could therefore attribute our findings to chance alone. Moreover, while sensitivity analysis yielded no significant reduction in the risk of mild hyperkalemia in both MRA and non-MRA users, the consistent trend towards reduction in mild hyperkalemia may harbor important clinical implications, and future trials investigating the same may potentially affirm a significant beneficial effect of concomitant MRA and SGLT2is therapy in this regard.
Limitations in the study should be noted. The exact mechanism by which SGLT2is interfere with MRA-induced hyperkalemia remains unknown. A recent meta-analysis of randomized controlled trials demonstrated that a considerable 46% of the 9.3% cases of hyperkalemia on MRA may in fact be due to non-MRA reasons, thus suggesting that the apparent MRA-induced hyperkalemia may likely be due to non-MRA reasons as well.
Nonetheless, it is of great importance to note that MRA reduced the risk mild or moderate/severe hyperkalemia, when added to SGLT2i. This reiterates the concept of polypharmacy and use of guideline-directed medication therapy (GDMT) in HF. Future clinical trials involving SGLT2is should directly assess the relative risk reduction in mild and moderate/severe hyperkalemia, and other important adverse effects such as renal insufficiency, hypotension, and volume depletion, when used concomitantly with MRA.