Mineralocorticoid Receptor Antagonists and SGLT2 Inhibitor Therapy: The Best of Both Worlds in HFrEF

Faiez Zannad, MD; Patrick Rossignol, MD


JACC Heart Fail. 2021;9(4):265-267. 

The concomitant use of multiple medicines in an individual patient is referred to as polypharmacy. Polypharmacy is commonly used in patients with multiple comorbidities, as each medication may be useful to treat each comorbid condition. Polypharmacy has had bad publicity, because it is commonly associated with high rates of adverse outcomes and multiple poorly understood pharmacological interactions. However, multiple medications may be indicated concomitantly in order to target multiple mechanisms underlying one main condition, such as heart failure with reduced ejection fraction (HFrEF). Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists act to mitigate the deleterious effects of renin-angiotensin system (RAS) activation, mineralocorticoid receptor antagonists (MRAs) uniquely oppose the harmful effects of aldosterone, beta-blockers distinctly modulate the excessive adrenergic drive, sacubutril-valsartan adds to the inhibition of the RAS via neprilysin, and gliflozins specifically inhibit the sodium-glucose cotransporters' (SGLT) disrupted regulation in the heart and the kidneys. The clinical benefit of each of these 4 drug classes, cited previously in their "order of appearance" on the clinical practice stage, relies on the highest level of clinical trial–based evidence. In each of the landmark consecutive HFrEF trials, subgroup analyses based on background heart failure (HF) therapy have consistently shown that the benefits of each newer drug class are independent of the use of all background therapies, thus providing cumulative benefit. It is then no surprise that successive international guidelines recommend incremental use of HFrEF therapies, adding up to the optimal quadruple therapy "polypharmacy."

In this issue of the JACC: Heart Failure, Shen et al.[1] report the effect of SGLT2 inhibition according to MRA use at baseline, in the DAPA-HF (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) trial. The hazard ratio (HR) of the primary endpoint of cardiovascular death or worsening HF episode, for dapagliflozin compared with placebo was 0.74 (95% confidence interval [CI]: 0.63 to 0.87) in MRA-treated patients versus 0.74 (95% CI: 0.57 to 0.95) in the no MRA subgroup (p-interaction 0.97).[1] This is consistent with the result of a similar subgroup analysis of empagliflozin treatment, in the EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial, whereby the HR of the primary endpoint was 0.76 (95% CI: 0.59 to 0.97) in non-MRA users and 0.75 (95% CI: 0.63 to 0.88) in MRA users.[2] Likewise, in both DAPA-HF and EMPEROR-Reduced, the benefit of SGLT2i therapy was shown to be independent from and additional to the use of sacubutril-valsartan.[3]

The benefit of "polypharmacy," with all 4 foundational classes of disease-modifying drugs (angiotensin receptor–neprilysin inhibitors, β-blocker, MRA, and SGLT2 inhibitor) in HFrEF, modeled in a cross-trial analysis, by Vaduganathan et al.[4] amounted to an HR for cardiovascular death or hospital admission for heart failure of 0.38 (95% CI: 0.30 to 0.47), compared with conventional therapy (consisting of an ACE inhibitor or angiotensin receptor blocker [ARB] and β-blocker). Depending on patient age at treatment onset, quadruple therapy may add 1.4 to 6.3 years of survival and 2.7 to 8.3 years free from cardiovascular death or hospital admission for heart failure, compared with treatment with ACE inhibitor or ARB and β blocker alone.[4]

DAPA-HF and EMPEROR-Reduced also targeted renal outcomes as secondary endpoints. Indeed, cardiorenal interactions deserve special attention in HFrEF. Shen et al.[1] reported that the prespecified composite renal efficacy outcome (≥50% sustained decline in estimated glomerular filtration rate [eGFR], end-stage renal disease, i.e., sustained eGFR <15 ml/min per 1.73 m2, chronic dialysis treatment or renal transplant, or renal death) was infrequent (28 in dapagliflozin vs. 39 in placebo patients) and was not reduced significantly by dapagliflozin (HR: 0.71; 95% CI: 0.44 to 1.16; p = 0.17). A similar analysis was performed in EMPEROR-Reduced and concluded that there was a significant effect of empagliflozin on renal outcomes.[3] A meta-analysis of study-level data showed that the effects of empagliflozin and dapagliflozin on renal outcomes were consistent across the 2 independent trials, suggesting that these agents also improve renal outcomes in patients with HFrEF.[4] In the subgroup analysis by Shen et al.,[1] the number of renal events was far too low to determine the impact of concomitant MRA therapy on renal benefits. A meta-analysis of patient-level data from DAPA-HF and EMPEROR-Reduced might help to better inform this possible interaction.

As mentioned previously, polypharmacy is more commonly discussed in the context of safety concerns. Actually, the concomitant use of multiple therapies in HFrEF trials consistently results in a favorable net benefit-to-risk ratio with the use of therapy incrementation. In the historic CONSENSUS (COoperative North Scandinavian ENalapril SUrvival Study) trial (1987), long before the RALES (Randomized ALdactone Evaluation Study) trial (1999), almost 50% of patients were receiving spironolactone at high "diuretic doses." Although spironolactone users had more frequent worsening renal failure and hyperkalemia when receiving enalapril, the survival benefit of adding the ACE inhibitor outweighed the risk associated with the renal and potassium adverse events. In the Shen et al. report,[1] safety outcomes were similar in patients randomized to dapagliflozin or placebo, whether they were receiving concomitant MRA therapy or not. Intriguingly, in the MRA group, moderate/severe hyperkalemia (potassium >6.0 mmol/l) occurred in 21 (1.3%) of 1,683 patients treated with dapagliflozin and in 40 (2.4%) of 1,666 patients treated with placebo, giving an HR of 0.50 (95% CI: 0.29 to 0.85). The corresponding numbers in patients not treated with an MRA were 13 (1.9%) of 675 and 11 (1.6%) of 695, respectively (HR: 1.17; 95% CI: 0.52 to 2.62); interaction p = 0.08. However, the rate of hyperkalemia >5.5 mmol/l was correspondingly 204 (12.6%) versus 180 (11%) in MRA users and 57 (8.4%) versus 63 (9.6%) in non-MRA users, which was not statistically different between and across subgroups (p value for interaction 0.13). Notably, in this analysis, subgroups were defined based on MRA use at baseline, which cannot necessarily be extended to MRA use initiated during the trial. Indeed, MRA use in patients with HFrEF was shown to vary over time in a longitudinal clinical observational study.[5] Whether the lower rate of hyperkalemia >6 mmol/l observed in DAPA-HF when dapagliflozin is added to MRAs might be a consequence of more patients discontinuing MRA therapy during the follow-up should be investigated further, if reliable data regarding MRA dosing or adherence over the course of the study are available. In addition, randomization in the DAPA-HF trial was not stratified according to MRA use, and, accordingly, one cannot exclude residual confounding. Therefore, and with no mechanistic plausibility to offer, it is likely that the seemingly lower rate of hyperkalemia >6 mmol/l with dapagliflozin added to MRA therapy is a chance finding, and whether the use of dapagliflozin may enhance the ability to use MRAs safely remains speculative.

Similar analyses as the one reported by Shen et al.[1] applied to EMPEROR-Reduced might further our understanding of the interaction between SGLT2i and MRA therapy. A meta-analysis of patient-level data might be the most appropriate way to gain further insight into infrequent outcomes in small subgroups, across the 2 twin trials.

Meanwhile, the current data from DAPA-HF and EMPEROR-Reduced support the main conclusion of Shen et al..[1] SGLT2i therapy is indeed similarly efficacious and safe in patients with HFrEF who are taking or not taking an MRA, supporting the use of both treatments together, and taking advantage of the best of both worlds.