Effect of mineralocorticoid receptor antagonist at baseline on the efficacy of sodium-glucose cotransporter-2 inhibitors in patients with heart failure: a meta-analysis of randomized controlled trials 

Mineralocorticoid receptor antagonists (MRAs) are considered part of the cornerstone of treatment in patients with heart failure (HF).¹ The European Society of Cardiology guidelines for the management of HF have given class Ia recommendations for the utilization of MRAs in patients with HF with reduced ejection fraction (HFrEF).² However, MRAs remain underused in clinical practice due to their risk of precipitating hyperkalemia and worsening renal function.¹ More recently, sodium-glucose cotransporter-2 inhibitors (SGLT2is) have shown beneficial effects in patients with HF across broad range of ejection fraction.^3–8 Although the combined diuretic action of these two drugs may carry the risk of volume depletion and hypotension, the potential benefits of concomitant administration of MRAs and SGLT2is on clinical outcomes may outweigh safety concerns. Data regarding whether concomitant MRA usage influences the efficacy of SGLT2is on clinical endpoints in patients with HF are ambiguous. Therefore, we conducted a meta-analysis to evaluate the effect of baseline MRA therapy on clinical outcomes in patients with HF receiving SGLT2is.

Medical Literature Analysis and Retrieval System Online (MEDLINE) and Cochrane were searched from inception through March 2022 without language restrictions. Studies were included if they: (i) were published randomized controlled trials or post-hoc analyses; (ii) included patients with HFrEF and/or HF with preserved ejection fraction (HFpEF) randomized to SGLT2i therapy versus placebo; and (iii) compared the effect of SGLT2i on clinical outcomes between MRA users and non-users. Outcomes of interest included composite of cardiovascular (CV) death/hospitalization for HF (HHF), CV death, HHF, and all-cause mortality. For each outcome, hazard ratios (HR) with 95% confidence intervals (CI) were extracted and pooled using a random-effects inverse variance model. To exclusively analyze patients with HFrEF, a sensitivity analysis was conducted by excluding the Empagliflozin Outcome Trial in Patients with Chronic HFpEF-Preserved and Effect of Sotagliflozin on CV Events in Patients with Type 2 Diabetes Post Worsening HF trials. A P-value of < 0.05 was considered significant. All analyses were conducted on Review Manager (Version 5.5; Cochrane Collaboration).

The initial search yielded 659 potential studies, of which 4 trials involving 15 684 patients with HF were included in this meta-analysis^3–5,8 (Supplementary material online, Figure). Baseline characteristics of the included patients are provided in Table 1. Pooled analysis demonstrated no significant difference in the incidence of composite of CV death and HHF between MRA users [HR: 0.75 (0.67–0.84); P < 0.00001] and non-users [HR: 0.74 (0.66–0.83); P < 0.00001] taking SGLT2is (P-interaction = 0.86) (Figure 1A). Similarly, significant reductions in the incidence of HHF were observed in both MRA users [HR: 0.75 (0.65–0.86); P < 0.0001] and non-users [HR: 0.65 (0.55–0.76); P < 0.00001] (P-interaction = 0.20) with a more pronounced effect in MRA non-users (Figure 1B). However, the risk of CV death was significantly reduced in MRA users [HR: 0.82 (0.72–0.93); P = 0.003)] but not in MRA non-users [HR: 0.97 (0.82–1.16); P = 0.75] (P-interaction = 0.12) (Figure 1C). SGLT2is did not significantly reduce the incidence of all-cause mortality in either MRA users [HR: 0.89 (0.80–1.01); P = 0.07] or non-users [HR: 0.97 (0.80–1.16); P = 0.72] (P-interaction = 0.49) (Figure 1D). Subgroup differences between the MRA users and non-users for all outcomes were not significant. Sensitivity analysis revealed consistent results except for all-cause mortality, where a significant reduction was noted in MRA users with HFrEF [HR: 0.85 (0.73–0.98); P = 0.02].

Figure 1

Forest plots for effect of sodium-glucose cotransporter-2 inhibitors on (A) primary composite endpoint, (B) hospitalization for heart failure, (C) CV death and (D) all-cause mortality, in patients with heart failure receiving and not receiving mineralocorticoid receptor antagonist therapy.

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The results of this meta-analysis demonstrate that SGLT2is reduced the composite of HHF/CV death and HHF in both MRA users and non-users similarly, but differing benefits were only observed in MRA users for CV death (and all-cause mortality in patients with HFrEF). The lack of significant subgroup differences between MRA users and non-users suggests that the MRA usage does not modify the treatment effect of SGLT2is on clinical outcomes in patients with HF. A marked 15% reduction noted in the risk of CV death in MRA users relative to non-users however may have important clinical implications. Although subgroup interactions failed to attain significance, this potential mortality benefit with concomitant usage of SGLT2is and MRAs should not be ignored and warrants further investigation. Supporting the administration of MRAs and SGLT2i together and taking advantage of different cardioprotective mechanisms of each drug may help to achieve cumulative benefit.⁹

Limitations in this study should be noted. This is a study-level meta-analysis since individual patient data were not available. Moreover, our analysis provides evidence for the overall HF population [both HFrEF (n = 9440) and HFpEF (n = 6244) patients] and HFrEF patients separately, but we were not able to ascertain the effect of concomitant SGLT2i and MRA therapy among HFpEF patients due to lack of pertinent data for meta-analysis. Finally, the effect of concomitant SGLT2is and MRAs administration on safety outcomes such as volume depletion and hypotension could not be assessed.

It is noteworthy to observe that MRA does not significantly modify the treatment effects of SGLT2i therapy, reinforcing the concept of polypharmacy and incremental use of therapies in HF. However, the existing differences for mortality outcomes and lack of trial analyses with respect to baseline MRA administration and aetiologies of HF necessitates future clinical trials to explore the concomitant effect of SGLT2is and MRAs in patients with HF even further.

Author contributions

M.S.A. and A.A. contributed to the conception or design of the work. A.E., W.A., and S.M.H.F. contributed to the acquisition, analysis, or interpretation of data for the work. M.S.A. and A.A. drafted the manuscript. M.M.M. and I.S. critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Supplementary material

Supplementary material is available at European Journal of Preventive Cardiology online.

Funding

None declared.

Data availability

This is a meta-analysis of previously published studies. Thus, the original extracted data can be found in Figure 1 and Table 1.

References

Author notes