Contemporary medical therapy for heart failure with mildly reduced or preserved ejection fraction

Abstract

Treatment for heart failure with mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) has evolved significantly in recent years. This period of therapeutic progress follows a span of over two decades during which randomized controlled trials (RCTs) of neurohormonal blockade and other therapies failed to definitively demonstrate clinical benefits. As such, traditionally, management guidelines for HFmrEF and HFpEF were limited to recommendations focused on optimization of volume status with diuretics, management of comorbidities, and consideration of certain medications such as angiotensin receptor-neprilysin inhibitor (ARNi) or steroidal mineralocorticoid receptor antagonists (MRA) to subsets of patients. After definitive results from multiple RCTs, sodium-glucose cotransporter 2 inhibitors (SGLT2i) are currently a main pillar in treating HFmrEF and HFpEF in European and American guidelines. However, other therapies, including non-steroidal mineralocorticoid receptor antagonists (nsMRA) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), are proving to be additional effective treatments for HFmrEF and HFpEF and preventing the progression of cardiovascular-kidney-metabolic (CKM) syndrome. There is now increasing justification for combining multiple proven treatments for HFmrEF and HFpEF to maximize potential benefits.

Graphical abstract

Plain language summary

Treatment for different types of heart failure has improved significantly in recent years. For many years, there were few treatments that clearly helped people with heart failure whose heart still pumps normally or nearly normally. Care mainly focused on treating symptoms, helping the body remove excess fluid, and managing related health conditions such as high blood pressure, diabetes, and obesity. Today, research has expanded the available treatment options. One important group of medicines helps the body remove excess sugar and salt through the urine, which also reduces excess fluid and lowers the strain on the heart. Newer studies have shown that medicines that block the effects of a hormone called mineralocorticoid can improve outcomes while causing fewer side effects than older steroid-based treatments. For people who also have obesity, another newer group of medicines that acts on natural gut hormones has been shown to improve symptoms, physical activity, and quality of life. Overall, using a combination of these newer treatments may help people with heart failure whose heart still pumps normally or nearly normally feel better, improve their quality of life, and achieve better long-term health outcomes.

Introduction

Heart failure (HF) affects 1%–3% of people worldwide [1], with a lifetime risk to 24% and its prevalence is expected to rise to 8.5 million Americans by 2030 [2]. The prevalence of HF with preserved ejection fraction (≥50%, HFpEF) is rising [3]. Among patients from 254 hospitals in the Get With The Guidelines–Heart Failure database who were admitted for HF between 2005 and 2009, 46% had HFpEF, 8% had HF with mildly reduced ejection fraction (41–49%, HFmrEF), and 46% had HF with reduced ejection fraction (≤40%, HFrEF) [4], while between 2014 and 2019, 55% of patients in the same database had HFmrEF/HFpEF [5]. Despite comprising most of the HF population, evidence-based treatment options for patients with HFmrEF and HFpEF have historically been limited. However, more recent data from randomized controlled trials (RCTs) have greatly altered the range of pharmacologic options to modify disease progression in HFpEF [6].

This treatment paradigm for HFmrEF/HFpEF, and many of the specific therapeutic agents themselves, borrow from adjacent medical conditions, such as HFrEF where multiple pillars of therapy have existed for some time. Herein, we review the updated evidence for the management of HFmrEF/HFpEF, with evidence on best practices with medical therapy. The available therapies for HFmrEF/HFpEF, namely sodium-glucose cotransporter-2 inhibitors (SGLT2i), non-steroidal mineralocorticoid receptor antagonists (nsMRAs), and glucagon-like peptide-1 receptor agonist (GLP-1 RA), also provide the opportunity to prevent the progression of the cardiovascular-kidney-metabolic (CKM) syndrome to overt HFmrEF/HFpEF through their known mechanistic effects on diabetes, albuminuria, and/or obesity [7, 8] In this review, we set the stage for the role of emerging therapies within the CKM-based framework and multi-pillar strategy.

Diagnosis of HFmrEF and HFpEF in the context of CKM

Heart failure is universally defined as a clinical syndrome characterized by symptoms and/or signs resulting from structural or functional cardiac abnormalities, confirmed by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion. Classification is further refined using echocardiography to identify subgroups with differing treatment strategies. The cornerstone of therapeutic implementation in HFmrEF/HFpEF lies in establishing a diagnosis [9]. Echocardiography-detected left ventricular diastolic dysfunction at rest as an indicator of raised left ventricular filling pressures is neither specific nor sensitive to the diagnosis of HFpEF [10]. HF with improved ejection fraction (HFimpEF), defined by an improved left ventricular ejection fraction (LVEF) among patients formerly with HFrEF, should be distinguished from HFpEF and HFmrEF, as it may have distinct pathobiology and prognosis [11].

Heart failure is classified as a Stage IV CKM; however, the CKM framework emphasizes the opportunity to prevent HF in earlier stages with appropriate therapies [12, 13]. High predicted risk of cardiovascular (CV) disease using the PREVENT score, and abnormal subclinical biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) are proposed to identify Stage III CKM [14]. However, early detection of HFpEF using abnormal biomarker is hampered by NT-proBNP suppression in the obesity phenotype HFpEF [15]. Because individuals with obesity have lower NT-pro BNP concentrations, lower thresholds are used in those with obesity and exertional dyspnea to avoid underdiagnosing HF in this population [16]. Stage II CKM overlaps with Stage A HF, where metabolic risk factors like diabetes, hypertension, and metabolic syndrome elevate the risk of developing HF [17].

Multiple risk scores, largely comprised of routinely available clinical data, have been validated for detecting patients with intermediate to high probability of having a diagnosis HFpEF (Fig. 1) [18, 19]. Before HFpEF is definitively diagnosed, important differential diagnoses should be ruled out. HFpEF should be diagnosed by exclusion after ruling out systemic or CV causes such as infiltrative/restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), valvular heart disease, or pericardial disease (i.e., HFpEF Mimics) (Table 1).

Fig. 1.

Application of multiparameter scores to facilitate diagnosis of HFpEF [6]

Table 1.

Diagnostic clues and recommended testing for HFpEF Mimics according to ACC Expert Consensus Decision Pathway on Management of HFpEF [20]

HFpEF Mimic	Clinical Clues	Diagnostic Testing
Cardiac amyloidosis	Increased LV wall thickness Musculoskeletal issues (carpal tunnel syndrome, lumbar spinal stenosis) Neuropathy (sensory or autonomic)	CMR Monoclonal protein screen (serum/urine immunofixation electrophoresis and serum free light chains) Technetium pyrophosphate scan (interpreted in the context of a negative monoclonal protein screen) Endomyocardial biopsy if monoclonal protein screen is positive
Hypertrophic cardiomyopathy	Unexplained LV hypertrophy LV outflow tract obstruction Family history	CMR if diagnosis is uncertain based on echocardiogram
Cardiac sarcoidosis	Extracardiac disease (pulmonary, ocular, dermatologic) High-degree atrioventricular block (especially if age < 60 y) Ventricular arrhythmias	CMR FDG-PET scan Tissue biopsy (cardiac or extracardiac)
Fabry disease	Angiokeratomas Sensory neuropathy Proteinuria X-linked inheritance	Serum alpha-galactosidase level (in men) GLA genetic testing Biopsy of affected tissue
Pericardial disease	Prior cardiac surgery, chest radiation, or pericarditis Right-sided HF symptoms	CMR Right and left heart catheterization to demonstrate discordance in LV/RV pressure tracings during inspiration

MR, Cardiac Magnetic Resonance imaging; LV, Left Ventricle; HF, Heart Failure; FDG-PET, Fluorodeoxyglucose Positron Emission Tomography; RV, Right Ventricle; GLA, alpha-galactosidase gene

General management concepts in HFmrEF and HFpEF

Currently, the recommended management of HFmrEF and HFpEF includes identifying and treating specific causes, emphasizing the role of therapies that improve outcomes, considering other therapies with potential benefits, and prescribing diuretics for relieving congestion [21, 22]. Even when HFpEF mimics such as amyloidosis and HCM are excluded, and a diagnosis of HFpEF is made, relevant CV and non-CV comorbidities should be identified to enhance management strategies [20, 23].

Drugs that have been unsuccessful in HFmrEF and HFpEF

Over the past 20 years, RCTs focusing on neurohormonal modulation by either beta-blockers or renin-angiotensin-aldosterone system (RAAS) blockade have not shown definitive clinical benefit for patients with HFpEF [24–28]. This stands in contrast to the clear survival and hospitalization benefit seen with these therapies in HFrEF [29, 30]. Several RCTs of initially promising interventions for HFpEF were ultimately neutral [31]. For instance, using organic and inorganic nitrates, direct stimulators of soluble guanylate cyclase, or phosphodiesterase-5 inhibitors failed to improve activity or quality of life [21] (Table 2).

Table 2.

Neutral clinical trials of drugs that target the nitric oxide (NO)pathway [32]

Clinical trial	Drug	Population	Results
INDIE-HFpEF [33]	Inhaled, nebulized inorganic nitrite	- LVEF ≥ 50% -Prior hospitalization for HF within 12 months, increased invasively measured LVFP, elevated NP, or echo-DD - N = 105, aged 68 years (median); 56% women	Did not improve peak aerobic capacity, daily activity levels, or KCCQ scores.
NEAT-HFpEF trial [34]	Isosorbide mononitrate	- LVEF ≥ 50% -Ambulatory HF patients, prior hospitalization for HF within 12 months, increased invasively measured LVFP, elevated NP or echo-DD - N = 110, aged 69 ± 9 years; 57% women	Did not improve daily activity and KCCQ
RELAX [35]	Sildenafil	- LVEF ≥ 50% - Elevated NP or elevated invasively measured LVFP - N = 216, aged 69 years (median); 48% women	No significant improvement in exercise capacity or clinical status
SOCRATES-PRESERVED [36]	Vericiguat*	- LVEF ≥ 45% - NYHA class II-IV, increased NP, echo-DD -N = 477, aged 73 ± 10 years; 48% women	-No change in NP and left atrial volume -Improvements in KCCQ
VITALITY-HFpEF [37]	Vericiguat*	- LVEF ≥ 45% - NYHA class II-III, within 6 months of a recent HF decompensation (hospitalization or intravenous diuretics for HF without hospitalization), and with elevated NP -N = 789, aged 73 ± 9 years; 49% women	Did not improve the physical limitation score of the KCCQ or the secondary end point of 6 minutes walk test

*Soluble guanylate cyclase stimulator

HF, Heart Failure; NYHA, New York Heart Association; LVFP; LVEF, Left Ventricular Filling Pressure; DD, Diastolic Dysfunction; NP, Natriuretic Peptide (BNP or NT-proBNP); KCCQ, Kansas City Cardiomyopathy Questionnaire for Quality of Life

Medical therapies supported by randomized clinical trial data for HFmrEF OR HFpEF

Sodium-glucose cotransporter-2 inhibitors (SGLT2i)

SGLT2i initially started as a recommended therapy for patients with diabetes at high risk of CV disease or with CV disease, and then expanded to additionally encompass all patients with HF (i.e., HFrEF, HFmrEF, and HFpEF) [38]. Among the specific SGLT2i agents tested in CV outcome trials, with respect to effects on HF prevention and treatment, there is a consistent treatment effect with no evidence of heterogeneity [8, 39]. In a meta-analysis of the 12,251 participants with LVEF > 40% from (DELIVER) and (EMPEROR-Preserved) studies, SGLT2i reduced the combined endpoint of CV death or first HF hospitalization, (HR 0.80 [0.73–0.87]), in addition to a consistent reduction in both CV death (HR 0.88; 95% CI: 0.77–1.00) and first HF hospitalization (HR 0.74; 95% CI: 0.67–0.83) [40].

Although effects towards controlling diabetes, hypertension, and the progression of chronic kidney disease (CKD) achieved by SGLT2i may have some impact in treating HFpEF, further research has identified additional potential mechanisms by which SGLT2i improve patient outcomes. These mechanisms include triggering autophagy, maintaining better ionic balance, and reducing inflammation and oxidative stress, all contributing to lessening adverse remodeling and diastolic dysfunction [41]. The beneficial effect of SGLT2i on CV outcomes among patients with HFpEF and HFmrEF persists across groups defined by age, diabetes status, CKD [42], and body mass index (BMI) [43].

Mineralocorticoid receptor antagonists (MRA)

Real-world evidence suggests that nsMRAs are associated with better 1-year clinical outcomes compared to steroidal mineralocorticoid receptor antagonists (MRAs) across various patients with HF identified through ICD codes, including those with HFpEF [44]. Although emerging data suggest that nsMRAs may offer therapeutic advantages over steroidal MRAs [45, 46], there are currently no direct head-to-head RCTs to confirm these differences. As a result, it remains uncertain whether observed variations in efficacy and safety are clinically meaningful or reflect a true class effect. A meta-analysis of HF trials evaluating spironolactone and finerenone in HFmrEF/HFpEF demonstrated little heterogeneity in the risk of hyperkalemia across MRAs, but nsMRAs have a shorter half-life and more balanced tissue distribution [47, 48].

Steroidal MRAs

The TOPCAT trial assessed the use of spironolactone in patients with HFpEF in a large global population. Although the trial did not demonstrate a benefit concerning its primary endpoint, this was potentially explained by heterogeneity in study conduct across the regions [49]. Post-hoc analyses indicated potential treatment benefits for participants from North and South America [50] who had lower LVEF; however, the risk of hyperkalemia was higher than in other regions [51]. This post-hoc analysis formed the basis for class IIb recommendation in guidelines and conducting SPIRRIT-HFpEF and SPIRIT-HF-DZHK8 trials (Table 3) [17, 52]. The recently presented SPIRIT‑HF‑DZHK8 trial showed no significant clinical benefit of spironolactone versus placebo. Although the trial was underpowered to assess efficacy, spironolactone was associated with higher rates of medication discontinuation compared to placebo, higher rates of hyperkalemia and a greater decline in eGFR [53].

Table 3.

Ongoing clinical trials

Trial	NCT NO.	Estimated end date	Estimated enrolment	Hypothesis	Intervention group	Comparison group	Primary Outcome
SPIRRIT-HFpEF	NCT02901184	2026-12	2000	Inconclusive studies such as TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) suggest spironolactone may be effective in HFPEF, but it is generic and will not be studied by industry.	Spironolactone	Standard care	Components of CV death and time to HF hospitalization.
SPIRIT-HF DZHK8	NCT04727073	Stopped enrollment at only 50% of target and fewer than 75% of expected events. Presented at ACC 3-2026	743	Determine whether the treatment of patients with HFmrEF and HFpEF at high risk of cardiovascular events with the mineralocorticoid receptor antagonist (MRA) spironolactone reduces a composite of recurrent heart failure hospitalizations and cardiovascular mortality.	Spironolactone	Standard care	CV death or Total (first and recurrent) HF hospitalizations in symptomatic HF patients (NYHA II-IV) with mid-range (LVEF 40–49%) or preserved (LVEF ≥ 50%). RR was 1.18 (0.72–1.92) P = 0.512
CONFIRMATION-HF	NCT06024746	2026-08	1500	Combination therapy of finerenone plus empagliflozin will be compared to usual care to determine the efficacy and safety of treatment in patients hospitalized with heart failure.	Finerenone + Empagliflozin	Standard care.	Hierarchical composite of time to all-cause mortality, number of total HF events, time to first HF event, and Difference of 5 points or greater on the Kansas City Cardiomyopathy Questionnaire - Total Symptom Score (KCCQ-TSS) assessed by the win-ratio method
BalanceD-HF	NCT06307652	2027-06-11	4800	The aim is to evaluate the effect of balcinrenone/dapagliflozin vs. dapagliflozin, given once daily on top of other classes of SoC, on CV death and HF events.	Balcinrenone/ dapagliflozin 15 mg/10 mg and matching placebo for dapagliflozin 10 mg	Dapagliflozin 10 mg and matching placebo for balcinrenone/dapagliflozin.	Components of the composite of CV death, HF hospitalization, or HF event without hospitalization
EASi-HF Preserved	NCT06424288	2028-05-22	6000	The purpose of this study is to find out whether vicadrostat (BI 690517) in combination with empagliflozin helps people with heart failure.	Vicadrostat + empagliflozin	Placebo + empagliflozin	Composite CV death, hospitalization for heart failure (HHF) and urgent heart failure (HF) visit
REDEFINE-HF	NCT06008197	2026-04	5200	Finerenone will be compared to placebo to determine efficacy and safety of treatment in patients hospitalized with acute decompensated heart failure (HF) and mildly reduced or preserved left ventricular ejection fraction.	Finerenone	Standard care	Composite total (first and subsequent) HF hospitalizations, urgent visits for worsening HF, and CV deaths

nsMRAs

The Food and Drug Administration (FDA) in the US, as well as other regulatory authorities in other countries, approved the nsMRA finerenone to treat patients with HF and LVEF ≥ 40% [54–57].

The benefit of finerenone in treating patients with symptomatic HFmrEF and HFpEF was demonstrated in the FINEARTS-HF trial that enrolled 6,001 adults with LVEF of 40% or higher, elevated natriuretic peptides, evidence of structural heart disease, and recent use of diuretics for at least 30 days. Patients with potassium ≥ 5.0 mmol/l and estimated glomerular filtration rate (eGFR) ≥ 25 mL/min/1.73m² were excluded. Compared with placebo, finerenone resulted in a significantly lower rate of a composite of total worsening HF events and death from CV causes (rate ratio, 0.84; 95% CI, 0.74 to 0.95) [58, 59].

The role of finerenone in treating HF was also emphasized in a prespecified pooled analysis (FINE-HEART) that used the data from FINEARTS-HF and finerenone trials that enrolled patients with CKD and type 2 diabetes who were on maximum tolerable dose of RAAS blockade (i.e., FIGARO-DKD and FIDELIO-DKD) [60]. The analysis showed consistent efficacy of finerenone in patients across a wide spectrum of cardiometabolic risk. Nonetheless, the degree to which efficacy of finerenone in clinical trials will translate to effectiveness in the real-world broad population with HFmrEF/HFpEF is unclear.

The REDEFINE-HF (NCT06008197) trial is planned under the MOONRAKER program of finerenone, to enhance evidence generation about the definitive role of finerenone in patients hospitalized with acute episodes of HFmrEF/HFpEF and eGFR ≥ 25 mL/min/1.73m², regardless of their baseline diabetic condition [58].The CONFIRMATION-HF trial (NCT06024746), conducted also within the MOONRAKER program of finerenone, is designed to evaluate the efficacy and safety of an early, intensive therapeutic strategy combining finerenone with SGLT2i compared with usual care in patients hospitalized with HF, aims to generate evidence supporting the early initiation of combination therapy across a broad spectrum of HF phenotypes during or shortly after hospitalization.(Table 3). Additionally, the role of finerenone in preventing CKM progression to new onset HFmrEF/HFpEF was demonstrated in FIGARO-DKD, which included only subjects with CKD and type 2 diabetes [61].

Glucagon-like peptide-1 receptor agonist (GLP-1 RA)

GLP-1 RA transformed the discussion of the impact of obesity on the development and progression of HFpEF from a sole comorbidity to a fundamental causal factor and a key treatment focus [62, 63]. In a pooled analysis of STEP-HFpEF DM and STEP-HFpEF trials, including patients with and without diabetes, respectively, semaglutide was more effective than placebo in improving symptoms related to HF, reducing physical limitations, and decreasing body weight [64]; whereas, SUMMIT trial showed the effect of tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, on symptomatic and HF hospitalization primary outcomes, regardless of diabetes status [65]. The previously mentioned GLP-1 RA RCTs included only patients with co-morbid obesity (i.e., BMI ≥30 kg/m²) with either symptomatic HFpEF as in SUMMIT or HFmrEF/HFpEF but with threshold LVEF ≥ 45% as in STEP-HFpEF DM, and STEP-HFpEF [62, 63, 65]. However, the totality of evidence suggests that the beneficial effect of GLP1 RA on HFpEF outcomes is not entirely due to weight loss [66, 67].

Early changes in plasma volume, in NT-proBNP, and relatively early improvement in symptoms before significant weight loss—all suggest a cardiac-specific effect of GLP-1 RA, in addition to overall benefits from weight loss [62, 63, 65]. GLP-1 RA can not only lower NT-proBNP levels but also decrease needed daily diuretic requirements [68, 69]. The effect of semaglutide in another STEP-HFpEF and STEP-HFpEF DM pooled analysis was consistent, regardless of loop diuretic use, and led to a reduction in the required dose of loop diuretics [70]. Additionally, tirzepatide showed a 38% reduction in the primary end-point of CV death or worsening HF compared with placebo (HR 0.62; 95% CI: 0.41–0.95; P = 0.026), over a median follow-up period of 104 weeks [65]. The composite of worsening HF event was defined as urgent HF visits, HF hospitalization, or oral diuretic intensification [65]. A recent meta-analysis of the GLP-1RA class of therapies shows that it improves quality of life while potentially reducing the risk of CV mortality and HF hospitalization across patients with HFmrEF/HFpEF and varying combinations of CKM comorbidities [71]. Although GLP-1RAs have various metabolic, cardiovascular, and anti-inflammatory effects that may explain improvement in patient symptom and functional outcomes, CV death in the context of HFpEF may be less likely to be caused by HF itself but more often from atherosclerotic cardiovascular disease [72]. The comparative effects of semaglutide and tirzepatide on HFpEF may conceivably vary depending on their differential effects on obesity [73]. However, it remains unclear whether a drug with a more potent weight loss effect will achieve greater HF benefits [16]. Despite their benefits, GLP-1 RA are often discontinued in real-world practice—about 50% of people using them for obesity and one-third of those using them for diabetes stop within a year. This may be due to limited insurance coverage and side effects [74].

Additional therapies for HFmrEF and HFpEF

Although the PARAGON-HF trial failed to achieve its primary endpoint of a statistically significant benefit of ARNi (Angiotensin Receptor/Neprilysin inhibitor) over ARBs (Angiotensin II Receptor Blocker) for total HF hospitalization or CV death, subgroup analyses suggested potential efficacy for patients with LVEF ≤ 57–60% [75]. Furthermore, in a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF, which included patients with HFmrEF or HFpEF (LVEF > 40% in PARAGLIDE-HF and ≥ 45% in PARAGON-HF) who were enrolled during or within 30 days of a worsening HF event, ARNi significantly reduced total worsening HF events and CV death in all participants (n = 5262; RR 0.86; 95% CI: 0.75–0.98) compared with ARB [76, 77]. However, the class of recommendation for using ARNi in treating both HFmrEF and HFpEF is IIb in the latest AHA/ACC/HFSA guidelines. The effect of beta-blockers on different outcomes among patients with HFpEF was minimal or uncertain [28]. Therefore, the current guidelines recommend beta-blockers only for patients with HFmrEF and HFrEF [22].

Combination therapy for HFmrEF and HFpEF

The four-pillar approach of HFrEF therapies represents an important paradigm in HF management [78]. A similar “pillar approach” has grown more prominent in the CKM landscape, as the CONFIDENCE trial showed that simultaneous initiation of finerenone plus empagliflozin in patients with diabetic CKD resulted in a greater reduction in albuminuria than either treatment alone [79]. The implementation of the “4 pillars” of therapy for patients with diabetic CKD– RAAS blockade, SGLT2 inhibitors, GLP-1 RA, and nsMRAs –can achieve 3.4% absolute risk reductions for hospitalization with HF over 3 years [80]. The possible combination of these protective drugs showed a graded protective effect compared to single medication (Fig. 2). Furthermore, more evidence for a pillar-based approach to non-diabetic CKD is emerging [81]. A similar synergetic effect can be extrapolated to the HFmrEF/HFpEF spectrum, as each of the emerging therapies has a unique mechanism of action with no known pharmacological interactions [7, 82].

Fig. 2.

Forest plot for the estimated treatment effects on HF hospitalization when SGLT2i, GLP-1RA, and nsMRA are added to RAAS blockade in patients with chronic kidney disease and type 2 diabetes [80]. The lowest three rows represent the protective effect of adding each of SGLT2i, GLP-1RA, nsMRA, the higher rows represent the hazard ratios of possible combinations

Although no dedicated RCTs have evaluated the simultaneous or rapid-sequence initiation of SGLT2 inhibitors, GLP-1 RAs, and nsMRAs in patients with heart failure and LVEF > 40%, the current evidence indicates that the potential clinical benefits of starting treatment simultaneously outweigh the risks, especially when compared to the traditional approach of gradual medication initiation optimization [83]. Subgroup analyses from individual trials suggest additive therapeutic benefits. For instance, in the FINEARTS-HF trial, the efficacy of finerenone was consistent regardless of background SGLT2 inhibitor use [84]. Among patients with HFmrEF and HFpEF included in the DELIVER and FINEARTS-HF trials, the potential long-term benefits of early combination therapy with SGLT2i and nsMRA are substantial, with an expected 3.6 (2.0-5.2) years difference in survival after age 65 compared to standard care [82]. Additionally, SOGALDI-PEF trial showed that the combination of dapagliflozin and spironolactone reduced NT-proBNP more than dapagliflozin alone [84], and there are several ongoing RCTs evaluating the effect of combining MRAs with SGLT2i in patients with HFpEF. The ongoing RCTs of nsMRAs recruit patients with either HFrEF or HFpEF, such as CONFIRMATION-HF of finerenone (NCT06024746) and BalanceD-HF of Balcinrenone (NCT06307652) [85].

GLP-1 RA is also likely to be used in HFpEF treatment options, as its effect on hospitalization for HF among patients with type 2 diabetes in a recent meta-analysis was consistent regardless of SGLT2i use (HR 0.58; 95% CI: 0.36–0.93 and HR 0.73; 95% CI: 0.63–0.85; P-heterogeneity = 0.26) [86]. Furthermore, individual participant level data (IPD) meta-analysis of four RCTs of semaglutide (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) showed a consistent effect irrespective of receiving SGLT2i or MRAs at baseline [87]. Likewise, in SUMMIT, the benefit of tirzepatide on CV death or worsening HF was consistent regardless of background MRAs use [65]. Thus, given the lack of obvious heterogeneity in treatment effect, there is no evidence to suggest that the treatment benefits of additional therapies are attenuated by the background use of others, even in the case of ARNi [82]. A meta-analysis involving 20,633 patients with HF and an LVEF ≥ 40% found that SGLT2i, ARNi, and MRAs were associated with a significant decrease in the risk of HF hospitalization compared to the placebo (SGLT2i: HR 0.71 [95%CI: 0.60–0.83]; ARNi: HR 0.76 [95%CI: 0.61–0.95]; MRAs: HR 0.83 [95%CI: 0.69–0.99]) [88]. While this meta-analysis quantified the potential cumulative benefits of combination medical therapy on HF hospitalization, no treatments were found to significantly reduce the risk of all-cause or CV death [88–90].

The combination strategy of triple therapy (i.e., SGLT2i, nsMRAs, GLP-1 RA) may encounter real-world implementation challenges and potential risks, including perceived intolerance, hypotension, electrolyte imbalance, polypharmacy, cost, and coverage gaps. Yet lessons from implementation of multiple pillars of therapy in HFrEF have shown that a serial, selective, one-at-a-time approach results in many patients never receiving each individual therapy, or at best, after a substantial delay. Given the effects of SGLT2i and nsMRAs on improved clinical outcomes accrue within days to weeks of initiation, delays of even a few weeks could needlessly expose patients to excess risk [91, 92]. Such risks of omission or delays are underrecognized in HF care, and time-to-initiation of combination guideline-directed medical therapy could be implemented as a metric in HF [93, 94].

Regarding HFmrEF, ACC/AHA/HFSA 2022 Guidelines recommended considering the four foundational HFrEF therapies for patients with HFmrEF (LVEF 41–49%), though with varying strength: SGLT2 inhibitors: Class IIa and ARNI, beta-blockers, MRAs: Class IIb [95]. The ESC 2023 update aligns with the ACC/AHA stance, recommending the same four drug classes for HFmrEF. It acknowledges that while SGLT2 inhibitors have stronger evidence, the other three classes are supported by subgroup data and expert consensus [96]. For the ACC, these weaker recommendations stem from subgroup analyses rather than dedicated RCTs that met primary endpoints [22]. In contrast to the above, there is now evidence with GLP-1 RA and nsMRAs for HFmrEF that comes from RCTs that met their primary endpoints. Updated clinical practice guidelines incorporating these data are still pending, but the evidence for nsMRAs and GLP-1 RA for improving clinical and/or patient-reported outcomes suggests a high level of certainty with regards to benefit [97, 98].

Future directions

A better understanding of the pathobiology of HFmrEF and HFpEF is needed to delineate the suitability of other emerging therapies in such a unique group of patients. The neurohormonal hypothesis holds a dominant place in explaining HFrEF, while the obesity, visceral adiposity, or comorbidity-driven hypothesis are potential key determinants of HFpEF [10]. Several nsMRAs are currently in clinical development, but unlike finerenone in FINEARTS-HF, they have not completed testing in RCTs of HF. These include: (1) esaxerenone which is approved in Japan for hypertension treatment; (2) apararenone, which is currently being tested in patients with CKD and type 2 diabetes (phase II) [99], and (3) balcinrenone, which did not meet the primary endpoint of albuminuria reduction in phase 2b MIRACLE study in patients with HF and CKD but has decreased levels of NT-proBNP when combined with SGLT2i compared to SGLT2i alone [100, 101]. Balcinrenone is currently being tested in a phase III cardiovascular outcome trial of patients with HF and comorbid CKD (NCT06307652).

Furthermore, aldosterone synthase inhibitors that work in a different mechanism than MRAs have an ongoing phase III study of vicadrostat (NCT06424288) in patients with HFmrEF and HFpEF. The study examines whether the combination of vicadrostat and empagliflozin is beneficial for people with HF and LVEF ≥ 40% in comparison to empagliflozin alone. Precision medicine and phenomapping offer promising tools to identify distinct HFpEF subgroups, potentially enabling tailored therapies that may improve outcomes beyond the current one-size-fits-all approach [102]. To validate these strategies and better understand implementation barriers such as clinical inertia, high drug costs, and limited medication access in underserved populations, pragmatic randomized controlled trials are urgently needed. These trials would assess the real-world effectiveness and safety of combination therapies across diverse HFpEF phenotypes [103].

Conclusion

Promising RCTs have been conducted to develop multiple effective therapies for HFmrEF and HFpEF. Three therapies – SGLT2i, nsMRA, and GLP-1RAs (if comorbid obesity) – are definitively proven to improve clinical and/or patient-reported outcomes for patients with HFmrEF or HFpEF. The combination strategy of all three therapies initiated and optimized simultaneously or in rapid sequence holds strong potential for maximally improving patient outcomes.

Author contributions

CJB and SJG contributed to the writing and reviewing of each draft and reviewing and approving the final draft for submission.

Funding

Bayer US, LLC. funded the article processing charge for this article. Bayer US, LLC. also funded ILM Consulting Services, LLC. for medical writing support and publication management.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Conflict of interest

CJB reports consultant fees from Bayer. SJG has received research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Otsuka, Pfizer, and Sanofi; has served on advisory boards or as consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Corcept Therapeutics, Corteria Pharmaceuticals, CSL Vifor, Cytokinetics, Idorsia, Lexicon, Lilly, Merck, Mineralys, Novo Nordisk, Otsuka, Roche Diagnostics, Sanofi, scPharmaceuticals, Sumitomo, Tricog Health, and Viatris.