HFpEF Treatment in 2026: New Therapeutic Pillars

Background

Heart failure with preserved ejection fraction (HFpEF) — defined as clinical heart failure with LVEF ≥50% — accounts for approximately half of all heart failure cases worldwide, consistent with heart failure prevalence data, and is the most rapidly growing HF subtype, driven by aging populations and the rising prevalence of obesity, hypertension, diabetes, and metabolic syndrome [1]. For decades, HFpEF was considered the “greatest unmet need in cardiovascular medicine,” with no therapies demonstrating clear mortality or morbidity benefit in randomized trials — in stark contrast to HFrEF, where multiple drug classes had established life-saving efficacy [2].

This landscape has transformed dramatically between 2021 and 2025. A series of positive randomized controlled trials have established multiple effective therapeutic pillars for HFpEF, fundamentally changing how clinicians approach this condition. This review examines the current evidence for each therapeutic class, the emerging paradigm of combination therapy, and practical guidance for treatment sequencing in 2026.

Pillar 1: SGLT2 Inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were the first drug class to demonstrate unequivocal benefit across the HFpEF spectrum. Two pivotal trials established the evidence base:

• EMPEROR-Preserved (empagliflozin, n=5,988): Reduced the composite of CV death or HF hospitalization by 21% (HR 0.79, 95% CI 0.69–0.90, p<0.001), driven primarily by reduction in HF hospitalizations [3].
• DELIVER (dapagliflozin, n=6,263): Reduced the composite of worsening HF or CV death by 18% (HR 0.82, 95% CI 0.73–0.92, p<0.001), with consistent benefit regardless of diabetes status, EF range (41–65%), or background therapy [4].

The mechanisms of SGLT2 inhibitors in HFpEF are multifactorial: natriuresis and osmotic diuresis reduce preload; improvements in myocardial and vascular metabolism reduce afterload; and anti-inflammatory and anti-fibrotic effects address underlying myocardial pathology [5]. SGLT2 inhibitors currently hold a Class 2a recommendation in HFpEF from major heart failure guidelines and are considered the cornerstone of pharmacotherapy across all EF categories [6].

Pillar 2: Finerenone (Nonsteroidal MRA)

The FINEARTS-HF trial, published in the New England Journal of Medicine in 2024, represents the most significant recent advance in HFpEF pharmacotherapy [7]. This landmark trial randomized 6,001 patients with HF and LVEF ≥40% (mean EF ~53%) to finerenone or placebo, with a notably high-risk population: 54% had experienced an HF-related event within 3 months of enrollment, and 20% were randomized within one week of an HF hospitalization.

Key results from FINEARTS-HF:

• Primary endpoint: Finerenone reduced CV death + total worsening HF events by 16% (rate ratio 0.84, 95% CI 0.74–0.95, p=0.007).
• Worsening HF events: 18% reduction in total worsening HF events (RR 0.82, 95% CI 0.71–0.94).
• Rapid onset: Benefit was evident within the first weeks of treatment.
• Additive to SGLT2i: Finerenone’s benefit was consistent regardless of baseline SGLT2 inhibitor use (RR 0.83 with SGLT2i vs. 0.85 without; p-interaction = 0.76) [8].
• Safety: Hyperkalemia requiring discontinuation was uncommon (1.3% finerenone vs. 0.4% placebo). The initial acute eGFR decline (−2.9 mL/min at 3 months) did not progress and was hemodynamically mediated [9].

Unlike steroidal MRAs (spironolactone, eplerenone) — which failed to demonstrate clear HFpEF benefit in the TOPCAT trial due to regional variability and tolerability issues — finerenone offers more selective mineralocorticoid receptor antagonism with lower rates of hyperkalemia and no anti-androgenic side effects. This positions finerenone as the preferred MRA for HFpEF, particularly in patients with concomitant CKD and diabetes [10].

Pillar 3: GLP-1 Receptor Agonists and Incretin-Based Therapies

For the substantial subset of HFpEF patients with co-existing obesity (BMI ≥30), GLP-1 receptor agonists in heart failure have demonstrated meaningful improvements in symptoms, exercise capacity, and body composition:

• STEP-HFpEF (semaglutide 2.4 mg/wk, n=529): Improved KCCQ score by +7.8 points vs. placebo (p<0.001), reduced body weight by 13.3% (vs. 2.6%), and decreased CRP by 38% at 52 weeks [11].
• SUMMIT (tirzepatide, n=731): Published in NEJM in early 2025, tirzepatide reduced the composite of CV death or worsening HF events and improved KCCQ scores in HFpEF patients with obesity, with even greater weight loss than semaglutide [12].

The mechanisms underlying GLP-1 RA benefit in HFpEF extend beyond weight loss: direct anti-inflammatory effects, improved myocardial metabolism, enhanced endothelial function, and reduction of epicardial adipose tissue all contribute to the therapeutic effect [13]. Importantly, emerging data suggest that GLP-1 RAs provide incremental benefit even when added to SGLT2 inhibitors in patients with HFpEF, obesity, and diabetes [14].

Combination Therapy: The New Frontier

With multiple effective drug classes now available, the question of optimal combination therapy is rapidly becoming the central clinical challenge in HFpEF management. Key evidence supporting multi-drug approaches includes:

• CONFIDENCE trial (2025): Combination therapy with finerenone + empagliflozin achieved a 52% reduction in urinary albumin-to-creatinine ratio (UACR) — an additional 29% reduction beyond finerenone alone and 32% beyond empagliflozin alone — in patients with CKD and T2D [15].
• FINEARTS-HF subanalysis: Finerenone benefit was maintained regardless of SGLT2i use, suggesting complementary rather than overlapping mechanisms [8].
• GLP-1 RA + SGLT2i: Retrospective data suggest incremental benefit of adding GLP-1 RAs to SGLT2 inhibitors in HFpEF patients with obesity and diabetes [14].

Expert consensus is converging toward phenotype-driven treatment sequencing: SGLT2 inhibitors as the universal foundation for all HFpEF patients, with finerenone added for those with CKD/diabetes/hyperaldosteronism features, and GLP-1 RAs/tirzepatide added for those with significant obesity [16].

Ongoing Trials

Several key trials will further define the HFpEF treatment landscape in the coming years:

• REDEFINE-HF: Evaluating finerenone in patients hospitalized for acute HFmrEF/HFpEF — a more acute population than FINEARTS-HF [17].
• CONFIRMATION-HF: Assessing early combination therapy with finerenone + SGLT2 inhibitors in acute HF regardless of EF.
• SELECT-HFpEF (sub-study): Evaluating semaglutide for MACE reduction specifically in the HFpEF subpopulation of the SELECT trial.
• GLP-1 RAs in HFrEF: Emerging data from SELECT subanalyses suggest potential benefit (HR 0.65 for HF composite endpoint), challenging the prior assumption that GLP-1 RAs should be avoided in reduced EF [18].

Clinical Implications

HFpEF has transitioned from a therapeutic void to a condition with multiple evidence-based treatment options. SGLT2 inhibitors should be initiated in all HFpEF patients as the foundational therapy, with finerenone and GLP-1 RAs added based on individual phenotype: CKD and diabetes favor finerenone, while obesity favors incretin-based therapies. The CONFIDENCE trial’s demonstration of synergistic effects with dual finerenone + SGLT2i therapy suggests that combination approaches addressing multiple pathophysiological pathways simultaneously may yield greater benefit than sequential monotherapy.

However, clinicians must balance therapeutic ambition with practical considerations: medication burden and cost (particularly for GLP-1 RAs), monitoring requirements for hyperkalemia (finerenone) and volume depletion (SGLT2i + diuretics), and the limited representation of elderly, frail, and non-White populations in pivotal trials. Additionally, while symptom and hospitalization endpoints are well-established, none of these therapies has yet demonstrated a statistically significant reduction in all-cause mortality specifically in HFpEF — a gap that ongoing trials may or may not close [19, 20].

References

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Disclaimer: This article is intended for healthcare professionals and is provided for educational purposes only. It does not constitute medical advice. Clinical decisions should be based on individual patient assessment and current clinical guidelines. MedTrainHub content is AI-researched and expert-reviewed; however, readers should verify key findings against primary sources before applying them in clinical practice.

Conflicts of Interest: None declared.
Funding: This article received no external funding.
Citation: MedTrainHub Editorial Team. Heart Failure with Preserved Ejection Fraction (HFpEF): Current Treatment Landscape in 2026. MedTrainHub.com. Published April 2026. Available at: https://medtrainhub.com/articles/cardiology/hfpef-treatment-2026