HFpEF Treatment: 5 Key Clinical Insights
An evidence synthesis on SGLT2 inhibitors, finerenone, and contemporary management of heart failure with preserved ejection fraction
One-Minute Takeaway on HFpEF Treatment
One-Minute Takeaway
- HFpEF treatment now includes SGLT2 inhibitors as foundational therapy based on consistent reductions in heart failure hospitalizations across EMPEROR-Preserved (empagliflozin) and DELIVER (dapagliflozin).
- The nonsteroidal mineralocorticoid receptor antagonist finerenone reduced cardiovascular death and worsening heart failure events in FINEARTS-HF, extending therapy options for HFmrEF and HFpEF.
- Across pivotal trials, the composite endpoint benefit is driven primarily by reductions in heart failure hospitalizations rather than cardiovascular mortality.
- Benefits appear consistent across diabetic and non-diabetic patients and across most of the ejection fraction range studied.
- Comorbidity management, loop diuretic optimization, and structured exercise remain essential foundations alongside disease-modifying pharmacotherapy.
Why HFpEF Treatment Has Changed
Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and a growing proportion of heart failure hospitalizations. For two decades, the management toolkit was largely limited to symptom control with diuretics and treatment of comorbidities, after a string of neutral or marginally positive trials with renin-angiotensin system blockers and steroidal mineralocorticoid antagonists.
That landscape changed when EMPEROR-Preserved (2021) and DELIVER (2022) demonstrated consistent reductions in heart failure hospitalization with SGLT2 inhibitors across the preserved and mildly reduced ejection fraction range. FINEARTS-HF (2024) added finerenone, a nonsteroidal mineralocorticoid receptor antagonist, to the disease-modifying toolkit.
For internists, contemporary HFpEF treatment is no longer a diagnosis of therapeutic exclusion. Two drug classes now have replicated evidence of clinical benefit, and major guidelines (AHA/ACC/HFSA 2022 and ESC 2023 Focused Update) have incorporated SGLT2 inhibitors as Class 1 or Class 2a recommendations for HFmrEF and HFpEF.
The clinical question this review addresses: how should internal medicine clinicians integrate SGLT2 inhibitors and finerenone into HFpEF treatment, and what does the evidence say about who benefits most?
What Evidence Was Reviewed
This synthesis draws on the three pivotal HFpEF/HFmrEF outcomes trials of the 2020s (EMPEROR-Preserved, DELIVER, FINEARTS-HF); patient-level pooled analyses across the ejection fraction spectrum; the prior generation of negative or marginally positive trials (TOPCAT, PARAGON-HF, I-PRESERVE); and the 2022 AHA/ACC/HFSA and 2023 ESC heart failure guidelines.
Studies were prioritized by design (large multinational RCT before subgroup analysis), sample size, primary outcome relevance, and replication across independent trials. Pooled analyses were used to interpret subgroup heterogeneity and effect modification by ejection fraction.
| Study / Source | Design | n | Key Finding Relevant to HFpEF Treatment |
|---|---|---|---|
| EMPEROR-Preserved (Anker 2021) | Phase 3 RCT, EF > 40% | 5,988 | Empagliflozin reduced CV death + HF hospitalization (HR 0.79, 95% CI 0.69–0.90) |
| DELIVER (Solomon 2022) | Phase 3 RCT, EF > 40% | 6,263 | Dapagliflozin reduced CV death + worsening HF (HR 0.82, 95% CI 0.73–0.92) |
| FINEARTS-HF (Solomon 2024) | Phase 3 RCT, EF ≥ 40% | 6,001 | Finerenone reduced CV death + total worsening HF events (RR 0.84, 95% CI 0.74–0.95) |
| Vaduganathan 2022 meta-analysis | Pooled meta-analysis of 5 SGLT2i HF RCTs | 21,947 | Pooled HR 0.80 for CV death + first HF hospitalization across the EF spectrum |
| Jhund 2022 pooled analysis | Patient-level pooled DAPA-HF + DELIVER | 11,007 | Dapagliflozin benefit consistent across the full EF range studied |
| TOPCAT (Pitt 2014) | Phase 3 RCT, EF ≥ 45% | 3,445 | Spironolactone neutral overall; regional heterogeneity (Americas vs Russia/Georgia) complicated interpretation |
| PARAGON-HF (Solomon 2019) | Phase 3 RCT, EF ≥ 45% | 4,822 | Sacubitril/valsartan narrowly missed primary endpoint; possible benefit at lower EF |
| I-PRESERVE (Massie 2008) | Phase 3 RCT, EF ≥ 45% | 4,128 | Irbesartan did not reduce primary outcome — an early signal that ARB monotherapy was insufficient |
| AHA/ACC/HFSA 2022 Guideline | Society guideline | NR | SGLT2i Class 2a recommendation for HFpEF; comprehensive comorbidity management framework |
| ESC 2023 Focused Update | Society guideline | NR | SGLT2i upgraded to Class 1 recommendation for HFmrEF and HFpEF |
Key Findings on HFpEF Treatment
Insight 1: SGLT2 Inhibitors Are Foundational in HFpEF and HFmrEF
EMPEROR-Preserved and DELIVER together randomized over 12,000 patients with ejection fraction above 40% and demonstrated concordant reductions in the composite of cardiovascular death and worsening heart failure. Empagliflozin produced a hazard ratio of 0.79, and dapagliflozin a hazard ratio of 0.82, with overlapping confidence intervals.
The Vaduganathan 2022 patient-level meta-analysis across five SGLT2 inhibitor heart failure trials confirmed the magnitude and consistency of effect, with a pooled hazard ratio of approximately 0.80 for cardiovascular death or first heart failure hospitalization. The Jhund 2022 DAPA-HF + DELIVER pooled analysis similarly demonstrated benefit across the full ejection fraction spectrum.
Both 2022 AHA/ACC/HFSA and 2023 ESC heart failure guidelines incorporate SGLT2 inhibitors as a Class 1 (ESC) or Class 2a (AHA/ACC/HFSA) recommendation for HFpEF and HFmrEF, framing these agents as foundational rather than adjunctive therapy.
Insight 2: Finerenone Extends Disease-Modifying Therapy Beyond SGLT2 Inhibitors
FINEARTS-HF, published in 2024, randomized 6,001 patients with HFmrEF or HFpEF (ejection fraction ≥ 40%) to finerenone or placebo and demonstrated a 16% relative reduction in the composite of cardiovascular death and total worsening heart failure events (rate ratio 0.84, 95% CI 0.74–0.95). The signal was driven primarily by reductions in worsening heart failure events.
Finerenone is a nonsteroidal mineralocorticoid receptor antagonist with greater receptor selectivity and lower androgen-related side-effect burden than spironolactone. Hyperkalemia and modest declines in eGFR were observed at expected rates and were generally manageable with monitoring.
The interpretation of finerenone in HFpEF has to be read alongside the historical TOPCAT trial of spironolactone, which was neutral overall but showed a benefit signal in the Americas regional subgroup. FINEARTS-HF provides cleaner replicated evidence of MRA-class benefit in the HFmrEF/HFpEF population.
Mechanism Note
Finerenone’s nonsteroidal structure produces more balanced cardiac and renal mineralocorticoid receptor antagonism with less off-target activity at progesterone, glucocorticoid, and androgen receptors. This translates into lower rates of gynecomastia and menstrual irregularities than steroidal MRAs, while preserving cardiorenal protection.
Insight 3: Hospitalization Reduction Drives Most of the Composite Endpoint Benefit
Across EMPEROR-Preserved, DELIVER, and FINEARTS-HF, the composite endpoint benefit is driven predominantly by reductions in heart failure hospitalization or worsening heart failure events rather than cardiovascular mortality. Cardiovascular death curves were largely overlapping in EMPEROR-Preserved and DELIVER and showed only modest separation in FINEARTS-HF.
This pattern stands in deliberate contrast to HFrEF, where multiple drug classes reduce both heart failure hospitalization and cardiovascular mortality. The HFpEF mortality signal is more modest, partly because non-cardiovascular causes of death contribute a larger share of total mortality in this older, more comorbid population.
Counseling patients should reflect this reality: the strongest evidence base supports symptom and hospitalization reduction, with mortality benefit treated as a more uncertain secondary outcome. This is clinically meaningful given the high quality-of-life impact of recurrent heart failure hospitalizations.
SGLT2 inhibitor effect sizes in HFrEF (DAPA-HF, EMPEROR-Reduced) showed both heart failure hospitalization reduction and cardiovascular mortality reduction. In HFpEF, the hospitalization signal is similarly robust but the mortality signal is attenuated, with cardiovascular death curves largely overlapping in the pivotal trials.
The finerenone story is parallel: clear hospitalization and worsening heart failure event reduction, with a smaller and less certain mortality effect. Patients moving from HFrEF to HFpEF guidance should expect symptom and hospitalization benefits to be the primary clinical outcome rather than longevity gains.
No randomized head-to-head trial has compared SGLT2 inhibitors with finerenone or evaluated combination versus monotherapy in HFmrEF/HFpEF. Decision-making rests on indirect comparison, comorbidity profile, and tolerability.
For most patients, an SGLT2 inhibitor is reasonable first-line based on a larger evidence base, broader cardiometabolic indications (type 2 diabetes, CKD), and a favorable safety profile. Finerenone is a strong second-line option, particularly in patients with comorbid type 2 diabetes and CKD or those with persistent symptoms despite SGLT2 inhibitor therapy.
Combination therapy is biologically plausible and is being actively studied, but current evidence does not yet establish whether combined SGLT2 inhibitor plus finerenone produces additive clinical benefit.
PARAGON-HF narrowly missed its primary endpoint for sacubitril/valsartan in HFpEF (rate ratio 0.87, 95% CI 0.75–1.01) but showed a benefit signal in patients with ejection fraction below the median (45–57%) and in women. Guidelines reflect this as a Class 2b option.
I-PRESERVE (irbesartan) and CHARM-Preserved (candesartan) showed limited benefit. ACE inhibitors and ARBs remain useful for blood pressure and comorbidity control but are no longer the centerpiece of HFpEF disease-modifying therapy.
For patients already on ARNI for blood pressure or other indications, continuation is reasonable; routine initiation in HFpEF for the heart failure indication alone is supported by weaker evidence than SGLT2 inhibitors or finerenone.
Insight 4: Benefit Is Consistent Across Diabetic Status and Most of the EF Range
Subgroup analyses across EMPEROR-Preserved, DELIVER, and the Vaduganathan 2022 meta-analysis show consistent SGLT2 inhibitor benefit in patients with and without type 2 diabetes. This was a critical finding, since the original SGLT2 inhibitor evidence base emerged from diabetes outcome trials.
Effect modification by ejection fraction has been examined extensively. Some signal of attenuation at the highest ejection fraction strata (above approximately 65%) has been observed in EMPEROR-Preserved subgroup analyses, but pooled analyses suggest the benefit persists across most of the studied range.
FINEARTS-HF similarly showed consistent finerenone benefit across diabetic status and ejection fraction subgroups, supporting an independent class effect rather than a benefit confined to specific patient subsets.
Insight 5: Comorbidity Management and Diuretics Remain Foundational
Disease-modifying therapy is layered onto a foundation of comorbidity management and symptom control. Loop diuretics remain the cornerstone of congestion management; titration to euvolemia using daily weights and clinical examination is essential.
Atrial fibrillation, hypertension, obesity, sleep-disordered breathing, and chronic kidney disease all worsen HFpEF outcomes when uncontrolled. Aggressive blood pressure control, rate or rhythm control of atrial fibrillation, weight management (with structured exercise and possibly GLP-1 receptor agonists in selected patients), and CKD-directed therapy form the indispensable comorbidity bundle.
Clinical Pearl: The STEP-HFpEF trial of semaglutide in obesity-phenotype HFpEF showed substantial improvements in symptoms and exercise capacity in patients with BMI ≥ 30. For obesity-phenotype HFpEF, weight loss is increasingly recognized as a disease-modifying intervention rather than a comorbidity adjustment.
Quality & Consistency of Evidence
The contemporary HFpEF evidence base rests on three large, well-conducted Phase 3 RCTs with concordant directional findings on the composite primary endpoint. Heterogeneity exists in mortality outcomes and in subgroup effects at the extremes of the ejection fraction range.
What the Evidence Does Not Show
Specific Evidence Gaps
Several clinically important questions about HFpEF management remain unresolved by current data. The named gaps below should shape patient counseling and ongoing trial design rather than be subsumed into a generic call for “more research.”
- Combination therapy. Whether SGLT2 inhibitor plus finerenone produces additive benefit versus either as monotherapy is unproven; head-to-head and combination trials are needed.
- Optimal sequencing. No evidence base defines whether SGLT2 inhibitor or finerenone should be initiated first in patients eligible for both.
- Effect at supranormal ejection fraction (> 65%). Subgroup signals suggest effect attenuation, but trials were underpowered to definitively characterize this.
- Mortality benefit magnitude. Whether longer follow-up or larger trials would reveal a clearer cardiovascular mortality reduction in HFpEF is unsettled.
- Frail and elderly patients. Patients with significant frailty were underrepresented in pivotal trials; tolerability and benefit in this population is incompletely characterized.
- Phenotype-specific therapy. HFpEF is heterogeneous (obesity-phenotype, hypertensive, infiltrative, ischemic), and the optimal therapy mix may differ across phenotypes.
Practical Implications for HFpEF Treatment
Based on the current evidence, the following considerations represent areas where data are sufficiently consistent to inform routine internal medicine workflows. They are framed as evidence-supported considerations, not directive recommendations.
Evidence supports empagliflozin or dapagliflozin in patients with HFpEF or HFmrEF, regardless of diabetes status, when no contraindications exist.
FINEARTS-HF supports finerenone in patients with HFmrEF/HFpEF, with appropriate potassium and renal monitoring. Particularly attractive in comorbid type 2 diabetes and CKD.
Loop diuretic titration to euvolemia is the foundation of symptom management. Disease-modifying therapy complements rather than replaces diuretic-based congestion control.
Atrial fibrillation, hypertension, obesity, sleep-disordered breathing, and CKD all require active management. Weight loss in obesity-phenotype HFpEF has emerging disease-modifying value.
Two further considerations complete the practical framework. Hospitalization reduction is the strongest patient-relevant outcome supported by current evidence; counseling should set realistic expectations about mortality benefit, which is more modest in HFpEF than in HFrEF. Cardiology referral is appropriate for patients with persistent symptoms despite guideline-directed therapy, suspected infiltrative cardiomyopathy, advanced disease, or candidacy for clinical trial enrollment.
Evidence Grade & Bottom Line
Overall Evidence Grade: Strong (heart failure hospitalization reduction) to Moderate (cardiovascular mortality, combination therapy) — Phase 3 evidence supporting hospitalization reduction with SGLT2 inhibitors and finerenone in HFmrEF/HFpEF is robust. Mortality effects, supranormal-EF efficacy, and combination strategies are areas where evidence is still maturing.
Bottom Line
- SGLT2 inhibitors are now foundational therapy for HFpEF and HFmrEF, with consistent benefit across EMPEROR-Preserved, DELIVER, and patient-level pooled analyses.
- Finerenone, supported by FINEARTS-HF, extends disease-modifying options into HFmrEF and HFpEF with cleaner evidence than the older spironolactone trial.
- Composite endpoint benefit is driven primarily by reductions in heart failure hospitalization, with more modest cardiovascular mortality effects than in HFrEF.
- Loop diuretics, comorbidity control, and structured lifestyle intervention remain essential complements to disease-modifying pharmacotherapy.
- Combination therapy, optimal sequencing, and benefit at the highest ejection fraction strata remain unresolved questions for future trials.
Article Information & References
Disclaimer
For Educational Purposes Only. This is an original evidence synthesis informed by the studies listed below. It does not replace clinical judgement. Drug dosages should be verified against current prescribing information.
References
- Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-1461. DOI: 10.1056/NEJMoa2107038
- Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089-1098. DOI: 10.1056/NEJMoa2206286
- Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2024;391(16):1475-1485. DOI: 10.1056/NEJMoa2407107
- Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022;400(10354):757-767. DOI: 10.1016/S0140-6736(22)01429-5
- Jhund PS, Kondo T, Butt JH, et al. Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER. Nat Med. 2022;28(9):1956-1964. DOI: 10.1038/s41591-022-01971-4
- Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383-1392. DOI: 10.1056/NEJMoa1313731
- Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019;381(17):1609-1620. DOI: 10.1056/NEJMoa1908655
- Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359(23):2456-2467. DOI: 10.1056/NEJMoa0805450
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. DOI: 10.1161/CIR.0000000000001063
- McDonagh TA, Metra M, Adamo M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023;44(37):3627-3639. DOI: 10.1093/eurheartj/ehad195
- Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity (STEP-HFpEF). N Engl J Med. 2023;389(12):1069-1084. DOI: 10.1056/NEJMoa2306963
- Borlaug BA. Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2020;17(9):559-573. DOI: 10.1038/s41569-020-0363-2
- Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015;131(1):34-42. DOI: 10.1161/CIRCULATIONAHA.114.013255