HFpEF: From Therapeutic Desert to Crowded Treatment Space

Introduction

Heart failure with preserved ejection fraction has long been one of the most difficult syndromes in cardiovascular medicine. Patients may experience exertional dyspnea, fatigue, exercise intolerance, edema, recurrent hospitalization, frailty, and substantial impairment in quality of life. For many years, treatment centered on loop diuretics for congestion and management of hypertension, atrial fibrillation, ischemic heart disease, obesity, diabetes, chronic kidney disease, sleep apnea, and other coexisting conditions.

That approach remains essential, but the therapeutic landscape has changed. Several interventions now reduce worsening heart failure events or improve symptoms, functional capacity, health status, or body weight in defined patient populations. The strength and type of benefit differ substantially among therapies. No contemporary HFpEF regimen has reproduced the broad, consistent survival benefits established with multidrug therapy in heart failure with reduced ejection fraction.

HFpEF is also not a simple medication checklist. The modern clinical task is to confirm the diagnosis, identify clinically important contributors and phenotypes, select interventions supported by evidence in a comparable population, and avoid extrapolating trial findings beyond the conditions in which they were established.

Some therapies reduce worsening heart failure events or hospitalization. Others primarily improve symptoms, exercise function, or health status. Sacubitril/valsartan and spironolactone have signals of benefit in selected populations despite neutral overall primary trial results. Semaglutide and tirzepatide were studied specifically in obesity-related HFpEF and should not be generalized to all preserved-ejection-fraction phenotypes.

The expanding treatment landscape therefore requires attention to evidence strength, regulatory status, patient selection, safety, and feasibility rather than indiscriminate addition of every available therapy.

Why HFpEF Matters Now

HFpEF is increasingly encountered as populations age and as obesity, hypertension, type 2 diabetes, chronic kidney disease, atrial fibrillation, and sleep apnea remain prevalent. Many patients have several overlapping contributors to dyspnea, exercise limitation, elevated filling pressures, and congestion.

HFpEF may occur in association with hypertensive remodeling, obesity, atrial myopathy, coronary or valvular disease, renal-metabolic dysfunction, pulmonary vascular disease, infiltrative cardiomyopathy, or frailty. These categories are neither mutually exclusive nor uniformly validated treatment phenotypes, but they can help organize diagnostic and therapeutic reasoning.

A patient with obesity-related HFpEF and severe functional limitation may require a different strategy from a patient with unexplained ventricular wall thickening, conduction disease, neuropathy, and possible transthyretin amyloid cardiomyopathy. Similarly, a patient with LVEF of 42% may respond more like a patient with heart failure with mildly reduced ejection fraction than one with an LVEF of 68%.

Ejection fraction alone cannot establish the diagnosis or define treatment. Many pivotal studies enrolled patients with LVEF greater than or equal to 40%, 45%, or 50%, creating substantial overlap between HFmrEF and conventionally defined HFpEF.

Diagnosis Comes First

HFpEF is not simply dyspnea accompanied by a normal ejection fraction. The diagnosis requires symptoms or signs compatible with heart failure and objective evidence of cardiac structural or functional abnormality or spontaneous or provoked elevation in filling pressures. Alternative and coexisting explanations must also be considered.[1,4,5]

HFpEF should be considered in patients with exertional dyspnea, fatigue, edema, orthopnea, bendopnea, elevated jugular venous pressure, pulmonary congestion, or recurrent unexplained volume overload. Obesity, hypertension, diabetes, chronic kidney disease, atrial fibrillation, older age, female sex, and sleep apnea increase clinical probability but do not confirm the syndrome.

Echocardiographic assessment should extend beyond LVEF. Relevant findings may include left atrial enlargement, left ventricular hypertrophy, abnormal diastolic indices, elevated estimated pulmonary pressures, right ventricular dysfunction, valvular disease, and abnormal strain patterns.

Natriuretic peptides are useful but must be interpreted in context. Obesity may suppress B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide concentrations, while atrial fibrillation and renal dysfunction may increase them. A normal value does not reliably exclude HFpEF in every patient, particularly in obesity or when elevated filling pressures occur primarily during exertion.

Structured tools can help when diagnostic probability is uncertain. The H2FPEF score estimates the likelihood that unexplained dyspnea is attributable to HFpEF using clinical and echocardiographic variables.[5] The HFA-PEFF algorithm integrates pretest assessment, echocardiography, natriuretic peptides, functional testing, and etiologic evaluation.[4] These tools supplement rather than replace clinical judgment.

Exercise echocardiography, cardiopulmonary exercise testing, or invasive exercise hemodynamic assessment may be appropriate when resting studies are nondiagnostic and clinically important uncertainty persists.

Clinicians should also evaluate common mimics and treatable subtypes. These include cardiac amyloidosis, hypertrophic cardiomyopathy, constrictive pericarditis, valvular disease, severe pulmonary disease, pulmonary vascular disease, anemia, thyroid disease, renal disease, medication-related edema, and deconditioning.

Cardiac amyloidosis should be considered when ventricular wall thickening is unexplained, especially when accompanied by conduction disease, atrial fibrillation, low-voltage electrocardiography, neuropathy, orthostatic symptoms, carpal tunnel syndrome, spinal stenosis, or biomarker elevation that appears disproportionate to the clinical presentation.

Current Guideline Position

The 2022 American Heart Association, American College of Cardiology, and Heart Failure Society of America guideline assigned SGLT2 inhibitors a Class 2a recommendation in HFpEF. Mineralocorticoid receptor antagonists, sacubitril/valsartan, and angiotensin receptor blockers received weaker Class 2b recommendations, with greater potential benefit anticipated when LVEF is closer to the lower end of the preserved range.[1]

The 2023 European Society of Cardiology focused update gave empagliflozin and dapagliflozin a strong recommendation in HFmrEF and HFpEF to reduce the risk of heart failure hospitalization or cardiovascular death.[2]

The 2023 American College of Cardiology expert consensus pathway emphasized diagnostic confirmation, phenotype-informed care, decongestion, and deliberate management of obesity, hypertension, diabetes, atrial fibrillation, sleep apnea, and chronic kidney disease.[3]

These guideline documents predate the expanded U.S. heart failure indication for finerenone. Finerenone should therefore be described on the basis of FINEARTS-HF and current U.S. labeling rather than represented as an established component of the older HFpEF guideline recommendations.[8,9]

SGLT2 Inhibitors: The Broadest Current Foundation

SGLT2 inhibitors have the broadest randomized outcomes evidence among contemporary HFpEF therapies. EMPEROR-Preserved enrolled patients with symptomatic heart failure and LVEF greater than 40%. Empagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure, with the effect driven primarily by fewer heart failure hospitalizations.[6]

DELIVER enrolled patients with LVEF greater than 40% and showed that dapagliflozin reduced the composite of worsening heart failure or cardiovascular death. Benefits were observed in patients with and without diabetes and across much of the mildly reduced and preserved ejection fraction spectrum.[7]

The most reliable clinical conclusion is that empagliflozin and dapagliflozin reduce worsening heart failure events and heart failure hospitalization. They should not be described as reversing HFpEF, eliminating the need for diuretics, or producing a consistent independent cardiovascular mortality benefit in every HFpEF population. Average improvements in symptoms or health status may occur, but they are generally more modest and variable than the event-reduction findings.

In patients with confirmed HFpEF or HFmrEF, an SGLT2 inhibitor should generally be considered early unless intolerance, contraindications, affordability, or competing safety concerns predominate. Empagliflozin and dapagliflozin are administered at 10 mg once daily for their heart failure indications, according to current U.S. labeling.[19,20]

Before initiation, clinicians should assess renal function, volume status, blood pressure, diuretic therapy, frailty, prior ketoacidosis, recurrent genitourinary infection, acute illness risk, and planned procedures. Volume depletion may be more consequential in older adults, patients with impaired kidney function, and those receiving loop diuretics.

SGLT2 inhibitors can cause ketoacidosis even when blood glucose is not markedly elevated. Risk increases with reduced caloric intake, acute illness, volume depletion, surgery, insulin deficiency, ketogenic diets, or excessive alcohol consumption. Patients should receive counseling about symptoms and temporary interruption during relevant acute illnesses.

Empagliflozin and dapagliflozin should generally be withheld for at least 3 days before major surgery or procedures associated with prolonged fasting and restarted after the patient is clinically stable and oral intake has resumed.[19,20]

Genital mycotic infections are common adverse effects. Serious genitourinary infections and Fournier gangrene are rare but clinically important label warnings. Product-specific renal recommendations and current labeling should be reviewed rather than applying a single glycemic-control eGFR threshold to all heart failure use.

Finerenone: Newer Evidence and Labeling for LVEF ≥40%

FINEARTS-HF enrolled patients with symptomatic heart failure and LVEF ≥40%. Finerenone reduced the composite of total worsening heart failure events and cardiovascular death compared with placebo. The treatment effect was driven largely by fewer worsening heart failure events rather than a separately established reduction in cardiovascular death.[8]

Current U.S. labeling indicates finerenone to reduce cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure and LVEF ≥40%.[9] Chronic kidney disease, diabetes, and albuminuria may influence the broader rationale for treatment, but they are not prerequisites for the heart failure indication.

Finerenone should not be treated as interchangeable with spironolactone. It is a nonsteroidal mineralocorticoid receptor antagonist with a distinct evidence base, dosing structure, regulatory indication, and interaction profile. Although it has less off-target activity at androgen and progesterone receptors than spironolactone, superior overall tolerability in HFpEF has not been established.

Serum potassium and eGFR should be measured before treatment. Finerenone should not be initiated when serum potassium exceeds 5.0 mEq/L, and initiation is not recommended in patients with heart failure and eGFR below 25 mL/min/1.73 m². Dose selection and target dosing depend on baseline renal function. Potassium and eGFR should be reassessed 4 weeks after initiation, 4 weeks after dose adjustment, and periodically thereafter.[9]

Finerenone is contraindicated in patients receiving strong CYP3A4 inhibitors, in patients with adrenal insufficiency, and in those with hypersensitivity to a product component. Grapefruit and grapefruit juice should be avoided. Strong or moderate CYP3A4 inducers should also generally be avoided because they may reduce finerenone exposure.

Hyperkalemia, worsening renal function, hypotension, and hyponatremia are important safety considerations. The current label specifically warns that finerenone can cause worsening renal function in patients with heart failure, including rare severe events requiring hospitalization.[9]

The optimal sequence for adding finerenone to SGLT2 inhibitors, diuretics, sacubitril/valsartan, spironolactone, or obesity-directed therapy remains uncertain because direct sequencing trials are lacking.

Steroidal Mineralocorticoid Receptor Antagonists: Selective Use

The principal HFpEF outcomes evidence for a steroidal mineralocorticoid receptor antagonist comes from TOPCAT, which evaluated spironolactone in patients with symptomatic heart failure and LVEF ≥45%.[10]

TOPCAT did not significantly reduce its primary composite endpoint of cardiovascular death, aborted cardiac arrest, or hospitalization for heart failure in the overall trial population. Spironolactone did reduce heart failure hospitalization, and substantial regional differences raised questions about patient selection and treatment exposure.

These findings support selective rather than universal use. Spironolactone may be considered in appropriately selected patients, particularly when LVEF is near the lower end of the preserved range or when another accepted indication, such as resistant hypertension, is present. Equivalent HFpEF outcomes evidence should not be assumed for eplerenone.

Hyperkalemia and worsening renal function are the major limitations. Hypotension, breast tenderness, gynecomastia, menstrual effects, and other endocrine adverse effects may also occur. Baseline and follow-up potassium and renal function monitoring are essential.

Additional caution is warranted in advanced chronic kidney disease, baseline hyperkalemia, recent acute kidney injury, unstable diuretic requirements, high potassium intake, use of potassium supplements, nonsteroidal anti-inflammatory drug exposure, or concurrent use of several renin-angiotensin-aldosterone system-active agents.

Sacubitril/Valsartan: Most Plausible Below Normal LVEF

Sacubitril/valsartan has a nuanced role in HFpEF. PARAGON-HF compared sacubitril/valsartan with valsartan in patients with heart failure and LVEF ≥45% but did not meet its primary endpoint in the overall trial population.[11]

Subgroup and pooled analyses suggest that benefit may be more plausible when LVEF is below normal or near the lower end of the preserved range, as well as in some women and patients with recent worsening heart failure. These findings should be interpreted as supportive of selective treatment rather than as proof of uniform benefit across HFpEF.

Current U.S. labeling states that sacubitril/valsartan reduces cardiovascular death and heart failure hospitalization in adults with chronic heart failure, with benefits most clearly evident in patients whose LVEF is below normal. The label also emphasizes that LVEF is a variable measure and that clinical judgment is required.[12]

Sacubitril/valsartan may be considered in patients with mildly reduced or low-normal LVEF, recurrent heart failure events, adequate blood pressure, and persistent symptoms despite appropriate foundational care.

Important risks include hypotension, renal dysfunction, hyperkalemia, angioedema, and fetal toxicity. Sacubitril/valsartan is contraindicated with concurrent ACE-inhibitor therapy and must not be administered within 36 hours of switching from or to an ACE inhibitor. It is contraindicated in patients with angioedema related to previous ACE-inhibitor or angiotensin-receptor-blocker therapy and with aliskiren in patients with diabetes.[12]

Obesity-Directed Therapy: Important but Phenotype-Specific

Obesity-related HFpEF is a clinically important and increasingly actionable presentation. Excess adiposity may contribute to plasma-volume expansion, systemic inflammation, impaired ventricular and vascular reserve, sleep apnea, insulin resistance, musculoskeletal limitation, and reduced exercise capacity. These pathways overlap, and the relative contribution of each varies among patients.

Semaglutide

STEP-HFpEF evaluated once-weekly semaglutide 2.4 mg in patients with obesity-related HFpEF. Semaglutide improved heart failure-related symptoms and physical limitations, increased 6-minute walking distance, reduced body weight, and lowered C-reactive protein compared with placebo.[13]

STEP-HFpEF DM demonstrated similar patient-centered benefits in patients with obesity-related HFpEF and type 2 diabetes, although average weight loss was less than in the trial population without diabetes.[14] A pooled analysis supported consistent improvements in symptoms, physical limitations, exercise function, and body weight across the two trials.[15]

These findings do not establish semaglutide as universal HFpEF therapy or demonstrate a broad HFpEF mortality benefit. The evidence applies primarily to patients resembling the obesity-related HFpEF trial populations.

Tirzepatide

SUMMIT evaluated tirzepatide in patients with HFpEF and obesity. Tirzepatide reduced the composite of cardiovascular death or worsening heart failure, with the effect driven primarily by fewer worsening heart failure events. It also improved health status, exercise function, and body weight.[16]

The event-reduction finding differentiates SUMMIT from the symptom-focused STEP-HFpEF program, but the medications should not be assumed to have equivalent evidence, mechanisms, or regulatory status.

Labeling and Safety

Neither semaglutide nor tirzepatide has a broad U.S. indication for HFpEF. Wegovy is indicated for long-term weight management in qualifying patients and for reduction of major adverse cardiovascular events in adults with established cardiovascular disease and obesity or overweight. Zepbound is indicated for long-term weight management in qualifying adults and for moderate to severe obstructive sleep apnea in adults with obesity.[17,18]

The HFpEF trial evidence should therefore be applied primarily to patients with obesity-related HFpEF who also meet an approved indication for the selected medication.

Both products carry boxed warnings concerning thyroid C-cell tumors observed in rodents. They are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 and in patients with serious hypersensitivity to the active drug or product excipients.[17,18]

Additional considerations include nausea, vomiting, diarrhea, constipation, severe gastrointestinal adverse effects, dehydration, acute kidney injury related to volume depletion, gallbladder disease, pancreatitis symptoms, delayed gastric emptying, and hypoglycemia when combined with insulin or an insulin secretagogue. Use is not recommended in severe gastroparesis. Periprocedural planning is important because delayed gastric emptying may increase aspiration risk during anesthesia or deep sedation.

Pregnancy, nutrition, frailty, and the potential loss of lean mass should be considered before and during treatment. Rapid or substantial weight reduction in older or frail adults should be accompanied by attention to protein intake, resistance exercise when feasible, and functional status.

The mechanisms responsible for improvement in obesity-related HFpEF are probably multifactorial. Weight reduction, changes in hemodynamic load, inflammation, metabolic function, sleep apnea, and physical mobility may all contribute. Current trials do not establish a single mechanism as the cause of the observed clinical benefits.

Diuretics Still Matter

Newer therapies do not eliminate the need for loop diuretics. Congestion remains one of the most important treatable contributors to dyspnea, edema, renal dysfunction, and hospitalization.

Diuretics improve symptoms and volume status but have not demonstrated a specific mortality benefit in HFpEF. Dose adjustment should account for symptoms, examination findings, body-weight trends, renal function, electrolytes, blood pressure, orthostatic symptoms, frailty, and treatment goals.

Overdiuresis may cause hypotension, worsening renal function, dizziness, falls, weakness, or low-output symptoms. Underdiuresis leaves patients congested and vulnerable to decompensation. A small rise in creatinine during effective decongestion does not invariably indicate harmful kidney injury, but the overall clinical context must guide interpretation.

Home weights, edema, orthopnea, jugular venous pressure, pulmonary congestion, sodium intake, kidney function, potassium, and patient-reported symptoms can help guide titration.

Blood Pressure, Atrial Fibrillation, and Comorbidity Management

HFpEF care should not focus exclusively on medications studied in preserved-ejection-fraction trials. Hypertension, atrial fibrillation, diabetes, chronic kidney disease, obesity, coronary disease, valvular disease, sleep apnea, anemia, iron deficiency, pulmonary disease, and medication-related edema may contribute to symptoms, decompensation, or adverse outcomes.

Blood pressure should be treated according to contemporary hypertension and heart failure guidance, while accounting for frailty, orthostatic hypotension, renal function, fall risk, and polypharmacy. Excessive blood-pressure reduction can worsen dizziness, renal perfusion, and treatment tolerance.

Atrial fibrillation may worsen symptoms through rapid ventricular rates, irregular rhythm, loss of atrial contribution to ventricular filling, and progression of atrial myopathy. Anticoagulation should follow validated thromboembolic-risk assessment and contemporary atrial fibrillation guidance. Rate control, rhythm control, antiarrhythmic therapy, and ablation referral should be individualized.

Obstructive sleep apnea should be identified and treated when appropriate. Coronary and valvular disease should be evaluated according to their own indications. Pulmonary hypertension in HFpEF is usually related to left-sided filling pressure elevation; pulmonary vasodilators should not be routinely prescribed unless a separate evidence-based indication has been established.

Thiazolidinediones can cause or worsen fluid retention and are generally inappropriate in symptomatic heart failure. Nonsteroidal anti-inflammatory drugs can promote sodium retention, increase blood pressure, impair renal function, and interfere with diuretic response.

Structured exercise and rehabilitation can improve functional capacity and quality of life, although programs should be adapted to frailty, musculoskeletal limitations, and patient goals.

Table 1. Pharmacologic Options in HFpEF and Heart Failure With LVEF ≥40%

Therapy	Best-supported role	Principal cautions and limitations
Empagliflozin or dapagliflozin	Early therapy to reduce worsening HF events and HF hospitalization across HFmrEF and HFpEF	Volume depletion, ketoacidosis, genital and urinary infections, perioperative interruption, product-specific renal recommendations
Finerenone	U.S.-labeled option for adults with HF and LVEF ≥40%; FINEARTS-HF benefit driven mainly by fewer worsening HF events	Hyperkalemia, worsening renal function, hypotension, eGFR and potassium thresholds, CYP3A4 interactions, adrenal insufficiency
Spironolactone	Selective use, particularly when LVEF is near the lower preserved range or another accepted indication is present	TOPCAT neutral for overall primary endpoint; hyperkalemia, renal dysfunction, hypotension, endocrine adverse effects
Sacubitril/valsartan	Selective use when LVEF is below normal or near the lower preserved range	PARAGON-HF neutral overall; hypotension, renal dysfunction, hyperkalemia, angioedema, fetal toxicity, ACE-inhibitor washout
Semaglutide 2.4 mg	Obesity-related HFpEF with an approved obesity indication; improves symptoms, function, and weight	No broad HFpEF indication; gastrointestinal effects, dehydration, gallbladder disease, pancreatitis warning, delayed gastric emptying, thyroid C-cell tumor contraindications
Tirzepatide	Obesity-related HFpEF with an approved obesity indication; reduces worsening HF composite and improves symptoms, function, and weight	No broad HFpEF indication; gastrointestinal effects, dehydration, gallbladder disease, pancreatitis warning, delayed gastric emptying, thyroid C-cell tumor contraindications
Loop diuretics	Relief of congestion and volume-related symptoms	No established HFpEF mortality benefit; electrolyte abnormalities, hypotension, renal dysfunction, overdiuresis

Table 2. Practical Pretreatment Checklist

Clinical question	Why it matters	Practical action
Is the HFpEF diagnosis secure?	Dyspnea with preserved LVEF has many mimics	Review symptoms, examination, echocardiography, natriuretic peptides, and volume status; consider H2FPEF, HFA-PEFF, exercise testing, or invasive hemodynamics
Is the patient congested?	Persistent congestion can mimic treatment failure and increase hospitalization risk	Optimize loop-diuretic therapy before assuming that another medication is ineffective
What are the potassium and eGFR?	Finerenone and steroidal MRAs may cause hyperkalemia and renal deterioration	Obtain baseline values and repeat after initiation or dose adjustment
Is blood pressure adequate?	Diuretics and sacubitril/valsartan may cause symptomatic hypotension	Individualize treatment order, dosing, and titration
Is obesity a dominant clinical feature?	Incretin evidence is strongest in obesity-related HFpEF	Consider structured weight management and labeled obesity pharmacotherapy
Is atrial fibrillation contributing?	Atrial fibrillation may worsen filling pressures and symptoms	Address anticoagulation, rate, rhythm, and referral needs
Are amyloid red flags present?	Misclassification may delay disease-specific evaluation and treatment	Evaluate unexplained wall thickening, neuropathy, carpal tunnel syndrome, conduction disease, orthostasis, and biomarker patterns
Are interacting medications present?	Polypharmacy increases adverse-event risk	Review NSAIDs, potassium products, CYP3A4 modifiers, renin-angiotensin system agents, insulin, and insulin secretagogues
Can monitoring be completed reliably?	Several therapies require laboratory or clinical surveillance	Confirm access to follow-up, laboratory testing, education, and medication supply

Device and Procedural Strategies

Pulmonary artery pressure monitoring may be considered in selected patients with recurrent heart failure hospitalization and difficult volume management. Trials have shown that hemodynamically guided care can reduce heart failure hospitalization in selected populations, but patient selection, procedural risk, cost, and the ability to respond consistently to pressure data are important.[22] This is not a routine intervention for every patient with HFpEF.

Interatrial shunt therapy remains investigational. REDUCE LAP-HF II did not establish a broad clinical benefit, and outcomes may differ according to exercise pulmonary vascular resistance and right-sided hemodynamics.[21] Some patients may be harmed. Device consideration should occur within a specialized heart failure or structural-heart program, preferably through an appropriate clinical trial or carefully defined protocol.

A Practical Sequencing Approach

Evidence does not establish one mandatory medication sequence for all patients. A practical approach can nevertheless organize decision-making.

Confirm the syndrome

Review symptoms, examination findings, natriuretic peptides, echocardiography, renal function, rhythm, pulmonary disease, anemia, thyroid status, ischemia, valve disease, pulmonary pressures, and infiltrative red flags. If uncertainty persists, consider structured scores, exercise echocardiography, cardiopulmonary exercise testing, invasive hemodynamics, or specialist referral.

Treat congestion

Adjust loop diuretics according to symptoms, body weight, physical examination, renal function, electrolytes, and blood pressure. Effective decongestion may improve function and permit safer initiation of other therapies.

Consider an SGLT2 inhibitor

Empagliflozin or dapagliflozin should generally be considered early in eligible patients with confirmed HFpEF or HFmrEF. Review renal function, volume status, ketoacidosis risk, genitourinary infection history, acute illness plans, and perioperative interruption.

Consider finerenone

Finerenone may be considered in eligible adults with heart failure and LVEF ≥40%. Confirm serum potassium, eGFR, interacting medications, absence of adrenal insufficiency, and the feasibility of follow-up monitoring. CKD or diabetes is not required for the heart failure indication.

Determine whether sacubitril/valsartan or spironolactone has a selective role

These decisions should be guided by LVEF, blood pressure, renal function, potassium, prior heart failure events, concurrent indications, and patient-specific risk. Their evidence is less uniform than that of SGLT2 inhibitors.

Identify obesity-related HFpEF

For patients with obesity and compatible HFpEF, integrate nutrition, exercise, sleep apnea evaluation, management of metabolic disease, and obesity pharmacotherapy when indicated. Semaglutide or tirzepatide may be appropriate when the patient meets current labeling and when contraindications, tolerability, frailty, nutrition, cost, and access have been considered.

Manage the comorbidity architecture

Hypertension, atrial fibrillation, diabetes, chronic kidney disease, coronary and valvular disease, sleep apnea, pulmonary disease, frailty, anemia, and medication-related edema may determine whether a treatment plan succeeds.

Monitoring and Safety

Patients with HFpEF are frequently older and have multimorbidity, polypharmacy, fluctuating renal function, and changing diuretic requirements. Monitoring should therefore be deliberate and individualized.

For SGLT2 inhibitors, assess renal function, volume status, diuretic dose, blood pressure, ketoacidosis risk, genitourinary infection risk, acute illness, and perioperative plans. A modest early decline in eGFR may occur, but clinically important renal deterioration, hypotension, or volume depletion requires reassessment.

For finerenone, monitor potassium and eGFR before treatment, 4 weeks after initiation, 4 weeks after dose changes, and periodically thereafter. Monitoring should be more frequent when kidney function is reduced, baseline potassium is high-normal, or concomitant medications increase potassium.

For spironolactone, monitor potassium, renal function, blood pressure, and endocrine adverse effects. Greater caution is warranted with advanced kidney disease, prior hyperkalemia, recent acute kidney injury, or concurrent potassium-raising therapy.

For sacubitril/valsartan, monitor blood pressure, renal function, potassium, and angioedema. Confirm the ACE-inhibitor washout period and assess pregnancy potential because of fetal toxicity.

For semaglutide and tirzepatide, monitor gastrointestinal tolerance, hydration, renal function during fluid loss, nutrition, functional status, gallbladder symptoms, possible pancreatitis, and hypoglycemia risk with insulin or sulfonylureas. Consider delayed gastric emptying before anesthesia or deep sedation.

Monitoring frequency should increase during acute illness, medication transitions, rapid weight loss, worsening congestion, changes in diuretic therapy, or deterioration in renal function.

Limitations of the Evidence

HFpEF trials use different ejection-fraction thresholds, diagnostic requirements, background therapies, and endpoint definitions. Some enroll patients with LVEF greater than 40%, while others require LVEF ≥45% or ≥50%. Patients near the lower end of this range may respond differently from those with very high LVEF.

Many positive HFpEF trials are driven predominantly by fewer worsening heart failure events or hospitalizations rather than independently significant reductions in cardiovascular death. These remain clinically meaningful outcomes, but the reported benefit should match the trial endpoint.

Symptom and health-status improvements also require context. Mean changes at the trial level do not imply that every patient will experience a clinically important response.

Subgroup analyses may generate useful hypotheses but should not be presented as definitive treatment effects unless replicated or supported by broader evidence. This is particularly important for sacubitril/valsartan and spironolactone.

Combination and sequencing evidence remains incomplete. A patient may appear eligible for an SGLT2 inhibitor, finerenone, sacubitril/valsartan, spironolactone, obesity pharmacotherapy, and intensified diuresis, yet trials rarely determine which treatment should be initiated first in an older adult with CKD, borderline blood pressure, atrial fibrillation, obesity, frailty, and recurrent congestion.

Access, adherence, tolerability, and monitoring feasibility also shape effectiveness in practice. A therapy cannot produce its expected benefit if it is unaffordable, poorly tolerated, or used without necessary clinical and laboratory surveillance.

Future Directions

HFpEF care is moving toward more phenotype-informed treatment, but formal phenotype classification has not itself been proven to improve outcomes. Obesity-related HFpEF, atrial myopathy, renal-metabolic disease, amyloid cardiomyopathy, pulmonary vascular involvement, inflammatory pathways, and frailty may require different diagnostic and therapeutic priorities.

Future research should clarify combination therapy, treatment sequence, very-high-LVEF populations, sex-related treatment differences, advanced chronic kidney disease, frailty, long-term obesity-treatment durability, and effects on mortality.

Implementation is equally important. Many patients remain undiagnosed, undertreated, or treated without adequate monitoring despite the growing evidence base.

References

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