HFpEF was, for most of cardiology's history, a diagnosis where the honest answer to a patient asking "what can we do?" was: manage the comorbidities and hope. The SGLT2 inhibitor data from EMPEROR-Preserved and DELIVER changed that — not dramatically, but genuinely — and the 2026 trial landscape is building on those results with a level of therapeutic ambition this patient population has never seen. SUMMIT showed a 38% reduction in HFpEF events with tirzepatide. FINEARTS-HF results are expected this year. Aficamten has expanded from obstructive HCM. Interatrial shunt devices are in Phase 3. For patients who've been told there's not much available, the story is changing.
This article is for informational purposes only and does not constitute medical advice. Clinical trial eligibility and availability vary. Always consult a qualified healthcare professional before making any medical decisions or considering participation in a clinical trial.
Summary
Heart failure affects over 64 million people worldwide. In 2026, research is concentrated on HFpEF — the form with fewest approved treatments — alongside device therapies, anti-inflammatory strategies, and myosin inhibitors for cardiomyopathy. SUMMIT trial: tirzepatide reduced HFpEF events by 38% in obese patients with significant KCCQ and exercise capacity improvements. FINEARTS-HF (finerenone in HFpEF): top-line results expected in 2026. SGLT2 inhibitors (empagliflozin, dapagliflozin) remain the only currently guideline-recommended pharmacotherapy for HFpEF ≥50%, but the pipeline is substantially deeper than it has ever been.
ClinicalMetric Analysis
- HFpEF's clinical heterogeneity is why trials keep producing mixed results in apparently similar populations. Obesity-driven HFpEF, inflammatory HFpEF (elevated CRP, ferritin), and hypertension-driven concentric remodeling likely have different underlying pathophysiology — but trials enroll them together by EF ≥50% and symptom criteria. SUMMIT enrolled specifically obese HFpEF patients and saw 38% event reduction with tirzepatide. EMPEROR-Preserved enrolled all-comer HFpEF and saw HRs in the 0.79–0.82 range. Until phenotypic subgroup trials become standard, interpreting why one trial succeeds and another fails in HFpEF requires knowing the patient composition, not just the drug.
- SUMMIT's tirzepatide result in HFpEF should not be extrapolated to non-obese patients. SUMMIT required BMI ≥30 — this was the obese phenotype specifically. The metabolic mechanism driving the benefit (reduced adipose inflammation, improved cardiac preload, insulin sensitization) may simply be absent in lean HFpEF patients, who likely have a fundamentally different disease driver. Applying tirzepatide's SUMMIT number to all HFpEF patients is the same error as applying semaglutide's STEP-1 weight loss to patients without significant obesity.
- Aficamten's rapid reversibility is a practical differentiator from mavacamten that matters more than efficacy comparisons. Mavacamten (camzyos) requires REMS enrollment, echocardiographic monitoring every 12 weeks, and dose adjustments based on LVOT gradient and EF — because EF suppression is a real dose-dependent risk. Aficamten's pharmacokinetics allow washout within days, removing the need for the same monitoring burden. For obstructive HCM patients who can't easily access frequent cardiac imaging follow-up (rural patients, those with monitoring burdens from other conditions), this reversibility profile translates to real-world accessibility.
HFpEF vs. HFrEF: Why the Distinction Determines Everything
Heart failure is classified primarily by ejection fraction — the percentage of blood pumped from the left ventricle per beat. HFrEF (reduced EF, below 40%) has an established, mortality-reducing pharmacological toolkit: ACE inhibitors or sacubitril/valsartan (ARNI), beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. Used optimally, these four classes together reduce mortality in HFrEF by roughly 60–70% — one of the most powerful pharmacological combinations in all of internal medicine. HFpEF (preserved EF, ≥50%) had none of that. The heart contracts adequately but the ventricles are stiff and don't relax properly — causing identical symptoms (dyspnea, exercise intolerance, fatigue) through a fundamentally different mechanism. Every treatment that worked in HFrEF failed in HFpEF for years.
SGLT2 inhibitors broke that pattern. EMPEROR-Preserved (empagliflozin) and DELIVER (dapagliflozin) both showed significant reductions in the primary composite of cardiovascular death or worsening heart failure events — HRs in the 0.79–0.82 range in both trials. The mechanisms are likely multiple: natriuresis reducing preload, direct cardiomyocyte effects, and metabolic substrate optimization in the stressed myocardium. These drugs are now guideline-recommended in HFpEF. The 2026 question is whether we can do substantially better.
GLP-1 Agonists in HFpEF: SUMMIT and the Obesity-HFpEF Phenotype
The STEP-HFpEF trial (semaglutide in HFpEF with obesity) showed significant improvement in KCCQ score and 6-minute walk distance, with a 19% relative risk reduction in the primary endpoint. Notable but expected — reducing obesity was always going to help a phenotype where obesity is a major pathophysiological driver, causing pericardial restraint, elevated filling pressures, and systemic inflammation simultaneously. The SUMMIT trial (tirzepatide, dual GLP-1/GIP agonist, in HFpEF with obesity) went further: a 38% reduction in the composite of cardiovascular death or worsening heart failure, plus clinically significant improvements in exercise capacity and quality of life. That number is large.
What we don't know is whether the benefit is purely mediated through weight reduction and hemodynamic improvement, or whether direct cardiac GLP-1 receptor effects contribute independently. That distinction matters for non-obese HFpEF patients, who are a meaningful subgroup. FLOW-HF is testing semaglutide in broader HFpEF populations beyond the obese phenotype, and the results will be instructive. Until then, GLP-1 agonists represent the most compelling new pharmacotherapy for obese HFpEF specifically.
Ziltivekimab, Finerenone, and the Anti-Inflammatory Hypothesis
Chronic systemic inflammation is a cardinal feature of HFpEF — hsCRP, IL-6, and other inflammatory markers are elevated in most patients and correlate with adverse outcomes. Ziltivekimab is a monoclonal antibody targeting the IL-6 ligand that reduces hsCRP by approximately 70% at therapeutic doses. The ZEUS Phase 3 trial enrolled heart failure patients with elevated inflammatory biomarkers, testing whether inflammation reduction translates to reduced cardiovascular events.
Finerenone is a non-steroidal mineralocorticoid receptor antagonist (MRA) approved for CKD with T2DM. The FINEARTS-HF trial is specifically testing finerenone in HFpEF and HFmrEF — populations where steroidal MRAs (spironolactone, eplerenone) previously failed partly due to tolerability issues the non-steroidal design addresses. Top-line results are expected in 2026, and this is among the most-watched cardiology trials currently running.
Myosin Inhibitors: Aficamten and HCM Management
Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease — approximately 1 in 500 people — and the leading cause of sudden cardiac death in young athletes. Treatment was limited to beta-blockers, calcium channel blockers, and septal reduction procedures until cardiac myosin inhibitors arrived. Mavacamten (Camzyos) was approved in 2022 based on EXPLORER-HCM data showing significant LVOT gradient reduction and symptom improvement. Aficamten (Cytokinetics) followed with SEQUOIA-HCM Phase 3 data and FDA approval in 2024, providing an alternative with slightly different pharmacokinetics and a shorter half-life allowing faster washout if complications arise.
In 2026, both agents are expanding beyond obstructive HCM into non-obstructive disease, pediatric populations, and combination therapy with SGLT2 inhibitors. The fundamental mechanism — reducing the proportion of myosin heads in the force-generating state, thereby directly counteracting the hypercontractility that causes obstruction and fibrosis — is the most targeted cardiac intervention available for an inherited cardiomyopathy.
Device-Based Therapies: Interatrial Shunts and CCM
The Alleviant System (and similar devices) creates a controlled opening between the left and right atria, allowing decompression of elevated left atrial pressure — the hemodynamic bottleneck that produces the dyspnea and exercise limitation defining HFpEF. Phase 3 trials are ongoing. The challenge is patient selection: earlier trials (REDUCE LAP-HF I and II) showed heterogeneous results, with certain subgroups benefiting substantially and others showing no benefit or harm. Defining the responder phenotype is the central work of current trials.
Cardiac contractility modulation (CCM) devices deliver non-excitatory electrical signals to the ventricular myocardium during the absolute refractory period, improving contractile performance without pacing. Phase 3 data shows meaningful improvements in quality of life and exercise capacity in HFrEF patients who remain symptomatic on optimal medical therapy but don't meet CRT criteria — a population with significant unmet need.
Trial Eligibility and Where to Look
Most heart failure trials require documented echo with ejection fraction, NYHA class II–III status, stability on optimized background therapy for 30–90 days, and elevated NT-proBNP confirming hemodynamic stress. For HFpEF specifically, NT-proBNP elevation is important — EF alone doesn't establish the diagnosis without biomarker confirmation. Common exclusions: acute decompensation hospitalization within 30–90 days, severe CKD (eGFR below 20–30 mL/min), unaddressed significant valvular disease, recent cardiac surgery or device implant. In older patients, ATTR-CM should be ruled out before HFpEF trial enrollment — both diagnoses coexist and require different treatments.
The Heart Failure Society of America and ACC maintain trial directories. Large cardiology practices and academic heart failure programs typically run multiple industry-sponsored trials simultaneously. Search ClinicalMetric for "heart failure" filtered to Phase 2 or 3, Recruiting — and have your most recent echocardiogram, NT-proBNP, eGFR, and medication list available before your first contact with a study site.