Mapping the global clinical landscape of pharmacological therapies for heart failure with preserved ejection fraction: An analysis based on ClinicalTrials.gov (2003-2025)

1 | Introduction

Heart failure with preserved ejection fraction (HFpEF) comprises more than half of heart failure diagnoses globally, influenced by aging populations and increasing burdens of comorbidities such as obesity, diabetes, hypertension, and atrial fibrillation (AF)[1-3]. HFpEF is characterized by diastolic dysfunction, systemic inflammation, microvascular rarefaction, and metabolic derangements, which contribute to its complex pathophysiology[2, 4, 5].

HFpEF treatment yielded largely neutral results in trials before 2020[6-9], contrasting with established neurohormonal blockade in heart failure with reduced ejection fraction (HFrEF)[10-14]. Pivotal shifts occurred from 2021 onward, with the first HFpEF-specific approval of sacubitril/valsartan[15], followed by sodium-glucose cotransporter-2 inhibitors (SGLT2i; e.g., empagliflozin[16], dapagliflozin[17]) and nonsteroidal mineralocorticoid receptor antagonists (MRAs) such as finerenone[18]. Emerging metabolic agents, including glucagon-like peptide-1 receptor agonists (GLP-1RAs; e.g., semaglutide[19], tirzepatide[20]), show promise particularly in obesity-associated phenotypes.

Despite these advances, no comprehensive, registry-based analysis has quantified the global landscape of clinical trials for HFpEF pharmacotherapies over the past two decades. Previous reviews have examined specific drug classes or guideline evolutions but lack a broad overview of trial distribution, status, and temporal dynamics. This study aimes to fill this gap by systematically reviewing trials registered on ClinicalTrials.gov from 2003 to 2025. Our objectives are to: (1) describe the geographical and temporal distribution of HFpEF drug trials; (2) evaluate trial phases, status, and drug class trends; (3) align findings with key regulatory milestones; and (4) discuss implications for addressing the therapeutic challenges of HFpEF, incorporating insights from recent evidence on disease heterogeneity and efficacy signals.

2 | Methods

2.1 | Data Source and Search Strategy

We performed a systematic search of ClinicalTrials.gov (https://clinicaltrials.gov/) on November 10, 2025. All analyses and results reflect trials registered up to and including this date. This U.S. National Library of Medicine-maintained registry is the most comprehensive public source of global clinical trial data. We utilized the advanced search function of ClinicalTrials.gov, entering terms across fields simultaneously in a single query. The search terms included: (1) Condition or disease: “Heart Failure with Preserved Ejection Fraction” OR “HFpEF” OR “Preserved Ejection Fraction Heart Failure”; (2) Intervention/treatment: “drug” OR “pharmacological” OR “agent”; (3) Study type: All studies. No filters for date, status, or location were applied.

2.2 | Inclusion and Exclusion Criteria

Two investigators independently screened all registered trial titles, conditions, interventions, and eligibility criteria on ClinicalTrials.gov. Any discrepancies were first discussed between the two reviewers to reach consensus. In cases where consensus could not be achieved through discussion, a third independent investigator was consulted to review the records and make the final determination. The inclusion criteria were as follows: (1) Population: Adult patients (≥18 years) with a primary diagnosis of HFpEF, typically defined as heart failure with a left ventricular ejection fraction (LVEF) ≥50%, according to trial-specific criteria[2, 15]; (2) Intervention: Investigational or approved pharmacological agents as the primary focus; (3) Trials that combined pharmacological agents with non-pharmacological interventions (e.g., devices) were included only if the pharmacological component could be isolated for analysis; (4) Timeframe: Registration dates ranging from January 1, 2003 to the search date (November 10, 2025).

Exclusions included trials focused on non-HFpEF subtypes and non-pharmacological interventions. Ang disagreements were resolved through discussion or consultation with a third reviewer.

2.3 | Data Extraction

From eligible records, we extracted the following data: NCT number, study title, status (e.g., completed, enrolling by invitation, recruiting, terminated, withdrawn, not yet recruiting, unknown, and active, not recruiting), conditions, phase, start and completion dates, age, sex, countries involved, sponsor type, intervention(s) and class (categorized by mechanism), and primary endpoints. Trials with statuses of “terminated” or “withdrawn” were retained in the overall descriptive analysis to provide a comprehensive landscape of HFpEF drug development, regardless of completion status. We categorized all candidate agents into 15 mutually exclusive drug classes: SGLT2i, novel/targeted therapies, pulmonary arterial hypertension (PAH) therapies, renin–angiotensin–aldosterone system inhibitors (RAASi), GLP-1RA, angiotensin receptor-neprilysin inhibitors (ARNI), nitrates, anti-inflammatory/immunomodulators, ion channel/signal pathway modulators, diuretics, β-blockers, metabolic modulators, traditional Chinese medicines, and cardiac myosin activators. The novel/targeted therapy class included PDE-9 inhibitors, FC-fusion protein targeting agents, ErbB4 agonists, antagomiRs directed at microRNAs, innovative non-coding RNA therapeutics, advanced glycation end product (AGE) inhibitors, bradykinin (BDK) inhibitors, myeloperoxidase (MPO) inhibitors, RXFP1 receptor agonists, and related molecules. Anti-inflammatory/immunomodulators were primarily represented by colchicine and interleukin-1 receptor antagonists, while GLP-1RA encompassed dual incretin agonists. Ferric derisomaltose, coenzyme Q10, and other micronutrient supplements were categorized as the other group. RAASi included direct renin inhibitors, ACE inhibitors/ARBs, and MRAs, whereas ARNI was analyzed as a standalone class. The data were compiled into a standardized Excel spreadsheet.

2.4 | Data Analysis

Descriptive analyses were conducted using R (version 4.3.1). Categorical variables (e.g., status, phase, drug class, geography) were summarized as frequencies and percentages. Temporal trends were evaluated by initiation year and quinquennia (2003–2008, 2009–2015, 2016–2020, 2021–2025). Drug classes were categorized mechanistically, with regulatory timelines cross-referenced against public databases from the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), and National Medical Products Administration (NMPA). Given the descriptive design, no inferential statistics were performed. Figures were generated using the ggplot2 package in R.

3 | Results

3.1 | Overall Trial Characteristics and Geographical Distribution

The search identified a total of 272 trials, of which 236 met the specified criteria (see Supplementary Table 1). As shown in Table 1, the United States was the leading contributor, accounting for 138 trials (58.5%), followed by China with 17 trials (7.2%), the United Kingdom with 12 trials (5.1%), and South Korea with 8 trials (3.4%) (refer to Figure 1). Other regions with three or more trials included Russia (7), Austria (5), Egypt (4), Germany (4), Italy (4), Netherlands (4), Spain (4), Canada (3) and Ireland (3). Notably, trial initiations prior to 2016 were limited, comprising only 56 trials (23.7%), whereas the number significantly increased to 180 trials (76.3%) thereafter (see Figure 2).

Table 1. Baseline Characteristics of Included HFpEF Pharmacological Trials (n=236)
Characteristic	n (%)
Geographical Region
United States	138 (58.5)
China	17 (7.2)
United Kingdom	12 (5.1)
South Korea	8 (3.4)
Other (≥3 trials)	38 (16.1)
Multiple regions	23 (9.7)
Period
2003–2015	56 (23.7)
2016–2025	180 (76.3)
Phase
Ⅰ	32 (13.6)
Ⅱ	92 (39.0)
Ⅲ	34 (14.4)
Ⅳ	54 (22.9)
Not available	24 (10.2)
Status
Completed	111 (47.0)
Recruiting	45 (19.1)
Terminated	27 (11.4)
Withdrawn	9 (3.8)
Not yet recruiting	14 (5.9)
Active, not recruiting	9 (3.8)
Enrolling by invitation	3 (1.3)
Unknown	18 (7.6)
Drug Class
SGLT2i	31 (13.1)
Novel/targeted therapies	31 (13.1)
RAASi	22 (9.3)
PAH therapies	22 (9.3)
GLP-1RA	16 (6.8)
ARNI	15 (6.4)
Nitrates	15 (6.4)
The remaining categories	84 (35.6)

HFpEF, heart failure with preserved ejection fraction; SGLT2i, sodium-glucose cotransporter 2 inhibitor; PAH, pulmonary arterial hypertension; RAASi, renin-angiotensin-aldosterone system inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; ARNI, angiotensin receptor-neprilysin inhibitors.

3.2 | Trial Phases and Status

Trial Phases and Status Phase Ⅱ trials were the most prevalent, comprising 92 trials (39.0%), followed by Phase Ⅳ with 54 trials (22.9%), Phase Ⅲ with 34 trials (14.4%), and Phase Ⅰ with 32 trials (13.6%) (see Figure 2). As of November 10, 2025, a total of 111 trials (47.0%) had been completed, while 45 trials (19.1%) were still recruiting. Additionally, 27 trials (11.4%) were terminated, 9 trials (3.8%) were withdrawn, 14 trials (5.9%) were not yet recruiting, 9 trials (3.8%) were active but not recruiting, and 18 trials (7.6%) had an unknown status (refer to Figure 3).

3.3 | Drug Classes

Figure 4 illustrates the distribution of the 236 included trials across the 15 pre-specified drug classes. SGLT2i and novel/targeted therapies dominated the evidence base, each contributing 31 studies (13.1%). These were followed immediately by PAH therapies and RAASi (each 22, 9.3%). GLP-1RA counted 16, while ARNI and Nitrates were represented by 15 trials apiece, whereas anti-inflammatory/immunomodulators and ion-channel/signal-pathway modulators each accounted for 12 trials. Diuretics (9), β-blockers (8), and metabolic modulators (7) all fell below the 10-trial threshold, while traditional Chinese medicines and cardiac myosin activators formed the smallest cohorts, each with 3 trials.

3.4 | Trends in Recent Trials (2021-2025)

Among the 110 trials initiated from 2021 to 2025, SGLT2i accounted for 22 trials (20.0%). The proportion of SGLT2i trials increased from 15.4% in 2021 to 30.4% in 2024, before declining to 7.4% in 2025, potentially due to the completion of trials and subsequent approvals. In contrast, the percentage of GLP-1RA trials rose significantly from 11.5% in 2021 to 29.6% in 2025. Additionally, trials for novel and targeted therapies increased from 7.7% in 2021 to 33.3% in 2025 (see Figure 5). These trends align with key regulatory milestones: sacubitril/valsartan received FDA approval in 2021; empagliflozin and dapagliflozin were approved by the FDA, EMA, and NMPA between 2022 and 2023; finerenone received FDA approval in July 2025, with EMA and NMPA approvals pending; semaglutide received a positive opinion from the EMA in September 2024 for HFpEF in patients with obesity; and tirzepatide's applications were submitted, but it was rejected by the NMPA in November 2025, while FDA and EMA reviews are still ongoing (see Figure 6).

4 | Discussion

This analysis of 236 HFpEF pharmacological trials reveals a maturing pipeline, with accelerated activity post-2016 and a pivot from neurohormonal to metabolic/targeted therapies. The majority of trials were conducted in the U.S. This likely reflects two factors: the ClinicalTrials.gov registration mandate for FDA-regulated research, and greater research funding and infrastructure in North America. This pattern aligns with prior registry-based reviews of heart failure trials. It does not indicate a lack of research activity elsewhere. Rather, it reflects differences in registration practices and market priorities across regions. While this concentration demonstrates robust infrastructure, it also limits generalizability. It further mirrors regional heterogeneity in HFpEF phenotypes, including atrial fibrillation-related, hypertension-driven, and obesity-associated subtypes. China's rising contributions (7.2%) suggest improving global equity, though disparities persist.

HFpEF's recognition as a distinct entity evolved with the 2021 universal definition (LVEF ≥50% plus symptoms and elevated natriuretic peptides), up from earlier thresholds (>40–45%). Prevalence has risen from 38% of heart failure cases (late 1980s) to approximately 50% currently, driven by aging populations and comorbidities[1]; 1-year post-discharge rehospitalization reaches approximately 22% all-cause and 14% HF-specific, with 30-day readmission rates around 20–21%[21]. Early trials (e.g., CHARM-Preserved [2003][9], PEP-CHF [2006][22], TOPCAT [2011][23]) focused on RAAS inhibitors and MRAs, yielding neutral primary endpoints but hospitalization reductions in subgroups. Controversies included regional biases (TOPCAT: HR 0.82 in Americas vs. null elsewhere[24]) and guideline hesitancy (e.g., no broad ARNI endorsement pre-2021 due to PARAGON-HF's marginal P=0.06[7]).

The prevalence of phase Ⅱ trials (39.0%) indicates ongoing exploratory work to navigate HFpEF's heterogeneity, while the 15.2% attrition rate aligns with broader cardiovascular drug development challenges, including recruitment barriers, endpoint ambiguities, and pathophysiological mismatches[25]. Completed trials (47.0%) coincide with efficacy signals from landmark studies, such as EMPEROR-Preserved [2021][16]and DELIVER [2022][17], which demonstrated SGLT2i reductions in heart failure hospitalizations across LVEF spectra and comorbidities, without consistent mortality benefits[26]. These findings underpin Class I recommendations in the 2023 European Society of Cardiology (ESC) guidelines[27] and the 2025 Chinese HFpEF consensus.

The phase-Ⅲ FINEARTS-HF (2024/2025) has now cemented the non-steroidal MRA finerenone in HFpEF, demonstrating a clear reduction in total heart-failure events and contrasting sharply with the inconsistent benefits previously reported for spironolactone[18, 28].

Metabolic agents have risen concomitantly: in the GLP-1RA, semaglutide (STEP-HFpEF, 2023) improved the Kansas City Cardiomyopathy Questionnaire score (KCCQ) by 16.6 points and lowered body-weight by 13.3%[19], whereas tirzepatide (SUMMIT, 2024) cut the composite of cardiovascular death or worsening heart failure by 46% (HR 0.54) in obese HFpEF[20]. These data have shifted the therapeutic narrative to a comorbidity-centred paradigm (obesity phenotypes account for 50–70% of cases), and prompted the 2025 Chinese consensus to grant a conditional recommendation for GLP-1RA in obese HFpEF subsets.

Trials examining weight-reduction strategies, whether dietary, surgical or pharmacological, are therefore critical both for preventing incident HF and for treating established disease[29, 30]. To date, dietary-intervention studies in HFpEF remain small and under-powered, and surgical weight-loss trials are absent[31]. Table 2 summarizes the key temporal milestones and their clinical implications.

Period	Dominant Classes/Trials	Key Outcomes (HR or Changes)	Guideline Implications
Pre-2010	RAASi (CHARM-Preserved, PEP-CHF)	Hospitalizations ↓ (0.63–0.89); no mortality benefit	Conditional for hypertension comorbidities
2010–2020	MRA (TOPCAT)	Composites marginal (0.87, P=0.06)	Class Ⅱb (AHA/ACC 2022)
	ARNI (PARAGON-HF)	Subgroups (women/LVEF≤57%: 0.73–0.78)
2021–2025	SGLT2i (EMPEROR/DELIVER)	Hospitalizations ↓ (0.74–0.82)	Class Ⅰ ESC 2023/Chinese consensus 2025
	GLP-1RA (STEP-HF/SUMMIT)	QoL/weight ↑ (+6.9–16.6 KCCQ, −13.3%)	Conditional (for obesity)
	Finerenone (FINEARTS-HF)	Events ↓ (0.74-0.95)	Chinese consensus 2025

HFpEF, heart failure with preserved ejection fraction; HR, hazard ratio; RAASi, renin-angiotensin-aldosterone system inhibitor; MRA, mineralocorticoid receptor antagonist; ARNI, angiotensin receptor-neprilysin inhibitor; SGLT2i, sodium-glucose cotransporter 2 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; LVEF, left ventricular ejection fraction; QoL, Quality of Life; KCCQ, Kansas City Cardiomyopathy Questionnaire.

This study was limited to trials registered on ClinicalTrials.gov, which may introduce geographic bias as studies from non-English-speaking regions or platforms with lower registration rates may be underrepresented. However, given that ClinicalTrials.gov captures the majority of drug development trials targeting global markets, we believe the observed patterns remain representative of the evolving therapeutic landscape for HFpEF. The second limitation is the evolving and sometimes overlapping definitions of HFpEF (LVEF ≥50%) and HFmrEF (41–49%). Many earlier trials pragmatically included patients with mildly reduced EF despite labeling the study as HFpEF. Although HFmrEF and HFpEF demonstrate similar prognoses and treatment responsiveness, this heterogeneity may affect generalizability. We recognize this as an inherent challenge in registry-based landscape analyses and note that more recent studies have increasingly adopted stricter LVEF criteria (≥50%), reflecting growing awareness of the pathophysiological heterogeneity within HFpEF.

The heterogeneity of HFpEF, encompassing vascular, metabolic-obese, and atrial fibrillation-related subtypes, complicates progress[32], as evidenced by variable responses (e.g., PARAGON-HF subgroup effects)[4, 7] and underdiagnosis of atrial fibrillation (prevalent in ~60%)[3, 33, 34]. Attrition may stem from broad inclusion criteria overlooking phenotypes. To advance:

1. Phenotype enrichment: Employ validated stratification (e.g., five-type classification: vascular, cardiomyopathy, pulmonary, valvular/arrhythmic, extracardiac) or scores like H2FPEF to align therapies (e.g., GLP-1RA for metabolic-obese).

2. Biomarker-guided selection: Integrate NT-proBNP, galectin-3, or C-reactive protein for responder identification, as in STEP-HFpEF.

3. Combination and endpoint strategies: Evaluate synergies (e.g., SGLT2i + GLP-1RA) using patient-centered composites, per recent consensuses.

4. Diverse, global designs: Prioritize multinational enrollment to capture Asian-specific etiologies.

These approaches, informed by post-2021 evidence, may mitigate failures and foster precision medicine.

5 | Conclusion

HFpEF pharmacological trials have proliferated since 2016, driven by metabolic innovations and regulatory progress, yet high failure rates underscore heterogeneity's toll. Integrating precision approaches will be key to translating pipeline momentum into clinical gains.

Data Availability Statement

The data that supports the findings of this study are available in the supplementary material of this article.

Tables and Figures

Table 1. Baseline Characteristics of Included HFpEF Pharmacological Trials (n=236).

Table 2. Key Temporal Shifts in HFpEF Therapeutic Evidence

Figure Legends

Figure 1: Number of trials by country/region (≥3 trials).

Figure 2: Trials by period (2003–2008, 2009–2015, 2016–2020, 2021–2025) and phase.

Figure 3: Distribution by status (November 10, 2025).

Figure 4: Drug class distribution (n=236).

Figure 5: Drug class trends (2021–2025).

Figure 6: Regulatory approval timeline (2021–2025).

Supplementary Table 1. Full trial list with details.

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