What's the latest update on the ongoing clinical trials related to Heart failure with normal ejection fraction?

Overview of Heart Failure with Normal Ejection FractionHFpEFEF, also commonly referred to as “heart failure with preserved ejection fraction” or “diastolic heart failure,” represents a distinct clinical entity within the heart failure spectrum.

Definition and Characteristics

Heart failure with normal ejection fraction is defined by the presence of clinical signs and symptoms of heart failure despite a left ventricular ejection fraction (LVEF) that is not significantly reduced—typically 50% or above. Pathophysiologically, patients with HFpEF display abnormal left ventricular (LV) relaxation, increased myocardial stiffness, and impaired filling properties. Unlike heart failure with reduced ejection fraction (HFrEF) where systolic dysfunction predominates, HFpEF is primarily of a diastolic nature. This condition is also characterized by overlapping features such as LV hypertrophy, increased left atrial size, and the presence of multiple comorbidities such as hypertension, obesity, diabetes, and renal dysfunction. Several studies have emphasized that despite a “normal” ejection fraction, these patients can have significant structural, functional, and vascular abnormalities that contribute to a poor quality of life and exercise intolerance. These intrinsic characteristics make accurate diagnosis challenging, and many clinical trials now employ strict inclusion criteria (for example using natriuretic peptide levels and imaging markers) in order to capture a homogenous HFpEF population in terms of both symptoms and underlying pathophysiology.

Epidemiology and Impact

HFpEF now accounts for nearly half of the total cases of heart failure worldwide, with estimates indicating a high prevalence in aging populations. Epidemiological data suggest that as many as 6–7 million individuals in the United States and tens of millions globally are affected by heart failure, with HFpEF representing an increasingly common subtype. Notably, patients with HFpEF are predominantly elderly and more often female. The burden on healthcare systems is significant because HFpEF is associated with frequent hospitalizations, high morbidity, and mortality rates that are comparable to those seen in HFrEF despite the absence of gross systolic dysfunction. Increased prevalence coupled with the lack of proven disease‐modifying therapies in these patients has driven the urgent need for targeted clinical trials aimed at improving quality of life and long‐term outcomes.

Current Clinical Trials for HFpEF

A growing number of clinical trials are now dedicated to elucidating the optimal therapeutic approaches for HFpEF. In addition to pharmacological agents, device‐based and biomarker-driven precision interventions are gaining momentum, as researchers work to address the heterogeneous nature of HFpEF.

Major Ongoing Trials

Several high‐profile and well‐designed clinical trials are currently underway. Among these, the STEP HFpEF trial has attracted attention for its focus on the effects of semaglutide on symptoms, physical function, and body weight in HFpEF patients who are also obese. In this trial, 529 patients with symptomatic HFpEF (LVEF ≥45%) and obesity (body mass index ≥30 kg/m²) are being evaluated, with dual primary endpoints including changes in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and body weight at week 52. In parallel, the STEP HFpEF-DM trial is addressing similar questions in an HFpEF population with type 2 diabetes, further emphasizing a precision medicine approach to different HFpEF subphenotypes.

Another major trial in the pipeline is a multiple-dose Phase 2 study of JK07, which is being pursued for both HFrEF and HFpEF populations. In a completed Phase 1b study, JK07 was administered at different doses (0.03, 0.09, and 0.27 mg/kg) and demonstrated dose-dependent improvements in left ventricular ejection fraction as well as robust changes in biomarker levels of target engagement. The trial notably reported meaningful improvements in clinical parameters such as LVEF over a period of up to 180 days and is expected to expand into a double-blind, randomized, multiple-dose Phase 2 trial beginning as early as the first half of 2024.

There is also an active role for phosphodiesterase (PDE) inhibitors in this domain. Imara, for instance, is advancing a proof-of-concept Phase 2 trial of a best-in-class PDE9 inhibitor in HFpEF patients. This study is designed to enroll around 170 patients aged 45 or older who show enriched PDE9 expression and persistent HFpEF symptoms. The study will utilize changes in NT-proBNP levels as the primary endpoint and further evaluate parameters such as the KCCQ and the 6-minute walk test as secondary quality-of-life and functional measures.

In addition to these clinical trials assessing purely pharmacological targets, device-based interventions are also being investigated. Patented systems that involve blood suction or pumping mechanisms implanted in the left ventricle have been designed to synchronize with the cardiac cycle for HFpEF patients and represent a novel technology-based approach. While these developments are still in the investigational stages, they underscore the multiplicity of approaches being pursued concurrently.

Recent Findings and Progress

Preclinical as well as early clinical data are beginning to shed light on promising therapeutic signals. For example, in preclinical studies using mouse models, the PDE9 inhibitor tovinontrine has shown encouraging effects by reducing cardiomyocyte size and lowering plasma B-type natriuretic peptide and atrial natriuretic peptide levels, all while preserving heart rate and blood pressure. These effects have warranted further clinical advancement into Phase 2 trials, with expected initiation in the near future.

Furthermore, in the Phase 1b data from the JK07 trial, the observed dose-dependent improvements in LVEF—along with sustained biomarker responses—offer a compelling argument for the continued investigation of this compound in larger, more definitive trials. The progressive improvement in LVEF across multiple timepoints (day 30 to day 180) and consistently acceptable tolerability have provided key insights that will guide the dosing regimens and patient selection in the forthcoming Phase 2 study.

Beyond these individual trials, there is an increasing recognition that endpoints in HFpEF trials need to extend beyond traditional mortality or hospitalization rates to incorporate quality-of-life metrics, functional capacity, and biomarker changes. Data from the STEP HFpEF trial, for instance, are designed to mirror these multidimensional outcomes with co-primary endpoints structured around both patient-reported outcomes (KCCQ-CSS) and objective measures (body weight and 6-minute walk distance). Such integrated endpoints reflect an evolving understanding of HFpEF as a multisystem disorder that requires comprehensive therapeutic assessment.

Moreover, regulatory agencies and expert panels have been engaged in discussions regarding the appropriate design and endpoint selection for these trials. Recent publications stress that even though some of the primary endpoints were not met in previous landmark trials for HFpEF, subgroup and secondary analyses often point toward potential benefits in certain phenogroups (e.g., females or those with borderline LVEF). This trend indicates that ongoing trials are increasingly honing in on precision medicine strategies by stratifying patients based on comorbid conditions and specific biomarkers, thereby improving the likelihood of detecting therapeutic benefits.

Therapeutic Approaches in Clinical Trials

The therapeutic landscape for HFpEF is rapidly evolving with both pharmacological and non-pharmacological interventions being explored. Given the heterogeneity of HFpEF, an integrated approach that addresses diverse pathophysiological mechanisms is becoming more common in clinical trial design.

Pharmacological Interventions

In the pharmacological sphere, several classes of drugs are being repurposed or newly developed for use in HFpEF. One of the most talked-about agents is semaglutide, a GLP-1 receptor agonist, examined in the STEP HFpEF trial. With nearly half of HFpEF patients concurrently suffering from obesity, semaglutide’s effects on weight reduction, improvement in KCCQ scores, and modulation of cardiac metabolism are under intensive investigation.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) also continue to garner interest after the success of trials in HFrEF. Although medications such as empagliflozin have shown positive phases in HFpEF patients, studies like EMPEROR-Preserved have paved the way for further evaluation of dapagliflozin. Patents related to methods of treating HFpEF with dapagliflozin have also been disclosed, underscoring the push toward integrating SGLT2 therapy in this patient population. These developments point to a dual benefit in controlling glycemic parameters and addressing the underlying cardiovascular remodeling that is part of HFpEF evolution.

Another promising pharmacological candidate is the PDE9 inhibitor being advanced by Imara. PDE inhibition represents a strategy to enhance cyclic guanosine monophosphate (cGMP) signaling, which is intimately involved in systolic and diastolic function. The Phase 2 trial for this agent is particularly interesting because it targets a specific biomarker profile (elevated PDE9 expression), potentially identifying a subgroup that is particularly responsive to this mechanism-based intervention.

In addition, novel compounds such as JK07, which has been evaluated in a Phase 1b trial prior to its planned expansion into Phase 2, have shown dose-responsive improvements in LVEF and beneficial trends in other cardiovascular parameters. Such results not only underscore the potential of JK07 as an emerging therapeutic for HFpEF but also support the strategy of incremental dose escalation to find an optimal therapeutic window.

Other pharmacological agents that have been studied include sacubitril/valsartan, though its role in HFpEF remains somewhat controversial given that most of the robust data have historically come from HFrEF populations. However, sub-analyses from trials like PARAGON-HF suggest that certain subgroups of patients with midrange or preserved EF may benefit from these agents, leading investigators to further explore the drug’s utility in accurately phenotyped HFpEF patients.

Furthermore, recent meta-analyses and pilot studies are evaluating combination therapeutic regimens that not only target the heart directly but also address the systemic inflammation, oxidative stress, and metabolic dysfunction that are frequently coexistent in HFpEF. Such multidimensional interventions offer promise in mitigating the high morbidity and mortality observed in HFpEF and are reflected in the design of many current trials.

Non-pharmacological Interventions

On the non-pharmacological front, device-based therapies are emerging as potential adjuncts or alternatives to drug therapy in HFpEF. Several patents describe innovative systems designed to mechanically support ventricular filling or modulate hemodynamics. For instance, devices that involve a blood suction or pumping mechanism are being developed to operate in synchronization with the patient’s cardiac cycle. These systems are intended to ease the burden on the stiff left ventricle during diastole by reducing filling pressures and enhancing overall cardiac output.

Lifestyle and exercise interventions are also recognized components of the therapeutic arsenal. Although exercise training is not new in the management of heart failure, its role in HFpEF is uniquely challenging and promising because of its potential to improve skeletal muscle function, peripheral vascular responsiveness, and reduce systemic inflammation. Studies have documented that even low-level exercise can have positive effects on diastolic function and quality-of-life measures. Current research is exploring how exercise training can be standardized and combined with pharmacotherapy to provide a truly comprehensive treatment approach.

Moreover, non-invasive diagnostic methods such as cardiopulmonary exercise testing and dynamic imaging are being increasingly utilized as both surrogate endpoints and stratification tools within clinical trials. These methodologies help in identifying responders and non-responders early in the trial process and may guide more personalized treatment plans. This patient-specific tailoring of therapy is an essential element of modern HFpEF research, aiming to maximize therapeutic benefits while minimizing adverse effects.

Implications and Future Directions

The latest updates from the ongoing trials not only provide encouraging signals regarding potential efficacies but also highlight significant challenges that remain in the clinical management of HFpEF. As the trial data continue to accumulate, several implications for clinical practice and future research directions are emerging.

Clinical Implications of Trial Results

The early data emerging from ongoing trials have several clinical implications:

1. Enhanced Phenotyping Leads to Personalized Therapy:
The heterogeneity of HFpEF has long been a barrier to successful clinical interventions. Current trials are addressing this by including rigorous inclusion criteria, such as elevated natriuretic peptides, specific imaging criteria, and even molecular phenotyping (e.g., PDE9 expression levels). This approach fosters patient stratification and allows for more tailored therapies, enhancing the likelihood of clinical benefit. It also changes the way clinicians might approach HFpEF in the future by emphasizing a personalized treatment strategy rather than a one-size-fits-all model.

2. Multidimensional Endpoints are Key:
Given that HFpEF affects quality-of-life, exercise capacity, and biomarker profiles in addition to traditional hard endpoints (such as mortality and hospitalizations), the integration of endpoints like KCCQ scores, 6-minute walk test distances, and NT-proBNP changes into trial designs is significant. Positive trends seen in these surrogate markers may translate into meaningful clinical benefits that improve daily living and long-term outcomes. For example, the STEP HFpEF trial’s dual primary endpoints offer critical insights into both symptomatic and physiological improvements.

3. Combination Therapies Provide a Promising Avenue:
The convergence of pharmacological agents (e.g., semaglutide, SGLT2 inhibitors, and PDE inhibitors) with non-pharmacological strategies (such as exercise training and device-based interventions) suggests future management may well involve a combination approach. Early signs in trials like JK07 and emerging PDE9 inhibitor studies reinforce the concept that targeting multiple pathways simultaneously might be necessary to address the multifactorial nature of HFpEF.

4. Innovative Device Therapies as Adjuncts:
Although still in the investigational phase, device-based therapies offer promise for patients with advanced HFpEF who may not respond adequately to pharmacotherapy. For example, systems designed to optimize ventricular filling and unloading have the potential to reduce symptoms and improve functional capacity. These devices, once refined and validated in clinical studies, could become an adjunct or alternative therapy in select populations.

5. Regulatory and Endpoint Considerations:
The evolving perspective from regulatory agencies—in which endpoints beyond mortality (such as quality-of-life indices) are given increasing weight—is also influencing trial design. This regulatory evolution supports a broader approval framework for new therapies in HFpEF, even when traditional endpoints are not met, so long as there is evidence of symptomatic and functional improvement. Thus, clinicians may soon have access to a suite of validated therapies that can be combined based on individual patient profiles.

Future Research Directions and Challenges

Ongoing clinical trials have provided a roadmap for the next generation of HFpEF research. However, several challenges remain which need to be addressed in future studies:

1. Need for Larger, Multicenter Trials with Stratified Populations:
Although many current trials are promising, many suffer from limited sample sizes and are often conducted within a relatively homogeneous patient population. Future research must focus on larger, multicenter, and ideally multinational trials that are powered to detect differences across diverse HFpEF phenogroups. This will require extensive collaboration and the adoption of innovative trial designs that allow adaptive patient enrollment based on interim biomarker and phenotypic data.

2. Harmonization of Diagnostic Criteria:
With HFpEF being a heterogenous syndrome, one of the primary challenges remains the standardization of diagnostic criteria. The ongoing use of advanced imaging, biomarker assays, and functional testing is likely to be supplemented by newer genomic and proteomic tools in future research. This integrative approach will not only enhance diagnostic accuracy but also allow trials to stratify patients into subgroups more likely to benefit from specific interventions.

3. Exploration of Combination Therapies:
Given the complex interplay of comorbidities and multiple pathophysiological processes in HFpEF, future trials will increasingly evaluate combination therapies. There is a need for studies that assess synergistic effects between drugs (for example, combining semaglutide with SGLT2 inhibitors) and interventions that merge pharmacological treatments with lifestyle modifications or device implantation. Designing these multifaceted trials in a manner that preserves statistical power while allowing for real-world applicability is a significant challenge for future investigators.

4. Focus on Non-invasive and Dynamic Endpoints:
Advances in non-invasive monitoring and dynamic assessment methods (such as cardiopulmonary exercise testing and wearable technology) will likely play a larger role in future research. These tools could provide real-time data on treatment efficacy and may even permit earlier identification of therapeutic response or failure. Incorporating these endpoints into clinical trial design will be vital—not only to assess improvements in functional capacity but also to allow early adjustments in therapy.

5. Integration of Patient-Reported Outcomes (PROs):
As new endpoints are validated, future studies must continue to integrate patient-reported outcomes to evaluate the impact of treatments on quality of life. The integration of tools like the Kansas City Cardiomyopathy Questionnaire across studies is crucial for linking improvements in biomarkers and functional status with tangible clinical benefits for patients. The challenge will be to standardize these measures across diverse trial settings and incorporate them into regulatory decision frameworks.

6. Exploration of Novel Mechanistic Targets:
Beyond the current candidates, future research is expected to explore newer mechanisms such as anti-inflammatory agents, therapies targeting myocardial fibrosis, and strategies aimed at modulating specific signaling pathways (for example, the NO-cGMP-PKG axis) in HFpEF. Early signals from trials targeting PDE9 and studies evaluating the molecular profiles of HFpEF patients provide a promising outlook for these novel interventions. However, rigorous confirmation in larger outcome-based studies will be necessary before these treatments can be widely implemented.

7. Optimization of Patient Selection and Trial Design:
Future trial designs will benefit from adaptive enrollment strategies and real-time monitoring to refine patient selection. This could mean stratifying patients not only by EF but also by comorbidity burden, biomarker profiles, or even genetic markers. A more granular understanding of the HFpEF population should ultimately lead to tailored therapies that maximize benefits and reduce adverse effects.

Conclusion

In summary, the latest updates on ongoing clinical trials related to heart failure with normal ejection fraction (HFpEF) reflect a dynamic and multifaceted research landscape. Defined by abnormal diastolic function despite normal LVEF, HFpEF remains a challenging and heterogeneous disorder with a high burden of morbidity and mortality. Major ongoing trials such as the STEP HFpEF and JK07 studies, alongside emerging investigations into PDE9 inhibitors and device-based therapies, are defining a new era of precision medicine in this field. Pharmacological interventions—including semaglutide, SGLT2 inhibitors, and innovative agents targeting cGMP signaling—are being evaluated in combination with non-pharmacological strategies like structured exercise programs and novel device implants.

Clinically, the integration of patient-reported outcomes, functional capacity measures, and biomarker changes is transforming trial endpoints, providing greater insights into the multifactorial benefits of these interventions. The progress observed in early-phase studies is encouraging and suggests that even modest improvements in surrogate markers may ultimately translate into meaningful gains in quality of life and clinical outcomes. Regulatory bodies appear to be evolving their frameworks to accommodate these multidimensional endpoints, and this will likely have long-lasting impacts on both drug approval and clinical practice guidelines.

Looking forward, sizable challenges remain. There is a pressing need for larger, more diverse, and better stratified clinical trials that can identify and target the specific phenotypes inherent in HFpEF. Future research must focus on combining therapeutic modalities, optimizing non-invasive monitoring, and refining patient selection criteria. The promise of personalized therapy—based on detailed phenotyping and biomarker profiling—offers a hopeful future wherein tailored treatments improve outcomes for this complex syndrome.

In conclusion, while the management of HFpEF has lagged behind that of HFrEF, the ongoing clinical trials and emerging research are beginning to fill this gap. The progress so far not only offers the potential for improved symptom management and functional restoration but also sets the stage for transforming the overall prognosis of HFpEF patients. The collective work from these diverse trials underscores a pivotal moment in the treatment paradigm—a move toward integrating multi-dimensional and precision-based interventions that promise to reshape the therapeutic landscape of heart failure with preserved ejection fraction.