Glucagon-like Peptide-1 Treatment in Obesity-Linked Heart Failure with Normal Pumping: How It Works, Evidence, and Importance

Heart failure with ejection fraction preservation (HFpEF) has become an increasingly important component of the global heart failure burden. However, effective treatment remains a challenge because HFpEF is not a single disease entity, but rather a heterogeneous syndrome shaped by multiple co-morbid factors [1,2]. Among these factors, obesity has emerged as one of the most important clinically and mechanistically contributing factors. Recent data confirm that obesity-related HFpEF is not simply HFpEF occurring in overweight patients, but a distinct cardiometabolic phenotype characterized by increased symptom severity, greater exercise intolerance, impaired adipose tissue function, and a hemodynamic profile marked by reduced cardiac reserve and increased susceptibility to congestion [3,4].

This phenotype is increasingly biologically consistent. In patients with HFpEF, obesity-related biomarkers, such as leptin and C-reactive protein, are associated with the presence of the disease and reduced exercise capacity, highlighting the role of obesity-induced inflammation in clinical presentation [3]. Furthermore, supra-pericardial adipose tissue is associated with circulatory disturbances, reduced peak oxygen consumption, and worsening outcomes, confirming that obesity in HFpEF is a potent pathophysiological factor and not merely a concomitant disease [1,4]. These characteristics help explain why conventional heart failure therapies often achieve only modest gains in symptoms and functional capacity in patients with HFpEF, leaving a substantial residual burden of limitations and frequently leading to heart failure relapses [5].

In this context, GLP-1-based therapy has garnered significant attention as a potential therapeutic strategy targeting the disease phenotype. Initially developed for hyperglycemia and obesity, GLP-1 receptor activation has demonstrated broader significance in cardiovascular health in patients with obesity and cardiovascular and metabolic diseases, including a reduction in major cardiovascular complications with semaglutide use in overweight or obese patients with known cardiovascular disease [6,7,8]. These findings provided an important clinical basis but did not directly establish its role in the treatment of HFpEF. This changed with the emergence of specialized clinical trials for obesity-related HFpEF, which demonstrated that semaglutide improved heart failure symptoms, physical limitations, body weight, exercise capacity, and markers of inflammation in obese patients with HFpEF, regardless of whether they had type 2 diabetes [9,10]. Subsequent meta-analyses have reinforced the consistency of these effects and suggested a potential benefit in improving heart failure outcomes in patients with a slight or preserved reduction in ejection fraction [11,12].

More recently, tirzepatide has expanded the scope of this therapeutic effect by reducing the risk of cardiovascular death or heart failure exacerbation, primarily by reducing the incidence of heart failure exacerbations, while simultaneously improving the health status of obese patients with HFpEF [13]. The results of the SUMMIT program indicate that the observed benefits may extend beyond weight loss, encompassing positive effects on blood volume and pressure, systemic inflammation, and cardiovascular and renal injury [13,14]. Based on these data, the clinical focus has shifted from simply reducing body weight to targeting the key pathophysiological factors underlying the HFpEF pattern associated with obesity.

Despite this growing body of evidence, published studies remain scattered across HFpEF studies, obesity trials, pooled analyses, and mechanistic sub-studies. To date, no comprehensive review has focused on GLP-1 therapy within the biologically coherent phenotype of obesity-associated HFpEF, where interrelated mechanisms such as obesity, inflammation, congestion, and metabolic dysfunction collectively contribute to disease progression and treatment response.

Accordingly, this review explores the current evidence supporting GLP-1-based therapy in obesity-associated HFpEF, with particular emphasis on the rationale for the mechanism, recent clinical trial data, and whether the observed benefits extend beyond weight loss alone. By framing GLP-1-based therapy within a phenotypic context rather than considering it as a standalone pharmacological intervention, this review seeks to clarify its current clinical role in the management of obesity-associated HFpEF and to highlight the key questions that remain before its role can be fully defined.

This study was conducted as a narrative review designed to comprehensively synthesize the evolving evidence supporting GLP-1-based therapy in HFpEF, with a particular focus on phenotype definition, biological rationale, clinical trial evidence, and mechanisms extending beyond weight loss alone. A structured literature search was performed using PubMed and Scopus to identify relevant studies published between January 2020 and March 2026.

The search strategy combined controlled vocabulary and free-text terms with Boolean operators, including: “HFpEF,” “heart failure with preserved ejection fraction,” “obesity-related HFpEF,” “obese HFpEF,” “glucagon-like peptide-1 receptor agonist,” “GLP-1-based therapy,” “semaglutide,” “tirzepatide,” “incretin-based therapy,” “dual GIP/GLP-1 agonist,” “symptoms,” “exercise capacity,” “6-min walk distance,” “Kansas City Cardiomyopathy Questionnaire,” “NT-proBNP,” “congestion,” “diuretic use,” “inflammation,” “cardiac remodeling,” and “epicardial adipose tissue.” Additional targeted searches were conducted to identify pooled analyses, mechanistic sub-studies, expert consensus documents, and recent scientific statements relevant to phenotype-specific interpretation.

Peer-reviewed original research articles were prioritized, with a focus on randomized clinical trials, pooled analyses, mechanistic studies, cohort studies, and translational research directly related to obesity-related HFpEF and incretin-based therapy. High-impact reviews and expert guidance documents were also included when they added meaningful context or clinical insight. Studies not relevant to HFpEF, obesity-related cardiometabolic disease, or GLP-1-based therapy were excluded. Older landmark studies were included when needed to better frame the broader HFpEF phenotype.

Studies were selected based on relevance, methodological quality, and contribution to the conceptual and clinical understanding of phenotype-specific HFpEF. A total of 55 studies were included in the final synthesis, comprising randomized clinical trials, pooled analyses, mechanistic studies, observational research, and key expert consensus documents. The majority of included studies originated from North America and Europe, reflecting the geographical distribution of major clinical trials in this field. No formal statistical synthesis was performed; findings were qualitatively integrated to provide a clinically meaningful, phenotype-oriented interpretation of the available evidence.

Due to the large number of included studies, Table 1 summarizes key landmark clinical trials, while the full evidence base is described narratively.

Understanding obesity-associated HFpEF as a distinct cardiac metabolic phenotype is essential to explaining the growing role of GLP-1-based therapy as a phenotype-targeted treatment strategy. Rather than simply reflecting the overlap between overweight and conventional HFpEF, obesity-associated HFpEF represents a unique cardiac metabolic phenotype. In contemporary HFpEF patient populations, overweight and obesity constitute a significant proportion of cases and are associated with increased symptom severity, reduced exercise capacity, and poorer health-related quality of life [3,15]. This distinction is important because it highlights that obesity is not merely a co-morbidity but a major factor in disease progression, functional impairment, and potentially treatment response in a significant subset of HFpEF patients [1,3].

The biological pattern of this phenotype is shaped by dysfunction in inflammatory and metabolic regulation [16]. In a mechanistic study of patients with preserved ejection fraction and chronic dyspnea who underwent invasive cardiopulmonary stress testing, elevated levels of leptin, resistin, C-reactive protein (CRP), and interleukin-6 (IL-6), adenoviral dysfunction, and insulin resistance were associated with decreased peak oxygen consumption. Both CRP and leptin were independently associated with an increased likelihood of developing HFpEF. Elevated CRP and IL-6 were also associated with decreased adverse event-free survival. These observations support the notion that exercise intolerance in obesity-related HFpEF results from activated inflammatory pathways and pathways derived from adipose tissue, rather than solely from body mass or poor physical fitness [3].

Epicardial adipose tissue is one of the most prominent structural markers of this phenotype. Increased adipose tissue has been associated with worsening hemodynamics, including increased right ventricular filling pressure and decreased peak oxygen consumption [5,17]. Separate observational studies indicate the importance of both qualitative and quantitative factors: decreased adipose tissue density is associated with worsening cardiac metabolic status and an increased likelihood of complications, while increased adipose tissue volume predicts an increased risk of all-cause death and hospitalization for heart failure in patients with mildly reduced or maintained ejection fraction. Based on these findings, these results suggest that adipose tissue in HFpEF is biologically active and clinically significant, and not merely a transient symptom [18,19,20].

The negative effects of obesity in HFpEF are not limited to the heart; they extend to other parts of the body. Peripheral body composition abnormalities appear to directly contribute to reduced exercise capacity and increased disease severity [21]. In patients with obesity-related HFpEF, improved skeletal muscle quality, as measured by phase angle, was associated with higher weight-adjusted absolute oxygen consumption (O₂), as well as lower edema index and NT-proBNP levels [22]. Lifestyle intervention studies support this view: calorie restriction combined with aerobic exercise improves oxygen levels and quality of life, while resistance training improves muscle quality and strength, and subsequent fat mass recovery is associated with reduced exercise capacity [15,23]. These data confirm that the syndrome reflects a comprehensive central and peripheral phenotype, rather than simply an isolated cardiac dysfunction.

In general, obesity-associated HFpEF can be considered a syndrome resulting from the accumulation of biologically active fats, chronic low-grade inflammation, hemodynamic disturbances with a tendency toward congestion, and peripheral dysfunction [22,24]. This perspective is supported by studies showing that modern obesity-related markers are associated with worse outcomes in HFpEF, without clear evidence of a protective obesity paradox [24]. Understanding this phenomenon is important because it provides a framework for therapies that target more than just fluid balance or neurohormonal pathways. It also helps explain why symptoms persist and exercise capacity is reduced in patients with conventional heart failure therapies, particularly when obesity and systemic metabolic inflammation play a major role in disease progression [1].

The current body of evidence suggests that glucagon-like peptide-1 (GLP-1)-based therapy represents a promising phenotype-directed approach in the management of obesity-related heart failure with preserved ejection fraction (HFpEF), a position also supported by recent focused reviews in this area [43]. The most consistent and clinically significant benefits are symptom relief, improved functional capacity, and increased health-related quality of life, along with reductions in congestion-related biomarkers and a decrease in heart failure [9,10,11,12,13,14,29]. However, these findings should be interpreted in light of current evidence, which remains stronger regarding disease-related outcomes than its apparent effects on cardiovascular mortality [12,13].

A key point to consider is the relative contribution of weight-related and non-weight-related effects. While greater weight loss is consistently associated with improved clinical outcomes [33,34], growing evidence suggests that additional mechanisms, such as reductions in inflammation, hemodynamic load, and cardiac remodeling, also play a significant role in overall therapeutic benefit [14,28,29,31]. This supports the view that GLP-1-based therapy provides integrated cardiac, metabolic, and hemodynamic effects, rather than being solely a weight-loss intervention. However, current evidence does not yet demonstrate that these therapies fully modify disease course in the traditional sense, particularly given the lack of reliable long-term mortality data. Significant questions also remain regarding long-term disease course modification, optimal patient selection, and the best ways to integrate these therapies into clinical practice [12,13,44].

Clinically, current evidence supports the use of GLP-1-based therapy in carefully selected patients with obesity-associated HFpEF, particularly those with severe symptoms, reduced exercise capacity, and a cardiac metabolic profile characterized by hyperlipidemia and metabolic disturbances [9,33]. These therapies should be used as adjuncts, not replacements, to established therapies, including sodium–glucose co-transporter-2 inhibitors, which remain the cornerstone of heart failure with preserved ejection fraction management [45,46]. Emerging clinical and observational data have also increased interest in the use of semaglutide and tirzepatide in patients with HFpEF, although these findings should be considered supportive rather than a change of practice [47,48]. The potential for complementary mechanisms of action among these therapies underscores the importance of a multimodal therapeutic approach that targets different aspects of the disease phenotype.

From a clinical perspective, GLP-1-based therapies should be considered adjunctive treatments within the current HFpEF management framework, rather than standalone interventions. Established therapies, particularly sodium–glucose cotransporter-2 (SGLT2) inhibitors, remain the cornerstone of HFpEF management. GLP-1-based therapies appear to provide complementary benefits by targeting obesity-related metabolic dysfunction, systemic inflammation, and congestion-related pathways.

Accordingly, their use may be most appropriate in selected patients with obesity-related HFpEF who remain symptomatic despite guideline-directed management, particularly those with prominent cardiometabolic features. However, optimal sequencing, combination strategies, and long-term impact on disease progression remain areas requiring further investigation.

At the same time, some important limitations in clinical practice must be considered. Most of the available evidence comes from studies conducted on select groups of stable outpatients, limiting its generalizability to patients with advanced disease, those whose condition has recently deteriorated, or those with serious comorbidities such as acute renal failure [25,49]. Furthermore, assessing drug tolerability (particularly gastrointestinal side effects) requires careful dose titration and continuous monitoring [50]. Consequently, current clinical use should focus on individualized patient selection, careful integration with existing therapies, and close monitoring of treatment response.

Patient selection: Glucagon-like peptide-1 (GLP-1)-based therapy appears to be most appropriate for patients with obesity-related HFpEF who have persistent symptoms, impaired exercise capacity, and a cardiac metabolic profile characterized by hyperlipidemia and metabolic disturbances, particularly in stable outpatient settings [9,10,33,51]. Current evidence does not support routine use in non-obesity-related heart failure with preserved ejection fraction or in patients with recently advanced or worsening disease [25,49].

Timing and Clinical Use: In clinical practice, GLP-1-based therapy should be considered for individuals who remain symptomatic despite guideline-directed management of HFpEF, with careful patient selection and gradual dose titration to improve tolerability and minimize gastrointestinal side effects [25,45,51].

Therapeutic positioning: These therapeutic agents are best suited as adjunctive therapies, not replacements for established treatments. Sodium-glucose cotransporter-2 inhibitors remain essential, while GLP-1-based therapies target complementary pathways associated with obesity, metabolic disorders, and inflammation [45,46]. Although recent evidence suggests potential additive or synergistic benefits with combination therapy, and comparative observational studies have reported positive outcomes for GLP-1 receptor agonists in diabetic HFpEF, optimal sequencing and integration strategies are still under investigation [25,46,52].

Monitoring and safety considerations: Patients receiving GLP-1-based therapy should be monitored for tolerability, hydration status, blood pressure, and nutritional adequacy, particularly in the elderly or frail individuals at risk of unintentional loss of lean body mass [23,25,51]. Concomitant therapies, including diuretics and glucose-lowering agents, may need to be adjusted [30].

Clinical Expectations: Clinically, these treatments are associated with improvements in symptoms, functional ability, and quality of life, along with a reduction in heart failure-related events, although current evidence is still more robust with respect to the reduction in morbidity than to the ultimate effects on cardiovascular mortality [9,10,11,12,13].

Several key priorities should guide the future development of GLP-1-based therapy in obesity-associated HFpEF. First, long-term outcome studies are needed to determine whether improvements in symptoms and morbidity rates translate into sustained benefits in cardiovascular disease progression and mortality [12,13]. While current findings are encouraging, they are limited by relatively short follow-up periods and a primary focus on functional and patient-reported outcomes.

Second, improving the classification of phenotypes is crucial. Body mass index alone is unlikely to adequately cover the complexity of obesity-related HFpEF. Future research should include more precise indicators, including measurements of visceral and pericardial fat, obesity-related anthropometric burden, inflammatory profiles, natriuretic peptide patterns, and imaging assessments of cardiac structure and function, to better identify patients most likely to benefit from treatment [20,29,53,54].

Third, the role of combination therapy requires further investigation. GLP-1-based drugs are likely to be used in conjunction with established treatments for heart failure that preserve contractile function, including sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists. Randomized studies are needed to evaluate the cumulative or synergistic effects of these combinations, optimal sequencing strategies, and their impact on various clinical endpoints [25,45,46].

Fourth, mechanistic studies should continue to explore the relative contributions of weight loss and non-weight-related effects. Integrated approaches combining advanced imaging, biomarker identification, and functional assessments may help to clarify the extent to which these therapies modify underlying disease processes versus primarily improving clinical expression [31,33].

Finally, validating the findings on a larger scale in realistic populations is crucial. Future studies should include elderly patients, individuals with multiple comorbidities, and those with different phenotypes of HFpEF to assess the generalizability and practical applicability of the results [25,49]. Furthermore, factors such as long-term adherence, cost, accessibility, and tolerability will play a significant role in determining the integration of glucagon-like peptide-1 (GLP-1)-based therapy into routine clinical practice [51].

The findings presented in this review should be considered in light of several important limitations in the current evidence base. Most of the available data are derived from a relatively small number of randomized clinical trials conducted on selected groups of stable outpatients with obesity-associated HFpEF. Consequently, it remains unclear how applicable these findings are to broader and more diverse populations of patients with HFpEF, including those with advanced disease, recent deterioration, significant renal impairment, or non-obesity-related phenotypes [25,49].

Second, although sustained improvements in symptoms, functional ability, and health-related quality of life have been observed, the follow-up period in most trials remains relatively short. Consequently, the long-term sustainability of these benefits and their impact on key clinical outcomes, particularly cardiovascular mortality, have not yet been definitively established [12,13]. This limits the potential for classifying glucagon-like peptide-1 (GLP-1)-based therapies as fully disease-modifying interventions.

Third, a complete understanding of the relative contribution of weight-dependent versus non-weight-dependent mechanisms remains incomplete. While mechanistic analyses point to beneficial effects on inflammation, congestion, and cardiac remodeling, separating these effects from those mediated by weight loss is challenging and requires further research using integrated approaches based on physiology and imaging [29,31,33].

Fourth, variations in study design, patient selection, and outcome measures among trials may limit the possibility of direct comparison of results. Differences in baseline characteristics, presence of diabetes, degree of obesity, and previous heart failure treatments introduce potential variability in treatment response and interpretation of pooled results [9,10,11,12].

Finally, practical applicability in real-world settings remains an important consideration, especially since some comparative evidence is drawn from broader cohorts of heart failure and diabetes patients, rather than from obesity-associated HFpEF cohorts [55]. Issues related to long-term adherence, tolerability (particularly gastrointestinal side effects), cost, and accessibility may affect the efficacy of GLP-1-based therapies outside of controlled clinical trials [51]. Furthermore, current evidence provides only limited guidance on optimal integration with existing HFpEF therapies or on treatment sequencing in routine clinical practice.

These limitations, taken together, highlight the need for long-term studies with sufficient statistical power, improved phenotypic characterization, and realistic assessments to better define the role of GLP-1-based therapy in managing obesity-related heart failure while preserving contractile function.

Obesity-related heart failure with preserved ejection fraction (HFpEF) represents a distinct cardiometabolic phenotype characterized by the interplay of excess adiposity, systemic inflammation, congestion, and adverse cardiac remodeling. In this context, glucagon-like peptide-1 (GLP-1)-based therapies have emerged as a promising phenotype-directed approach in the management of this condition.

Current evidence suggests that GLP-1-based therapies, including semaglutide and tirzepatide, may improve symptoms, functional capacity, and health-related quality of life in patients with obesity-related HFpEF. These clinical benefits appear to be mediated through integrated mechanisms involving weight reduction, attenuation of inflammatory pathways, improvement in hemodynamic load, and favorable effects on cardiac and adipose tissue remodeling. However, these findings should be interpreted with caution, as the available evidence is more consistent for improvements in morbidity and patient-reported outcomes than for definitive reductions in cardiovascular mortality.

Importantly, GLP-1-based therapies should be viewed as adjunctive treatments within the broader HFpEF management framework, complementing established therapies such as sodium–glucose cotransporter-2 (SGLT2) inhibitors. Their role appears particularly relevant in selected patients with obesity-related HFpEF who remain symptomatic despite guideline-directed management and exhibit prominent cardiometabolic features.

Despite these encouraging findings, several uncertainties remain. The long-term impact of GLP-1-based therapies on disease progression and mortality, optimal patient selection, treatment sequencing, and integration with existing therapeutic strategies requires further investigation. In addition, variability in study populations and relatively short follow-up durations limit the generalizability of current evidence.

Overall, GLP-1-based therapy may represent an important step toward more personalized, phenotype-oriented management of HFpEF, although further high-quality, long-term studies are needed to define its role within routine clinical practice.

The following abbreviations are used in this manuscript:

Conceptualization, I.A. and R.A.A.S.; methodology, I.A., W.I.I.A. and R.A.A.S.; investigation, M.M.A., I.A., W.I.I.A., K.A.H.A.L., H.M., B.R.R.S. and S.A.S.; data curation, M.M.A., I.A. and W.I.I.A.; writing—original draft preparation, M.M.A., I.A. and W.I.I.A.; writing—review and editing, R.A.A.S., S.S.K. and N.A.E.M.; visualization, W.I.I.A.; supervision, R.A.A.S., S.S.K. and N.A.E.M.; project administration, I.A. and R.A.A.S. All authors have read and agreed to the published version of the manuscript.

No new data were created or analyzed in this study. Data sharing does not apply to this article.

The authors declare no conflicts of interest.

This research received no external funding.