Semaglutide in Obesity-Related HFpEF: Weight-Independent Mechanisms, Trial Outcomes and Dosing

Key Takeaways

• Obesity-related heart failure with preserved ejection fraction is a distinct phenotype rather than heart failure occurring incidentally in a heavy patient; it is characterized by plasma volume expansion, epicardial and visceral adipose inflammation, pericardial restraint, chronotropic incompetence and disproportionately low natriuretic peptide concentrations that routinely defeat conventional diagnostic algorithms.
• Once-weekly subcutaneous semaglutide 2.4 mg produces large improvements in heart failure symptoms, physical limitation scores and six-minute walk distance in this population, with effect sizes on health status substantially greater than those historically achieved by conventional pharmacological therapies for preserved ejection fraction heart failure.
• The benefit is only partly attributable to mechanical unloading from weight reduction: parallel reductions in C-reactive protein and N-terminal pro-B-type natriuretic peptide, signals of favorable cardiac structural remodeling, and preclinical data showing superiority over calorie-matched weight loss together support genuinely weight-independent disease modification.
• Diagnosis should combine a left ventricular ejection fraction of 45 to 50 percent or higher, a body mass index of 30 kg/m2 or above, objective congestion, and confirmatory evidence from natriuretic peptides interpreted against obesity-adjusted thresholds, echocardiographic filling indices, validated probability scores or invasive exercise hemodynamics.
• Dose escalation follows a fixed sixteen-week ladder from 0.25 mg weekly to the 2.4 mg maintenance dose, with four-week intervals, tolerability-driven pauses, proactive down-titration of insulin and sulfonylureas to prevent hypoglycemia, anticipatory diuretic reduction as congestion resolves, deliberate protection of lean mass, and vigilance for pancreatitis, biliary disease, retinopathy progression and perioperative aspiration risk.

Introduction and Clinical Background

Heart failure with preserved ejection fraction (HFpEF) now accounts for roughly half of all prevalent heart failure worldwide, and its epidemiological trajectory tracks the obesity epidemic almost exactly. Among the recognized subphenotypes of HFpEF, the obesity-related variant represents a predominant clinical phenotype where the pathophysiological link between the comorbidity and the myocardial syndrome is strongest, far exceeding the association observed in heart failure with reduced ejection fraction^[1]. These patients are typically younger than the classic hypertensive-elderly HFpEF archetype, carry a heavier burden of sleep-disordered breathing, atrial fibrillation and osteoarthritis, and describe a symptom burden that is disproportionate to their echocardiographic abnormalities.

For two decades, this population was therapeutically orphaned. Renin-angiotensin blockade, spironolactone and beta-blockade produced at best marginal signals in HFpEF trials, and none of them addressed adiposity itself. Lifestyle intervention retains a central place but suffers from poor durability, and bariatric surgery — although associated with reductions in heart failure hospitalization and medium-term mortality in observational and registry series — is applicable to a minority of patients and has never been tested prospectively against a heart failure endpoint. Historical anxiety about anti-obesity pharmacotherapy, rooted in the withdrawal of sibutramine and fenfluramine, further discouraged aggressive weight management in cardiac patients.

The arrival of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reset this landscape. Semaglutide 2.4 mg demonstrated reductions in three-point major adverse cardiovascular events in people with overweight or obesity and established atherosclerotic disease without diabetes, and mediation analyses of those data suggest that a substantial fraction of the cardiovascular benefit is not explained by the magnitude of weight loss achieved^[2]. That observation reframed the central question for HFpEF: is semaglutide simply an efficient means of removing mechanical load from a congested circulation, or does it modify the underlying inflammatory and myocardial biology of the syndrome? The missed diagnostic opportunity is equally important. Obese patients with exertional dyspnea are frequently labelled as deconditioned, and their suppressed natriuretic peptide concentrations are misread as excluding heart failure, delaying recognition of a now-treatable phenotype by years.

Molecular and Pathophysiological Mechanisms

Adipose Tissue Inflammation and the Systemic Inflammatory Milieu

Visceral and epicardial adipose tissue in obesity is not an inert energy depot but a secretory organ generating interleukin-6, tumor necrosis factor alpha, leptin and monocyte chemoattractant protein-1. The resulting low-grade systemic inflammation drives coronary microvascular endothelial dysfunction, reduces nitric oxide bioavailability, and lowers protein kinase G activity in cardiomyocytes, permitting hypophosphorylation of titin and increased passive myocardial stiffness. This inflammatory paradigm predicts that a biomarker of systemic inflammation should both stratify risk and respond to effective therapy. Within the STEP-HFpEF Program, C-reactive protein was elevated across a wide spectrum at baseline and fell significantly with semaglutide 2.4 mg, and the analysis was explicitly designed to test whether baseline inflammatory burden modified treatment effect and how tightly the change in C-reactive protein tracked the change in body weight^[3]. The relative independence of these two trajectories is one of the strongest clinical arguments against a purely mechanical explanation of benefit.

Plasma Volume, Filling Pressures and Natriuretic Peptide Kinetics

Obesity-related HFpEF is a high plasma volume state. Total blood volume expands in proportion to fat mass, epicardial fat and increased pericardial restraint amplify ventricular interdependence, and left ventricular transmural filling pressure rises steeply with exercise. Natriuretic peptide concentrations, paradoxically, are suppressed — a consequence of increased clearance receptor expression in adipose tissue, neprilysin activity and altered corin-mediated processing. A prespecified analysis of the pooled STEP-HFpEF data specifically addressed whether semaglutide reduced N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 52 weeks and whether treatment response differed according to baseline NT-proBNP, framing the question as one of mechanical unloading versus modification of heart failure pathobiology^[4]. A fall in NT-proBNP in a population undergoing substantial weight loss is not trivially explained by adipose-mediated clearance, since fat mass reduction would be expected to raise, not lower, circulating levels.

Reverse Remodeling of the Left Atrium and Left Ventricle

Chronic volume loading and elevated filling pressures produce left atrial dilatation, which is the structural signature of HFpEF and the substrate for atrial fibrillation. The echocardiographic substudy of the STEP-HFpEF Program enrolled 491 of the 1,145 randomized participants, or 43 percent, and prespecified change in left atrial volume as its primary structural outcome, with additional chamber dimensions and functional indices assessed as secondary measures^[5]. Demonstrating atrial reverse remodeling over a 52-week horizon in an older, comorbid cohort would place semaglutide in a very small group of interventions capable of altering HFpEF cardiac structure rather than only symptoms.

Direct Myocardial, Endothelial and Skeletal Muscle Effects

The most persuasive mechanistic evidence for weight-independent action comes from controlled preclinical work. In a murine model of HFpEF driven by advanced age, female sex, obesity and type 2 diabetes, semaglutide was compared not against untreated animals but against pair-fed mice achieving equivalent weight loss; semaglutide improved cardiometabolic profile, cardiac structure and cardiac function beyond what calorie restriction alone accomplished, with transcriptomic and proteomic signatures indicating improved left ventricular cytoskeletal function, restored endothelial function and normalized protective immune responses within visceral adipose tissue^[6]. These are animal data and must not be equated with proven human myocardial effects, but the pair-feeding design isolates the pharmacological signal in a way no clinical trial has yet achieved.

Complementary mechanisms plausibly contribute in humans: natriuresis through GLP-1 receptor-mediated inhibition of proximal tubular sodium-hydrogen exchanger 3, reduction in epicardial adipose thickness, improved myocardial substrate flexibility away from lipotoxic intermediates, attenuation of sympathetic overactivation and improved sleep-disordered breathing. Skeletal muscle also matters: peripheral oxygen extraction is impaired in obesity-related HFpEF, and reduced body mass lowers the oxygen cost of ambulation independently of any cardiac change.

Clinical Evidence and Guideline Comparison

STEP-HFpEF

The index trial randomized 529 patients with HFpEF and a body mass index of 30 kg/m2 or higher, without diabetes, to once-weekly semaglutide 2.4 mg or placebo for 52 weeks, with dual primary endpoints of change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and change in body weight; the mean improvement in KCCQ-CSS with semaglutide was 16.6 points, accompanied by significant gains in six-minute walk distance, a favorable hierarchical composite including death and heart failure events, and reductions in C-reactive protein^[7]. For context, a KCCQ-CSS improvement of five points is generally regarded as clinically meaningful; the between-group difference observed here exceeds that threshold by a wide margin and is larger than that reported for any prior HFpEF pharmacotherapy.

STEP-HFpEF DM and the Prespecified Pooled Analysis

Because glycemic status attenuates weight loss with GLP-1 RAs and because diabetes alters HFpEF biology, a parallel trial enrolled 616 participants with obesity-related HFpEF and type 2 diabetes using the identical design and endpoints^[8]. The prespecified pooled analysis of individual patient data from both trials, conducted across 129 clinical research sites in 18 countries in participants with ejection fraction of at least 45 percent, body mass index of at least 30 kg/m2, New York Heart Association class II to IV symptoms and baseline KCCQ-CSS below 90 points, provided the definitive estimate of treatment effect and permitted subgroup testing with adequate power^[9]. Consistency across the diabetic and non-diabetic strata, despite systematically smaller weight loss in the diabetic cohort, is itself a mechanistic argument.

Consistency Across Ejection Fraction, Sex, Rhythm and Frailty

A prespecified analysis stratified participants by baseline ejection fraction into 45 to 49 percent, 50 to 59 percent and 60 percent or higher; estimated treatment differences in KCCQ-CSS were 5.0 points (95 percent CI −2.7 to 12.8), 9.8 points (95 percent CI 5.0 to 14.6) and 7.4 points (95 percent CI 2.8 to 12.0) respectively, with a p value for interaction of 0.56, and corresponding weight reductions of −7.6, −10.6 and −11.9 percent^[10]. Sex-specific analysis of the pooled program, in which 570 of 1,145 participants (49.7 percent) were women, examined whether the dual primary and confirmatory secondary endpoints diverged between men and women^[11]. Further prespecified analyses evaluated whether a history of atrial fibrillation, and its paroxysmal versus persistent subtypes, modified efficacy^[12], and whether baseline functional impairment measured as six-minute walk distance at 20 and 52 weeks predicted or modified response^[13]. Change in New York Heart Association functional class was assessed as a clinician-reported counterpart to the patient-reported KCCQ^[14], and a cumulative-deficit frailty index comprising 34 variables was used to test efficacy and safety across frailty strata — a critical question given legitimate concern that intentional weight loss in frail older adults may be harmful^[15].

Hard Clinical Events

The STEP trials were powered for symptoms, not events. To address this, a post-hoc participant-level pooled analysis combined four randomized placebo-controlled trials — SELECT, FLOW, STEP-HFpEF and STEP-HFpEF DM — encompassing participants with obesity-related HFpEF, atherosclerotic disease with overweight or obesity, and type 2 diabetes with chronic kidney disease, using semaglutide 2.4 mg in three trials and 1.0 mg in FLOW, to examine effects on clinical heart failure events in those with mildly reduced or preserved ejection fraction^[16]. Separately, a prespecified analysis of SELECT examined ischemic and heart failure outcomes in the subgroup with a documented history of heart failure, comparing preserved and reduced ejection fraction subtypes^[17]. These analyses are hypothesis-generating rather than definitive, since none of the constituent trials was designed with heart failure hospitalization as a primary endpoint.

Real-World Comparative Effectiveness

Two large observational programs have attempted to extend the trial findings. A series of five cohort studies using national United States health care claims data from 2018 to 2024 emulated STEP-HFpEF DM and SUMMIT for benchmarking, using sitagliptin as a placebo proxy, before broadening eligibility to routine-practice populations and performing a head-to-head comparison of semaglutide and tirzepatide with follow-up to 52 weeks and a primary composite of heart failure hospitalization or death^[18]. A global federated network analysis identified 3,983 adults with obesity and HFpEF initiating semaglutide (n = 2,719) or tirzepatide (n = 1,264) between November 2023 and May 2025, with 1,258 per group after propensity score matching at a mean age of 66 years, and assessed a composite of all-cause mortality and heart failure hospitalization^[19]. Both efforts are non-randomized and vulnerable to residual confounding by indication, prescriber preference and differential access.

Guideline Positioning

Current major heart failure guidelines predate the mature STEP-HFpEF dataset and therefore contain only conditional statements about weight management in HFpEF. Contemporary expert consensus documents and focused updates increasingly recommend considering semaglutide 2.4 mg in symptomatic patients with HFpEF and a body mass index of 30 kg/m2 or greater, generally as an addition to — not a substitute for — a sodium-glucose cotransporter-2 inhibitor, which retains a stronger event-based evidence base in this syndrome. Practitioners should verify the indication status of semaglutide for HFpEF in their own jurisdiction, as regulatory labelling continues to evolve.

Practical Implications and Safety Profile

Diagnostic Workflow

Confirm the phenotype before committing to a year of injectable therapy. Step one is documentation of a left ventricular ejection fraction of at least 50 percent (the STEP program used a threshold of 45 percent, which also captures mildly reduced ejection fraction) together with a body mass index of 30 kg/m2 or higher and symptoms of NYHA class II to IV. Step two is objective corroboration of elevated filling pressures. Natriuretic peptides remain the first-line test but must be interpreted with an obesity correction: the conventional ambulatory rule-out thresholds of NT-proBNP below 125 pg/mL or BNP below 35 pg/mL should be lowered by approximately 50 percent in patients with a body mass index above 35 kg/m2, and in atrial fibrillation the rule-out threshold rises to roughly 365 pg/mL for NT-proBNP. A normal natriuretic peptide in an obese dyspneic patient does not exclude HFpEF.

Step three is echocardiography, seeking a left atrial volume index above 34 mL/m2, septal e-prime below 7 cm/s or lateral e-prime below 10 cm/s, average E/e-prime above 14, and tricuspid regurgitant velocity above 2.8 m/s. Where the picture remains ambiguous, apply the H2FPEF or HFA-PEFF scores; intermediate scores warrant either exercise stress echocardiography or invasive hemodynamics, with a pulmonary capillary wedge pressure of 15 mmHg or more at rest, or 25 mmHg or more during exercise, being confirmatory. Screen concurrently for obstructive sleep apnea, iron deficiency (ferritin below 100 ng/mL, or 100 to 299 ng/mL with transferrin saturation below 20 percent), and cardiac amyloidosis in the older patient with unexplained wall thickening.

Patient Selection and Dose Escalation

The target maintenance dose is semaglutide 2.4 mg subcutaneously once weekly. Escalation follows a fixed ladder: 0.25 mg weekly for four weeks, then 0.5 mg weekly for four weeks, then 1.0 mg weekly for four weeks, then 1.7 mg weekly for four weeks, reaching 2.4 mg weekly at week 17. If a step is poorly tolerated — most often because of nausea, early satiety or constipation — remain at the current dose for an additional four weeks rather than abandoning therapy; if 2.4 mg cannot be tolerated after two attempts, 1.7 mg weekly is an acceptable long-term maintenance dose. Injections are given on the same day each week, rotating between abdomen, thigh and upper arm, with or without food. A missed dose may be taken within five days; if longer, omit and resume the schedule.

Contraindications include a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2; exercise extreme caution or avoid therapy in patients with prior pancreatitis, active severe gastroparesis, pregnancy or planned conception within two months, and end-stage renal disease on dialysis. In frail or sarcopenic patients, proceed only with a structured resistance training prescription and a protein intake target of 1.0 to 1.5 g/kg ideal body weight per day.

Safety Monitoring and Drug Interactions

Review the patient at four weeks after initiation and at each escalation step, then at three-month intervals once maintenance is reached. Record weight, blood pressure, heart rate, orthostatic symptoms and volume status at every visit. Check renal function and electrolytes at baseline, at eight to twelve weeks and every six months thereafter, more frequently if vomiting or diarrhea occurs, since dehydration-related acute kidney injury is the commonest serious renal event. Obtain HbA1c and lipids at six and twelve months in patients with dysglycemia.

In patients taking insulin, reduce the basal dose by approximately 20 percent at initiation and intensify glucose self-monitoring; sulfonylureas should be halved or stopped outright, as the hypoglycemia risk arises from the combination rather than from semaglutide alone. Delayed gastric emptying alters absorption of drugs with narrow therapeutic indices — monitor the international normalized ratio more closely with warfarin, and observe for altered levothyroxine and immunosuppressant levels. Counsel on the perioperative aspiration hazard: for elective procedures under general anesthesia or deep sedation, consider withholding the weekly dose for one week beforehand and extending clear-fluid fasting, in line with current anesthesiology guidance. Advise immediate presentation for severe persistent epigastric pain radiating to the back (pancreatitis), right upper quadrant pain with fever (cholelithiasis or cholecystitis, whose incidence rises with rapid weight loss), or new visual deterioration in long-standing diabetes with retinopathy.

Managing Background Heart Failure Therapy

Decongestion accompanies weight loss, and loop diuretic requirements commonly fall. Anticipate this: review diuretic dosing at every visit during escalation and reduce proactively when orthostatic symptoms, rising creatinine or a low jugular venous pressure appear. Continue the sodium-glucose cotransporter-2 inhibitor, and be aware that the combination amplifies natriuresis. Blood pressure typically falls by 3 to 6 mmHg systolic, so antihypertensive de-escalation is frequently required. Weight loss of more than 20 percent of baseline, or a body mass index falling below 22 kg/m2, should prompt reassessment of the maintenance dose. Confirm all dosing details against the approved product label in your jurisdiction before prescribing.

Future Perspectives and Open Questions

The central unresolved issue is whether semaglutide reduces hard outcomes in obesity-related HFpEF. Existing event data derive from pooled and post-hoc analyses of trials designed for other purposes, and a dedicated, adequately powered, event-driven trial with heart failure hospitalization and cardiovascular death as the primary endpoint remains the outstanding requirement. Until such data exist, the recommendation to use semaglutide in HFpEF rests on symptom, function and biomarker endpoints, however impressive their magnitude.

A second question concerns the relative contribution of weight loss to benefit. Mediation analyses can partition variance statistically, but they cannot establish causation, and the observation that patients achieving the least weight loss still derive symptomatic benefit is compatible with both a threshold effect and a genuinely pleiotropic mechanism. Head-to-head comparison against equivalent weight loss achieved by another means — dietary, surgical or via a mechanistically distinct agent — is the only design that could resolve this definitively in humans.

Third, the field is moving rapidly toward multi-receptor agonism. Dual GIP/GLP-1 and triple GIP/GLP-1/glucagon agonists, oral peptide and non-peptide formulations, and rational combination strategies with sodium-glucose cotransporter-2 inhibitors and non-steroidal mineralocorticoid receptor antagonists are reshaping cardiometabolic treatment algorithms^[20]. Whether greater weight loss translates linearly into greater cardiac benefit, or whether receptor-specific signaling matters more than the absolute kilograms removed, is unknown, and the currently available comparative data between semaglutide and tirzepatide in HFpEF are observational.

Finally, several practical uncertainties persist. The durability of benefit after discontinuation has not been characterized in a heart failure population, and weight regain is the rule once GLP-1 RA therapy stops. The consequences of accompanying lean mass loss for long-term functional capacity in an already sarcopenic older cohort require dedicated body composition endpoints. Cost, supply and equitable access remain substantial barriers, and the trial populations, while international, under-represent several ethnic groups and patients with advanced renal dysfunction. These limitations should temper, but not negate, what is the most substantial therapeutic advance yet achieved in obesity-related HFpEF.

References

1. Vest AR, Schauer PR, Rodgers JE, Sanderson E, LaChute CL, Seltz J, et al. Obesity and Weight Loss Strategies for Patients With Heart Failure. JACC Heart Fail. 2024;12(9):1509-1527. doi:10.1016/j.jchf.2024.06.006. PubMed
2. Teli B, Sathe S, Kalra R, Mahajan V, Mehta A, Shinde R, et al. Evaluating the Cardiovascular Benefits of Innovator Semaglutide 2.4 mg (Recombinant DNA (r-DNA)) in Patients With Overweight or Obesity: A Critical Review of Current Evidence. Cureus. 2026;18(6):e111322. doi:10.7759/cureus.111322. PubMed
3. Verma S, Petrie MC, Borlaug BA, Butler J, Davies MJ, Kitzman DW, et al. Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program. J Am Coll Cardiol. 2024;84(17):1646-1662. doi:10.1016/j.jacc.2024.08.028. PubMed
4. Petrie MC, Borlaug BA, Butler J, Davies MJ, Kitzman DW, Shah SJ, et al. Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program. J Am Coll Cardiol. 2024;84(1):27-40. doi:10.1016/j.jacc.2024.04.022. PubMed
5. Solomon SD, Ostrominski JW, Wang X, Shah SJ, Borlaug BA, Butler J, et al. Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure. J Am Coll Cardiol. 2024;84(17):1587-1602. doi:10.1016/j.jacc.2024.08.021. PubMed
6. Withaar C, Meems LMG, Nollet EE, Schouten EM, Schroeder MA, Knudsen LB, et al. The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF. JACC Basic Transl Sci. 2023;8(10):1298-1314. doi:10.1016/j.jacbts.2023.05.012. PubMed
7. Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023;389(12):1069-1084. doi:10.1056/NEJMoa2306963. PubMed
8. Kosiborod MN, Petrie MC, Borlaug BA, Butler J, Davies MJ, Hovingh GK, et al. Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes. N Engl J Med. 2024;390(15):1394-1407. doi:10.1056/NEJMoa2313917. PubMed
9. Butler J, Shah SJ, Petrie MC, Borlaug BA, Abildstrøm SZ, Davies MJ, et al. Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. Lancet. 2024;403(10437):1635-1648. doi:10.1016/S0140-6736(24)00469-0. PubMed
10. Butler J, Abildstrøm SZ, Borlaug BA, Davies MJ, Kitzman DW, Petrie MC, et al. Semaglutide in Patients With Obesity and Heart Failure Across Mildly Reduced or Preserved Ejection Fraction. J Am Coll Cardiol. 2023;82(22):2087-2096. doi:10.1016/j.jacc.2023.09.811. PubMed
11. Verma S, Butler J, Borlaug BA, Davies M, Kitzman DW, Shah SJ, et al. Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials. J Am Coll Cardiol. 2024;84(9):773-785. doi:10.1016/j.jacc.2024.06.001. PubMed
12. Verma S, Butler J, Borlaug BA, Davies MJ, Kitzman DW, Petrie MC, et al. Atrial Fibrillation and Semaglutide Effects in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Program. J Am Coll Cardiol. 2024;84(17):1603-1614. doi:10.1016/j.jacc.2024.08.023. PubMed
13. Borlaug BA, Kitzman DW, Patel S, Chinnakondepalli KM, Butler J, Davies MJ, et al. Semaglutide and Exercise Function in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program. JACC Heart Fail. 2025;13(11):102660. doi:10.1016/j.jchf.2025.102660. PubMed
14. Schou M, Petrie MC, Borlaug BA, Butler J, Davies MJ, Kitzman DW, et al. Semaglutide and NYHA Functional Class in Obesity-Related Heart Failure With Preserved Ejection Fraction: The STEP-HFpEF Program. J Am Coll Cardiol. 2024;84(3):247-257. doi:10.1016/j.jacc.2024.04.038. PubMed
15. Pandey A, Kitzman DW, Chinnakondepalli KM, Patel S, Borlaug BA, Butler J, et al. Frailty and Effects of Semaglutide in Obesity-Related HFpEF: Findings From the STEP-HFpEF Program. JACC Heart Fail. 2025;13(10):102610. doi:10.1016/j.jchf.2025.102610. PubMed
16. Kosiborod MN, Deanfield J, Pratley R, Borlaug BA, Butler J, Davies MJ, et al. Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials. Lancet. 2024;404(10456):949-961. doi:10.1016/S0140-6736(24)01643-X. PubMed
17. Deanfield J, Verma S, Scirica BM, Kahn SE, Emerson SS, Ryan D, et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. Lancet. 2024;404(10454):773-786. doi:10.1016/S0140-6736(24)01498-3. PubMed
18. Krüger N, Schneeweiss S, Fuse K, Matseyko S, Sreedhara SK, Hahn G, et al. Semaglutide and Tirzepatide in Patients With Heart Failure With Preserved Ejection Fraction. JAMA. 2025;334(14):1255-1266. doi:10.1001/jama.2025.14092. PubMed
19. Monzo L, Savarese G, Duarte K, Baudry G, Petrie MC, Girerd N. Semaglutide vs tirzepatide in patients with obesity and HFpEF: a report from a global federated research network. ESC Heart Fail. 2026;13(1). doi:10.1093/eschf/xvag042. PubMed
20. Qiu L, Liu J, Hu N. Incretin-based cardiovascular protection beyond diabetes: evidence, mechanisms, and therapeutic frontiers from GLP-1 receptor agonists to multi-agonist therapy. Front Endocrinol (Lausanne). 2026;17:1870649. doi:10.3389/fendo.2026.1870649. PubMed

Share this article

LinkedIn X Facebook WhatsApp Copy Link