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Dodangeh S, Hasani-Ranjbar S. Old and new anti-obesity drugs. J Diabetes Metab Disord 2025; 24:16. [PMID: 39712336 PMCID: PMC11659566 DOI: 10.1007/s40200-024-01512-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 11/24/2024] [Indexed: 12/24/2024]
Abstract
Obesity is a pandemic problem that correlates with a cluster of metabolic factors leading to poor cardiovascular outcomes, morbidity, and an increased risk of overall mortality. It is necessary to approach obesity with a comprehensive treatment plan, which may involve lifestyle modifications (diet, exercise, and behavioral therapy) and pharmacological interventions. This article provides an overview of the mechanisms of action, efficacy, and safety of available long-term anti-obesity drugs and introduces other potential agents under investigation.
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Affiliation(s)
- Salimeh Dodangeh
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shirin Hasani-Ranjbar
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Javaid A, Hariri E, Ozkan B, Lang K, Khan SS, Rangaswami J, Stone NJ, Blumenthal RS, Ndumele CE. Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Case-Based Narrative Review. AMERICAN JOURNAL OF MEDICINE OPEN 2025; 13:100089. [PMID: 40104608 PMCID: PMC11919292 DOI: 10.1016/j.ajmo.2025.100089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 01/17/2025] [Indexed: 03/20/2025]
Abstract
These 4 hypothetical cases highlight new features of the American Heart Association cardiovascular-kidney-metabolic (CKM) health construct. The cases incorporate the CKM staging system, estimates from the PREVENT risk calculator, and clinical approaches related to CKM stages and individual risk profiles. Topics include management considerations for (1) a patient with stage 1 obesity and impaired glucose tolerance, (2) a patient with metabolic risk factors and moderate-risk chronic kidney disease (CKD), (3) a patient with subclinical atherosclerotic cardiovascular disease and multiple comorbid conditions, and (4) a patient with metabolic risk factors, prior myocardial infarction, new-onset heart failure, atrial fibrillation, and CKD.
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Affiliation(s)
- Aamir Javaid
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Essa Hariri
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Bige Ozkan
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Katherine Lang
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Sadiya S Khan
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Janani Rangaswami
- Division of Nephrology, Washington DC VA Medical Center
- George Washington University School of Medicine and Health Sciences, Washington, D.C
| | - Neil J Stone
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Roger S Blumenthal
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Chiadi E Ndumele
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
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3
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Costa TA, Harrington JL. Advances in the management of obesity and heart failure: latest evidence from clinical trials. Curr Opin Cardiol 2025; 40:164-171. [PMID: 39998461 DOI: 10.1097/hco.0000000000001214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Abstract
PURPOSE OF REVIEW Obesity is an important risk factor for heart failure with preserved ejection fraction (HFpEF). In patients who already have HFpEF, obesity contributes to high symptom burden and increased risk for heart failure (HF) hospitalization. This review examines the latest clinical trials assessing the efficacy of pharmacological interventions in the treatment of obesity-related HFpEF. RECENT FINDINGS Recent results from randomized clinical trials (RCTs) suggest that incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (e.g., semaglutide) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs (e.g., tirzepatide), can improve quality of life, exercise tolerance, and markers of HF severity while promoting weight loss in patients with obesity and HFpEF. Some evidence also suggests that these therapies may reduce risk for HF hospitalizations. Additionally, exploratory analyses of the nonsteroidal mineralocorticoid receptor antagonist finerenone has been associated with reduced cardiovascular mortality and total worsening HF events across all body mass index (BMI) levels, with greater benefits observed in patients with higher BMIs. SUMMARY Antiobesity medications such as semaglutide and tirzepatide may represent important treatment options for patients with obesity-related HFpEF. Additional evidence suggests that certain other HF medications may have increased efficacy in patients with obesity.
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Affiliation(s)
| | - Josephine L Harrington
- Department of Medicine, University of Colorado School of Medicine
- Colorado Prevention Center, Aurora, Colorado, USA
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4
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Goubar T, Kim S, Cistulli D, Fenton-Lee D, Rushworth RL, Macdonald PS, Keogh AM. Sleeve gastrectomy as a bridge to cardiac recovery - A retrospective comparative cohort study. JHLT OPEN 2025; 8:100224. [PMID: 40144731 PMCID: PMC11935463 DOI: 10.1016/j.jhlto.2025.100224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
Background Obesity in patients with heart failure with reduced ejection fraction (HFrEF) increases morbidity and may preclude them from accessing advanced heart failure therapies. Bariatric surgery, specifically sleeve gastrectomy (SG), may improve eligibility for cardiac transplant; however, its impact on heart failure outcomes is not well defined. Methods We conducted a retrospective cohort study of patients with obesity (body mass index [BMI] ≥35 kg/m2) and (left ventricular ejection fraction [LVEF] ≤40%) who underwent SG at a tertiary heart transplant center. Outcomes were compared with controls matched for age, sex, LVEF, and BMI receiving standard care. We evaluated BMI, New York Heart Association (NYHA) functional class, medications, echocardiographic parameters, time to advanced heart failure therapies, and survival. Results Twenty patients (median BMI 42.8 kg/m², LVEF 25%) underwent SG compared to 40 matched patients. Both groups demonstrated reductions in BMI; however, weight loss was significantly greater in the treatment group (-9.9 [95% CI -12.2, -7.6] vs. -2.7 [-4.3, -1.1] kg/m², p < 0.05). Despite this, improvements in LVEF (+16.6% [10.2, 23.0] vs. +0.1% [-4.4, 4.7], p < 0.05) along with NYHA class (-0.8 [95% CI: -1.3, -0.3] vs. +0.4 [0.1, 0.7], p < 0.05) were only observed in those receiving SG. Overall survival was significantly higher in the treatment group [HR: 0.2 (0.07, 0.62), p < 0.01], which had no deaths compared to 35% in the comparison group. Conclusion In patients with HFrEF and obesity, SG is associated with significant improvements in cardiac function and survival compared to standard care, supporting its role as a safe and effective bridge to recovery or candidacy.
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Affiliation(s)
- Thomas Goubar
- St Vincent’s Hospital Sydney, 390 Victoria St, Darlinghurst, NSW 2010, Australia
- The University of Notre Dame, School of Medicine, Sydney, 160 Oxford St, Darlinghurst, NSW 2010, Australia
| | - Samuel Kim
- Northern Beaches Hospital, 105 Frenchs Forest Rd W, Frenchs Forest, Sydney, NSW 2086, Australia
| | - David Cistulli
- Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown, Sydney, NSW 2050, Australia
| | - Douglas Fenton-Lee
- St Vincent’s Hospital Sydney, 390 Victoria St, Darlinghurst, NSW 2010, Australia
- The University of Notre Dame, School of Medicine, Sydney, 160 Oxford St, Darlinghurst, NSW 2010, Australia
| | - R. Louise Rushworth
- The University of Notre Dame, School of Medicine, Sydney, 160 Oxford St, Darlinghurst, NSW 2010, Australia
| | - Peter S. Macdonald
- St Vincent’s Hospital Sydney, 390 Victoria St, Darlinghurst, NSW 2010, Australia
| | - Anne M. Keogh
- St Vincent’s Hospital Sydney, 390 Victoria St, Darlinghurst, NSW 2010, Australia
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Faruque L, Yau K, Cherney DZI. Glucagon-like peptide-1 receptor agonists to improve cardiorenal outcomes: data from FLOW and beyond. Curr Opin Nephrol Hypertens 2025; 34:232-240. [PMID: 40047207 DOI: 10.1097/mnh.0000000000001066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
PURPOSE OF REVIEW Glucagon-like peptide-1 receptor agonists (GLP1RA), initially approved for glycemic control in type 2 diabetes mellitus (T2DM), have emerged as agents for weight loss, cardiovascular and kidney protection. This review summarizes the evidence supporting the benefits of these therapies on cardiorenal outcomes. RECENT FINDINGS Clinical trials have consistently demonstrated reductions in major adverse cardiovascular events with GLP1RA treatments. Recently, the FLOW trial revealed that semaglutide reduced the composite outcome of kidney failure, at least 50% decline in estimated glomerular filtration rate, kidney or cardiovascular mortality by 24% in patients with T2DM, thereby establishing GLP1RA as a pillar of therapy in this population. New evidence suggests favorable effects on kidney endpoints in nondiabetic individuals with overweight or obesity. Dedicated trials have also provided evidence for reduction in the risk for heart failure hospitalization and improvement in symptoms in individuals with heart failure with preserved ejection fraction. Subgroup analyses have suggested that GLP1RAs confer additive cardiorenal benefits irrespective of background medication use. SUMMARY There is increasing evidence that GLP1RA reduces the risk for cardiovascular events, chronic kidney disease progression, and heart failure hospitalizations. Further data on the effect of dual and triple GLP1-based therapies on cardiorenal outcomes is required.
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Affiliation(s)
- Labib Faruque
- Department of Medicine, Division of Nephrology, University Health Network
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kevin Yau
- Department of Medicine, Division of Nephrology, University Health Network
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Yagi K, Chujo D, Usui I, Liu JH, Nohara A, Shirozu AE, Takikawa A, Honoki H, Fujisaka S, Origasa H, Tada H. B-type natriuretic peptide efficacy compared to fragmented QRS for diastolic dysfunction screening in patients with type 2 diabetes. World J Diabetes 2025; 16:103551. [DOI: 10.4239/wjd.v16.i4.103551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/04/2025] [Accepted: 01/21/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND Early diagnosis of left ventricular diastolic dysfunction (LVDD) is essential for preventing heart failure. B-type natriuretic peptide (BNP) is a viable marker for predicting LVDD, as elevated BNP levels have been associated with worsening LVDD in patients with diabetes over time. However, the utility of BNP as a diagnostic marker in diabetes is controversial, as BNP levels are often low in overweight individuals.
AIM To examine the effectiveness of BNP levels and fragmented QRS (fQRS) on electrocardiography for diagnosing LVDD in patients with type 2 diabetes.
METHODS This retrospective cohort study included 303 patients with type 2 diabetes (67.4 ± 12.3 years old) with preserved ejection fraction (EF) ≥ 50% admitted to Toyama University Hospital for glycemic management and comorbidity evaluation between November 2017 and April 2021. All participants underwent plasma BNP measurement, electrocardiography, and echocardiography. Cardiologists who were blinded to the BNP results assessed the electrocardiograms and echocardiograms. Subgroup analyses were conducted for overweight individuals.
RESULTS Receiver operating characteristic (ROC) curve analysis determined optimal BNP cut-off values of 34.8 pg/mL and 7.2 pg/mL for diagnosing LVDD in non-overweight [area under the ROC curve (AUC): 0.70] and overweight (AUC: 0.55) groups, respectively (P = 0.040). In the overweight subgroup, fQRS showed greater diagnostic accuracy for LVDD (AUC: 0.67), indicating moderate diagnostic utility compared with the low performance of the BNP cutoff of 35 pg/mL (AUC: 0.52) (P = 0.010). Multivariate analyses confirmed that fQRS was superior to BNP for LVDD diagnosis regardless of the patient’s weight.
CONCLUSION A BNP level ≥ 35 pg/mL in non-overweight individuals may be a reliable LVDD marker. Additionally, fQRS was more effective than BNP in diagnosing LVDD irrespective of the patient’s weight. fQRS can complement BNP in the early detection of LVDD, especially in overweight patients, potentially improving early detection and mitigating progression to heart failure with preserved EF in patients with type 2 diabetes.
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Affiliation(s)
- Kunimasa Yagi
- Department of Internal Medicine, Kanazawa Medical University Hospital, Kahoku 920-0293, Ishikawa, Japan
| | - Daisuke Chujo
- Center for Clinical and Translational Research, Toyama University Hospital, Toyama 930-0152, Toyama, Japan
| | - Isao Usui
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Utsunomiya 321-0293, Tochigi, Japan
| | - Jian-Hui Liu
- Department of Cardiology, Ningbo Medical Center of Lihuili Hospital, Ningbo 315041, Zhejiang Province, China
| | - Atsushi Nohara
- Department of Clinical Genetics, Ishikawa Prefectural Central Hospital, Kanazawa 920-8530, Ishikawa, Japan
| | - Asako Enkaku Shirozu
- The First Department of Internal Medicine, Toyama University Hospital, Toyama 930-0152, Toyama, Japan
| | - Akiko Takikawa
- The First Department of Internal Medicine, Toyama University Hospital, Toyama 930-0152, Toyama, Japan
| | - Hisae Honoki
- The First Department of Internal Medicine, Toyama University Hospital, Toyama 930-0152, Toyama, Japan
| | - Shiho Fujisaka
- The First Department of Internal Medicine, Toyama University Hospital, Toyama 930-0152, Toyama, Japan
| | - Hideki Origasa
- Data Science and AI Innovation Research Promotion Center, Institute of Statistical Mathematics, Shiga University, Hikone 525-0034, Shiga, Japan
| | - Hayato Tada
- Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa 920-8640, Ishikawa, Japan
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Simonis G, Schatz U. Obesity and heart failure-the role of GLP-1 receptor agonists. Herz 2025:10.1007/s00059-025-05312-2. [PMID: 40172656 DOI: 10.1007/s00059-025-05312-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2025] [Indexed: 04/04/2025]
Abstract
Patients with obesity-driven heart failure with preserved ejection fraction (HFpEF) often suffer from symptoms despite guideline-recommended treatment with diuretics, sodium glucose cotransporter 2 (SGLT2) inhibition, and mineralocorticoid antagonists. Obesity by itself drives heart failure via multiple pathophysiological mechanisms. This review summarizes current data on glucagon-like peptide‑1 (GLP-1) receptor agonists and the dual GIP/GLP‑1 agonist tirzepatide, including symptoms and outcomes in patients with obesity-driven HFpEF with or without diabetes.
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Affiliation(s)
- Gregor Simonis
- Kardiologische Ambulanz und Herzkatheterlabor, MVZ Praxisklinik Herz und Gefäße, Forststraße 3, 01099, Dresden, Germany.
| | - Ulrike Schatz
- Medizinische Klinik III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany
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Odigwe C, Mulyala R, Malik H, Ruiz B, Riad M, Sayiadeh MA, Honganur S, Parks A, Rahman MU, Lakkis N. Emerging role of GLP-1 agonists in cardio-metabolic therapy - Focus on Semaglutide. AMERICAN HEART JOURNAL PLUS : CARDIOLOGY RESEARCH AND PRACTICE 2025; 52:100518. [PMID: 40115122 PMCID: PMC11923757 DOI: 10.1016/j.ahjo.2025.100518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 03/23/2025]
Abstract
Semaglutide, a GLP-1 receptor agonist, has emerged as a promising agent in cardiovascular disease management, particularly for patients with obesity and diabetes. Recent studies have demonstrated significant benefits of Semaglutide beyond glycemic control, including reduced major adverse cardiovascular events (MACE), improvements in heart failure symptoms, and weight reduction. Notably, the STEP-HFpEF trial highlighted improved exercise capacity and a reduction in NT-proBNP levels, offering a novel therapeutic pathway for heart failure management. Additionally, Semaglutide has shown anti-inflammatory effects, reducing C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α), thereby mitigating atherosclerotic risks. Moreover, the SELECT trial demonstrated Semaglutide's cardiovascular benefits in non-diabetic, obese patients, suggesting that its effects extend beyond weight loss. These findings represent a potential paradigm shift in cardiovascular risk management, although access and affordability remain key challenges.
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Affiliation(s)
- Celestine Odigwe
- Division of Cardiovascular Disease, Department of Medicine, University of South Alabama, United States of America
| | - Rajasekhar Mulyala
- Division of Cardiovascular Disease, Department of Medicine, University of South Alabama, United States of America
| | - Haijra Malik
- Division of Cardiovascular Disease, Department of Medicine, University of South Alabama, United States of America
| | - Brent Ruiz
- Division of Cardiovascular Disease, Department of Medicine, University of South Alabama, United States of America
| | - Mariam Riad
- Division of Cardiovascular Disease, Department of Medicine, University of South Alabama, United States of America
| | - Mohammad As Sayiadeh
- Division of Cardiovascular Disease, Department of Medicine, University of South Alabama, United States of America
| | - Sanchitha Honganur
- Division of Cardiovascular Disease, Department of Medicine, University of South Alabama, United States of America
| | - Alexis Parks
- Division of Cardiovascular Disease, Department of Medicine, University of South Alabama, United States of America
| | - Mustafeez Ur Rahman
- Division of Cardiovascular Disease, Department of Medicine, University of South Alabama, United States of America
| | - Nasser Lakkis
- Division of Cardiovascular Disease, Department of Medicine, University of South Alabama, United States of America
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Zupec J, Munger R, Scaletta A, Quinn DH. Use of glucagon-like peptide-1 receptor agonists and incretin mimetics for type 2 diabetes and obesity: A narrative review. Nutr Clin Pract 2025; 40:327-349. [PMID: 39961620 DOI: 10.1002/ncp.11279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 03/06/2025] Open
Abstract
Incretin mimetics, including glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide agonists, have become first-line treatment options for the treatment of type 2 diabetes and obesity. Their therapeutic status is attributed to their high level of efficacy as well as positive impact on related comorbidities, such as sleep apnea and heart failure. Multiple incretin mimetics are currently available with different durations of drug action, dosing frequencies, and delivery devices. Patients may benefit from education on the proper drug administration, anticipated adverse effects, and nutrition considerations with treatment. Practitioners must monitor progress and support the patient to achieve maintenance doses for optimal weight reduction and diabetes-related outcomes. This review aims to present the current literature supporting US Food and Drug Administration-approved indications of incretin mimetics, equip healthcare professionals to optimize care for patients who are prescribed these agents, and provide insights into potential future applications, which may include dual- or triple-mechanism agents that are injected or administered orally. Additional studies are anticipated with existing and future incretin mimetics for the treatment of type 2 diabetes, obesity, and related comorbidities in a rapidly developing therapeutic pipeline.
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Affiliation(s)
- Jason Zupec
- Department of Pharmacy Practice, Philadelphia College of Pharmacy at Saint Joseph's University, Philadelphia, Pennsylvania, USA
| | - Rebecca Munger
- Department of Pharmacy Practice, Philadelphia College of Pharmacy at Saint Joseph's University, Philadelphia, Pennsylvania, USA
| | - Alice Scaletta
- Department of Pharmacy Practice, Philadelphia College of Pharmacy at Saint Joseph's University, Philadelphia, Pennsylvania, USA
| | - Diane H Quinn
- Department of Pharmacy Practice, Philadelphia College of Pharmacy at Saint Joseph's University, Philadelphia, Pennsylvania, USA
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Davis BJ, Kim M, Burton Y, Elman M, Hodovan J, Shah AM, Maurer MS, Solomon SD, Masri A. Myocardial contraction fraction predicts outcomes in patients enrolled in the TOPCAT trial. Int J Cardiol 2025; 424:133038. [PMID: 39914629 DOI: 10.1016/j.ijcard.2025.133038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 01/29/2025] [Accepted: 02/03/2025] [Indexed: 02/11/2025]
Abstract
BACKGROUND Myocardial contraction fraction (MCF)-the ratio of left ventricular stroke volume to myocardial volume-is a volumetric measure of myocardial shortening that distinguishes between pathologic and physiologic hypertrophy. In this post-hoc analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial, we investigated the prognostic value of MCF and its association with heterogeneity of treatment effect in heart failure with preserved ejection fraction (HFpEF). METHODS TOPCAT randomized patients with HFpEF to spironolactone or placebo. Patients with echocardiography data allowing for the calculation of MCF were included. The primary outcome was a composite of all-cause mortality, HF hospitalization, myocardial infarction, and stroke. RESULTS 588 patients (median age 72.0 [63.0-79.3] years; 49.1 % female) were included. Median MCF was 27.0 % (21.8-32.8 %) for the overall group and was not different in the spironolactone and placebo groups. Over a median follow-up of 3.0 (1.9-4.5) years, MCF below median was associated with a worse prognosis (p = 0.003). On multivariable regression analysis (HR, 95 % CI), only New York Heart Association class (1.47, 1.14-1.91, p = 0.003) and MCF (0.76, 0.64-0.90, p = 0.001) were associated with the composite outcome. In this subset, spironolactone as compared to placebo was not associated with improved outcomes, but stratifying by MCF showed differential outcomes to spironolactone therapy (p = 0.010). CONCLUSIONS Among patients with HFpEF enrolled in TOPCAT, reduced MCF was independently associated with worse outcomes. Larger prospectively designed studies are needed to further assess the role of MCF in patients with HFpEF.
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Affiliation(s)
| | - Morris Kim
- Oregon Health & Science University, Portland, OR, USA
| | - Yunwoo Burton
- Oregon Health & Science University, Portland, OR, USA
| | - Miriam Elman
- Oregon Health & Science University, Portland, OR, USA
| | - James Hodovan
- Oregon Health & Science University, Portland, OR, USA
| | - Amil M Shah
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Mathew S Maurer
- Columbia University College of Physicians & Surgeons, New York, NY, USA
| | | | - Ahmad Masri
- Oregon Health & Science University, Portland, OR, USA.
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11
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Sequeira V, Theisen J, Ermer KJ, Oertel M, Xu A, Weissman D, Ecker K, Dudek J, Fassnacht M, Nickel A, Kohlhaas M, Maack C, Dischinger U. Semaglutide normalizes increased cardiomyocyte calcium transients in a rat model of high fat diet-induced obesity. ESC Heart Fail 2025; 12:1386-1397. [PMID: 39482267 PMCID: PMC11911617 DOI: 10.1002/ehf2.15152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 10/14/2024] [Indexed: 11/03/2024] Open
Abstract
AIMS Obesity increases the risk of heart failure with preserved (HFpEF), but not reduced ejection fraction (HFrEF). The glucagon-like peptide-1 receptor agonist (GLP-1-RA) semaglutide improves outcome of patients with obesity with or without HFpEF, while GLP-1-RAs were associated with adverse outcome in patients with HFrEF. Here, we investigate the effect of in vivo treatment with semaglutide on excitation-contraction coupling in a rat model of obesity. METHODS AND RESULTS Rats received high-fat/high-fructose diet for 8 weeks and were then randomized to semaglutide (HFD/Sema) or vehicle (HFD/Veh) for another 8 weeks, during which they could choose between HFD and a low-fat/high-fructose diet (LFD). Control rats received either standard chow (CON), HFD or LFD only, without treatment. After 16 weeks, sarcomere shortening and cytosolic Ca2+ concentrations ([Ca2+]c) were determined in isolated cardiomyocytes. Compared with CON, HFD/Veh increased the amplitude of [Ca2+]c transients and systolic sarcomere shortening in absence or presence of β-adrenergic stimulation, which was reversed by HFD/Sema. Caffeine-induced sarcoplasmic reticulum (SR) Ca2+ release and L-type Ca2+ channel (LTCC) currents were reduced by HFD/Sema versus HFD/Veh, while SR Ca2+ ATPase activity remained unaffected. Compared with HFD, LFD increased [Ca2+]c transients and sarcomere shortening further despite similar effects on body weight. CONCLUSIONS While HFD increased cardiomyocyte [Ca2+]c transients and systolic sarcomere shortening, semaglutide normalized these alterations, mediated by reduced SR Ca2+ load and LTCC currents. Because increased LTCC currents were previously traced to cardiac hypertrophy, these effects may explain why GLP-1-RAs provide benefits for patients with obesity with or without HFpEF, but rather adverse outcome in HFrEF.
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Affiliation(s)
- Vasco Sequeira
- Department of Translational Science Universitätsklinikum, DZHI, Würzburg, Germany
| | - Julia Theisen
- Department of Translational Science Universitätsklinikum, DZHI, Würzburg, Germany
| | - Katharina J Ermer
- Department of Translational Science Universitätsklinikum, DZHI, Würzburg, Germany
| | - Marie Oertel
- Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Würzburg, Würzburg, Germany
| | - Anton Xu
- Department of Translational Science Universitätsklinikum, DZHI, Würzburg, Germany
| | - David Weissman
- Department of Translational Science Universitätsklinikum, DZHI, Würzburg, Germany
| | - Katharina Ecker
- Department of Translational Science Universitätsklinikum, DZHI, Würzburg, Germany
| | - Jan Dudek
- Department of Translational Science Universitätsklinikum, DZHI, Würzburg, Germany
| | - Martin Fassnacht
- Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Würzburg, Würzburg, Germany
| | - Alexander Nickel
- Department of Translational Science Universitätsklinikum, DZHI, Würzburg, Germany
| | - Michael Kohlhaas
- Department of Translational Science Universitätsklinikum, DZHI, Würzburg, Germany
| | - Christoph Maack
- Department of Translational Science Universitätsklinikum, DZHI, Würzburg, Germany
| | - Ulrich Dischinger
- Department of Translational Science Universitätsklinikum, DZHI, Würzburg, Germany
- Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Würzburg, Würzburg, Germany
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12
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Karakasis P, Fragakis N, Ruža I, Stachteas P, Patoulias D. Treatment of obesity-related HFpEF: a STEP closer to the SUMMIT. Future Cardiol 2025; 21:261-264. [PMID: 40055143 DOI: 10.1080/14796678.2025.2477429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 03/06/2025] [Indexed: 04/05/2025] Open
Affiliation(s)
- Paschalis Karakasis
- Second Department of Cardiology, Faculty of Medicine, School of Health Sciences Aristotle, University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Fragakis
- Second Department of Cardiology, Faculty of Medicine, School of Health Sciences Aristotle, University of Thessaloniki, Thessaloniki, Greece
| | - Ieva Ruža
- Department of Endocrinology, Riga East Clinical University Hospital, Riga, Latvia
| | - Panagiotis Stachteas
- Second Department of Cardiology, Faculty of Medicine, School of Health Sciences Aristotle, University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, Faculty of Medicine, School of Health Sciences Aristotle, University of Thessaloniki, Thessaloniki, Greece
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13
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Sattar N, Lee MMY. Estimating direct tissue effects versus weight loss effects of incretin-based drugs for obesity on various chronic conditions. Lancet Diabetes Endocrinol 2025; 13:347-354. [PMID: 39870097 DOI: 10.1016/s2213-8587(24)00363-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 01/29/2025]
Abstract
The extent to which newer, incretin-based drugs for obesity improve disease outcomes via weight loss versus the direct effects of these drugs is the subject of intense interest. Although reductions in major adverse cardiovascular events appear to be predominantly driven by the direct tissue effects of such drugs, the associated weight loss effects must be relevant to the benefits observed in other major outcomes, albeit to differing extents. In this Personal View, we draw on evidence to support that weight loss is at least partly responsible (albeit to differing extents) for the reported benefits of incretin-based drugs for obesity in people living with heart failure with preserved ejection fraction, hypertension, chronic kidney disease, and type 2 diabetes. Concurrently, we propose that drug-induced weight loss is largely responsible for the reported improvements in osteoarthritis, obstructive sleep apnoea, and metabolic dysfunction-associated steatohepatitis outcomes. However, more evidence is needed to solidify these observations, including, when possible, trials comparing the effects of incretin-based drugs for obesity with calorie-reduced diets on both outcomes and mechanistic pathways. Such evidence has implications for public health and the design of future trials of novel drugs for obesity.
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Affiliation(s)
- Naveed Sattar
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK.
| | - Matthew M Y Lee
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
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14
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Nasoufidou A, Stachteas P, Karakasis P, Kofos C, Karagiannidis E, Klisic A, Popovic DS, Koufakis T, Fragakis N, Patoulias D. Treatment options for heart failure in individuals with overweight or obesity: a review. Future Cardiol 2025; 21:315-329. [PMID: 40098467 DOI: 10.1080/14796678.2025.2479378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 03/11/2025] [Indexed: 03/19/2025] Open
Abstract
Obesity and heart failure are interlaced global epidemics, each contributing to significant morbidity and mortality. Obesity is not only a risk-factor for heart failure, but also complicates its management, by distinctive pathophysiological mechanisms and cumulative comorbidities, requiring tailored treatment plan. To present current treatment options for heart failure in individuals with overweight/obesity, emphasizing available pharmacological therapies, non-pharmacological strategies, and the management of related comorbidities. We conducted a comprehensive literature review regarding the results of heart failure treatments in individuals with overweight/obesity, including cornerstone interventions as well as emerging therapeutic options. Specific drug classes, including angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors, have demonstrated consistent efficacy in heart failure irrespective of body mass index, while diuretics remain a key for fluid management. Glucagon-like peptide-1 receptor agonists have shown promising results in improving relevant outcomes and warrant further research. Non-pharmacological approaches, including weight-loss strategies and lifestyle modifications, have shown to improve symptoms, exercise tolerance and quality of life. Managing heart failure in individuals with overweight/obesity requires a multidisciplinary, individualized approach integrating pharmacological and non-pharmacological options. Emerging therapies and preventive strategies arise to address the unique challenges in this population and provide improved outcomes.
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Affiliation(s)
- Athina Nasoufidou
- Second Department of Cardiology, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Hippokration General Hospital of Thessaloniki, Thessaloniki Greece
| | - Panagiotis Stachteas
- Second Department of Cardiology, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Hippokration General Hospital of Thessaloniki, Thessaloniki Greece
| | - Paschalis Karakasis
- Second Department of Cardiology, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Hippokration General Hospital of Thessaloniki, Thessaloniki Greece
| | - Christos Kofos
- Second Department of Cardiology, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Hippokration General Hospital of Thessaloniki, Thessaloniki Greece
| | - Efstratios Karagiannidis
- Department of Emergency Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
- AHEPA University Hospital, Thessaloniki, Greece
| | - Aleksandra Klisic
- Faculty of Medicine, University of Montenegro, Podgorica, Montenegro
| | - Djordje S Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Medical Faculty, University of Novi Sad, Novi Sad, Serbia
| | - Theocharis Koufakis
- Hippokration General Hospital of Thessaloniki, Thessaloniki Greece
- Second Propedeutic Department of Internal Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece
| | - Nikolaos Fragakis
- Second Department of Cardiology, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Patoulias
- Hippokration General Hospital of Thessaloniki, Thessaloniki Greece
- Second Propedeutic Department of Internal Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece
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15
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Syed AA, Adam S, Miller CA, Alkhaffaf B. Obesity Management for Patients with Coronary Artery Disease and Heart Failure. Heart Fail Clin 2025; 21:257-271. [PMID: 40107803 DOI: 10.1016/j.hfc.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/22/2025]
Abstract
Obesity is causally linked to heart disease directly by triggering various adverse pathophysiological changes and indirectly through convergent risk factors such as type 2 diabetes, hypertension, dyslipidemia, and sleep disorder. Weight reduction is an important intervention for obesity-related cardiomyopathy, and antiobesity medications that target both obesity and heart failure (HF), particularly sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists, have a role in treatment. Bariatric surgery offers a viable treatment option for patients with severe obesity associated with coronary artery disease and HF but requires careful patient selection, preoperative optimization, choice of procedure, and postoperative management to minimize risks.
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Affiliation(s)
- Akheel A Syed
- Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PL, UK; Department of Diabetes, Endocrinology & Obesity Medicine, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK.
| | - Safwaan Adam
- Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PL, UK; Department of Diabetes & Endocrinology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK
| | - Christopher A Miller
- Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PL, UK; BHF (British Heart Foundation) Manchester Centre for Heart and Lung Magnetic Resonance Research, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Wythenshawe Hospital, Manchester M23 9LT, UK
| | - Bilal Alkhaffaf
- Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PL, UK; Department of Oesophago-Gastric & Bariatric Surgery, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK
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16
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Kittleson MM. Guidelines for treating heart failure. Trends Cardiovasc Med 2025; 35:141-150. [PMID: 39442740 DOI: 10.1016/j.tcm.2024.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 10/12/2024] [Accepted: 10/13/2024] [Indexed: 10/25/2024]
Abstract
Optimal guideline-directed medical therapy for heart failure with reduced ejection fraction comprises the angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan), an evidence-based beta-blocker (bisoprolol, carvedilol, or sustained-release metoprolol), a mineralocorticoid antagonist (spironolactone or eplerenone), and a sodium-glucose cotransporter-2 inhibitor (dapagliflozin or empagliflozin). Optimal guideline-directed medical therapy for heart failure with preserved ejection fraction comprises a sodium-glucose cotransporter-2 inhibitor with emerging evidence to support the use of a mineralocorticoid antagonist and glucagon-like peptide-1 receptor agonists. This review will summarize the evidence behind the guideline recommendations, the impact of newer trials on management of patients with HF, and strategies for implementation into clinical practice.
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Affiliation(s)
- Michelle M Kittleson
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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17
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Yao Z, Tchang BG, Albert M, Blumenthal RS, Nasir K, Blaha MJ. Associations between Class I, II, or III Obesity and Health Outcomes. NEJM EVIDENCE 2025; 4:EVIDoa2400229. [PMID: 40130972 DOI: 10.1056/evidoa2400229] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
BACKGROUND The burden of obesity-related health conditions remains incompletely explored. Previous studies have been underpowered to study severe obesity, focused on a limited set of health outcomes, and lacked diversity in study populations. METHODS We studied 270,657 participants from the All of Us research program with linked electronic health records and body mass index (the weight in kilograms divided by the square of the height in meters) greater than or equal to 18.5. We investigated the prevalence and incidence of 16 a priori-identified outcomes covering cardiovascular-kidney-metabolic syndrome and others: hypertension, type 2 diabetes mellitus, hyperlipidemia/dyslipidemia, heart failure, atrial fibrillation, atherosclerotic cardiovascular disease, chronic kidney disease, pulmonary embolism, deep vein thrombosis, gout, metabolic dysfunction-associated steatotic liver disease, biliary calculus, obstructive sleep apnea, asthma, gastroesophageal reflux disease, and osteoarthritis. Adjusted hazard ratios were calculated for each BMI category and compared with normal weight. The population-attributable fraction was calculated for different obesity classifications. RESULTS The included population was 62.0% women and 22.0% Black. Class I, II, and III obesity was observed in 21.2%, 11.3%, and 9.8% of participants, respectively. Obesity was strongly associated with all incident outcomes, with graded associations across higher classes of obesity. Class III obesity was most strongly associated with obstructive sleep apnea, type 2 diabetes mellitus, and metabolic dysfunction-associated steatotic liver disease (hazard ratio [95% confidence interval {CI}], 10.94 [9.97 to 12.00], 7.74 [7.03 to 8.53], and 6.72 [6.01 to 7.50], respectively), with weaker associations for asthma, osteoarthritis, and atherosclerotic cardiovascular disease (hazard ratio [95% CI], 2.14 [1.95 to 2.35], 2.06 [1.94 to 2.19], and 1.96 [1.70 to 2.25], respectively). Associations were consistent across sex and race. The obesity-related population-attributed fraction ranged from 14.0% (osteoarthritis) to 51.5% (obstructive sleep apnea) in this population. CONCLUSIONS Obesity, particularly severe obesity, was strongly associated with the incidence of 16 common health outcomes.
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Affiliation(s)
- Zhiqi Yao
- Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, Baltimore
| | - Beverly G Tchang
- Department of Internal Medicine, Division of Endocrinology, Weill Cornell Medical College, New York
| | - Michael Albert
- University of Oklahoma Health Sciences Center, Oklahoma City
| | - Roger S Blumenthal
- Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, Baltimore
| | - Khurram Nasir
- Division of Cardiovascular Prevention and Wellness, Department of Cardiology, Houston Methodist DeBakey Heart and Vascular Center, Houston
| | - Michael J Blaha
- Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, Baltimore
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18
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Theodorakis N, Kreouzi M, Nikolaou M. Semaglutide in heart failure and atherosclerotic cardiovascular disease: the current state-of-the-art. Heart Fail Rev 2025:10.1007/s10741-025-10506-1. [PMID: 40163257 DOI: 10.1007/s10741-025-10506-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/06/2025] [Indexed: 04/02/2025]
Abstract
Cardiovascular disease mortality rates, which had steadily declined over decades, are now plateauing or reversing due to the global rise in type 2 diabetes mellitus (T2DM) and obesity. These cardiometabolic conditions contribute significantly to atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease. Among emerging pharmacological treatments, glucagon-like peptide-1 receptor agonists, particularly semaglutide, have shown benefits beyond diabetes and obesity management, including cardioprotective and renoprotective effects. This state-of-the-art review comprehensively analyzes current evidence from clinical trials, identifies critical insights, and outlines research directions regarding semaglutide use in HF, ASCVD, and diabetic nephropathy. In ASCVD, semaglutide has demonstrated significant reductions in major adverse cardiovascular events, supported by findings from meta-analyses of trials in patients with T2DM and the SELECT trial for patients without T2DM. In a prespecified analysis of the SELECT trial, semaglutide demonstrated significant reductions in cardiovascular mortality and HF hospitalizations for patients with HF and ASCVD. In HF with preserved ejection fraction and mildly reduced ejection fraction, semaglutide improved symptoms, physical function, natriuretic peptide levels, echocardiographic parameters, and HF hospitalizations, as shown in the STEP-HFpEF program and a pooled analysis of trials. Furthermore, evidence from the FLOW trial underscores semaglutide's renal and cardiovascular benefits in diabetic nephropathy, irrespective of body mass index. While these findings suggest semaglutide's efficacy in cardiorenal diseases, gaps in evidence remain, including the need for event-driven trials in HF populations without ASCVD and irrespective of obesity. Future research should address these gaps, which could potentially update guideline recommendations.
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Affiliation(s)
- Nikolaos Theodorakis
- Department of Cardiology & Heart Failure Outpatient Clinic, Sismanogleio-Amalia Fleming General Hospital, 14, 25th Martiou Str., 15127, Melissia, Greece.
- School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias, 11527, Athens, Greece.
| | - Magdalini Kreouzi
- Department of Internal Medicine, Sismanogleio-Amalia Fleming General Hospital, 14, 25th Martiou Str., 15127, Melissia, Greece
| | - Maria Nikolaou
- Department of Cardiology & Heart Failure Outpatient Clinic, Sismanogleio-Amalia Fleming General Hospital, 14, 25th Martiou Str., 15127, Melissia, Greece
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19
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Bonaca MP, Catarig AM, Houlind K, Ludvik B, Nordanstig J, Ramesh CK, Rasouli N, Sourij H, Videmark A, Verma S. Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): a phase 3b, double-blind, randomised, placebo-controlled trial. Lancet 2025:S0140-6736(25)00509-4. [PMID: 40169145 DOI: 10.1016/s0140-6736(25)00509-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/13/2025] [Accepted: 03/13/2025] [Indexed: 04/03/2025]
Abstract
BACKGROUND Peripheral artery disease is a highly morbid type of atherosclerotic vascular disease involving the legs and is estimated to affect over 230 million individuals globally. Few therapies improve functional capacity and health-related quality of life in people with lower limb peripheral artery disease. We aimed to evaluate whether semaglutide improves function as measured by walking ability as well as symptoms, quality of life, and outcomes in people with peripheral artery disease and type 2 diabetes. METHODS STRIDE was a double-blind, randomised, placebo-controlled trial done at 112 outpatient clinical trial sites in 20 countries in North America, Asia, and Europe. Participants were aged 18 years and older, with type 2 diabetes and peripheral artery disease with intermittent claudication (Fontaine stage IIa, able to walk >200 m) and an ankle-brachial index of less than or equal to 0·90 or toe-brachial index of less than or equal to 0·70. Participants were randomly assigned (1:1) using an interactive web response system to receive subcutaneous semaglutide 1·0 mg once per week for 52 weeks or placebo. The primary endpoint was the ratio to baseline of the maximum walking distance at week 52 measured on a constant load treadmill in the full analysis set. Safety was evaluated in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT04560998 and is now completed. FINDINGS From Oct 1, 2020, to July 12, 2024, 1363 patients were screened for eligibility, of whom 792 were randomly assigned to semaglutide (n=396) or placebo (n=396). 195 (25%) participants were female and 597 (75%) were male. Median age was 68·0 years (IQR 61·0-73·0). The estimated median ratio to baseline in maximum walking distance at week 52 was significantly greater in the semaglutide group than the placebo group (1·21 [IQR 0·95-1·55] vs 1·08 [0·86-1·36]; estimated treatment ratio 1·13 [95% CI 1·06-1·21]; p=0·0004). Six serious adverse events in five (1%) participants in the semaglutide group and nine serious adverse events in six (2%) participants in the placebo group were possibly or probably treatment related, with the most frequent being serious gastrointestinal events (two events reports by two [1%] in the semaglutide group and five events reported by three [1%] in the placebo group). There were no treatment-related deaths. INTERPRETATION Semaglutide increased walking distance in patients with symptomatic peripheral artery disease and type 2 diabetes. Research implications include the need for future studies to further elucidate mechanisms of benefit and to assess the efficacy and safety in patients with peripheral artery disease who do not have type 2 diabetes. FUNDING Novo Nordisk.
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Affiliation(s)
- Marc P Bonaca
- CPC Clinical Research, Cardiovascular Division, University of Colorado School of Medicine, Aurora, CO, USA.
| | | | - Kim Houlind
- Department of Vascular Surgery, Lillebaelt Hospital, Kolding, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
| | - Bernhard Ludvik
- 1st Medical Department and Karl Landsteiner Institute for Obesity and Metabolic Disorders, Landstrasse Clinic, Vienna, Austria
| | - Joakim Nordanstig
- Institute of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Neda Rasouli
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Harald Sourij
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | | | - Subodh Verma
- Division of Cardiovascular Surgery, St Michael's Hospital, University of Toronto, Toronto, ON, Canada
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20
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Ostapenko A, Ahmed B. Impact of medical versus surgical weight loss on cardiovascular outcomes. Trends Cardiovasc Med 2025:S1050-1738(25)00036-2. [PMID: 40158762 DOI: 10.1016/j.tcm.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 03/08/2025] [Accepted: 03/18/2025] [Indexed: 04/02/2025]
Abstract
Obesity contributes to cardiovascular disease in two ways - directly, as an independent risk factor, and indirectly, through its contribution to comorbidities such as hypertension, diabetes, dyslipidemia. This cascade of multiplicative effects means that early management of obesity is instrumental in risk reduction and prevention of adverse cardiovascular outcomes. The amount and sustainability of weight loss has been extensively studied and stratified by medical versus surgical weight loss. Medical weight loss has historically been inferior by both parameters; however, new therapies targeting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptors have demonstrated very promising results independently for both weight loss and cardiovascular disease. In this review, we compare cardiovascular outcomes between bariatric surgical approaches and novel GLP-1/GIP medications. We aim to answer the following question: In this era of new pharmacological weight loss options, does the method of weight loss-surgical or medical-impact cardiovascular risk mitigation, or is the key factor the maintenance of a healthier weight, regardless of the method?
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Affiliation(s)
- Alexander Ostapenko
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
| | - Bestoun Ahmed
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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21
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Bryant E, Laing K, Langdon KD, Salisbury H, Villavaso CD. Leading the Charge in Obesity Management: A Call to Action for Cardiovascular Nursing. J Cardiovasc Nurs 2025:00005082-990000000-00279. [PMID: 40146810 DOI: 10.1097/jcn.0000000000001192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
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22
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Lam CY, Lin DY, Endlich Y. A case series of incidents reported to webAIRS relating to glucagon-like peptide 1 agonist use. Anaesth Intensive Care 2025:310057X241311597. [PMID: 40145463 DOI: 10.1177/0310057x241311597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
The increasing prescription of glucagon-like peptide 1 (GLP-1) agonists presents a peri-operative challenge for anaesthetists. These drugs delay gastric emptying, potentially increasing pulmonary aspiration risk. Despite recent recommendations from the Australian and New Zealand College of Anaesthetists, Australian Society of Anaesthetists, and American Society of Anesthesiologists, there remain no formalised guidelines regarding preoperative optimisation for patients taking GLP-1 agonists. Given the current lack of evidence, we present a case series of incidents involving patients treated with GLP-1 agonists reported to webAIRS, a web-based anaesthetic incident reporting system in Australia and New Zealand. Among 11,700 reports from July 2009 to April 2024, 13 incidents related to GLP-1 agonist use were identified, including seven cases concerning aspiration. Patient factors potentially contributing to increased aspiration risks in these incidents included a higher body mass index, type 2 diabetes mellitus, gastro-oesophageal reflux disease, emergency case, and time from GLP-1 agonist cessation. Most incidents involved a rapid sequence induction for general anaesthesia with no cases utilising gastric ultrasound, preoperative nasogastric tube insertion, or intravenous erythromycin use. This case series highlights the potential concerns relating to GLP-1 treatment in the perioperative setting. Interdisciplinary collaboration and communication between anaesthetists, surgeons, general practitioners and endocrinologists are required to further investigate and establish preoperative guidelines for safe GLP-1 agonist use. Specifically, consideration in determining actual gastric contents of each patient despite generic fasting guidelines is needed. Early preoperative risk stratification should also improve patient safety and outcomes.
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Affiliation(s)
- Clayton Yx Lam
- Flinders Medical Centre, Department of Anaesthesia and Pain Medicine, Adelaide, Australia
- Flinders University College of Medicine and Public Health, Adelaide, Australia
| | - D-Yin Lin
- Flinders Medical Centre, Department of Anaesthesia and Pain Medicine, Adelaide, Australia
- Flinders University College of Medicine and Public Health, Adelaide, Australia
| | - Yasmin Endlich
- Royal Adelaide Hospital, Department of Anaesthesia and Pain Medicine, Adelaide, Australia
- The University of Adelaide, Faculty of Medicine, Adelaide, Australia
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23
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Kitai T, Kohsaka S, Kato T, Kato E, Sato K, Teramoto K, Yaku H, Akiyama E, Ando M, Izumi C, Ide T, Iwasaki YK, Ohno Y, Okumura T, Ozasa N, Kaji S, Kashimura T, Kitaoka H, Kinugasa Y, Kinugawa S, Toda K, Nagai T, Nakamura M, Hikoso S, Minamisawa M, Wakasa S, Anchi Y, Oishi S, Okada A, Obokata M, Kagiyama N, Kato NP, Kohno T, Sato T, Shiraishi Y, Tamaki Y, Tamura Y, Nagao K, Nagatomo Y, Nakamura N, Nochioka K, Nomura A, Nomura S, Horiuchi Y, Mizuno A, Murai R, Inomata T, Kuwahara K, Sakata Y, Tsutsui H, Kinugawa K. JCS/JHFS 2025 Guideline on Diagnosis and Treatment of Heart Failure. J Card Fail 2025:S1071-9164(25)00100-9. [PMID: 40155256 DOI: 10.1016/j.cardfail.2025.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
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24
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Elangovan H, Gunton JE, Zheng MH, Fan JG, Goh GBB, Gronbaek H, George J. The promise of incretin-based pharmacotherapies for metabolic dysfunction-associated fatty liver disease. Hepatol Int 2025:10.1007/s12072-025-10795-6. [PMID: 40140191 DOI: 10.1007/s12072-025-10795-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 02/07/2025] [Indexed: 03/28/2025]
Abstract
BACKGROUND The presence of excess liver fat secondary to metabolic dysregulation represents the end-organ manifestation of a systemic disease that can progress to steatohepatitis, cirrhosis and its feared complications of clinical decompensation and hepatocellular cancer. Since metabolic dysfunction-associated fatty liver disease (MAFLD) is highly prevalent globally, there is a pressing need to augment lifestyle interventions with pharmacotherapies to ameliorate disease burden and reduce adverse liver-related events. PURPOSE This review summarises current evidence for the utility of incretin mimetics in the MAFLD/MASH arena. METHODS A literature review that encompassed multiple database searches to inform the evidence base for incretin drugs in MAFLD/MASH. RESULTS Incretin mimetics demonstrate multifarious benefits across the metabolic diseases spectrum with mounting evidence for their role in remitting steatohepatitis and liver fibrosis. Weight loss and insulin sensitisation contribute, but additional mechanisms may also be engaged. Gastrointestinal adverse effects are common but for most, can be managed while preserving the hepatic and cardiometabolic benefits. CONCLUSION The literature reveals benefits from incretin-based therapies for MASH, but data on whether they improve long-term hepatic outcomes are awaited to support their future incorporation into routine clinical care.
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Affiliation(s)
- Harendran Elangovan
- Storr Liver Centre, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
- Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, NSW, Australia
| | - Jenny Elizabeth Gunton
- Centre for Diabetes, Obesity and Endocrinology (CDOE), Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, NSW, Australia
| | - Ming Hua Zheng
- Department of Hepatology, MAFLD Research Centre, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jian-Gao Fan
- Centre for Fatty Liver Disease, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - George Boon Bee Goh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Henning Gronbaek
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.
- Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, NSW, Australia.
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
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Thapa R, Lara-Breitinger KM, Lopez-Jimenez F, Shama N, Egbe AC, Miranda WR, Connolly HM, Jain CC, Jokhadar M, Kosec AM, Alm S, Burchill LJ. Glucagon-Like Peptide-1 Agonist Use in Adults With Congenital Heart Disease: Effect, Safety, and Outcomes. JACC. ADVANCES 2025; 4:101674. [PMID: 40132346 DOI: 10.1016/j.jacadv.2025.101674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 03/27/2025]
Abstract
BACKGROUND Obesity is prevalent among patients with adult congenital heart disease (ACHD) and contributes to adverse cardiovascular outcomes. There is a paucity of data regarding glucagon-like peptide-1 receptor agonists (GLP-1 RA) for weight loss in patients with ACHD. OBJECTIVES The purpose of this study was to assess the effect, safety, and outcomes of GLP-1 RA among patients with ACHD. METHODS This is a retrospective cohort study of patients with ACHD at Mayo Clinic (01/2013-01/2024) who were prescribed semaglutide or liraglutide. The primary endpoint was weight loss. Secondary endpoints were changes in New York Heart Association class, hemoglobin A1c, estimated glomerular filtration rate, and safety endpoints of renal adverse event, hypoglycemia, hospitalization/drug discontinuation due to side effects. RESULTS Seventy patients received GLP-1 RA over a mean duration of 21 ± 20 months. Majority (85.7%) had moderate/severe complexity congenital heart disease. Weight loss >5% was achieved in 30 (42.9%) patients. Patients with body mass index ≥35 kg/m2 were more likely to achieve weight loss >5% [66.7% vs 40%, P = 0.027]. Younger age resulted in improved weight loss of 0.17 kg per 1-year age difference (P = 0.014). Hemoglobin A1c lowered by a mean of 0.6% (P = 0.054). There were no significant changes in New York Heart Association class or estimated glomerular filtration rate. One-third of patients experienced side effects, mostly from gastrointestinal intolerance (20%); 11.4% discontinued the medication due to side effects. CONCLUSIONS GLP-1 RAs are safe and effective for weight loss in patients with ACHD with beneficial effects on glycemic control.
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Affiliation(s)
- Rashmi Thapa
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | - Nishat Shama
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
| | - Alexander C Egbe
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - William R Miranda
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Heidi M Connolly
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - C Charles Jain
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Maan Jokhadar
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Angela M Kosec
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Svea Alm
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Luke J Burchill
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.
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Hathorn B, Haykowsky MJ, Almandoz J, Pandey A, Sarma S, Hearon CM, Babb TG, Balmain BN, Fu Q, Zaha VG, Levine BD, Nelson MD. Insights into the role of obesity in Heart Failure with Preserved Ejection Fraction pathophysiology and management. Can J Cardiol 2025:S0828-282X(25)00199-0. [PMID: 40122162 DOI: 10.1016/j.cjca.2025.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/11/2025] [Accepted: 03/15/2025] [Indexed: 03/25/2025] Open
Abstract
Heart failure (HF) is a significant global health issue, categorized by left ventricular ejection fraction, being either reduced (HFrEF: <0.40) or preserved (HFpEF: >0.50), or in the middle of this range. While the overall incidence of HF remains stable, HFpEF cases are increasing, representing about 50% of all HF cases. Outcomes for HFpEF are similar to HFrEF, leading to substantial healthcare resource utilization. Despite extensive research over the past two decades, the prognosis and mortality rates for HFpEF remain high. A key feature of HFpEF is exercise intolerance, characterized by severe exertional dyspnea and fatigue, which significantly impacts quality of life. The underlying mechanisms of exercise intolerance are not fully understood due to the complex pathophysiology and multi-system involvement. Obesity is a common comorbidity in HFpEF, especially in North America, leading to worsening symptoms, hemodynamics, and mortality rates. Increased adiposity leads to inflammation, hypertension, dyslipidemia, and insulin resistance, and impairing cardiac, vascular, pulmonary, and skeletal muscle function. Therefore, managing obesity is crucial in treating HFpEF. This review explores the pathophysiologic mechanisms of HFpEF, emphasizing obesity's role, and discusses current management strategies while identifying areas needing further research.
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Affiliation(s)
- Brandon Hathorn
- Applied Physiology and Advanced Imaging Lab, University of Texas at Arlington, TX, United States
| | - Mark J Haykowsky
- College of Health Sciences, Faculty of Nursing, University of Alberta, Canada
| | - Jaime Almandoz
- Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ambarish Pandey
- Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States
| | - Satyam Sarma
- Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States; Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas
| | - Christopher M Hearon
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas
| | - Tony G Babb
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States
| | - Bryce N Balmain
- Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States
| | - Qi Fu
- Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States; Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas
| | - Vlad G Zaha
- Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States; Clinical Imaging Research Center, University of Texas at Arlington, Arlington, TX, United States
| | - Benjamin D Levine
- Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States; Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas
| | - Michael D Nelson
- Applied Physiology and Advanced Imaging Lab, University of Texas at Arlington, TX, United States; Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States; Clinical Imaging Research Center, University of Texas at Arlington, Arlington, TX, United States.
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27
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Dilaver RG, Afsar RE, Crescenzi R, Gamboa J, Ikizler TA. Effects of Dulaglutide on Ectopic Fat Deposition in Chronic Kidney Disease (CKD): A Pilot and Feasibility Study (GLIMP). MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.03.19.25324266. [PMID: 40166561 PMCID: PMC11957094 DOI: 10.1101/2025.03.19.25324266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Introduction Patients with chronic kidney disease (CKD) often exhibit ectopic fat accumulation, including intermuscular adipose tissue (IMAT), which is associated with metabolic and muscular dysfunctions. This study aimed to evaluate the effects of dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), on reducing IMAT and improving metabolic and physical functions in patients with CKD stage 3-4. Methods Seven patients were recruited between April 2022 and November 2023. A 12-week dulaglutide (1.5 mg/wk) intervention was conducted with pre-and post-treatment assessments, including magnetic resonance imaging (MRI) for the IMAT evaluation and systemic physical performance battery test (SPPB) for physical performance evaluation. Their body mass indexes (BMI) were calculated and blood samples were analyzed for inflammatory and metabolic markers, including high sensitive C-reactive protein (Hs-CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), glucose, insulin resistance (IR), total cholesterol, triglyceride, adiponectin, leptin, and leptin-adiponectin ratio (LAR) before and after treatment. Paired t-tests and Mann-Whitney U tests were used for statistical analysis, with significance set at p < 0.05. Results Out of 58 assessed patients with CKD stage 3-4, 7 were enrolled, with 5 completing the full 12-week dulaglutide treatment. The total 7 people had a mean age of 59 years, mean BMI of 31.4 kg/m², and baseline eGFR of 31.7 mL/min/1.73m². IMAT decreased in 4 patients and increased in 3 patients, with no statistically significant changes overall (p = 0.69). The quadriceps muscle cross-sectional area (CSA) also showed no significant difference (p = 0.73). BMI and serum leptin levels significantly decreased after treatment (p < 0.05), while other inflammatory and metabolic markers, and physical performance scores showed no significant changes. No serious adverse events were reported. Conclusions This study examined the effects of a 12-week dulaglutide treatment on IMAT accumulation in patients with CKD stage 3-4. While BMI significantly decreased, changes in IMAT were modest and not statistically significant, with potential but unproven clinical and metabolic benefits. Many metabolic and inflammatory markers improved, though not statistically significantly, and physical performance remained unchanged. Muscle CSA and function were maintained, which may alleviate concerns about potential GLP-1RA-induced muscle loss. Dulaglutide was well-tolerated, with minimal side effects. The small sample size and short duration highlight the need for further research. Trial Registration Name of the Registry : ClinicalTrials.gov Trial Registration Number : NCT05254418 Date of Registration : 2022-02-01.
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Ebrahimi P, Batlle JC, Ayati A, Maqsood MH, Long C, Tarabanis C, McGowan N, Liebers DT, Laynor G, Hosseini K, Heffron SP. Suicide and Self-Harm Events With GLP-1 Receptor Agonists in Adults With Diabetes or Obesity: A Systematic Review and Meta-Analysis. JAMA Psychiatry 2025:2831637. [PMID: 40105856 PMCID: PMC11923776 DOI: 10.1001/jamapsychiatry.2025.0091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Importance Bariatric surgery, once the criterion standard in obesity treatment, has a small but concerning association with increased suicidality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed to treat diabetes, now provide substantial efficacy in the treatment of obesity. However, concerns of risk of suicidality with these medicines have been raised. Objective To evaluate the risk of suicidality and self-harm in randomized, placebo-controlled trials of GLP-1 RAs in adults with diabetes or obesity. Data Sources MEDLINE, Embase, ClinicalTrials.gov, and Cochrane databases were systematically searched from inception to August 29, 2023. Study Selection Reports of randomized clinical trials (RCTs) lasting 6 or more months comparing GLP-1 RAs with placebo for the treatment of diabetes or obesity published in peer-reviewed journals were identified. Two independent reviewers screened all search-identified studies for inclusion. Records of outcomes were queried from primary papers, ClinicalTrials.gov entries, and corresponding authors. Data Extraction and Synthesis Two independent researchers abstracted data and assessed data quality and validity using PRISMA guidelines. Data were pooled using random-effects models. Main Outcomes and Measures Pooled incidence of completed or attempted suicide, occurrences of suicidal ideation, or self-harm. Results A total of 27 of 144 RCTs meeting inclusion criteria systematically recorded suicide and/or self-harm-related events and included 32 357 individuals receiving GLP-1 RAs and 27 046 treated with placebo, over 74 740 and 68 095 person-years of follow-up, respectively. Event incidence was very low in the GLP-1 RA (0.044 per 100 person-years) and placebo (0.040 per 100 person-years) groups, with no statistically significant difference (rate ratio [RR], 0.76; 95% CI, 0.48-1.21; P = .24). Subgroup analyses did not suggest differences in outcomes based on diabetes status or GLP-1 RA used. Five studies were considered at risk of bias due to the loss of more than 5% of participants to follow-up. Otherwise, studies were not found to be heterogeneous nor at high risk of bias. Conclusions and Relevance There is unlikely to be an increase in the very low incidence of suicide-related adverse events among individuals receiving GLP-1 RAs within the context of RCTs. While these findings may further ease concerns about these adverse effects, continued monitoring is warranted to identify particular patients who may be at risk as extended use of GLP-1 RAs expands.
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Affiliation(s)
- Pouya Ebrahimi
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Juan Carlos Batlle
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Aryan Ayati
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - M Haisum Maqsood
- Department of Cardiology, DeBakey Heart and Vascular Center, Houston Methodist Hospital, Houston, Texas
| | - Clarine Long
- Department of Medicine, New York University Grossman School of Medicine, New York
| | | | - Natalie McGowan
- Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine, New York
- New York University Center for the Prevention of Cardiovascular Disease, New York University Grossman School of Medicine, New York
| | - David T Liebers
- Department of Psychiatry, New York University Grossman School of Medicine, New York
| | - Gregory Laynor
- Medical Library, New York University Grossman School of Medicine, New York
| | - Kaveh Hosseini
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sean P Heffron
- Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine, New York
- New York University Center for the Prevention of Cardiovascular Disease, New York University Grossman School of Medicine, New York
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29
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Whitman J, Kozaily E, Michos ED, Silverman DN, Fudim M, Mentz RJ, Tedford RJ, Rao VN. Epicardial Fat in Heart Failure and Preserved Ejection Fraction: Novel Insights and Future Perspectives. Curr Heart Fail Rep 2025; 22:13. [PMID: 40106059 PMCID: PMC11922990 DOI: 10.1007/s11897-025-00700-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/05/2025] [Indexed: 03/22/2025]
Abstract
PURPOSE OF REVIEW Cardiovascular effects of obesity may be driven, in part, by the distribution of fat. More recently, epicardial adipose tissue (EAT) has gained recognition as an adverse visceral fat impacting cardiac dysfunction in heart failure with preserved ejection fraction (HFpEF). RECENT FINDINGS EAT can be identified and measured using several non-invasive imaging techniques, including transthoracic echocardiography, computed tomography, and cardiac magnetic resonance. The presence of EAT is associated with increased risk of HFpEF and worse clinical outcomes among patients with established HFpEF, independent of total adiposity. EAT may serve a pivotal role in the pathogenesis of HFpEF by worsening volume distribution, enhancing pericardial restraint and ventricular interaction, worsening right ventricular dysfunction, and diminishing exercise tolerance. No large trials have tested the effects of reducing fat in specific areas of the body on cardiovascular outcomes, but some studies that followed people in communities and trials over time have suggested that drug and non-drug treatments that lower EAT could improve the risk factors for heart problems in patients with HFpEF. Further understanding the role that pathogenic fat depots play in HFpEF incidence and progression may provide future therapeutic targets in treating the obese-HFpEF phenotype.
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Affiliation(s)
- Jacob Whitman
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Elie Kozaily
- Division of Cardiology, Medical University of South Carolina, 30 Courtenay Drive, MSC Code: 592, Charleston, SC, 29425, USA
| | - Erin D Michos
- Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel N Silverman
- Division of Cardiology, Medical University of South Carolina, 30 Courtenay Drive, MSC Code: 592, Charleston, SC, 29425, USA
- Division of Cardiology, Ralph H. Johnson Department of Veterans Affairs Heath Care System, Charleston, SC, USA
| | - Marat Fudim
- Division of Cardiology and Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
| | - Robert J Mentz
- Division of Cardiology and Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
| | - Ryan J Tedford
- Division of Cardiology, Medical University of South Carolina, 30 Courtenay Drive, MSC Code: 592, Charleston, SC, 29425, USA
| | - Vishal N Rao
- Division of Cardiology, Medical University of South Carolina, 30 Courtenay Drive, MSC Code: 592, Charleston, SC, 29425, USA.
- Division of Cardiology, Ralph H. Johnson Department of Veterans Affairs Heath Care System, Charleston, SC, USA.
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30
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Krammer T, Baier MJ, Hegner P, Zschiedrich T, Lukas D, Wolf M, Le Phu C, Lutz V, Evert K, Kozakov K, Li J, Holzamer A, Maier LS, Provaznik Z, Bers DM, Wagner S, Mustroph J. Cardioprotective effects of semaglutide on isolated human ventricular myocardium. Eur J Heart Fail 2025. [PMID: 40107718 DOI: 10.1002/ejhf.3644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/19/2024] [Accepted: 03/03/2025] [Indexed: 03/22/2025] Open
Abstract
AIMS Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown promising effects in reducing cardiovascular events in patients with obesity and heart failure (HF) with preserved ejection fraction (HFpEF) irrespective of concomitant diabetes. However, the exact mechanisms underlying its cardioprotective actions remain unclear. Our study investigates the direct effects of semaglutide on human cardiomyocytes, focusing on calcium (Ca) and sodium (Na) handling and its potential to improve myocardial contractility. METHODS AND RESULTS Human left ventricular cardiomyocytes were isolated from non-failing (NF) hearts, patients with aortic stenosis and a HFpEF-like phenotype (AS), and those with end-stage HF with reduced ejection fraction (HFrEF). Late Na current (INa), sarcoplasmic reticulum (SR) Ca leak, and contractility were assessed in isolated cardiomyocytes treated with semaglutide. CaMKII inhibitor autocamtide-2-related inhibitory peptide and GLP-1 receptor antagonist exendin 9-39 (Ex-9-39) were used to elucidate signalling pathways. Semaglutide reduced late INa in AS and HFrEF cardiomyocytes to levels comparable to NF. Additionally, semaglutide decreased diastolic SR Ca leak and improved systolic Ca transients and contractility in AS and HFrEF tissue. These effects were mediated through GLP-1 receptor agonism and were comparable to CaMKII inhibition. In multicellular preparations, semaglutide differentially improved myocardial contractility in AS and HFrEF in a dose-dependent manner. CONCLUSION Semaglutide directly modulates ion homeostasis in human cardiomyocytes, reducing proarrhythmic diastolic SR Ca leak and enhancing systolic function, which may explain its observed clinical benefits. These findings provide mechanistic insights into the cardioprotective effects of semaglutide and suggest its potential therapeutic use in HF.
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Affiliation(s)
- Thomas Krammer
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Maria J Baier
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Philipp Hegner
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Tilman Zschiedrich
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - David Lukas
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Matthias Wolf
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Christian Le Phu
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Vanessa Lutz
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Katja Evert
- Institute for Pathology, University of Regensburg, Regensburg, Germany
| | - Kostiantyn Kozakov
- Cardiothoracic Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Jing Li
- Cardiothoracic Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Andreas Holzamer
- Cardiothoracic Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Lars S Maier
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Zdenek Provaznik
- Cardiothoracic Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Donald M Bers
- Department of Pharmacology, University of California, Davis, CA, USA
| | - Stefan Wagner
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Julian Mustroph
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
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31
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Jani VP, Yoo EJ, Binek A, Guo A, Kim JS, Aguilan J, Keykhaei M, Jenkin SR, Sidoli S, Sharma K, Van Eyk JE, Kass DA, Hahn VS. Myocardial Proteome in Human Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc 2025; 14:e038945. [PMID: 40079330 DOI: 10.1161/jaha.124.038945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 12/16/2024] [Indexed: 03/15/2025]
Abstract
BACKGROUND Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all HF but has few effective therapies. Recent human myocardial transcriptomics and metabolomics have identified major differences between HFpEF and controls. How this translates at the protein level is unknown. METHODS AND RESULTS Myocardial tissue from patients with HFpEF and nonfailing donor controls was analyzed by data-dependent acquisition (n=10 HFpEF, n=10 controls) and data-independent acquisition (n=44 HFpEF, n=5 controls) mass spectrometry-based proteomics. Differential protein expression analysis, pathway overrepresentation, weighted coexpression network analysis, and machine learning were integrated with clinical characteristics and previously reported transcriptomics. Principal component analysis (data-dependent acquisition-mass spectrometry) found HFpEF separated into 2 subgroups: one similar to controls and the other disparate. Downregulated proteins in HFpEF versus controls were enriched in mitochondrial transport/organization, translation, and metabolism including oxidative phosphorylation. Proteins upregulated in HFpEF were related to immune activation, reactive oxygen species, and inflammatory response. Ingenuity pathway analysis predicted downregulation of protein translation, mitochondrial function, and glucose and fat metabolism in HFpEF. Expression of oxidative phosphorylation and metabolism genes (higher) versus proteins (lower) was discordant in HFpEF versus controls. Data-independent acquisition-mass spectrometry proteomics also yielded 2 HFpEF subgroups; the one most different from controls had a higher proportion of patients with severe obesity and exhibited lower proteins related to fuel metabolism, oxidative phosphorylation, and protein translation. Three modules of correlated proteins in HFpEF that correlated with left ventricular hypertrophy and right ventricular load related to (1) proteasome; (2) fuel metabolism; and (3) protein translation, oxidative phosphorylation, and sarcomere organization. CONCLUSIONS Integrative proteomics, transcriptomics, and pathway analysis supports a defect in both metabolism and translation in HFpEF. Patients with HFpEF with more distinct proteomic signatures from control more often had severe obesity, supporting therapeutic efforts targeting metabolism and translation, particularly in this subgroup.
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Affiliation(s)
- Vivek P Jani
- Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore MD USA
| | - Edwin J Yoo
- Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore MD USA
| | - Aleksandra Binek
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars-Sinai Medical Center Los Angeles CA USA
| | - Alina Guo
- Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore MD USA
| | - Julie S Kim
- Department of Biochemistry Albert Einstein College of Medicine Bronx NY USA
| | - Jennifer Aguilan
- Department of Pathology Albert Einstein College of Medicine Bronx NY USA
| | - Mohammad Keykhaei
- Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore MD USA
| | - Sydney R Jenkin
- Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore MD USA
| | - Simone Sidoli
- Department of Biochemistry Albert Einstein College of Medicine Bronx NY USA
| | - Kavita Sharma
- Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore MD USA
| | - Jennifer E Van Eyk
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars-Sinai Medical Center Los Angeles CA USA
| | - David A Kass
- Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore MD USA
- Department of Pharmacology and Molecular Sciences, and Department of Biomedical Engineering Johns Hopkins University Baltimore MD USA
| | - Virginia S Hahn
- Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine Baltimore MD USA
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32
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Stolfo D, Iacoviello M, Chioncel O, Anker MS, Bayes-Genis A, Braunschweig F, Cannata A, El Hadidi S, Filippatos G, Jhund P, Mebazaa A, Moura B, Piepoli M, Ray R, Ristic AD, Seferovic P, Simpson M, Skouri H, Tocchetti CG, Van Linthout S, Vitale C, Volterrani M, Keramida K, Wassmann S, Lewis BS, Metra M, Rosano GMC, Savarese G. How to handle polypharmacy in heart failure. A clinical consensus statement of the Heart Failure Association of the ESC. Eur J Heart Fail 2025. [PMID: 40091554 DOI: 10.1002/ejhf.3642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 12/23/2024] [Accepted: 02/18/2025] [Indexed: 03/19/2025] Open
Abstract
The multiplicity of coexisting comorbidities affecting patients with heart failure (HF), together with the availability of multiple treatments improving prognosis in HF with reduced ejection fraction, has led to an increase in the number of prescribed medications to each patient. Polypharmacy is defined as the regular use of multiple medications, and over the last years has become an emerging aspect of HF care, particularly in older and frailer patients who are more frequently on multiple treatments, and are therefore more likely exposed to tolerability issues, drug-drug interactions and practical difficulties in management. Polypharmacy negatively affects adherence to treatment, and is associated with a higher risk of adverse drug reactions, impaired quality of life, more hospitalizations and worse prognosis. It is important to adopt and implement strategies for the management of polypharmacy from other medical disciplines, including medication reconciliation, therapeutic revision and treatment prioritization. It is also essential to develop new HF-specific strategies, with the primary goal of avoiding the use of redundant treatments, minimizing adverse drug reactions and interactions, and finally improving adherence. This clinical consensus statement document from the Heart Failure Association of the European Society of Cardiology proposes a rationale, pragmatic and multidisciplinary approach to drug prescription in the current era of multimorbidity and 'multi-medication' in HF.
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Affiliation(s)
- Davide Stolfo
- Department of Clinical Science and Education, Södersjukhuset; Karolinska Institutet, Stockholm, Sweden
- Division of Cardiology, Cardiothoracic Department, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
| | - Massimo Iacoviello
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Ovidiu Chioncel
- University of Medicine Carol Davila, Bucharest, Romania
- Emergency Institute for Cardiovascular Diseases 'Prof. C.C. Iliescu', Bucharest, Romania
| | - Markus S Anker
- German Heart Center Charité CBF and German Centre for Cardiovascular Research DZHK, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies BCRT, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
| | - Antoni Bayes-Genis
- Heart Institute, Hospital Universitari Germans Trias i Poujol, Badalona, Spain
| | | | - Antonio Cannata
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine, Faculty of Life Science, King's College London, London, UK
- Cardiovascular Department, King's College Hospital NHS Foundation Trust, London, UK
| | | | - Gerasimos Filippatos
- National & Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece
| | - Pardeep Jhund
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Alexandre Mebazaa
- Université de Paris, INSERM, U942 MASCOT, Paris, France
- Department of Anesthesia and Critical Care Medicine, AP-HP, Hôpital Lariboisière, Paris, France
| | - Brenda Moura
- Armed Forces Hospital, Faculty of Medicine of University of Porto, Porto, Portugal
| | - Massimo Piepoli
- Clinical Cardiology, IRCCS Policlinico San Donato, Milan, Italy
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Robin Ray
- Cardiovascular Clinical Academic Group and Cardiology Research Centre, St. George's, University of London, St. George's University Hospitals NHS Foundation Trust, London, UK
| | - Arsen D Ristic
- Medical Faculty, University of Belgrade, Belgrade, Serbia
- Clinic for Cardiology, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Petar Seferovic
- Serbian Academy of Sciences and Arts, Heart Failure Center, Faculty of Medicine, Belgrade University Medical Center, Belgrade, Serbia
| | - Maggie Simpson
- Department of Cardiology, Queen Elizabeth University Hospital, NHS Greater Glasgow & Clyde, Glasgow, UK
| | - Hadi Skouri
- Department of Cardiology, Balamand university school of Medicine, Beirut, Lebanon
| | - Carlo Gabriele Tocchetti
- Department of Translational Medical Sciences (DISMET), Center for Basic and Clinical Immunology Research (CISI), Interdepartmental Center of Clinical and Translational Sciences (CIRCET), Interdepartmental Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy
| | - Sophie Van Linthout
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany
- German Center for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany
| | - Cristiana Vitale
- Cardiovascular Clinical Academic Group and Cardiology Research Centre, St. George's, University of London, St. George's University Hospitals NHS Foundation Trust, London, UK
| | - Maurizio Volterrani
- Department of Human Science and Promotion of Quality of Life, San Raffaele Open University, Rome, Italy
- Cardio-Pulmonary Department, IRCCS San Raffaele, Rome, Italy
| | - Kalliopi Keramida
- General Anti-Cancer Oncological Hospital 'Agios Savvas', Athens, Greece
| | - Sven Wassmann
- Cardiology Pasing, Munich, and Faculty of Medicine, University of the Saarland, Homburg, Germany
| | - Basil S Lewis
- Lady Davis Carmel Medical Center, Technion-Israel Institute of Technology, Haifa, Israel
| | - Marco Metra
- ASST Spedali Civili di Brescia, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy
| | - Giuseppe M C Rosano
- Department of Human Sciences and Promotion of Quality of Life, Chair of Pharmacology, San Raffaele University of Rome, Rome, Italy
- Cardiology, San Raffaele Cassino Hospital, Cassino, Italy
| | - Gianluigi Savarese
- Department of Clinical Science and Education, Södersjukhuset; Karolinska Institutet, Stockholm, Sweden
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Rroji M, Spahia N, Figurek A, Spasovski G. Targeting Diabetic Atherosclerosis: The Role of GLP-1 Receptor Agonists, SGLT2 Inhibitors, and Nonsteroidal Mineralocorticoid Receptor Antagonists in Vascular Protection and Disease Modulation. Biomedicines 2025; 13:728. [PMID: 40149704 PMCID: PMC11940462 DOI: 10.3390/biomedicines13030728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 03/03/2025] [Accepted: 03/12/2025] [Indexed: 03/29/2025] Open
Abstract
Atherosclerosis is a closely related complication of diabetes mellitus (DM), driven by endothelial dysfunction, inflammation, and oxidative stress. The progression of atherosclerosis is accelerated by hyperglycemia, insulin resistance, and hyperlipidemia. Novel antidiabetic agents, SGLT2 inhibitors, and GLP-1 agonists improve glycemic control and offer cardiovascular protection, reducing the risk of major adverse cardiovascular events (MACEs) and heart failure hospitalization. These agents, along with nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), promise to mitigate metabolic disorders and their impact on endothelial function, oxidative stress, and inflammation. This review explores the potential molecular mechanisms through which these drugs may prevent the development of atherosclerosis and cardiovascular disease (CVD), supported by a summary of preclinical and clinical evidence.
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Affiliation(s)
- Merita Rroji
- Department of Nephrology, University of Medicine Tirana, 1001 Tirana, Albania
- Department of Nephrology, University Hospital Center Mother Tereza, 1001 Tirana, Albania;
| | - Nereida Spahia
- Department of Nephrology, University Hospital Center Mother Tereza, 1001 Tirana, Albania;
| | - Andreja Figurek
- Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland;
| | - Goce Spasovski
- Department of Nephrology, University Sts. Cyril and Methodius, 1000 Skopje, North Macedonia;
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Lin YM, Wu JY, Lee MC, Su CL, Toh HS, Chang WT, Chen SY, Kuo FH, Tang HJ, Liao CT. Comparative cardiovascular effectiveness of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors in atherosclerotic cardiovascular disease phenotypes: a systematic review and meta-analysis. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2025; 11:174-189. [PMID: 39923808 PMCID: PMC11905764 DOI: 10.1093/ehjcvp/pvae093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 10/30/2024] [Accepted: 12/18/2024] [Indexed: 02/11/2025]
Abstract
BACKGROUND Atherosclerotic cardiovascular disease (ASCVD) encompasses various phenotypes with elevated risks of major adverse cardiovascular events (MACEs). This study aimed to assess the comparative cardiovascular effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) across diverse ASCVD phenotypes. METHODS AND RESULTS We conducted a systematic review and meta-analysis of randomized controlled trials evaluating GLP-1 RAs or SGLT2is against placebo or standard care in ASCVD patients. Primary outcomes included MACE, defined as cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. Risk ratios (RRs) with 95% confidence interval (CI) were calculated using a random-effects model.Twenty-six trials (151 789 patients) were included. Both GLP-1 RAs and SGLT2is significantly reduced MACE rates in ASCVD patients (RR 0.85; 95% CI 0.80-0.91 for both). GLP-1 RAs showed significant effectiveness in peripheral artery disease (RR 0.86; 95% CI 0.76-0.98) and post-acute cardiovascular events (RR 0.90; 95% CI 0.83-0.97). In ASCVD with heart failure, both drug classes reduced MACE (GLP-1 RAs: RR 0.73; 95% CI 0.63-0.84; SGLT2is: RR 0.86; 95% CI 0.78-0.95). SGLT2is significantly reduced MACE in ASCVD with chronic kidney disease (RR 0.84; 95% CI 0.72-0.99), particularly in severe albuminuria (RR 0.61; 95% CI 0.37-0.99). CONCLUSION GLP-1 RAs and SGLT2is exhibit distinct cardiovascular effectiveness profiles across ASCVD phenotypes. GLP-1 RAs show particular benefits in peripheral artery disease and post-acute cardiovascular events, while SGLT2is demonstrate unique advantages in ASCVD with comorbid chronic kidney disease. Both are effective in heart failure. These findings support tailored treatment strategies for diverse ASCVD participants based on specific comorbidities and risk factors.
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Affiliation(s)
- Yu-Min Lin
- Division of Cardiology, Department of Internal Medicine, Chi Mei Hospital, Chiali, Tainan City, 722, Taiwan
| | - Jheng-Yan Wu
- Department of Nutrition, Chi Mei Medical Centre, Tainan City, 710, Taiwan
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan City, 704, Taiwan
| | - Mei-Chuan Lee
- Department of Pharmacy, Chi Mei Medical Centre, Tainan City, 710, Taiwan
| | - Chen-Lun Su
- Department of Internal Medicine, Chi Mei Medical Centre, Tainan City, 710, Taiwan
| | - Han Siong Toh
- Department of Intensive Care Medicine, Chi Mei Medical Centre, Tainan City, 710, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan City, 704, Taiwan
| | - Wei-Ting Chang
- Division of Cardiovascular Medicine, Chi Mei Medical Centre, School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung City, 804, Taiwan
| | - Sih-Yao Chen
- Division of Cardiology, Department of Internal Medicine, Chi Mei Medical Centre, 704, Taiwan
| | - Fang-Hsiu Kuo
- Division of Cardiology, Department of Internal Medicine, Chi Mei Medical Centre, 704, Taiwan
| | - Hsin-Ju Tang
- Department of Nursing, Chang Gung University of Science and Technology, Chiayi County, 613, Taiwan
| | - Chia-Te Liao
- Division of Cardiovascular Medicine, Chi Mei Medical Centre, School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung City, 804, Taiwan
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Pecchia B, Samuel R, Shah V, Newman E, Gibson GT. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction (HFpEF). Heart Fail Rev 2025:10.1007/s10741-025-10504-3. [PMID: 40080287 DOI: 10.1007/s10741-025-10504-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/04/2025] [Indexed: 03/15/2025]
Abstract
Exercise intolerance is a well-established symptom of heart failure with preserved ejection fraction (HFpEF) and is associated with impaired quality of life and worse clinical outcomes. Historically attributed to diastolic dysfunction of the left ventricle, exercise intolerance in HFpEF is now known to result not only from diastolic dysfunction, but also from impairments in left ventricular systolic function, left atrial pathology, right ventricular dysfunction, and valvular disease. Disorders of heart rate and rhythm such as chronotropic incompetence and atrial fibrillation have also been implicated in exercise intolerance in this population. Pathologic changes to extra-cardiac organ systems including the respiratory, vascular, hormonal, and skeletal muscle systems are also thought to play a role in exercise impairment. Finally, comorbidities such as obesity, inflammation, and anemia are common and likely contributory in many cases. The role of each of these factors is discussed in this review of exercise intolerance in patients with HFpEF.
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Affiliation(s)
- Brandon Pecchia
- Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA
| | - Roy Samuel
- Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA
| | - Vacha Shah
- Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA
| | - Emily Newman
- Division of Cardiology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, US, Philadelphia, PA, 19107, USA
| | - Gregory T Gibson
- Division of Cardiology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, US, Philadelphia, PA, 19107, USA.
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Salvador R, Moutinho CG, Sousa C, Vinha AF, Carvalho M, Matos C. Semaglutide as a GLP-1 Agonist: A Breakthrough in Obesity Treatment. Pharmaceuticals (Basel) 2025; 18:399. [PMID: 40143174 PMCID: PMC11944337 DOI: 10.3390/ph18030399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/08/2025] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
This review addresses the role of semaglutide (SMG), a GLP-1 receptor agonist, in the treatment of obesity and its related comorbidities. Originally developed for type 2 diabetes (DM2), SMG has shown significant efficacy in weight reduction, with superior results compared to other treatments in the same class. Its effects include appetite suppression, increased satiety, and improvements in cardiovascular, renal, and metabolic parameters. Studies such as SUSTAIN, PIONEER, and STEP highlight its superiority compared to other GLP-1 receptor agonists and anti-obesity drugs. The oral formulation showed promising initial results, with higher doses (50 mg) showing weight losses comparable to those of subcutaneous administration. Despite its benefits, there are challenges, such as weight regain after cessation of treatment, gastrointestinal adverse effects, and variability of response. Future studies should explore strategies to mitigate these effects, identify predictive factors of efficacy, and expand therapeutic indications to other conditions related to obesity and insulin resistance. The constant innovation in this class of drugs reinforces the potential of SMG to transform treatment protocols for chronic weight-related diseases.
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Affiliation(s)
- Rui Salvador
- Faculty of Health Sciences, Fernando Pessoa University, Rua Carlos da Maia 296, 4200-150 Porto, Portugal; (R.S.); (C.G.M.); (C.S.); (A.F.V.)
| | - Carla Guimarães Moutinho
- Faculty of Health Sciences, Fernando Pessoa University, Rua Carlos da Maia 296, 4200-150 Porto, Portugal; (R.S.); (C.G.M.); (C.S.); (A.F.V.)
- LAQV/REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira, 228, 4050-313 Porto, Portugal
- RISE-Health, Faculty of Health Sciences, Fernando Pessoa University, Fernando Pessoa Teaching and Culture Foundation, Rua Carlos da Maia 296, 4200-150 Porto, Portugal
| | - Carla Sousa
- Faculty of Health Sciences, Fernando Pessoa University, Rua Carlos da Maia 296, 4200-150 Porto, Portugal; (R.S.); (C.G.M.); (C.S.); (A.F.V.)
- LAQV/REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Ana Ferreira Vinha
- Faculty of Health Sciences, Fernando Pessoa University, Rua Carlos da Maia 296, 4200-150 Porto, Portugal; (R.S.); (C.G.M.); (C.S.); (A.F.V.)
- LAQV/REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Márcia Carvalho
- Faculty of Health Sciences, Fernando Pessoa University, Rua Carlos da Maia 296, 4200-150 Porto, Portugal; (R.S.); (C.G.M.); (C.S.); (A.F.V.)
- LAQV/REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira, 228, 4050-313 Porto, Portugal
- RISE-Health, Faculty of Health Sciences, Fernando Pessoa University, Fernando Pessoa Teaching and Culture Foundation, Rua Carlos da Maia 296, 4200-150 Porto, Portugal
| | - Carla Matos
- Faculty of Health Sciences, Fernando Pessoa University, Rua Carlos da Maia 296, 4200-150 Porto, Portugal; (R.S.); (C.G.M.); (C.S.); (A.F.V.)
- LAQV/REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira, 228, 4050-313 Porto, Portugal
- RISE-Health, Faculty of Health Sciences, Fernando Pessoa University, Fernando Pessoa Teaching and Culture Foundation, Rua Carlos da Maia 296, 4200-150 Porto, Portugal
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Bailey CJ, Flatt PR, Conlon JM. Multifunctional incretin peptides in therapies for type 2 diabetes, obesity and associated co-morbidities. Peptides 2025; 187:171380. [PMID: 40081498 DOI: 10.1016/j.peptides.2025.171380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/16/2025]
Abstract
Recent studies with peptide-based incretin herapies have focussed mainly on the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide and the dual agonist tirzepatide that engages receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Randomised clinical trials and 'real-world' studies have confirmed the marked glucose-lowering and weight-lowering efficacy of these agents across diverse populations. These include different ethnic groups, young and elderly individuals with and without diabetes and/or overweight or obesity. Recent studies have also confirmed protections against the development and progression of cardiovascular and renal diseases that are additive to the benefits conferred by improved control of blood glucose and body weight. Emerging evidence suggests that incretin therapies could additionally ameliorate fatty liver disease, chronic inflammation, sleep apnea and possibly degenerative bone disorders and cognitive decline. New incretin-based peptide therapies in development include a long-acting glucagon receptor agonist (LY3324954), dual GLP-1/glucagon receptor agonists (survodutide, pemvidutide, mazdutide, G49), triple GLP-1/GIP/glucagon receptor agonists (retatrutide, efocipegtrutide), a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), a unimolecular GLP-1/amylin receptor dual agonist (amycretin), and a GIP receptor antibody with GLP-1 receptor agonism (MariTide). The creation of multi-targeting incretin-based synthetic peptides provides opportunities for improved management of type 2 diabetes and obesity as well as new therapeutic approaches to an expanding list of associated co-morbidities. The aim of the review is to acquaint the reader with developments in the field from 2023 to the present (February 2025).
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Affiliation(s)
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA Northern Ireland, UK
| | - J Michael Conlon
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA Northern Ireland, UK.
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38
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Zile MR, Borlaug BA, Kramer CM, Baum SJ, Litwin SE, Menon V, Ou Y, Weerakkody GJ, Hurt KC, Kanu C, Murakami M, Packer M. Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity. Circulation 2025; 151:656-668. [PMID: 39556714 DOI: 10.1161/circulationaha.124.072679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 11/11/2024] [Indexed: 11/20/2024]
Abstract
BACKGROUND Patients with heart failure with preserved ejection fraction and obesity have significant disability and frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical end points, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden, in these patients. METHODS We randomized (double-blind) 731 patients with class II to IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m2 to tirzepatide (titrated up to 15 mg SC weekly; n=364) or placebo (n=367) added to background therapy for a median of 104 weeks (quartile 1, 66; quartile 3, 126 weeks). The primary end points were whether tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. The current expanded analysis included sensitivity analyses of the primary end points, 6-minute walk distance, EQ-5D-5L health state index, Patient Global Impression of Severity Overall Health score, New York Heart Association class, use of heart failure medications, and a hierarchical composite based on all-cause death, worsening heart failure, and 52-week changes in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and 6-minute walk distance. RESULTS Patients were 65.2±10.7 years of age; 53.8% (n=393) were female; body mass index was 38.2±6.7 kg/m2; Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was 53.5±18.5; 6-minute walk distance was 302.8±81.7 m; and 53% (n=388) had a worsening heart failure event in the previous 12 months. Compared with placebo, tirzepatide produced a consistent beneficial effect across all composites of death and worsening heart failure events, analyzed as time to first event (hazard ratios, 0.41-0.67). At 52 weeks, tirzepatide increased the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score by 6.9 points (95% CI, 3.3-10.6; P<0.001), 6-minute walk distance 18.3 meters (95% CI, 9.9-26.7; P<0.001), and EQ-5D-5L 0.06 (95% CI, 0.03-0.09; P<0.001). The tirzepatide group shifted to a more favorable Patient Global Impression of Severity Overall Health score (proportional odds ratio, 1.99 [95% CI, 1.44-2.76]) and New York Heart Association class (proportional odds ratio, 2.26 [95% CI, 1.54-3.31]; both P<0.001) and required fewer heart failure medications (P=0.015). The broad spectrum of effects was reflected in benefits on the hierarchical composite (win ratio, 1.63 [95% CI, 1.17-2.28]; P=0.004). CONCLUSIONS Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance, and well-being; and reduced symptoms and medication burden in patients with heart failure with preserved ejection fraction and obesity. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT04847557.
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Affiliation(s)
- Michael R Zile
- RHJ Department of Veterans Affairs, Health Care System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.)
| | - Barry A Borlaug
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.)
| | - Christopher M Kramer
- Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (C.M.K.)
| | | | - Sheldon E Litwin
- RHJ Department of Veterans Affairs, Health Care System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.)
| | - Venu Menon
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, OH (V.M.)
| | - Yang Ou
- Eli Lilly and Company, Indianapolis, IN (Y.O., G.J.W., K.C.H., C.K., M.M.)
| | | | - Karla C Hurt
- Eli Lilly and Company, Indianapolis, IN (Y.O., G.J.W., K.C.H., C.K., M.M.)
| | - Chisom Kanu
- Eli Lilly and Company, Indianapolis, IN (Y.O., G.J.W., K.C.H., C.K., M.M.)
| | - Masahiro Murakami
- Eli Lilly and Company, Indianapolis, IN (Y.O., G.J.W., K.C.H., C.K., M.M.)
| | - Milton Packer
- Baylor University Medical Center, Dallas, TX (M.P.)
- Imperial College, London, UK (M.P.)
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Wang A, Bitzas S, Perez D, Schwartz J, Zaidi S, Oster J, Bergese SD. Perioperative Considerations of Novel Antidiabetic Agents in Heart Failure Patients Undergoing Cardiac Surgery. Life (Basel) 2025; 15:427. [PMID: 40141772 PMCID: PMC11944163 DOI: 10.3390/life15030427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/22/2025] [Accepted: 03/03/2025] [Indexed: 03/28/2025] Open
Abstract
Diabetes mellitus (DM) is a major risk factor for cardiovascular disease, including heart failure (HF). A high proportion of DM patients eventually require cardiac surgery. While the traditional approach to DM therapy focuses on tight glucose control with insulin and oral hypoglycemic agents, novel antidiabetic drugs have emerged over the past two decades that offer not only improved glycemic control but also cardiovascular and renal protection, such as benefits in HF management. The aim of this review is to examine and evaluate the perioperative risk and benefits of novel antidiabetic agents in HF treatment for both DM and non-DM patients undergoing cardiac surgery. We specifically studied glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose cotransporter 2 inhibitors (SGLT2is). Although studies on novel antidiabetic therapy in cardiac surgeries were limited, the results showed all three agents to be safe for use in the perioperative period, with SLGT2i demonstrating the most benefits in HF management for those with or without DM and kidney impairment undergoing cardiac surgery. Future research on larger study populations and using a more rigorous study design is necessary in bridging current knowledge to improve patient outcomes.
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Affiliation(s)
- Ashley Wang
- Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (A.W.); (J.S.); (S.Z.); (J.O.)
| | - Savannah Bitzas
- Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; (S.B.); (D.P.)
| | - Dilsa Perez
- Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; (S.B.); (D.P.)
| | - Jonathon Schwartz
- Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (A.W.); (J.S.); (S.Z.); (J.O.)
| | - Saleem Zaidi
- Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (A.W.); (J.S.); (S.Z.); (J.O.)
| | - Jonathan Oster
- Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (A.W.); (J.S.); (S.Z.); (J.O.)
| | - Sergio D. Bergese
- Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (A.W.); (J.S.); (S.Z.); (J.O.)
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Geers J, Manral N, Razipour A, Park C, Tomasino GF, Xing E, Grodecki K, Kwiecinski J, Pawade T, Doris MK, Bing R, White AC, Droogmans S, Cosyns B, Slomka PJ, Newby DE, Dweck MR, Dey D. Epicardial adipose tissue, myocardial remodelling and adverse outcomes in asymptomatic aortic stenosis: a post hoc analysis of a randomised controlled trial. Heart 2025:heartjnl-2024-324925. [PMID: 40050004 DOI: 10.1136/heartjnl-2024-324925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 02/11/2025] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND Epicardial adipose tissue represents a metabolically active visceral fat depot that is in direct contact with the left ventricular myocardium. While it is associated with coronary artery disease, little is known regarding its role in aortic stenosis. We sought to investigate the association of epicardial adipose tissue with aortic stenosis severity and progression, myocardial remodelling and function, and mortality in asymptomatic patients with aortic stenosis. METHODS In a post hoc analysis of 124 patients with asymptomatic mild-to-severe aortic stenosis participating in a prospective clinical trial, baseline epicardial adipose tissue was quantified on CT angiography using fully automated deep learning-enabled software. Aortic stenosis disease severity was assessed at baseline and 1 year. The primary endpoint was all-cause mortality. RESULTS Neither epicardial adipose tissue volume nor attenuation correlated with aortic stenosis severity or subsequent disease progression as assessed by echocardiography or CT (p>0.05 for all). Epicardial adipose tissue volume correlated with plasma cardiac troponin concentration (r=0.23, p=0.009), left ventricular mass (r=0.46, p<0.001), ejection fraction (r=-0.28, p=0.002), global longitudinal strain (r=0.28, p=0.017), and left atrial volume (r=0.39, p<0.001). During the median follow-up of 48 (IQR 26-73) months, a total of 23 (18%) patients died. In multivariable analysis, both epicardial adipose tissue volume (HR 1.82, 95% CI 1.10 to 3.03; p=0.021) and plasma cardiac troponin concentration (HR 1.47, 95% CI 1.13 to 1.90; p=0.004) were associated with all-cause mortality, after adjustment for age, body mass index and left ventricular ejection fraction. Patients with epicardial adipose tissue volume >90 mm3 had 3-4 times higher risk of death (adjusted HR 3.74, 95% CI 1.08 to 12.96; p=0.037). CONCLUSIONS Epicardial adipose tissue volume does not associate with aortic stenosis severity or its progression but does correlate with blood and imaging biomarkers of impaired myocardial health. The latter may explain the association of epicardial adipose tissue volume with an increased risk of all-cause mortality in patients with asymptomatic aortic stenosis. CLINICALTRIALS gov (NCT02132026).
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Affiliation(s)
- Jolien Geers
- Biomedical Imaging Research Institute, department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Department of Cardiology, Centrum voor Hart- en Vaatziekten (CHVZ), Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussel, Belgium
| | - Nipun Manral
- Biomedical Imaging Research Institute, department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Aryabod Razipour
- Biomedical Imaging Research Institute, department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Caroline Park
- Biomedical Imaging Research Institute, department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Guadalupe Flores Tomasino
- Biomedical Imaging Research Institute, department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Emily Xing
- Biomedical Imaging Research Institute, department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Kajetan Grodecki
- Biomedical Imaging Research Institute, department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
- 1st Department of Cardiology, Medical University of Warsaw, Warszawa, Poland
| | - Jacek Kwiecinski
- Department of Interventional Cardiology and Angiology, Institute of Cardiology, Warsaw, Poland
| | - Tania Pawade
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Mhairi K Doris
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Rong Bing
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Audrey C White
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Steven Droogmans
- Department of Cardiology, Centrum voor Hart- en Vaatziekten (CHVZ), Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussel, Belgium
| | - Bernard Cosyns
- Department of Cardiology, Centrum voor Hart- en Vaatziekten (CHVZ), Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussel, Belgium
| | - Piotr J Slomka
- Division of Artificial Intelligence in Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - David E Newby
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Marc R Dweck
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Damini Dey
- Biomedical Imaging Research Institute, department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Theodorakis N, Nikolaou M, Krentz A. Cardiovascular-Endocrine-Metabolic Medicine: Proposing a New Clinical Sub-Specialty Amid the Cardiometabolic Pandemic. Biomolecules 2025; 15:373. [PMID: 40149908 PMCID: PMC11940337 DOI: 10.3390/biom15030373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 02/26/2025] [Accepted: 03/04/2025] [Indexed: 03/29/2025] Open
Abstract
Cardiovascular-Renal-Hepatic-Metabolic diseases are on the rise worldwide, creating major challenges for patient care and clinical research. Although these conditions share common mechanisms and often respond to similar treatments-such as lifestyle changes and newer cardiometabolic drugs (e.g., SGLT2 inhibitors, GLP-1 receptor agonists)-clinical management remains divided among multiple specialties. Recently proposed curricula in Cardiometabolic Medicine and Preventive Cardiology reflect an effort to address this fragmentation. In addition, recent studies reveal that hormonal deficiencies may increase cardiovascular risk and worsen heart failure, with emerging data showing that correcting these imbalances can improve exercise capacity and possibly reduce major cardiac events. To overcome gaps in care, we propose a new sub-specialty: Cardiovascular-Endocrine-Metabolic Medicine. This approach unifies three main pillars: (1) Lifestyle medicine, emphasizing nutrition, physical activity, and smoking cessation; (2) the Integrated Medical Management of obesity, diabetes, hypertension, dyslipidemia, heart failure with preserved ejection fraction, early-stage kidney disease, metabolic-associated liver disease, and related conditions; and (3) hormonal therapies, focused on optimizing sex hormones and other endocrine pathways to benefit cardiometabolic health. By bridging cardiology, endocrinology, and metabolic medicine, this sub-specialty offers a more seamless framework for patient care, speeds up the adoption of new treatments, and sets the stage for innovative research-all critical steps in addressing the escalating cardiometabolic pandemic.
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Affiliation(s)
- Nikolaos Theodorakis
- NT-CardioMetabolics, Clinic for Metabolism and Athletic Performance, 47 Tirteou Str., 17564 Palaio Faliro, Greece
- Department of Cardiology & Preventive Cardiology Outpatient Clinic, Amalia Fleming General Hospital, 14, 25th Martiou Str., 15127 Melissia, Greece
- School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias, 11527 Athens, Greece
| | - Maria Nikolaou
- Department of Cardiology & Preventive Cardiology Outpatient Clinic, Amalia Fleming General Hospital, 14, 25th Martiou Str., 15127 Melissia, Greece
| | - Andrew Krentz
- School of Life Course & Population Health Sciences, King’s College London, London WC2R 2LS, UK;
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Thompson SE, Roy A, Geberhiwot T, Gehmlich K, Steeds RP. Fabry Disease: Insights into Pathophysiology and Novel Therapeutic Strategies. Biomedicines 2025; 13:624. [PMID: 40149601 PMCID: PMC11940501 DOI: 10.3390/biomedicines13030624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/23/2025] [Accepted: 02/27/2025] [Indexed: 03/29/2025] Open
Abstract
Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by deficiency of α-galactosidase A (α-GalA), leading to the accumulation of glycosphingolipids and multi-organ dysfunction, particularly affecting the cardiovascular and renal systems. Disease-modifying treatments such as enzyme replacement therapy (ERT) and oral chaperone therapy (OCT) have limited efficacy, particularly in advanced disease, prompting a need for innovative therapeutic approaches targeting underlying molecular mechanisms beyond glycosphingolipid storage alone. Recent insights into the pathophysiology of FD highlights chronic inflammation and mitochondrial, lysosomal, and endothelial dysfunction as key mediators of disease progression. Adjunctive therapies such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRAs) demonstrate significant cardiovascular and renal benefits in conditions including heart failure and chronic kidney disease. These drugs also modulate pathways involved in the pathophysiology of FD, such as autophagy, oxidative stress, and pro-inflammatory cytokine signaling. While theoretical foundations support their utility, dedicated trials are necessary to confirm efficacy in the FD-specific population. This narrative review highlights the importance of expanding therapeutic strategies in FD, advocating for a multi-faceted approach involving evidence-based adjunctive treatments to improve outcomes. Tailored research focusing on diverse FD phenotypes, including females and non-classical variants of disease, will be critical to advancing care and improving outcomes in this complex disorder.
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Affiliation(s)
- Sophie Elizabeth Thompson
- Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK
- Department of Cardiology, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
| | - Ashwin Roy
- Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK
- Department of Cardiology, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
| | - Tarekegn Geberhiwot
- Department of Diabetes, Endocrinology and Metabolism, University Hospital Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
- Institute of Metabolism and System Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK
| | - Katja Gehmlich
- Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX1 2JD, UK
| | - Richard Paul Steeds
- Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK
- Department of Cardiology, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
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Hansen BL, Deis T, Larsson JE, Ersbøll M, Rossing K, Schou M, Lim HS, Gustafsson F. Influence of Obesity on Invasive Hemodynamics and Prognosis in Patients With Heart Failure. JACC. HEART FAILURE 2025:S2213-1779(25)00087-3. [PMID: 40117394 DOI: 10.1016/j.jchf.2024.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 12/03/2024] [Accepted: 12/10/2024] [Indexed: 03/23/2025]
Abstract
BACKGROUND Previous studies have suggested that obesity may cause heart failure with preserved left ventricular ejection and report strong association between body mass index (BMI) and invasive hemodynamics. However, sparse information exists in patients who have heart failure with reduced ejection fraction (HFrEF). OBJECTIVES This study aimed to investigate associations between BMI and invasive hemodynamics in patients with HFrEF and the influence of obesity on clinical outcomes. METHODS Referred patients with HFrEF evaluated for advanced heart failure were studied. All patients had right heart catheterization performed. Obesity was defined as BMI ≥30 kg/m2. Clinical events included death, heart transplantation, and durable left ventricular assist device implantation. RESULTS The study population comprises 578 patients with a mean age of 52 ± 13 years and BMI of 26 ± 5 kg/m2. Patients with obesity (BMI range: 30-45 kg/m2) counted 126 (22%) and had significantly higher cardiac output and slightly higher central venous pressure compared to patients without obesity. Cardiac output increased by 89 mL/min per 1-U increase in BMI. Vascular resistances were significantly inversely related to BMI. Pulmonary arterial pressure and pulmonary capillary wedge pressure were not associated with BMI. In patients with obesity, symptoms seem to be dissociated from filling pressures and cardiac index, whereas a clear association is observed in patients without. Obesity did not predict survival over a median follow-up of 5.9 years (Q1-Q3: 2.0-10.1 years). CONCLUSIONS In patients with HFrEF, BMI and CO correlate significantly. Symptoms and hemodynamics appear dissociated in patients with obesity. Finally, survival in patients with obesity did not differ from those without.
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Affiliation(s)
| | - Tania Deis
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Johan E Larsson
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Mads Ersbøll
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Kasper Rossing
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Morten Schou
- Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Denmark
| | - Hoong Sern Lim
- Department of Cardiology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; Institute of Cardiovascular Sciences, University of Birmingham, United Kingdom
| | - Finn Gustafsson
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark
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Guo FS, Guo C, Dou JH, Wang JX, Wu RY, Song SF, Sun XL, Hu YW, Wei J. Association of surrogate adiposity markers with prevalence, all-cause mortality and long-term survival of heart failure: a retrospective study from NHANES database. Front Endocrinol (Lausanne) 2025; 16:1430277. [PMID: 40104133 PMCID: PMC11913658 DOI: 10.3389/fendo.2025.1430277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 02/13/2025] [Indexed: 03/20/2025] Open
Abstract
Introduction Obesity, especially abdominal obesity, is more common in patients with heart failure (HF), but body mass index (BMI) cannot accurately describe fat distribution. Several surrogate adiposity markers are available to reflect fat distribution and quantity. The objective of this study was to explore which adiposity marker is most highly correlated with HF prevalence, all-cause mortality and patients' long-term survival. Methods The National Health and Nutrition Examination Survey (NHANES) database provided all the data for this study. Logistic regression analyses were adopted to compare the association of each surrogate adiposity marker with the prevalence of HF. Cox proportional hazards models and restricted cubic spline (RCS) analysis were employed to assess the association between surrogate adiposity markers and all-cause mortality in HF patients. The ability of surrogate adiposity markers to predict long-term survival in HF patients was assessed using time-dependent receiver operating characteristic (ROC) curves. Results 46,257 participants (1,366 HF patients) were encompassed in this retrospective study. An area under the receiver operating characteristic curve (AUC) for the prevalence of HF assessed by weight-adjusted-waist index (WWI) was 0.70 (95% CI: 0.69-0.72). During a median follow-up of 70 months, 700 of 1366 HF patients' death were recorded. The hazard ratio (HR) for HF patients' all-cause mortality was 1.33 (95% CI: 1.06-1.66) in the a body shape index (ABSI) quartile 4 group and 1.43 (95% CI: 1.13-1.82) in the WWI quartile 4 group, compared with the lowest quartile group. The AUC for predicting 5-year survival of HF patients using the ABSI was 0.647 (95% CI: 0.61-0.68). Conclusions WWI is strongly correlated with the prevalence of HF. In HF patients, those with higher WWI and ABSI tend to higher all-cause mortality. ABSI can predict patients' long-term survival. We recommend the use of WWI and ABSI for assessing obesity in HF patients.
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Affiliation(s)
- Fan-Shun Guo
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Clinical Research Center for Endemic Disease of Shaanxi Province, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Chen Guo
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Clinical Research Center for Endemic Disease of Shaanxi Province, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jia-Hao Dou
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Clinical Research Center for Endemic Disease of Shaanxi Province, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jun-Xiang Wang
- Medicine Department of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Rui-Yun Wu
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Clinical Research Center for Endemic Disease of Shaanxi Province, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Shou-Fang Song
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Clinical Research Center for Endemic Disease of Shaanxi Province, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xue-Lu Sun
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Clinical Research Center for Endemic Disease of Shaanxi Province, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yi-Wei Hu
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Clinical Research Center for Endemic Disease of Shaanxi Province, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jin Wei
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Clinical Research Center for Endemic Disease of Shaanxi Province, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Davies MJ, van der Meer P, Verma S, Patel S, Chinnakondepalli KM, Borlaug BA, Butler J, Kitzman DW, Shah SJ, Harring S, Salsali A, Rasmussen S, von Lewinski D, Abhayaratna W, Petrie MC, Kosiborod MN. Semaglutide in obesity-related heart failure with preserved ejection fraction and type 2 diabetes across baseline HbA 1c levels (STEP-HFpEF DM): a prespecified analysis of heart failure and metabolic outcomes from a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2025; 13:196-209. [PMID: 39848268 DOI: 10.1016/s2213-8587(24)00304-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/09/2024] [Accepted: 09/16/2024] [Indexed: 01/25/2025]
Abstract
BACKGROUND About half of patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF) have type 2 diabetes. In the STEP-HFpEF DM trial of adults with obesity-related HFpEF and type 2 diabetes, subcutaneous once weekly semaglutide 2·4 mg conferred improvements in heart failure-related symptoms and physical limitations, bodyweight, and other heart failure outcomes. We aimed to determine whether these effects of semaglutide differ according to baseline HbA1c. METHODS STEP-HFpEF DM, a double-blind, randomised, placebo-controlled trial conducted at 108 clinical research sites across 16 countries in Asia, Europe, and North and South America, included individuals aged 18 years or older with documented HFpEF (left ventricular ejection fraction ≥45%), type 2 diabetes, and obesity (BMI ≥30 kg/m2). Participants were randomly assigned (1:1), with a block size of four within each stratum using an interactive web response system, stratified by baseline BMI (<35 kg/m2vs ≥35 kg/m2), to receive either semaglutide 2·4 mg or placebo subcutaneously. The effects of semaglutide versus placebo on the efficacy endpoints were evaluated by HbA1c categories at baseline: low (<6·5%; <48 mmol/mol), medium (6·5% to <7·5%; 48 mmol/mol to <58 mmol/mol), and high (≥7·5%; ≥58 mmol/mol). The dual primary endpoints were change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and bodyweight percentage from baseline to 52 weeks and were assessed in all randomly assigned participants by intention to treat. Hypoglycaemia events were also analysed to assess safety in all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04916470. FINDINGS Between June 27, 2021 and Sept 2, 2022, 616 participants were enrolled and randomly assigned (mean age 68·4 years [SD 8·9]; 273 [44%] were female, 343 [56%] were male, and 519 [84%] were White). The low baseline HbA1c group included 227 participants (112 assigned to semaglutide and 115 to placebo), the medium baseline HbA1c group included 226 participants (124 assigned to semaglutide and 102 to placebo), and the high baseline HbA1c group included 163 participants (74 assigned to semaglutide and 89 to placebo). The median duration of follow-up in the overall trial was 401 days (IQR 400-405). The change in KCCQ-CSS from baseline to 52 weeks was 12·4 points (95% CI 8·8 to 16·0) with semaglutide versus 5·7 points (2·1 to 9·2) with placebo (mean difference 6·7 points [1·6 to 11·8]) in the low baseline HbA1c group, 14·5 points (11·0 to 17·9) versus 8·5 points (4·8 to 12·2; 6·0 points [0·9 to 11·1]) in the medium baseline HbA1c group, and 14·5 points (10·0 to 19·0) versus 4·8 points (0·7 to 8·9; 9·6 points [3·5 to 15·7]) in the high baseline HbA1c group (pinteraction=0·64; ptrend=0·46). The change in bodyweight percentage from baseline to 52 weeks was -10·8 (95% CI -12·1 to -9·5) with semaglutide versus -3·3% (-4·6 to -2·0) with placebo (mean difference -7·5% [-9·4 to -5·6]) in the low baseline HbA1c group, -9·6% (-10·8 to -8·3) versus -3·3% (-4·7 to -1·9; -6·3 [-8·2 to -4·4]) in the medium baseline HbA1c group, and -8·6% (-10·2 to -7·0) versus -3·6% (-5·2 to -2·1; -5·0 [-7·2 to -2·7]) in the high baseline HbA1c group (pinteraction=0·22; ptrend=0·083). Hypoglycaemia events occurred in 30 (10%) of 310 participants (70 events; 22·9 events per 100 person-years) in the semaglutide group compared with 21 (7%) of 306 participants in the placebo group (90 events; 29·5 events per 100 person-years). INTERPRETATION Semaglutide 2·4 mg improved heart failure-related symptoms and physical limitations, and reduced bodyweight in patients with obesity-related HFpEF and type 2 diabetes, all independently of baseline HbA1c, and resulted in lower rates of hypoglycaemia than placebo, despite a well controlled baseline HbA1c and broad use of concomitant glucose-lowering medications. FUNDING Novo Nordisk.
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Affiliation(s)
- Melanie J Davies
- Diabetes Research Centre, University of Leicester, Leicester, UK; NIHR Leicester Biomedical Research Centre, Leicester, UK
| | - Peter van der Meer
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Subodh Verma
- Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
| | - Shachi Patel
- Department of Cardiovascular Disease, Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Khaja M Chinnakondepalli
- Department of Cardiovascular Disease, Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Barry A Borlaug
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, TX, USA; Department of Medicine, University of Mississippi, Jackson, MS, USA
| | - Dalane W Kitzman
- Department of Cardiovascular Medicine and Section on Geriatrics and Gerontology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Sanjiv J Shah
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | | | | | | | - Walter Abhayaratna
- College of Health and Medicine, The Australian National University, Canberra, ACT, Australia
| | - Mark C Petrie
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Mikhail N Kosiborod
- Department of Cardiovascular Disease, Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
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Marian AJ. "The unbearable lightness" of the primary end point in clinical trials. Mol Cell Biochem 2025; 480:1403-1406. [PMID: 39212891 DOI: 10.1007/s11010-024-05098-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 08/18/2024] [Indexed: 09/04/2024]
Abstract
In this Perspective, I discuss the limitations of a soft primary endpoint that is used in some of the recent randomized phase II/III clinical trials. Unfortunately, many clinicians and investigators do not interpret the data critically to recognize the limitations of such findings. I advise against over-interpreting the effects of an intervention on a soft primary endpoint.
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Affiliation(s)
- A J Marian
- Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Sciences Center at Houston, 6770 Bertner Street, Suite C900A, Houston, TX, 77030, USA.
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Kany S, Al-Alusi MA, Rämö JT, Pirruccello JP, Ajufo E, Churchill TW, Lubitz SA, Maddah M, Guseh JS, Ellinor PT, Khurshid S. "Weekend Warrior" Physical Activity and Adipose Tissue Deposition. JACC. ADVANCES 2025; 4:101603. [PMID: 39954344 PMCID: PMC11872521 DOI: 10.1016/j.jacadv.2025.101603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 01/07/2025] [Accepted: 01/07/2025] [Indexed: 02/17/2025]
Abstract
BACKGROUND Attaining guideline-recommended levels of physical activity is associated with substantially lower risk of cardiometabolic diseases. OBJECTIVES Although physical activity commonly follows a weekend warrior pattern, in which most moderate-to-vigorous physical activity is concentrated in 1 to 2 days rather than spread more evenly across the week (regular), the effects of activity pattern on imaging-based biomarkers of cardiometabolic health are unknown. METHODS We analyzed 17,146 UK Biobank participants who wore accelerometers for 1 week, and later underwent cardiac magnetic resonance imaging. Activity was categorized as inactive, regular, or "weekend warrior". Associations between activity pattern and magnetic resonance imaging-derived visceral adipose tissue (VAT) and epicardial and pericardial adipose tissue (EPAT) were assessed using multiple linear regression adjusted for confounding factors. RESULTS Compared to inactive, VAT was progressively lower with weekend warrior (-0.71 L, 95% CI -0.78 to -0.64, P < 0.001) followed by regular activity (-0.96 L, 95% CI -1.04 to -0.88, P < 0.001). Observations were similar for EPAT (weekend warrior activity -2.84 cm2, 95% CI -3.20 to -2.49, P < 0.001; regular activity -3.62 cm2, 95% CI -4.03 to -3.20, P < 0.001). When compared directly, weekend warriors had modestly higher adipose tissue than regular activity (VAT difference 0.25 L, 95% CI 0.17-0.32, P < 0.001; EPAT 0.78 cm2, 95% CI 0.40-1.15, P < 0.001). No differences were observed after adjustment for total moderate-to-vigorous physical activity minutes (VAT 0.07 L, 95% CI -0.01 to 0.14, P = 0.09; EPAT 0.04 cm2, 95% CI -0.35 to 0.43, P = 0.84). CONCLUSIONS Guideline-adherent physical activity is associated with favorable quantitative measures of cardiometabolic health, with no differences based on activity pattern for a given activity volume.
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Affiliation(s)
- Shinwan Kany
- Department of Cardiology, University Heart and Vascular Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Mostafa A Al-Alusi
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Joel T Rämö
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
| | - James P Pirruccello
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Division of Cardiology, University of California San Francisco, San Francisco, California, USA; Institute for Human Genetics, University of California - San Francisco, San Francisco, California, USA
| | - Ezimamaka Ajufo
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cardiology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Timothy W Churchill
- Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA; Cardiovascular Performance Program, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Steven A Lubitz
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA; Demoulas Center for Cardiac Arrhythmias, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Mahnaz Maddah
- Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - J Sawalla Guseh
- Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA; Cardiovascular Performance Program, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Patrick T Ellinor
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA; Demoulas Center for Cardiac Arrhythmias, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Shaan Khurshid
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA; Demoulas Center for Cardiac Arrhythmias, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
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Dong H, Hu P, Wang J, Lu N. Serum magnesium and calcium were inversely associated with hemoglobin glycation index and triglyceride-glucose index in adults with coronary artery disease. Biol Trace Elem Res 2025; 203:1422-1430. [PMID: 38913294 DOI: 10.1007/s12011-024-04287-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/19/2024] [Indexed: 06/25/2024]
Abstract
Little is known about the associations of magnesium (Mg) and calcium (Ca) with hemoglobin glycation index (HGI) and triglyceride-glucose index (TyG) in adults. In this study, we examined the associations of serum Mg and Ca with HGI and TyG in adults with coronary artery disease (CAD). This hospital-based cross-sectional study included 10757 CAD patients with a mean age of 61.6 years. Serum concentrations of Mg and Ca were measured in clinical laboratory. Overall, serum Mg and Ca were inversely associated with HGI and TyG. In multivariable analyses, Mg and Ca were inversely associated with HGI (MgQ4 vs. Q3: -0.601 vs. -0.528; CaQ4 vs. Q1: -0.769 vs. -0.645). In terms of TyG, inverse associations of serum Mg and Ca with TyG were observed. The corresponding TyG values were 9.054 (vs. 9.099) for Mg and 9.068 (vs. 9.171) for Ca in the fourth quartile compared with the first quartile. Moreover, Mg, Ca or Mg/Ca ratio were also inversely associated with HbA1c and FBG. In path analysis, no mediating effects of obesity on "serum Mg (or Ca)- HGI (or TyG)" associations were observed. Generally, our study identified the inverse associations of the serum Mg and Ca levels with HGI and TyG in adults with CAD. Large sample longitudinal study, and particularly randomized controlled trials, are warranted to validate our findings and overcome the limitations of cross-sectional studies.
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Affiliation(s)
- Hongli Dong
- Department of Child Healthcare and Scientific Education Section, Affiliated Maternity & Child Health Care Hospital of Nantong University, Nantong, 226018, Jiangsu, People's Republic of China
| | - Ping Hu
- Image Center, Wuhan Asia Heart Hospital, Wuhan, 430022, Hubei, People's Republic of China
| | - Jie Wang
- Image Center, Wuhan Asia Heart Hospital, Wuhan, 430022, Hubei, People's Republic of China
| | - Nan Lu
- Department of Psycho-Cardiology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing, 100029, People's Republic of China.
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Yang M, Kondo T, Dewan P, Desai AS, Lam CSP, Lefkowitz MP, Packer M, Rouleau JL, Vaduganathan M, Zile MR, Jhund PS, Køber L, Solomon SD, McMurray JJV. Impact of Multimorbidity on Mortality in Heart Failure With Mildly Reduced and Preserved Ejection Fraction. Circ Heart Fail 2025; 18:e011598. [PMID: 40026147 DOI: 10.1161/circheartfailure.124.011598] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 08/28/2024] [Indexed: 03/04/2025]
Abstract
BACKGROUND How different combinations of comorbidities influence risk at the patient level and population level in patients with heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction is unknown. We aimed to investigate the prevalence of different combinations of cardiovascular and noncardiovascular comorbidities (ie, multimorbidity) and associated risk of death at the patient level and population level. METHODS Using patient-level data from the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) and PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction), we investigated the 5 most common cardiovascular and noncardiovascular comorbidities and the resultant 45 comorbidity pairs. Cox proportional hazard models were used to calculate the population-attributable fractions for all-cause mortality and the relative excess risk due to interaction for each comorbidity pair. RESULTS Among 6504 participants, 95.2% had at least 2 of the 10 most prevalent comorbidities. The comorbidity pair with the greatest patient-level risk was stroke and peripheral artery disease (adjusted hazard ratio, 1.88 [95% CI, 1.27-2.79]), followed by peripheral artery disease and chronic obstructive pulmonary disease (1.81 [95% CI, 1.31-2.51]), and coronary artery disease and stroke (1.67 [95% CI, 1.33-2.11]). The pair with the highest population-level risk was hypertension and chronic kidney disease (CKD; adjusted population-attributable fraction, 14.8% [95% CI, 9.2%-19.9%]), followed by diabetes and CKD (13.3% [95% CI, 10.6%-16.0%]), and hypertension and diabetes (11.9% [95% CI, 7.1%-16.5%). A synergistic interaction (more than additive risk) was found for the comorbidity pairs of stroke and coronary artery disease (relative excess risk due to interaction, 0.61 [95% CI, 0.13-1.09]), diabetes and CKD (relative excess risk due to interaction, 0.46 [95% CI, -0.15 to 0.77]), and obesity and CKD (relative excess risk due to interaction, 0.24 [95% CI, 0.01-0.46]). CONCLUSIONS The risk associated with comorbidity pairs differs at the patient and population levels in heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction. At the population level, hypertension, CKD, and diabetes account for the greatest risk, whereas at the patient level, polyvascular disease and chronic obstructive pulmonary disease are the most important.
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Affiliation(s)
- Mingming Yang
- School of Cardiovascular and Metabolic Health, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (M.Y., T.K., P.D., P.S.J., J.J.V.M.)
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China (M.Y.)
| | - Toru Kondo
- School of Cardiovascular and Metabolic Health, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (M.Y., T.K., P.D., P.S.J., J.J.V.M.)
- Department of Cardiology, Nagoya University Graduate School of Medicine, Japan (T.K.)
| | - Pooja Dewan
- School of Cardiovascular and Metabolic Health, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (M.Y., T.K., P.D., P.S.J., J.J.V.M.)
| | - Akshay S Desai
- Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (A.S.D., M.V., S.D.S.)
| | - Carolyn S P Lam
- National Heart Centre, Singapore and Duke-National University of Singapore (C.S.P.L.)
| | | | - Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.)
| | - Jean L Rouleau
- Institut de Cardiologie de Montréal, Université de Montréal, QC, Canada (J.L.R.)
| | - Muthiah Vaduganathan
- Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (A.S.D., M.V., S.D.S.)
| | - Michael R Zile
- RHJ Department of Veterans Affairs Medical Center, Medical University of South Carolina, Charleston (M.R.Z.)
| | - Pardeep S Jhund
- School of Cardiovascular and Metabolic Health, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (M.Y., T.K., P.D., P.S.J., J.J.V.M.)
| | - Lars Køber
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (L.K.)
| | - Scott D Solomon
- Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (A.S.D., M.V., S.D.S.)
| | - John J V McMurray
- School of Cardiovascular and Metabolic Health, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (M.Y., T.K., P.D., P.S.J., J.J.V.M.)
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50
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Neves JS, Leite AR, Mentz RJ, Holman RR, Zannad F, Butler J, Packer M, Ferreira JP. Cardiovascular outcomes with exenatide in type 2 diabetes according to ejection fraction: The EXSCEL trial. Eur J Heart Fail 2025; 27:540-551. [PMID: 39381950 DOI: 10.1002/ejhf.3478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/28/2024] [Accepted: 09/16/2024] [Indexed: 10/10/2024] Open
Abstract
AIMS Glucagon-like peptide-1 receptor agonists reduce major adverse cardiovascular events (MACE) and cardiovascular mortality in people with type 2 diabetes (T2D). However, previous studies suggest the effects on heart failure outcomes vary according to left ventricular ejection fraction (LVEF). We aimed to evaluate the effects of exenatide on cardiovascular events according to LVEF in people with T2D. METHODS AND RESULTS Post-hoc analysis of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial evaluating the effects of once-weekly exenatide (EQW) versus placebo on cardiovascular outcomes according to baseline LVEF (<40% or ≥40%). Outcomes were also evaluated according to New York Heart Association (NYHA) class and obesity. The main outcome was hospitalization for heart failure (HHF). A treatment-by-LVEF interaction was used. In EXSCEL (n = 14 752), 4749 participants had LVEF available at baseline; 455 (10%) with LVEF <40%, 4294 (90%) with LVEF ≥40%. LVEF modified the EQW effect on hHF: hazard ratio (HR) = 1.52 (95% confidence interval [CI] = 0.95-2.43) in participants with LVEF < 40% and HR = 0.74 (95% CI = 0.55-1.01) in those with LVEF ≥ 40% (p-interaction = 0.012). No significant treatment-by-LVEF interactions (p-interaction >0.10) were observed for MACE, cardiovascular death or all-cause mortality. The risk of HHF was also modified by baseline NYHA class (HR 0.91, 95% CI 0.65-1.27 for NYHA class I/II; HR 1.84, 95% CI 0.95-3.59 for NYHA class III/IV; p-interaction = 0.062), mostly driven by the LVEF <40% subgroup. Obesity did not modify the effects of EQW on HHF. CONCLUSIONS The EQW effect on HHF was influenced by LVEF, with a potentially decreased risk in participants with LVEF ≥40% and increased risk in those with LVEF <40%. The risk of HHF was particularly high in participants with LVEF <40% and NYHA class III/IV. LVEF did not modify the effect of EQW on atherosclerotic outcomes.
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Affiliation(s)
- João Sérgio Neves
- Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Department of Endocrinology, Diabetes and Metabolism, ULS São João, Porto, Portugal
| | - Ana Rita Leite
- Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Department of Endocrinology, Diabetes and Metabolism, ULS São João, Porto, Portugal
| | - Robert J Mentz
- Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Rury R Holman
- Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques - Plurithématique 14-33, and Inserm U1116, CHRU Nancy, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, TX, USA
- University of Mississippi, Jackson, MS, USA
| | - Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA
- Imperial College, London, UK
| | - João Pedro Ferreira
- Cardiovascular R&D Centre - UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques - Plurithématique 14-33, and Inserm U1116, CHRU Nancy, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
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