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1
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Pennisi G, Petta S, Maggio V, Rizzo M. GLP-1 receptor agonists and MASLD in diabetes: A promising path? J Diabetes Complications 2025; 39:109041. [PMID: 40288935 DOI: 10.1016/j.jdiacomp.2025.109041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2025] [Accepted: 04/12/2025] [Indexed: 04/29/2025]
Affiliation(s)
- Grazia Pennisi
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE), University of Palermo, Italy.
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Maternal and Child Health, Internal and Specialty Medicine of Excellence (PROMISE), University of Palermo, Italy
| | - Viviana Maggio
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy
| | - Manfredi Rizzo
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy; Ras Al Khaimah Medical and Health Sciences University (RAKMHSU), Ras Al Khaimah, United Arab Emirates; Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai, United Arab Emirates
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2
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Askeland-Gjerde DE, Westlye LT, Andersson P, Korbmacher M, de Lange AM, van der Meer D, Smeland OB, Halvorsen S, Andreassen OA, Gurholt TP. Mediation Analyses Link Cardiometabolic Factors and Liver Fat With White Matter Hyperintensities and Cognitive Performance: A UK Biobank Study. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2025; 5:100488. [PMID: 40330223 PMCID: PMC12052680 DOI: 10.1016/j.bpsgos.2025.100488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/19/2025] [Accepted: 03/10/2025] [Indexed: 05/08/2025] Open
Abstract
Background Liver fat is associated with cardiometabolic disease, cerebrovascular disease, and dementia. Cerebrovascular disease, most often cerebral small vessel disease, identified by magnetic resonance imaging as white matter hyperintensities (WMHs) often contributes to dementia. However, liver fat's role in the relationship between cardiometabolic risk, WMHs, and cognitive performance is unclear. Methods In the UK Biobank cohort (N = 32,461, 52.6% female; mean age 64.2 ± 7.7 years; n = 23,354 in the cognitive performance subsample), we used linear regression to investigate associations between cardiometabolic factors measured at baseline and liver fat, WMHs, and cognitive performance measured at follow-up, which was 9.3 ± 2.0 years later on average. We used structural equation modeling to investigate whether liver fat mediated associations between cardiometabolic factors and WMHs and whether WMHs mediated associations between liver fat and cognitive performance. Results Nearly all cardiometabolic factors were significantly associated with liver fat (|r| range = 0.03-0.41, p = 3.4 × 10-8 to 0) and WMHs (|r| = 0.04-0.15, p = 5.8 × 10-13 to 7.0 × 10-159) in regression models. Liver fat was associated with WMHs (r = 0.11, p = 4.3 × 10-82) and cognitive performance (r = -0.03, p = 1.6 × 10-7). Liver fat mediated the associations between cardiometabolic factors and WMHs (|βmediation| = 0.003-0.027, p mediation = 1.9 × 10-8 to 0), and WMHs mediated the associations between liver fat and cognitive performance (βmediation = -0.01, p mediation = 0). Conclusions Our findings indicate that liver fat mediates associations between cardiometabolic factors and WMHs and that WMHs mediate the association between liver fat and cognitive performance. This suggests that liver fat may be important for understanding the effects of cardiometabolic factors on cerebrovascular disease and cognitive function. Experimental studies are warranted to determine relevant targets for preventing vascular-driven cognitive impairment.
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Affiliation(s)
- Daniel E. Askeland-Gjerde
- Section for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Lars T. Westlye
- Section for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Department of Psychology, University of Oslo, Oslo, Norway
- K.G. Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway
| | | | - Max Korbmacher
- Neuro-SysMed Center of Excellence for Clinical Research in Neurological Diseases, Department of Neurology, Haukeland University Hospital, Bergen, Norway
- Mohn Medical Imaging and Visualization Centre, Department of Radiology, Haukeland University Hospital, Bergen, Norway
- Department of Health and Functioning, Western Norway University of Applied Sciences, Bergen, Norway
| | - Ann-Marie de Lange
- Department of Psychology, University of Oslo, Oslo, Norway
- Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Department of Psychiatry, University of Oxford, Oxford, United Kingdom
| | - Dennis van der Meer
- Section for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Olav B. Smeland
- Section for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Sigrun Halvorsen
- Department of Cardiology, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Ole A. Andreassen
- Section for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- K.G. Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway
| | - Tiril P. Gurholt
- Section for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
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3
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Fernando K, Connolly D, Darcy E, Evans M, Hinchliffe W, Holmes P, Strain WD. Advancing Cardiovascular, Kidney, and Metabolic Medicine: A Narrative Review of Insights and Innovations for the Future. Diabetes Ther 2025; 16:1155-1176. [PMID: 40272772 PMCID: PMC12085743 DOI: 10.1007/s13300-025-01738-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 04/01/2025] [Indexed: 05/18/2025] Open
Abstract
Cardiovascular, kidney and metabolic (CKM) conditions are interrelated, significantly contributing to morbidity, mortality and healthcare burden. Despite therapeutic advances, traditional disease-specific approaches often fail to address their complex interplay. Key therapeutic agents-including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dual GLP-1/glucose-dependent insulinotropic polypeptide RAs, sodium glucose co-transporter inhibitors and the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone-offer multi-organ benefits. Emerging therapies, such as triple receptor agonists and second-generation MRAs, target new pathways further expanding treatment options for CKM conditions. A holistic CKM management approach must address and recognise that conditions such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, obstructive sleep apnoea and obesity are part of the CKM spectrum. Frailty assessment is also important alongside CKM conditions, warranting comprehensive geriatric assessment and deprescribing when appropriate. Multidisciplinary care-including lifestyle interventions, pathway redesign, pharmacological advances and novel technologies-is essential for improving outcomes. As the CKM landscape evolves, future strategies should prioritise early intervention, personalised treatment and addressing unmet needs in high-risk populations. This review advocates for an integrated CKM framework, exploring treatment strategies, emerging therapies and technological innovations. It also examines the role of artificial intelligence and digital health tools in risk stratification, early diagnosis and long-term condition management, alongside ethical and regulatory considerations.
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Affiliation(s)
| | - Derek Connolly
- Birmingham City Hospital, Birmingham, UK
- Aston University, Birmingham, UK
| | | | - Marc Evans
- University Hospital Llandough, Cardiff, UK
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4
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Chen VL, Morgan TR, Rotman Y, Patton HM, Cusi K, Kanwal F, Kim WR. Reply: AASLD Resmetirom Guidance. Hepatology 2025; 81:E164-E165. [PMID: 39951255 DOI: 10.1097/hep.0000000000001267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 05/20/2025]
Affiliation(s)
- Vincent L Chen
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Timothy R Morgan
- VA Long Beach Healthcare System, Long Beach, California, USA
- Department of Medicine, Division of Gastroenterology, University of California Irvine, Irvine, California, USA
| | - Yaron Rotman
- Liver and Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Heather M Patton
- VA San Diego Healthcare System, San Diego, California, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, San Diego, California, USA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes, and Metabolism, University of Florida, Gainesville, Florida, USA
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- VA Health Services Research and Development Service, Center for Innovations in Quality, Effectiveness, and Safety, Houston, Texas, USA
- Michael E DeBakey VA Medical Center, Houston, Texas, USA
| | - W Ray Kim
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Phoenix, Arizona, USA
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5
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Sherker AH, Hoofnagle JH. Letter to the Editor: Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease-October 2024 updates to AASLD practice guidance. Hepatology 2025; 81:E158-E159. [PMID: 39960317 DOI: 10.1097/hep.0000000000001264] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 11/08/2024] [Indexed: 05/20/2025]
Affiliation(s)
- Averell H Sherker
- Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Zafer M, Tavaglione F, Romero-Gómez M, Loomba R. Review Article: GLP-1 Receptor Agonists and Glucagon/GIP/GLP-1 Receptor Dual or Triple Agonists-Mechanism of Action and Emerging Therapeutic Landscape in MASLD. Aliment Pharmacol Ther 2025; 61:1872-1888. [PMID: 40364529 DOI: 10.1111/apt.70196] [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: 03/21/2025] [Revised: 04/14/2025] [Accepted: 05/03/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily managed through diet and lifestyle modifications. However, these behavioural interventions alone may not achieve disease regression or remission, and maintaining long-term adherence is challenging. Incretin mimetics and other gastrointestinal hormones targeting the pleiotropic pathophysiological pathways underlying MASLD have now emerged as promising disease-modifying therapies. AIMS This is a comprehensive review summarising the role of glucagon-like peptide-1 (GLP-1) receptor agonists and glucagon/glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor dual or triple agonists in the treatment of metabolic dysfunction-associated steatohepatitis (MASH). METHODS Only clinical trials with endpoints assessed by liver histology were included for a robust evaluation of therapeutic efficacy. RESULTS Recent evidence from phase 2 clinical trials for MASH demonstrated that pharmacological agents based on GLP-1 receptor agonism are effective in improving disease activity. Additionally, tirzepatide and survodutide showed potential clinical benefits in reducing fibrosis. Other cardiometabolic benefits observed include weight loss and improvements in glycaemic control and lipid profile. Adherence to treatment may be limited by gastrointestinal side effects, though they were found to be generally mild to moderate in severity. An interim analysis of the semaglutide phase 3 trial confirmed its efficacy in improving steatohepatitis and demonstrated its potential to improve fibrosis. CONCLUSIONS GLP-1 receptor agonists, alone or in combination with GIP and/or glucagon receptor agonists, represent promising, effective pharmacotherapies for the treatment of MASLD/MASH. Larger and longer-duration clinical trials are needed to further evaluate the efficacy and safety of GIP receptor and glucagon receptor agonism.
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Affiliation(s)
- Maryam Zafer
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, California, USA
| | - Federica Tavaglione
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, California, USA
| | - Manuel Romero-Gómez
- UCM Digestive Diseases and Ciberehd, Virgen Del Rocío University Hospital, Institute of Biomedicine of Seville (CSIC/HUVR/US), University of Seville, Seville, Spain
| | - Rohit Loomba
- MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, California, USA
- School of Public Health, University of California at San Diego, La Jolla, California, USA
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Iruzubieta P, Alonso-Peña M, Jimenez-Gonzalez C, Crespo J. Letter to the Editor: Optimizing MASLD treatment-A "lead-in phase" before resmetirom. Hepatology 2025; 81:E156-E157. [PMID: 39976586 PMCID: PMC12077332 DOI: 10.1097/hep.0000000000001263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 10/24/2024] [Indexed: 05/16/2025]
Affiliation(s)
- Paula Iruzubieta
- Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital
- Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Santander, Spain
| | - Marta Alonso-Peña
- Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Santander, Spain
| | - Carolina Jimenez-Gonzalez
- Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Santander, Spain
| | - Javier Crespo
- Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital
- Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Santander, Spain
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Panganiban J, Kehar M, Ibrahim SH, Hartmann P, Sood S, Hassan S, Ramirez CM, Kohli R, Censani M, Mauney E, Cuda S, Karjoo S. Metabolic dysfunction-associated steatotic liver disease (MASLD) in children with obesity: An Obesity Medicine Association (OMA) and expert joint perspective 2025. OBESITY PILLARS 2025; 14:100164. [PMID: 40230708 PMCID: PMC11995806 DOI: 10.1016/j.obpill.2025.100164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 04/16/2025]
Abstract
Introduction This Obesity Medicine Association (OMA) Expert Joint Perspective examines steatotic liver disease (SLD), which is composed of metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH) in children with obesity. The prevalence of obesity is increasing, rates have tripled since 1963 from 5 % to now 19 % of US children affected in 2018. MASLD, is the most common liver disease seen in children, can be a precursor to the development of Type 2 Diabetes (T2DM) and is the primary reason for liver transplant listing in young adults. We must be vigilant in prevention and treatment of MASLD in childhood to prevent further progression. Methods This joint clinical perspective is based upon scientific evidence, peer and clinical expertise. The medical literature was reviewed via PubMed search and appropriate articles were included in this review. This work was formulated from the collaboration of eight hepatologists/gastroenterologists with MASLD expertise and two physicians from the OMA. Results The authors who are experts in the field, determined sentinel questions often asked by clinicians regarding MASLD in children with obesity. They created a consensus and clinical guideline for clinicians on the screening, diagnosis, and treatment of MASLD associated with obesity in children. Conclusions Obesity and the comorbidity of MASLD is increasing in children, and this is a medical problem that needs to be addressed urgently. It is well known that children with metabolic associated chronic disease often continue to have these chronic diseases as adults, which leads to reduced life expectancy, quality of life, and increasing healthcare needs and financial burden. The authors of this paper recommend healthy weight reduction not only through lifestyle modification but through obesity pharmacotherapy and bariatric surgery. Therefore, this guidance reviews available therapies to achieve healthy weight reduction and reverse MASLD to prevent progressive liver fibrosis, and metabolic disease.
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Affiliation(s)
| | - Mohit Kehar
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | - Samar H. Ibrahim
- Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Phillipp Hartmann
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Division of Gastroenterology, Hepatology & Nutrition, Rady Children’s Hospital San Diego, San Diego, CA, USA
| | - Shilpa Sood
- Division of Pediatric Gastroenterology, Boston Children's Health Physicians, New York Medical College, Valhalla, NY, USA
| | - Sara Hassan
- University of Texas Southwestern, Dallas, TX, United States
| | | | - Rohit Kohli
- Children's Hospital Los Angeles, CA, United States
| | - Marisa Censani
- Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, United States
| | - Erin Mauney
- Tufts Medical Center, Boston, MA, United States
| | - Suzanne Cuda
- Alamo City Healthy Kids and Families, San Antonio, TX, United States
| | - Sara Karjoo
- Johns Hopkins All Children's Hospital, St. Petersburg, FL, United States
- University of South Florida, Tampa, FL, United States
- Florida State University, Tallahassee, FL, United States
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9
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Isakov V. Metabolic dysfunction-associated steatotic liver disease: A story of muscle and mass. World J Gastroenterol 2025; 31:105346. [DOI: 10.3748/wjg.v31.i20.105346] [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: 01/18/2025] [Revised: 04/13/2025] [Accepted: 05/09/2025] [Indexed: 05/28/2025] Open
Abstract
Skeletal muscle alterations (SMA) are increasingly recognized as both contributors and consequences of metabolic dysfunction-associated steatotic liver disease (MASLD), affecting disease progression and outcomes. Sarcopenia is common in patients with MASLD, with a prevalence ranging from 20% to 40% depending on the population and diagnostic criteria used. In advanced stages, such as metabolic dysfunction-associated steatohepatitis and fibrosis, its prevalence is even higher. Sarcopenia exacerbates insulin resistance, systemic inflammation, and oxidative stress, all of which worsen MASLD. It is an independent risk factor for fibrosis progression and poor outcomes including mortality. Myosteatosis refers to the abnormal accumulation of fat within muscle tissue, leading to decreased muscle quality. Myosteatosis is prevalent (> 30%) in patients with MASLD, especially those with obesity or type 2 diabetes, although this can vary with the imaging techniques used. It reduces muscle strength and metabolic efficiency, further contributing to insulin resistance and is usually associated with advanced liver disease, cardiovascular complications, and lower levels of physical activity. Altered muscle metabolism, which includes mitochondrial dysfunction and impaired amino acid metabolism, has been reported in metabolic syndromes, including MASLD, although its actual prevalence is unknown. Altered muscle metabolism limits glucose uptake and oxidation, worsening hyperglycemia and lipotoxicity. Reduced muscle perfusion and oxygenation due to endothelial dysfunction and systemic metabolic alterations are common in MASLD associated with comorbidities, such as obesity, hypertension, and atherosclerosis. It decreases the muscle capacity for aerobic metabolism, leading to fatigue and reduced physical activity in patients with MASLD, aggravating metabolic dysfunction. Various SMA in MASLD worsen insulin resistance and hepatic fat accumulation, may accelerate progression to fibrosis and cirrhosis, and increase the risk of cardiovascular disease and mortality. Management strategies for SMA include resistance training, aerobic exercise, and nutritional support (e.g., high-protein diets, vitamin D, and omega-3 fatty acids), which are essential for mitigating skeletal muscle loss and improving outcomes. However, pharmacological agents that target the muscle and liver (such as glucagon-like peptide-1 receptor agonists) show promise but have not yet been approved for the treatment of MASLD.
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Affiliation(s)
- Vasily Isakov
- Department of Gastroenterology and Hepatology, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow 115446, Russia
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Zeng X, Huang D, Zhu Z, Cai Q, Yang Y, Lu H, Chen J. Mechanism-guided drug development and treatment for liver fibrosis: a clinical perspective. Front Pharmacol 2025; 16:1574385. [PMID: 40492139 PMCID: PMC12146339 DOI: 10.3389/fphar.2025.1574385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 05/07/2025] [Indexed: 06/11/2025] Open
Abstract
Liver fibrosis is a common response to chronic liver injury due to multiple etiologies and plays a crucial in the progression of chronic liver disease to cirrhosis, hepatocellular carcinoma, and other liver-related clinical outcomes. Currently, available treatments to block liver fibrosis are designed to eliminate the underlying causes of liver disease. The lack of truly effective drugs to regress or reverse fibrosis is a major unmet clinical need. In this context, this article briefly describes the pathological process of hepatic fibrosis and focuses on reviewing the progress of clinical studies on mechanism-based anti-fibrotic drug development and therapy, highlighting that the positive effect of thyroid hormone receptor-β (THR-β) analogs, fibroblast growth factor 21 (FGF21) analogues, Glucagon-like peptide 1 receptor (GLP-1R) agonists, pan-peroxisome proliferator-activated receptor (pan-PPAR) agonists, fatty acid synthase (FASN) inhibitors, and hydronidone in reducing liver fibrosis caused by specific etiologies. Moreover, multi-pathway guided combination therapy or traditional Chinese medicine demonstrate significant advantages in combating liver fibrosis. Finally, new technologies and approaches affecting the clinical development of anti-hepatic fibrosis drugs were discussed.
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Affiliation(s)
- Xiangchang Zeng
- Department of Liver Diseases, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Deliang Huang
- Department of Liver Diseases, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Zhibin Zhu
- Department of Liver Diseases, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Qingxian Cai
- Department of Liver Diseases, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Yang Yang
- Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, The Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Hongzhou Lu
- Department of Liver Diseases, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Jun Chen
- Department of Liver Diseases, Shenzhen Third People's Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China
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11
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Oe Y, Omori T, Aimono E, Furukawa S, Kitakawa H, Tateno M, Sakai K, Cho KY. Case Report: Amelioration of severe metabolic dysfunction-associated steatohepatitis after switching from conventional GLP-1RAs to tirzepatide. Front Endocrinol (Lausanne) 2025; 16:1501984. [PMID: 40491599 PMCID: PMC12146166 DOI: 10.3389/fendo.2025.1501984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 04/25/2025] [Indexed: 06/11/2025] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) has cardiometabolic risk factors, such as obesity and type 2 diabetes, and has been reported to have a potentially higher risk of mortality than conventional steatotic liver diseases. Liver fibrosis develops and can progress to cirrhosis and hepatocellular carcinoma. Although some antidiabetic agents have been reported to ameliorate the condition, no specific medical treatment has been developed to date. Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) that has shown efficacy against MASH in some clinical trials. However, these trials were limited to those with mild-to-moderate fibrosis and their history of treatment was often unclear. Here, we report the case of a 50-year-old man with a 16-year history of diabetes. He demonstrated poor control of his diabetes with elevated liver enzymes. A liver biopsy was performed and he was diagnosed with steatohepatitis. Liraglutide was administered for 3 years but his liver function and glycemic control deteriorated gradually and a second liver biopsy was performed in 2023. The histological examination found cirrhosis and liraglutide was switched to tirzepatide. Over 6 months of administration of tirzepatide, the patient's glycated hemoglobin and elevated liver enzyme levels improved. A third biopsy was performed, which showed a marked improvement in histology, with the amelioration of liver fibrosis. A diagnosis of steatotic liver disease was made. Although some previous studies had demonstrated an amelioration of liver fibrosis and an improvement in the prognosis of patients following GLP-1RA treatment, effective medications for patients with severe fibrosis or who are refractory to treatment with GLP-1RAs has not been identified to date. We reported a case with severe MASH whose condition had ameliorated by switching from conventional GLP-1RAs to tirzepatide.
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Affiliation(s)
- Yuki Oe
- Department of Internal Medicine, Kushiro Red Cross Hospital, Kushiro, Japan
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takashi Omori
- Department of Internal Medicine, Kushiro Red Cross Hospital, Kushiro, Japan
| | - Eriko Aimono
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Shin Furukawa
- Department of Internal Medicine, Kushiro Red Cross Hospital, Kushiro, Japan
| | - Hirohiko Kitakawa
- Department of Internal Medicine, Kushiro Red Cross Hospital, Kushiro, Japan
| | - Masatoshi Tateno
- Department of Pathology, Kushiro Red Cross Hospital, Kushiro, Japan
| | - Kiyoshi Sakai
- Department of Internal Medicine, Kushiro Red Cross Hospital, Kushiro, Japan
| | - Kyu Yong Cho
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- Clinical Research and Medical Innovation Center, Institute of Health Science Innovation for Medical Care, Hokkaido University Hospital, Sapporo, Japan
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12
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Ge Z, Wu Q, Lv C, He Q. The Roles of T Cells in the Development of Metabolic Dysfunction-Associated Steatohepatitis. Immunology 2025. [PMID: 40414629 DOI: 10.1111/imm.13943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/28/2025] [Accepted: 04/28/2025] [Indexed: 05/27/2025] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH), the progressed period of metabolic dysfunction-associated steatotic liver disease (MASLD), is a multifaceted liver disease characterised by inflammation and fibrosis that develops from simple steatosis, even contributing to hepatocellular carcinoma and death. MASH involves several immune cell-mediated inflammation and fibrosis, where T cells play a crucial role through the release of pro-inflammatory cytokines and pro-fibrotic factors. This review discusses the complex role of various T cell subsets in the pathogenesis of MASH and highlights the progress of ongoing clinical trials involving T cell-targeted MASH therapies.
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Affiliation(s)
- Zhifa Ge
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qingwei Wu
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chengyu Lv
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qifeng He
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Gattu AK, Fourman LT. Metabolic dysfunction-associated steatotic liver disease in people with HIV. Curr Opin HIV AIDS 2025:01222929-990000000-00165. [PMID: 40397552 DOI: 10.1097/coh.0000000000000952] [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: 05/23/2025]
Abstract
PURPOSE OF REVIEW Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent among people with HIV (PWH) and increasingly recognized as a major contributor to morbidity and mortality. The field of MASLD is rapidly evolving with adoption of a new nomenclature and approval of the first FDA-approved therapy within the past year. These developments underscore the need to consider the current state of the science specifically in the context of HIV. RECENT FINDINGS MASLD in PWH (MASLD-HIV) follows a more aggressive clinical course compared to HIV-negative individuals. While MASLD-HIV shares common pathogenic mechanisms with MASLD in the general population, HIV-specific factors - including altered body composition, chronic immune activation, enhanced gut permeability, and antiretroviral therapy - exacerbate disease progression. Despite an expanding pipeline of MASLD therapies, a critical gap remains in evaluating these interventions specifically among PWH. Nonetheless, dedicated studies of glucagon-like peptide-1 receptor agonists and the growth hormone-releasing hormone analog tesamorelin have shown promise in MASLD-HIV. SUMMARY MASLD is a key contributor to liver-related and cardiovascular-morbidity in PWH. While there have been exciting advances to improve diagnosis and management of MASLD in the general population, differences in MASLD pathophysiology demonstrate the need to tailor our approach specifically for PWH.
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Affiliation(s)
- Arijeet K Gattu
- Metabolism Unit and Division of Endocrinology, Massachusetts General Hospital
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center
- Harvard Medical School, Boston, Massachusetts, USA
| | - Lindsay T Fourman
- Metabolism Unit and Division of Endocrinology, Massachusetts General Hospital
- Harvard Medical School, Boston, Massachusetts, USA
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Messer EK, Petroff D, Schattenberg J, Zeuzem S, von der Ohe M, Ludwig L, Demir M, Buggisch P, Stein K, Serfert Y, Wedemeyer H, Berg T, Hofmann WP, Geier A, Wiegand J. Evaluating Resmetirom Eligibility Among Patients with MASH: Insights from the German Steatotic Liver Disease-Registry. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025. [PMID: 40373810 DOI: 10.1055/a-2592-6109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2025]
Abstract
The THR-β agonist resmetirom is the first treatment approved for metabolic dysfunction-associated steatohepatitis (MASH) in the US so far. It can be prescribed given MASH and F2/F3-fibrosis ("at-risk MASH").We analyzed how many patients qualify for resmetirom in a recently recruited Steatotic Liver Disease-cohort involving both tertiary and secondary care centers, the German SLD-Registry.Indication for resmetirom was assessed by three different approaches: (i) biopsy-proven MASH with F2/3 fibrosis and NAS-score ≥ 4; (ii) FibroScan-AST (FAST) score ≥ 0.67 and vibration controlled transient elastography (VCTE) < 15 kPa; (iii) US expert recommendations with VCTE 10-15 kPa and platelets ≥ 140×109/L or VCTE 8-15 kPa.1113 patients were recruited across 8 tertiary and 12 secondary care centers. NAS grading and staging were available for 180 cases (16%) with 179/180 conducted at tertiary care level. Of these, 61 (34%) qualified for resmetirom. FAST score without histologic assessment was available for 638 cases (57.3%), of which 612 (87%) were from tertiary and 26 (11%) from secondary care centers. Based on approach (ii), 41 (6%) of these individuals qualified for resmetirom compared to 117 (18.3%) using approach (iii). Combining approach (iii) with FAST ≥ 0.67 leads to 191 (30.0%) eligible patients. Using VCTE 8-15 kPa results in 182 (28.5%) eligible patients.Eligibility for resmetirom treatment depends on the available method used to identify "at-risk MASH". Availability of VCTE was highest among different levels of care.
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Affiliation(s)
- Eva Katharina Messer
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - David Petroff
- Clinical Trial Centre Leipzig, Leipzig University, Leipzig, Germany, Leipzig, Germany
| | - Jörn Schattenberg
- Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Stefan Zeuzem
- Medical Clinic I, Johann Wolfgang Goethe University Hospital, Frankfurt am Main, Germany
| | | | | | - Münevver Demir
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Peter Buggisch
- ifi-Institute for Interdisciplinary Medicine, Hamburg, Germany
| | | | | | - Heiner Wedemeyer
- Leberstiftungs-GmbH Deutschland, Hannover, Germany
- Dept. of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Wolf P Hofmann
- Leberstiftungs-GmbH Deutschland, Hannover, Germany
- Gastroenterologie am Bayerischen Platz, Berlin, Germany
| | - Andreas Geier
- Division of Infectious Diseases, Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
| | - Johannes Wiegand
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
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15
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Sarkar M, Kushner T. Metabolic dysfunction-associated steatotic liver disease and pregnancy. J Clin Invest 2025; 135:e186426. [PMID: 40371643 PMCID: PMC12077888 DOI: 10.1172/jci186426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is rising among reproductive-aged individuals and in pregnancy. MASLD in pregnancy does increase such risks as gestational diabetes, preeclampsia, and preterm birth. Although routine screening for MASLD has not been established in pregnancy, individuals with metabolic comorbidities, such as type 2 diabetes mellitus, should be evaluated by liver imaging and liver panel. Preconception counseling should address potential risks as well as need for optimized metabolic health before and during pregnancy. Fibrosis assessment should ideally be completed before pregnancy, to identify cases of cirrhosis that may warrant additional preconception management, such as variceal screening, as well as comanagement with maternal-fetal medicine specialists. In patients with MASLD, aspirin is advised at 12 weeks of gestational age to lower preeclampsia risk. In the absence of cirrhosis, no additional blood test monitoring is needed. In the general population, breastfeeding has beneficial effects on metabolic health in birthing parents and offspring and thus should be encouraged in the setting of MASLD, including access to enhanced lactation support. Research needs include evaluation of the long-term risks of MASLD in pregnancy on metabolic health in birthing parents and infants, as well as safety data for MASLD-directed therapies during pregnancy and lactation.
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Affiliation(s)
- Monika Sarkar
- Division of Gastroenterology and Hepatology, Department of Medicine, UCSF, San Francisco, California, USA
| | - Tatyana Kushner
- Department of Obstetrics & Gynecology, Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New York, USA
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16
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Wen S, Zhang H, Huang X, Wang C, Dong M, Wang C, Xu C, Yuan Y, Li Y, Zhou L, Yuan X. The Therapeutic Effect and Mechanism of Traditional Chinese Medicine in Type 2 Diabetes Mellitus and Its Complications. Diabetes Metab Syndr Obes 2025; 18:1599-1627. [PMID: 40391051 PMCID: PMC12087792 DOI: 10.2147/dmso.s517874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 05/07/2025] [Indexed: 05/21/2025] Open
Abstract
Traditional Chinese Medicine (TCM) has recently emerged as a beacon for the treatment of diabetes and its complications. Many TCMs that are commonly used, have the potentially demonstrated significant anti-diabetic effects. The mechanisms of these effects have been extensively discussed using modern techniques, such as genomics, mass spectrometry, and network pharmacology. Studies have demonstrated that TCM can influence glucose metabolism and pancreatic function via a diverse array of mechanisms including PI3K/AKT and AMPK pathways. TCM not only exhibits potential in the treatment of diabetes but also reduces the risk of diabetic complications. It is effective in the treatment of diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic neuropathy (DPN), diabetic cardiomyopathy, and peripheral angiopathy. Research has demonstrated that prescriptions, Chinese herbal medicines, and their extracts play a role in a variety of molecular mechanisms such as antioxidation, apoptosis regulation, hypoxia improvement, autophagy, and promotion of glucose and lipid metabolism. The antioxidant properties of TCM have received considerable attention. Recent studies have demonstrated that they are capable of effectively eliminating free radicals from the body and reducing damage to cells caused by oxidative stress. Consequently, they are crucial in the treatment of diabetes and its associated complications. This review summarizes the ever-expanding scope of TCM applicability in the field of diabetes, providing crucial support and innovative ideas for modern healthcare. TCMs could help seek more effective pharmacological targets in basic study and as well serve as the complement to the strategy of diabetic prevention and treatment benefiting the patients. More and more large series of RCT and clinical investigations will eventually examine the efficacy of specific TCM formulas on the therapeutic effect of DM and its complication where currently treatments could not be satisfied.
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Affiliation(s)
- Song Wen
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, People’s Republic of China
- Fudan Zhangjiang Institute, Fudan University, Shanghai, 201203, People’s Republic of China
| | - Haina Zhang
- Department of General Medicine, Shanghai Pudong Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Xing Huang
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Congcong Wang
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Meiyuan Dong
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Chaoxun Wang
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Chenglin Xu
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Yue Yuan
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Yanyan Li
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Ligang Zhou
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Xinlu Yuan
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, People’s Republic of China
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17
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Carbone F, Després JP, Ioannidis JPA, Neeland IJ, Garruti G, Busetto L, Liberale L, Ministrini S, Vilahur G, Schindler TH, Macedo MP, Di Ciaula A, Krawczyk M, Geier A, Baffy G, Faienza MF, Farella I, Santoro N, Frühbeck G, Yárnoz-Esquiroz P, Gómez-Ambrosi J, Chávez-Manzanera E, Vázquez-Velázquez V, Oppert JM, Kiortsis DN, Sbraccia P, Zoccali C, Portincasa P, Montecucco F. Bridging the gap in obesity research: A consensus statement from the European Society for Clinical Investigation. Eur J Clin Invest 2025:e70059. [PMID: 40371883 DOI: 10.1111/eci.70059] [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: 01/09/2025] [Accepted: 04/12/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Most forms of obesity are associated with chronic diseases that remain a global public health challenge. AIMS Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation. MATERIALS AND METHODS This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood. RESULTS The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies. DISCUSSION The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity. CONCLUSION This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.
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Affiliation(s)
- Federico Carbone
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| | - Jean-Pierre Després
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Québec, Canada
- VITAM - Centre de Recherche en santé Durable, Centre intégré Universitaire de santé et de Services Sociaux de la Capitale-Nationale, Québec, Québec, Canada
| | - John P A Ioannidis
- Department of Medicine, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
- Department of Epidemiology and Population Health, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
- Department of Biomedical Science, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
| | - Ian J Neeland
- Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Cardiovascular Disease, Harrington Heart and Vascular Institute, Cleveland, Ohio, USA
| | - Gabriella Garruti
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Luca Busetto
- Department of Medicine, University of Padua, Padua, Italy
| | - Luca Liberale
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| | - Stefano Ministrini
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
- Cardiology Department, Luzerner Kantonspital, Lucerne, Switzerland
| | - Gemma Vilahur
- Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, IIB-Sant Pau, Barcelona, Spain
- CiberCV, Institute Carlos III, Madrid, Spain
| | - Thomas H Schindler
- Washington University in St. Louis, Mallinckrodt Institute of Radiology, Division of Nuclear Medicine, Cardiovascular Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Maria Paula Macedo
- APDP - Diabetes Portugal, Education and Research Center, Lisbon, Portugal
- iNOVA4Health, NOVA Medical School | Faculdade de Ciências Médicas, NMS | FCM, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Agostino Di Ciaula
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Marcin Krawczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Andreas Geier
- Interdisciplinary Amyloidosis Center of Northern Bavaria, University Hospital of Würzburg, Würzburg, Germany
- Department of Internal Medicine II, Hepatology, University Hospital of Würzburg, Würzburg, Germany
| | - Gyorgy Baffy
- Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts, USA
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Ilaria Farella
- Department of Medicine and Surgery, LUM University, Casamassima, Italy
| | - Nicola Santoro
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Medicine and Health Sciences, "V. Tiberio" University of Molise, Campobasso, Italy
| | - Gema Frühbeck
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Yárnoz-Esquiroz
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Gómez-Ambrosi
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Emma Chávez-Manzanera
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - Jean-Michel Oppert
- Department of Nutrition, Pitié-Salpêtrière Hospital (AP-HP), Human Nutrition Research Center Ile-de-France (CRNH IdF), Sorbonne University, Paris, France
| | - Dimitrios N Kiortsis
- Atherothrombosis Research Centre, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Paolo Sbraccia
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Carmine Zoccali
- Renal Research Institute, New York, New York, USA
- Institute of Molecular Biology and Genetics (Biogem), Ariano Irpino, Italy
- Associazione Ipertensione Nefrologia Trapianto Renale (IPNET), c/o Nefrologia, Grande Ospedale Metropolitano, Reggio Calabria, Italy
| | - Piero Portincasa
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Fabrizio Montecucco
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
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Sardà H, Genua I, Miñambres I. GLP-1 receptor agonists in obesity treatment: Effects on cardiometabolic variables and cardiovascular disease. Med Clin (Barc) 2025; 165:106951. [PMID: 40378625 DOI: 10.1016/j.medcli.2025.106951] [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: 11/19/2024] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 05/19/2025]
Abstract
Obesity is associated with an increased cardiovascular risk. Drugs with glucagon-like peptide-1 receptor agonist (arGLP-1) action for overweight/obesity, such as liraglutide, semaglutide, and tirzepatide, have shown improvements in weight and body composition, as well as in parameters related to glucose metabolism, hypertension, dyslipidemia (reduction of triglycerides and increase in HDL cholesterol), and metabolic dysfunction-associated steatotic liver disease. Additionally, semaglutide 2.4mg sc has shown a reduction in cardiovascular mortality, non-fatal myocardial infarction or stroke, and symptoms of heart failure, while tirzepatide has demonstrated a reduction in cardiovascular mortality and heart failure symptoms in patients with obesity and heart failure. The availability of these new drugs with arGLP-1 action represents a paradigm shift in the treatment of obesity, as they achieve greater weight loss and improvements in cardiometabolic comorbidities.
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Affiliation(s)
- Helena Sardà
- Servicio de Endocrinología y Nutrición, Hospital de la Santa Creu i Sant Pau, Barcelona, España; Departamento de Medicina, Universitat Autònoma de Barcelona, Barcelona, España; Institut de Recerca de Sant Pau (IIB Sant Pau), Barcelona, España
| | - Idoia Genua
- Servicio de Endocrinología y Nutrición, Hospital de la Santa Creu i Sant Pau, Barcelona, España; Departamento de Medicina, Universitat Autònoma de Barcelona, Barcelona, España; Institut de Recerca de Sant Pau (IIB Sant Pau), Barcelona, España; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, España
| | - Inka Miñambres
- Servicio de Endocrinología y Nutrición, Hospital de la Santa Creu i Sant Pau, Barcelona, España; Departamento de Medicina, Universitat Autònoma de Barcelona, Barcelona, España; Institut de Recerca de Sant Pau (IIB Sant Pau), Barcelona, España; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, España.
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19
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Jackson E, Dennis A, Alkhouri N, Samala N, Vuppalanchi R, Sanyal AJ, Muthiah M, Banerjee R, Banerjee A. Cardiac and liver impairment on multiorgan MRI and risk of major adverse cardiovascular and liver events. Nat Med 2025:10.1038/s41591-025-03654-2. [PMID: 40335668 DOI: 10.1038/s41591-025-03654-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 03/11/2025] [Indexed: 05/09/2025]
Abstract
Cardiovascular disease and metabolic dysfunction-associated steatotic liver disease are common conditions associated with high mortality and morbidity, yet opportunities for integrated prevention are underinvestigated. We explored the association between impairment in the liver (defined by increased iron-corrected T1 (cT1) time) and/or heart (reduced left ventricular ejection fraction ≤ 50) and risk of experiencing cardiovascular- or liver-related events or all-cause mortality among 28,841 UK Biobank participants who underwent magnetic resonance imaging. Using Cox proportional hazard models, adjusted for age, sex, body mass index, type 2 diabetes and dyslipidaemia, we observed that cardiac impairment was associated with increased incidence of cardiovascular events (hazard ratio (HR) 2.3 (1.9-2.7)) and hospitalization (HR 2.1 (1.8-2.4)). Liver impairment was associated with incident cardiovascular hospitalization (cT1 ≥ 800 ms, HR 1.3 (1.1-1.5)), liver events (cT1 ≥ 875 ms, HR 9.2 (3.2-26) and hospitalization (cT1 ≥ 875 ms, HR 5.5 (3.2-9.3). Associations between cT1 and liver events were maintained in participants with metabolic dysfunction-associated steatotic liver disease (N = 6,223). Reduced left ventricular ejection fraction (≤50) combined with elevated cT1 (≥800 ms) were associated with earlier cardiovascular events (time to event 0.8 versus 2.4 years; P < 0.05). Cardiac and liver impairment are independently, or in combination, associated with cardiovascular or liver events, suggesting a dual role for magnetic resonance imaging in integrated prevention pathways.
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Affiliation(s)
| | | | - Naim Alkhouri
- Arizona Liver Health, Phoenix, AZ, USA
- Summit Clinical Research, San Antonio, AZ, USA
| | | | | | | | - Mark Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Rajarshi Banerjee
- Perspectum Ltd, Oxford, UK
- Oxford University Hospitals NHS Trust, Oxford, UK
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20
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Romeo S, Vidal-Puig A, Husain M, Ahima R, Arca M, Bhatt DL, Diehl AM, Fontana L, Foo R, Frühbeck G, Kozlitina J, Lonn E, Pattou F, Plat J, Quaggin SE, Ridker PM, Rydén M, Segata N, Tuttle KR, Verma S, Roeters van Lennep J, Benn M, Binder CJ, Jamialahmadi O, Perkins R, Catapano AL, Tokgözoğlu L, Ray KK. Clinical staging to guide management of metabolic disorders and their sequelae: a European Atherosclerosis Society consensus statement. Eur Heart J 2025:ehaf314. [PMID: 40331343 DOI: 10.1093/eurheartj/ehaf314] [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] [Indexed: 05/08/2025] Open
Abstract
Obesity rates have surged since 1990 worldwide. This rise is paralleled by increases in pathological processes affecting organs such as the heart, liver, and kidneys, here termed systemic metabolic disorders (SMDs). For clinical management of SMD, the European Atherosclerosis Society proposes a pathophysiology-based system comprising three stages: Stage 1, where metabolic abnormalities such as dysfunctional adiposity and dyslipidaemia occur without detectable organ damage; Stage 2, which involves early organ damage manifested as Type 2 diabetes, asymptomatic diastolic dysfunction, metabolic-associated steatohepatitis (MASH), and chronic kidney disease (CKD); and Stage 3, characterized by more advanced organ damage affecting multiple organs. Various forms of high-risk obesity, driven by maintained positive energy balance, are the most common cause of SMD, leading to ectopic lipid accumulation and insulin resistance. This progression affects various organs, promoting comorbidities such as hypertension and atherogenic dyslipidaemia. Genetic factors influence SMD susceptibility, and ethnic disparities in SMD are attributable to genetic and socioeconomic factors. Key SMD features include insulin resistance, inflammation, pre-diabetes, Type 2 diabetes, MASH, hypertension, CKD, atherogenic dyslipidaemia, and heart failure. Management strategies involve lifestyle changes, pharmacotherapy, and metabolic surgery in severe cases, with emerging treatments focusing on genetic approaches. The staging system provides a structured approach to understanding and addressing the multi-faceted nature of SMD, which is crucial for improving health outcomes. Categorization of SMD abnormalities by presence and progression is aimed to improve awareness of a multi-system trait and encourage a tailored and global approach to treatment, ultimately aiming to reduce the burden of obesity-related comorbidities.
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Affiliation(s)
- Stefano Romeo
- Department of Medicine, H7 Medicin, Huddinge, H7 Endokrinologi och Diabetes Romeo, Karolinska Institutet, 171 77 Stockholm, Sweden
- Department of Endocrinology, Karolinska University Hospital Huddinge, 141 57 Huddinge, Stockholm, Sweden
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
- Department of Cardiology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Viale Europa, 88100 Catanzaro, Italy
| | - Antonio Vidal-Puig
- MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
- Centro de Investigacion Principe Felipe, C/ d'Eduardo Primo Yufera, 3, 46012 Valencia, Spain
- Cambridge University Nanjing Centre of Technology and Innovation, No. 23, Rongyue Road, Jiangbei New Area, Nanjing, Jiangsu, China
| | - Mansoor Husain
- Ted Rogers Centre for Heart Research, Department of Medicine, University of Toronto, 661 University Avenue, Toronto, ON, Canada M5G 1M1
| | - Rexford Ahima
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Marcello Arca
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
- Unit of Internal Medicine and Metabolic Diseases, Hospital Policlinico Umberto I, Rome, Italy
| | - Deepak L Bhatt
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anna Mae Diehl
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA
| | - Luigi Fontana
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
- Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Roger Foo
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Singapore
- Cardiovascular Metabolic Disease Translational Research Programme, National University Health Systems, Singapore
| | - Gema Frühbeck
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain
- Metabolic Research Laboratory, CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
| | - Julia Kozlitina
- The Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Eva Lonn
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada
| | - Francois Pattou
- Department of Endocrine and Metabolic Surgery, CHU Lille, University of Lille, Inserm, Institut Pasteur Lille, Lille, France
| | - Jogchum Plat
- Department of Nutrition and Movement Sciences, NUTRIM School of Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Susan E Quaggin
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Division of Nephrology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Paul M Ridker
- Center for Cardiovascular Disease Prevention, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Mikael Rydén
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Nicola Segata
- Department CIBIO, University of Trento, Trento, Italy
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Katherine R Tuttle
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA
- Providence Medical Research Center, Providence Inland Northwest Health, Spokane, WA, USA
| | - 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
| | - Jeanine Roeters van Lennep
- Department of Internal Medicine, Cardiovascular Institute, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Marianne Benn
- Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Centre of Diagnostic Investigation, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christoph J Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Oveis Jamialahmadi
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
| | - Rosie Perkins
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
| | - Alberico L Catapano
- Center for the Study of Atherosclerosis, IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Lale Tokgözoğlu
- Department of Cardiology, Hacettepe University Medical Faculty, Ankara, Turkey
| | - Kausik K Ray
- Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK
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21
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Godwin KM, Grigoryan L, Thrift AP, Duong H, Kanwal F, Giardina T, Kadiyala H, Zimolzak A, Patidar KR, El-Serag HB. A cluster randomized trial of a Multicomponent Clinical Care Pathway (MCCP) to improve MASLD diagnosis and management in primary care: study protocol. BMC Health Serv Res 2025; 25:645. [PMID: 40325466 PMCID: PMC12054218 DOI: 10.1186/s12913-025-12737-2] [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: 11/02/2024] [Accepted: 04/11/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common chronic liver disorder in the world. Most patients with MASLD are undiagnosed, untreated and unreferred. Treatment depends on diagnosis and accurate staging of fibrosis risk, and therefore screening at the primary care setting coupled with consistent, timely, evidence-based, widely accessible, and testable management processes is critical. Randomized controlled trials of methods for screening, diagnosis, severity stratification, and referral are lacking. We previously validated the MASLD clinical care pathway (MCCP), a multistep algorithmic process geared to support primary care settings in screening, diagnosis, risk stratification, and suggested referral and treatment of patients with MASLD. We will evaluate the effectiveness of the MCCP intervention compared to usual care in improving MASLD care process and patient outcomes. METHODS A two-arm, parallel, cluster-randomized trial will assess the effect of the MCCP intervention comprised of an e-trigger and structured provider education on screening, diagnosis, referral, and treatment for MASLD. Clusters are Veterans Affairs (VA) patient-centered primary care clinics, called Patient Aligned Care Teams (PACTs). This 4-year study will include three phases: (1) formative assessment to explore barriers to feasibility and acceptability of intervention among providers and patients and adapt MCCP for utilization by VA PACTs, (2) cluster-randomized trial to examine the effectiveness of the MCCP compared to usual care, and (3) summative evaluation to identify patient and provider characteristics associated with effectiveness of MCCP and plan for future implementation. The primary outcome will be a composite dichotomous variable for making a new MASLD diagnosis and completing severity risk stratification of MASLD. Secondary outcomes include referral and receipt of hepatology specialty care for patients with MASLD and advanced fibrosis. DISCUSSION Our randomized controlled trial will be the first to systematically implement the MCCP using strategies that are clinically relevant, adaptable and scalable. If successful, the MCCP will improve outcomes for patients with MASLD through early detection, accurate risk stratification, and timely treatment within primary care settings. TRIAL REGISTRATION This trial has been registered on clinicaltrails.gov (# NCT06671886), registration date: 10-31-2024.
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Affiliation(s)
- Kyler M Godwin
- Department of Medicine, Section of Health Services Research, Baylor College of Medicine, Houston, TX, USA.
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd. (152), Houston, TX, 77030, USA.
| | - Larissa Grigoryan
- Department of Medicine, Section of Health Services Research, Baylor College of Medicine, Houston, TX, USA
- Department of Family and Community Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Aaron P Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Hao Duong
- Department of Medicine, Section of Health Services Research, Baylor College of Medicine, Houston, TX, USA
| | - Fasiha Kanwal
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd. (152), Houston, TX, 77030, USA
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Traber Giardina
- Department of Medicine, Section of Health Services Research, Baylor College of Medicine, Houston, TX, USA
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd. (152), Houston, TX, 77030, USA
| | - Himabindu Kadiyala
- Section of General Internal Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Andrew Zimolzak
- Department of Medicine, Section of Health Services Research, Baylor College of Medicine, Houston, TX, USA
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd. (152), Houston, TX, 77030, USA
| | - Kavish R Patidar
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Hashem B El-Serag
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd. (152), Houston, TX, 77030, USA
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
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22
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Schnell O, Almandoz J, Anderson L, Barnard-Kelly K, Battelino T, Blüher M, Busetto L, Catrinou D, Ceriello A, Cos X, Danne T, Dayan CM, Del Prato S, Fernández-Fernández B, Fioretto P, Forst T, Gavin JR, Giorgino F, Groop PH, Harsch IA, Heerspink HJL, Heinemann L, Ibrahim M, Jadoul M, Jarvis S, Ji L, Kanumilli N, Kosiborod M, Landmesser U, Macieira S, Mankovsky B, Marx N, Mathieu C, McGowan B, Milenkovic T, Moser O, Müller-Wieland D, Papanas N, Patel DC, Pfeiffer AFH, Rahelić D, Rodbard HW, Rydén L, Schaeffner E, Spearman CW, Stirban A, Tacke F, Topsever P, Van Gaal L, Standl E. CVOT summit report 2024: new cardiovascular, kidney, and metabolic outcomes. Cardiovasc Diabetol 2025; 24:187. [PMID: 40316962 PMCID: PMC12048985 DOI: 10.1186/s12933-025-02700-0] [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: 02/18/2025] [Accepted: 03/21/2025] [Indexed: 05/04/2025] Open
Abstract
The 10th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on December 5-6, 2024. This year, discussions about cardiovascular (CV) and kidney outcome trials centered on the recent findings from studies involving empagliflozin (EMPACT-MI), semaglutide (STEP-HFpEF-DM and FLOW), tirzepatide (SURMOUNT-OSA and SUMMIT), and finerenone (FINEARTS-HF). These studies represent significant advances in reducing the risk of major adverse cardiovascular events (MACE) and improving metabolic outcomes in heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), and obstructive sleep apnea (OSA). The congress also comprised sessions on novel and established therapies for managing HFpEF, CKD, and obesity; guidelines for managing CKD and metabolic dysfunction-associated steatotic liver disease (MASLD); organ crosstalk and the development of cardio-kidney-metabolic (CKM) syndrome; precision medicine and person-centered management of diabetes, obesity, cardiovascular disease (CVD) and CKD; early detection of type 1 diabetes (T1D) and strategies to delay its onset; continuous glucose monitoring (CGM) and automated insulin delivery (AID); cardiovascular autonomic neuropathy (CAN) and the diabetic heart; and the role of primary care in the early detection, prevention and management of CKM diseases. The contribution of environmental plastic pollution to CVD risk, the increasing understanding of the efficacy and safety of incretin therapies in the treatment of CKM diseases, and the latest updates on nutrition strategies for CKM management under incretin-based therapies were also topics of interest for a vast audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians, who actively engaged in online discussions. The 11th CVOT Summit will be held virtually on November 20-21, 2025 ( http://www.cvot.org ).
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Affiliation(s)
- Oliver Schnell
- Forschergruppe Diabetes e. V., Helmholtz Center Munich, Ingolstaedter Landstraße 1, 85764, Neuherberg (Munich), Germany.
| | - Jaime Almandoz
- Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Lisa Anderson
- Molecular and Clinical Sciences Research Institute, St. George's University of London, London, UK
- St. George's University Hospitals NHS Foundation Trust, London, UK
| | | | - Tadej Battelino
- University Medical Center, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
| | - Luca Busetto
- Department of Medicine (DIMED), University of Padova, Padua, Italy
| | - Doina Catrinou
- Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania
| | | | - Xavier Cos
- DAP Cat Research Group, Foundation University Institute for Primary Health Care Research Jordi Gol i Gorina, Barcelona, Spain
| | | | | | - Stefano Del Prato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Beatriz Fernández-Fernández
- Division of Nephrology and Hypertension, University Hospital Fundación Jiménez Díaz, Madrid, Spain
- Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain
| | | | - Thomas Forst
- CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany
| | - James R Gavin
- Emory University School of Medicine, Atlanta, GA, USA
| | - Francesco Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Bari, Italy
| | - Per-Henrik Groop
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Folkhälsan Research Center, Biomedicum, Helsinki, Finland
- Department of Diabetes, Central Medical School, Monash University, Melbourne, Australia
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Igor A Harsch
- Division of Endocrinology and Metabolism, Department of Internal Medicine II, Thuringia Clinic Saalfeld "Georgius Agricola", Saalfeld, Germany
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Lutz Heinemann
- Science Consulting in Diabetes GmbH, Dusseldorf, Germany
| | | | - Michel Jadoul
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | | | - Linong Ji
- Peking University People's Hospital, Xicheng District, Beijing, China
| | | | - Mikhail Kosiborod
- Department of Cardiovascular Disease, Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Ulf Landmesser
- Department of Cardiology Angiology and Intensive Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | - Boris Mankovsky
- Depatment of Diabetology, Shupyk National Healthcare University of Ukraine, Kiev, Ukraine
| | - Nikolaus Marx
- Clinic for Cardiology, Pneumology, Angiology and Internal Intensive Care Medicine (Medical Clinic I), RWTH Aachen University Hospital, Aachen, Germany
| | - Chantal Mathieu
- Department of Endocrinology, Catholic University of Louvain, Louvain, Belgium
| | - Barbara McGowan
- Guy's and St Thomas' Hospital, Kings College London, London, UK
| | - Tatjana Milenkovic
- University Clinic of Endocrinology, Diabetes and Metabolic Diseases, Skopje, North Macedonia
- Faculty of Medicine "St. Cyril and Methodius" University, Skopje, North Macedonia
| | - Othmar Moser
- Institute of Sports Science, University of Bayreuth, Bayreuth, Germany
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | | | - Nikolaos Papanas
- Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Dipesh C Patel
- Royal Free London, University College London, London, UK
| | - Andreas F H Pfeiffer
- Department of Endocrinology and Metabolic Diseases, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- Deutsches Zentrum für Diabetesforschung e.V., Helmholtz Center Munich, Neuherberg, Germany
| | - Dario Rahelić
- Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases at Merkur University Hospital, Zagreb, Croatia
| | | | - Lars Rydén
- Department of Medicine K2, Karolinska Institute, Stockholm, Sweden
| | - Elke Schaeffner
- Institute of Public Health, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - C Wendy Spearman
- Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Alin Stirban
- Asklepios Klinik Birkenwerder, Birkenwerder, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Pinar Topsever
- Department of Family Medicine, Acıbadem Mehmet Ali Aydınlar University School of Medicine, Istanbul, Turkey
| | - Luc Van Gaal
- Department of Endocrinology-Diabetology and Metabolism, Antwerp University Hospital, Antwerp, Belgium
| | - Eberhard Standl
- Forschergruppe Diabetes e. V., Helmholtz Center Munich, Ingolstaedter Landstraße 1, 85764, Neuherberg (Munich), Germany
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23
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Zampino R, Patauner F, Durante-Mangoni E. Clinical trajectories in liver cirrhosis: An evidence-based reappraisal for the internist. Eur J Intern Med 2025:S0953-6205(25)00169-4. [PMID: 40318914 DOI: 10.1016/j.ejim.2025.04.028] [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: 10/24/2024] [Revised: 04/19/2025] [Accepted: 04/20/2025] [Indexed: 05/07/2025]
Abstract
Over the last few years, the approach to clinical recognition and risk stratification of advanced liver disease has changed substantially, and liver cirrhosis has been increasingly conceptualized as a clinical rather than a histopathologic condition. In this Clinical Insight, we summarize the latest developments on recognition and management of 'clinically' advanced chronic liver disease.
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Affiliation(s)
- Rosa Zampino
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", P.zza L. Miraglia 2, 80138 Napoli, Italy; Unit of Internal Medicine & Transplants, A.O.R.N. Ospedali dei Colli - Ospedale Monaldi, Piazzale Ettore Ruggieri, 80131 Napoli Italy
| | - Fabian Patauner
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", P.zza L. Miraglia 2, 80138 Napoli, Italy
| | - Emanuele Durante-Mangoni
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via de Crecchio 7, 80138 Napoli, Italy; Unit of Internal Medicine & Transplants, A.O.R.N. Ospedali dei Colli - Ospedale Monaldi, Piazzale Ettore Ruggieri, 80131 Napoli Italy.
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24
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Kaya E, Yilmaz Y, Alkhouri N. Clinical Insights on Resmetirom: Clinical Indications, Patient Selection, and Monitoring Response to Therapy. J Clin Gastroenterol 2025; 59:412-419. [PMID: 40193288 DOI: 10.1097/mcg.0000000000002150] [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: 04/09/2025]
Abstract
The recent conditional approval by the Food and Drug Administration of resmetirom for treating metabolic dysfunction-associated steatohepatitis (MASH) with significant or advanced fibrosis represents a pivotal milestone in the history of metabolic dysfunction-associated steatotic liver disease (MASLD) treatment. As the first liver-directed pharmacological therapy option for MASLD, resmetirom offers a novel approach that specifically targets liver pathology, marking a transformative step forward in managing this widespread and challenging condition. For initiating therapy with resmetirom, a liver biopsy is not required. Consequently, accurately excluding patients with less severe liver histology or cirrhosis using noninvasive tests (NITs) is essential. In addition, monitoring the therapy response should be conducted using NITs. Given the recent approval, our current clinical understanding of resmetirom is primarily informed by phase 3 clinical trials. The long-term effects of the drug should be evaluated in further studies by encouraging the use of the drug in eligible patients. This review highlights key aspects of clinical resmetirom use, including identifying the target population, monitoring therapeutic response, determining appropriate discontinuation criteria, and strategies to prevent unnecessary treatment interruptions.
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Affiliation(s)
- Eda Kaya
- Department of Medicine, Knappschaftskrankenhaus Bochum, Ruhr University, Bochum, Germany
- The Global NASH Council, Washington, DC
| | - Yusuf Yilmaz
- The Global NASH Council, Washington, DC
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Türkiye
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25
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Nauck MA, Lim S. Promising treatment options with tirzepatide for Japanese individuals with obesity disease. Lancet Diabetes Endocrinol 2025; 13:357-358. [PMID: 40031942 DOI: 10.1016/s2213-8587(25)00024-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 01/22/2025] [Indexed: 03/05/2025]
Affiliation(s)
- Michael A Nauck
- Diabetes, Endocrinology, Metabolism Section, Medical Department I, Katholisches Klinikum Bochum, St Josef Hospital (Ruhr University Bochum), Bochum 44791, Germany.
| | - Soo Lim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
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26
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Capinha F, Carvalhana S, Cortez-Pinto H. Role of Alcohol in Steatotic Liver Disease: Impact on Patients with Cardiometabolic Risk Factors. Dig Dis Sci 2025; 70:1746-1756. [PMID: 40025309 DOI: 10.1007/s10620-025-08912-4] [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: 07/23/2024] [Accepted: 02/03/2025] [Indexed: 03/04/2025]
Abstract
The new definition of steatotic liver disease (SLD), as a broader concept, was a step forward in the increasing recognition of the substantial overlap between alcohol and cardiometabolic risk factors (CMRFs), in a continuum way. The spectrum of pathophysiological aspects, ranging from liver steatosis to fibrosis, has similarities in MASLD and ALD. Also, there is now considerable evidence that the association of metabolic dysfunction with increased alcohol consumption impacts on the risk of severe liver disease and prognosis. The new MetALD class, as recently proposed, shows clear differences in prognosis when comparing with MASLD and ALD groups. However, there is room for improvement, such as considering the role of previous alcohol intake, fluctuations of consumption over time, including binge drinking, refinement of alcohol assessment, and better understanding of the role of biomarkers. In summary, SLD is no doubt a significant improvement, but the new classification needs to be dynamic and adapting to patients needing frequent reassessment. Furthermore, it brings opportunities for research on the interaction between alcohol consumption and CMRFs.
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Affiliation(s)
- Francisco Capinha
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal
| | - Sofia Carvalhana
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal
| | - Helena Cortez-Pinto
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal.
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Ostrominski JW, Ortega-Montiel J, Tesfaye H, Alix C, DiCesare E, Cromer SJ, Wexler DJ, Paik JM, Patorno E. Trends in Utilization of Glucose- and Weight-Lowering Medications After Tirzepatide Approval in the United States : A Population-Based Cohort Study. Ann Intern Med 2025; 178:620-633. [PMID: 40228298 DOI: 10.7326/annals-24-02870] [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] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Recent trends in use of tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptor agonist (RA), versus other glucose-lowering medications (GLMs) and weight-lowering medications (WLMs) remain unexplored. OBJECTIVE To describe trends in insurance claims for GLMs and WLMs after tirzepatide approval. DESIGN Population-based cohort study. SETTING Claims data from a large U.S. commercial database (January 2021 to December 2023). PARTICIPANTS Adults (aged ≥18 years) with type 2 diabetes (T2D) and without diabetes with dispensations for GLMs and WLMs. Any use was defined as medication dispensation regardless of prior use. Incident use was defined as dispensation without use in the preceding year. MEASUREMENTS Monthly trends in medication dispensations before and after tirzepatide market entry. Tirzepatide uptake was additionally compared with initial postapproval uptake of other GLMs and WLMs. RESULTS Tirzepatide dispensations increased markedly among adults with T2D prescribed GLMs, reaching 12.3% of all GLM dispensations by December 2023. Similar patterns were observed for sodium-glucose cotransporter-2 inhibitors (14.5% to 24.4%) and GLP-1 RAs (19.5% to 28.5%). Dispensations of other GLMs, including metformin, declined. Among adults without diabetes but prescribed WLMs, tirzepatide (0.0% to 40.6%) and semaglutide (2.4 mg) (0.0% to 32.2%) dispensations increased sharply, but semaglutide (2.0 mg) was the most frequently dispensed WLM, increasing from 37.8% to 45.7%. Dispensations of other WLMs declined. Similar trends were observed among incident users. Tirzepatide uptake was more rapid and sustained compared with initial postapproval periods for other medications. LIMITATION Generalizability to U.S. adults without commercial health insurance is uncertain. CONCLUSION These findings highlight the sharp uptake of tirzepatide after U.S. market entry and enhance understanding of the rapidly shifting landscape of prescribing patterns for GLMs and WLMs. PRIMARY FUNDING SOURCE National Institute of Diabetes and Digestive and Kidney Diseases.
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Affiliation(s)
- John W Ostrominski
- Cardiovascular Division, Division of Endocrinology, Diabetes and Hypertension, and Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (J.W.O.)
| | - Janinne Ortega-Montiel
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (J.O.-M., H.T., C.A., E.D., E.P.)
| | - Helen Tesfaye
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (J.O.-M., H.T., C.A., E.D., E.P.)
| | - Caroline Alix
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (J.O.-M., H.T., C.A., E.D., E.P.)
| | - Elyse DiCesare
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (J.O.-M., H.T., C.A., E.D., E.P.)
| | - Sara J Cromer
- Diabetes Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (S.J.C., D.J.W.)
| | - Deborah J Wexler
- Diabetes Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (S.J.C., D.J.W.)
| | - Julie M Paik
- Division of Pharmacoepidemiology and Pharmacoeconomics and Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (J.M.P.)
| | - Elisabetta Patorno
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (J.O.-M., H.T., C.A., E.D., E.P.)
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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] [MESH Headings] [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 therapies 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, Northern Ireland BT52 1SA, UK
| | - J Michael Conlon
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK.
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Moolla A, Poolman T, Othonos N, Dong J, Smith K, Cornfield T, White S, Ray DW, Mouchti S, Mózes FE, Thomaides-Brears H, Neubauer S, Cobbold JF, Hodson L, Tomlinson JW. Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD. JHEP Rep 2025; 7:101363. [PMID: 40342635 PMCID: PMC12060445 DOI: 10.1016/j.jhepr.2025.101363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 02/06/2025] [Accepted: 02/11/2025] [Indexed: 05/11/2025] Open
Abstract
Background & Aims Glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies deliver histological benefit in people with metabolic dysfunction-associated steatotic liver disease (MASLD). Multiple mechanisms may be important including weight loss, improved glycaemic control and putative direct tissue-specific actions. Following cessation of GLP1-RA therapy, weight regain is common. To dissect the mechanisms underpinning their benefits, we conducted a prospective, randomised, experimental medicine study in people with MASLD, comparing GLP-1RA treatment (liraglutide) to matched lifestyle-induced weight loss and assessed the impact of treatment withdrawal. Methods Twenty-nine participants with MASLD, without type 2 diabetes underwent metabolic phenotyping including measurement de novo lipogenesis (DNL), liver magnetic resonance imaging, body composition, adipose tissue RNA sequencing, circulating proteome, and stool microbiome analysis. Participants were randomised to lifestyle (∼500 kcal energy deficit) or GLP1-RA treatment for 12 weeks, after which investigations were repeated, and treatment stopped; investigations were also repeated 12 weeks after treatment withdrawal. Results Matched weight loss was achieved in both arms. Body composition changes, reductions in alanine aminotransferase, liver steatosis, and disease activity were similar following both treatments. GLP-1RA treatment, but not lifestyle, improved glucose handling, fasting lipids, and significantly deceased DNL. The subcutaneous adipose transcriptome, circulating proteome profile and stool microbiome were not different between groups after treatment. However, 12 weeks after GLP1-RA (but not lifestyle) withdrawal, circulating MMP-10, IL10RB, FGF-23, and Flt3L were elevated, alongside dysregulated adipose gene expression. Conclusions Although matched weight loss through lifestyle or GLP-1RA have comparable effects on hepatic steatosis, GLP-1RA treatment had additional metabolic benefits on glucose homeostasis, lipid profiles, and DNL. However, GLP-1RA withdrawal may adversely impact the circulating proteome, adipose tissue gene expression, and the stool microbiome, predisposing to weight regain. Impact and implications Weight loss, through either lifestyle intervention or pharmacotherapy with GLP-1RA has an equally beneficial impact on the liver, and both strategies should be considered in the management of people with MASLD. GLP-1RA therapy may have additional benefits to improve glucose homeostasis even in the absence of pre-existing type 2 diabetes. Further research is needed to explore the differential impact of treatment withdrawal and the resultant metabolic consequences. Clinical Trials Registration This study is registered at EudraCT (2016-002045-36).
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Affiliation(s)
- Ahmad Moolla
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Toryn Poolman
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
- Structural and Molecular Biology, Faculty of Life Sciences, University College London, London, UK
| | - Nantia Othonos
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Jiawen Dong
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Kieran Smith
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Thomas Cornfield
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Sarah White
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - David W. Ray
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
- NIHR Oxford Health Biomedical Research Centre, University of Oxford, Oxford, UK
- Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
| | | | - Ferenc E. Mózes
- Oxford Centre for Clinical Magnetic Resonance Research (OCMR), John Radcliffe Hospital, University of Oxford, Oxford, UK
| | | | - Stefan Neubauer
- Oxford Centre for Clinical Magnetic Resonance Research (OCMR), John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Jeremy F. Cobbold
- Department of Gastroenterology and Hepatology, Oxford University Hospitals, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Jeremy W. Tomlinson
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
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Chen H, Simons PIHG, Brouwers MCGJ. Is cardiovascular disease in PCOS driven by MASLD? Trends Endocrinol Metab 2025; 36:389-391. [PMID: 39510952 DOI: 10.1016/j.tem.2024.10.005] [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: 07/05/2024] [Revised: 10/12/2024] [Accepted: 10/15/2024] [Indexed: 11/15/2024]
Abstract
Recent genetic studies have implicated an active role for intrahepatic lipid accumulation in the pathogenesis of both polycystic ovary syndrome (PCOS) and cardiovascular disease. These new insights may provide novel (non)pharmacological opportunities for the prevention and treatment of PCOS and cardiovascular disease at both the societal and clinical level.
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Affiliation(s)
- Huadong Chen
- Department of Internal Medicine, Division of Endocrinology and Metabolic Diseases, Maastricht University Medical Center, Maastricht, The Netherlands; Laboratory for Metabolism and Vascular Medicine, Maastricht University, Maastricht, The Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Pomme I H G Simons
- Department of Internal Medicine, Division of Endocrinology and Metabolic Diseases, Maastricht University Medical Center, Maastricht, The Netherlands; Laboratory for Metabolism and Vascular Medicine, Maastricht University, Maastricht, The Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Martijn C G J Brouwers
- Department of Internal Medicine, Division of Endocrinology and Metabolic Diseases, Maastricht University Medical Center, Maastricht, The Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
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Byrne CD, Armandi A, Pellegrinelli V, Vidal-Puig A, Bugianesi E. Μetabolic dysfunction-associated steatotic liver disease: a condition of heterogeneous metabolic risk factors, mechanisms and comorbidities requiring holistic treatment. Nat Rev Gastroenterol Hepatol 2025; 22:314-328. [PMID: 39962331 DOI: 10.1038/s41575-025-01045-z] [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] [Accepted: 01/27/2025] [Indexed: 03/09/2025]
Abstract
Μetabolic dysfunction-associated steatotic liver disease (MASLD) comprises a heterogeneous condition in the presence of steatotic liver. There can be a hierarchy of metabolic risk factors contributing to the severity of metabolic dysfunction and, thereby, the associated risk of both liver and extrahepatic outcomes, but the precise ranking and combination of metabolic syndrome (MetS) traits that convey the highest risk of major adverse liver outcomes and extrahepatic disease complications remains uncertain. Insulin resistance, low-grade inflammation, atherogenic dyslipidaemia and hypertension are key to the mechanisms of liver and extrahepatic complications. The liver is pivotal in MetS progression as it regulates lipoprotein metabolism and secretes substances that affect insulin sensitivity and inflammation. MASLD affects the kidneys, heart and the vascular system, contributing to hypertension and oxidative stress. To address the global health burden of MASLD, intensified by obesity and type 2 diabetes mellitus epidemics, a holistic, multidisciplinary approach is essential. This approach should focus on both liver disease management and cardiometabolic risk factors. This Review examines the link between metabolic dysfunction and liver dysfunction and extrahepatic disease outcomes, the diverse mechanisms in MASLD due to metabolic dysfunction, and a comprehensive, personalized management model for patients with MASLD.
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Affiliation(s)
- Christopher D Byrne
- National Institute for Health and Care Research, Southampton Biomedical Research Centre, University Hospital Southampton and University of Southampton, Southampton, UK
| | - Angelo Armandi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Vanessa Pellegrinelli
- Institute of Metabolic Science, MRC MDU Unit, University of Cambridge, Cambridge, UK
- Centro de Investigacion Principe Felipe, Valencia, Spain
| | - Antonio Vidal-Puig
- Institute of Metabolic Science, MRC MDU Unit, University of Cambridge, Cambridge, UK
- Centro de Investigacion Principe Felipe, Valencia, Spain
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy.
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Müller TD, Adriaenssens A, Ahrén B, Blüher M, Birkenfeld AL, Campbell JE, Coghlan MP, D'Alessio D, Deacon CF, DelPrato S, Douros JD, Drucker DJ, Figueredo Burgos NS, Flatt PR, Finan B, Gimeno RE, Gribble FM, Hayes MR, Hölscher C, Holst JJ, Knerr PJ, Knop FK, Kusminski CM, Liskiewicz A, Mabilleau G, Mowery SA, Nauck MA, Novikoff A, Reimann F, Roberts AG, Rosenkilde MM, Samms RJ, Scherer PE, Seeley RJ, Sloop KW, Wolfrum C, Wootten D, DiMarchi RD, Tschöp MH. Glucose-dependent insulinotropic polypeptide (GIP). Mol Metab 2025; 95:102118. [PMID: 40024571 PMCID: PMC11931254 DOI: 10.1016/j.molmet.2025.102118] [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: 12/06/2024] [Revised: 02/06/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP. SCOPE OF REVIEW In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases. MAJOR CONCLUSIONS Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.
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Affiliation(s)
- Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich (LMU), Germany.
| | - Alice Adriaenssens
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Bo Ahrén
- Department of Clinical Sciences, Lund, Lund University, Lund, Sweden
| | - Matthias Blüher
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen 72076, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Matthew P Coghlan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - David D'Alessio
- Department of Medicine, Division of Endocrinology, Duke University, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - Carolyn F Deacon
- School of Biomedical Sciences, Ulster University, Coleraine, UK; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefano DelPrato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy
| | | | - Daniel J Drucker
- The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Natalie S Figueredo Burgos
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Brian Finan
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Ruth E Gimeno
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Fiona M Gribble
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Matthew R Hayes
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christian Hölscher
- Neurodegeneration Research Group, Henan Academy of Innovations in Medical Science, Xinzheng, China
| | - Jens J Holst
- Department of Biomedical Sciences and the Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Patrick J Knerr
- Indianapolis Biosciences Research Institute, Indianapolis, IN, USA
| | - Filip K Knop
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christine M Kusminski
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Arkadiusz Liskiewicz
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Guillaume Mabilleau
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France; CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France
| | | | - Michael A Nauck
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany; German Center for Diabetes Research, DZD, Germany
| | - Frank Reimann
- Institute of Metabolic Science-Metabolic Research Laboratories & MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Anna G Roberts
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark
| | - Ricardo J Samms
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Philip E Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kyle W Sloop
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Christian Wolfrum
- Institute of Food, Nutrition and Health, ETH Zurich, 8092, Schwerzenbach, Switzerland
| | - Denise Wootten
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | | | - Matthias H Tschöp
- Helmholtz Munich, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany
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Wong SW, Yang YY, Chen H, Xie L, Shen XZ, Zhang NP, Wu J. New advances in novel pharmacotherapeutic candidates for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) between 2022 and 2024. Acta Pharmacol Sin 2025; 46:1145-1155. [PMID: 39870846 PMCID: PMC12032127 DOI: 10.1038/s41401-024-01466-7] [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] [Accepted: 12/18/2024] [Indexed: 01/29/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hepatic fibrosis, further progressing to cirrhosis and hepatocellular carcinoma (HCC). MASLD has become a prevalent disease with 25% in average over the world. MASH is an active stage, and requires pharmacological intervention when there is necroptotic damage with fibrotic progression. Although there is an increased understanding of MASH pathogenesis and newly approved resmetirom, given its complexity and heterogeneous pathophysiology, there is a strong necessity to develop more drug candidates with better therapeutic efficacy and well-tolerated safety profile. With an increased list of pharmaceutical candidates in the pipeline, it is anticipated to witness successful approval of more potential candidates in this fast-evolving field, thereby offering different categories of medications for selective patient populations. In this review, we update the advances in MASH pharmacotherapeutics that have completed phase II or III clinical trials with potential application in clinical practice during the latest 2 years, focusing on effectiveness and safety issues. The overview of fast-evolving status of pharmacotherapeutic candidates for MASH treatment confers deep insights into the key issues, such as molecular targets, endpoint selection and validation, clinical trial design and execution, interaction with drug administration authority, real-world data feedback and further adjustment in clinical application.
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Affiliation(s)
- Shu Wei Wong
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Yong-Yu Yang
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Hui Chen
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Li Xie
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Xi-Zhong Shen
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Ning-Ping Zhang
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, 200032, China.
| | - Jian Wu
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China.
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, 200032, China.
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Ayares G, Diaz LA, Idalsoaga F, Alkhouri N, Noureddin M, Bataller R, Loomba R, Arab JP, Arrese M. MetALD: New Perspectives on an Old Overlooked Disease. Liver Int 2025; 45:e70017. [PMID: 40179033 PMCID: PMC11967760 DOI: 10.1111/liv.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/02/2025] [Accepted: 01/24/2025] [Indexed: 04/05/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are the major contributors to the liver disease burden globally. The rise in these conditions is linked to obesity, type 2 diabetes, metabolic syndrome and increased alcohol consumption. MASLD and ALD share risk factors, pathophysiology and histological features but differ in their thresholds for alcohol use, and the ALD definition does not require the presence of metabolic dysfunction. A recent multi-society consensus overhauled the nomenclature of liver steatosis and introduced the term MetALD to describe patients with metabolic dysfunction who drink more than those with MASLD and less than those with ALD. This new terminology aims to enhance the understanding and management of liver disease but poses challenges, such as the need to accurately measure alcohol consumption in research and clinical practice settings. Recent studies show that MetALD has significant implications for patient management, as it is associated with increased mortality risks and more severe liver outcomes compared to MASLD alone. MetALD patients face increased risks of liver disease progression, cancer and cardiovascular disease. The diagnosis of MetALD involves the adequate quantification of alcohol use through standardised questionnaires and/or biomarkers as well as proper assessment of liver disease stage and progression risk using non-invasive tools including serologic markers, imaging, elastography techniques and genetic testing. Effective management requires addressing both metabolic and alcohol-related factors to improve outcomes. This review intends to provide a comprehensive overview of MetALD, covering pathogenesis, potential diagnostic approaches, management strategies and emerging therapies.
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Affiliation(s)
- Gustavo Ayares
- Departamento de GastroenterologíaEscuela de Medicina, Pontificia Universidad Católica de ChileSantiagoChile
- Escuela de Medicina, Universidad Finis TerraeSantiagoChile
| | - Luis Antonio Diaz
- Departamento de GastroenterologíaEscuela de Medicina, Pontificia Universidad Católica de ChileSantiagoChile
- MASLD Research Center, Division of Gastroenterology and HepatologyUniversity of California San DiegoCaliforniaUSA
| | - Francisco Idalsoaga
- Departamento de GastroenterologíaEscuela de Medicina, Pontificia Universidad Católica de ChileSantiagoChile
- Division of Gastroenterology Department of MedicineSchulich School of Medicine, Western University & London Health Sciences CentreLondonOntarioCanada
| | - Naim Alkhouri
- Department of HepatologyArizona Liver HealthChandlerArizonaUSA
| | | | - Ramon Bataller
- Liver UnitHospital Clinic and Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS)BarcelonaSpain
| | - Rohit Loomba
- MASLD Research Center, Division of Gastroenterology and HepatologyUniversity of California San DiegoCaliforniaUSA
| | - Juan Pablo Arab
- Departamento de GastroenterologíaEscuela de Medicina, Pontificia Universidad Católica de ChileSantiagoChile
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal MedicineVirginia Commonwealth University School of MedicineVirginiaUSA
| | - Marco Arrese
- Departamento de GastroenterologíaEscuela de Medicina, Pontificia Universidad Católica de ChileSantiagoChile
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Zhang A, Liu Q, Xiong Y, Li J, Xu Y, Song H, Jing X, Xu H, Yang N, Li Y, Mo L, Tang Q, He J. Tirzepatide reduces body weight by increasing fat utilization via the central nervous system-adipose tissue axis in male mice. Diabetes Obes Metab 2025; 27:2844-2856. [PMID: 40000395 DOI: 10.1111/dom.16294] [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: 10/10/2024] [Revised: 02/13/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025]
Abstract
AIMS Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates promise as a potent medication for obesity. However, the extent to which its weight-reducing effects go beyond suppressing appetite remains unclear. This study aimed to elucidate this by establishing a pair-fed control group, effectively eliminating the influence of reduced caloric intake. MATERIALS AND METHODS Mice fed on a chow diet or a high-fat diet received single or long-term intracerebroventricular (i.c.v.) injections of tirzepatide or vehicle. The vehicle-treated mice were pair-fed to the tirzepatide-treated group to avoid the impact induced by different caloric intakes. Body weight and food intake were monitored daily. Respiratory exchange ratio (RER) was determined in metabolic cages. Fat utilization was calculated based on RER. Parameters of lipid metabolism were evaluated. RESULTS Mice receiving i.c.v. administration of tirzepatide exhibited significant reductions in body weight and fat content compared with pair-fed controls. These effects were mediated by increased lipolytic capacity in white adipose tissue and enhanced thermogenesis in brown and beige adipose tissues, leading to decreased RER and increased lipid utilization. Mechanistic investigations revealed that these effects were primarily mediated by sympathetic nervous system innervation of adipose tissues. This innervation, in turn, might be associated with the neuronal activity changes in the dorsomedial hypothalamus and the nucleus of the solitary tract within the hindbrain. CONCLUSIONS These findings establish a critical role for tirzepatide in shifting the substrate preference to fat utilization through the central nervous system-adipose tissue axis, promoting weight loss independent of food intake.
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Affiliation(s)
- Ailin Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China
| | - Qinhui Liu
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yimin Xiong
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jiahui Li
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Ying Xu
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Haiying Song
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xiandan Jing
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Haixia Xu
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Na Yang
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yanping Li
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Li Mo
- Center of Gerontology and Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Qin Tang
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jinhan He
- West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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Rohmann N, Hollstein T, Laudes M. [Principles of obesity treatment: What has changed in the updated S3 guideline?]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2025; 66:453-460. [PMID: 40198359 DOI: 10.1007/s00108-025-01900-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/01/2025] [Indexed: 04/10/2025]
Abstract
A comprehensive update of the S3 guideline for the prevention and treatment of obesity was published in October 2024. In contrast to the former version, the literature search included not only data on weight reduction but also data on patient-reported outcomes and co-morbidity. The new recommendations for nutritional therapy, besides fat and carbohydrate reduction, now also include novel aspects like the Mediterranean diet and intermittent fasting. These will enable individualization and will avoid an unbalanced diet. Pharmacotherapy, especially incretin-based, is recommended in an adjuvant setting, especially since current clinical trials indicate beneficial effects on the heart, liver and kidney in addition to weight reduction. A novel chapter was included regarding eHealth strategies, since these are efficient as supportive measures for multidimensional treatment programs, including nutritional advice, behavioural coaching and exercise training. Finally, a novel aspect was incorporated: discrimination and stigmatization of subjects suffering from obesity. This is important not only for the general environment but also for the medical sector, including the handling of patients as well as the infrastructure of the medical institution (e.g. heavy-duty chairs). Hence, the novel guideline will guarantee high quality in the medical care of subjects suffering from obesity.
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Affiliation(s)
- Nathalie Rohmann
- Institut für Diabetologie und klinische Stoffwechselforschung, Universitätsklinikum Schleswig-Holstein (UKSH), Campus Kiel, Düsternbrooker Weg 17, 24105, Kiel, Deutschland
- Abteilung für Endokrinologie, Diabetologie und klinische Ernährungsmedizin, Klinik für Innere Medizin 1, Universitätsklinikum Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Deutschland
| | - Tim Hollstein
- Institut für Diabetologie und klinische Stoffwechselforschung, Universitätsklinikum Schleswig-Holstein (UKSH), Campus Kiel, Düsternbrooker Weg 17, 24105, Kiel, Deutschland
- Abteilung für Endokrinologie, Diabetologie und klinische Ernährungsmedizin, Klinik für Innere Medizin 1, Universitätsklinikum Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Deutschland
| | - Matthias Laudes
- Institut für Diabetologie und klinische Stoffwechselforschung, Universitätsklinikum Schleswig-Holstein (UKSH), Campus Kiel, Düsternbrooker Weg 17, 24105, Kiel, Deutschland.
- Abteilung für Endokrinologie, Diabetologie und klinische Ernährungsmedizin, Klinik für Innere Medizin 1, Universitätsklinikum Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Deutschland.
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Kaya E, Syn WK, Manka P. Glucagon like peptide-1 receptor agonists as a promising therapeutic option of metabolic dysfunction associated steatotic liver disease and obesity: hitting two targets with one shot. Curr Opin Gastroenterol 2025; 41:104-109. [PMID: 39998880 DOI: 10.1097/mog.0000000000001083] [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] [Indexed: 02/27/2025]
Abstract
PURPOSE OF REVIEW Obesity and type 2 diabetes mellitus (T2DM) are significant global health challenges, closely linked to metabolic dysfunction-associated steatotic liver disease (MASLD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise in treating T2DM and obesity, but their potential for managing MASLD is still being explored. This review aims to examine the current progress in using GLP-1RAs for MASLD treatment and evaluate emerging dual and triple hormonal agonists as future therapeutic options. RECENT FINDINGS GLP-1RAs have been effective in controlling blood sugar levels, promoting weight loss, and improving cardiovascular and kidney function. Furthermore, they have shown potential benefits for liver function in patients with MASLD. GLP-1, a key incretin hormone, influences glucose metabolism, appetite, and insulin sensitivity while affecting gastric emptying and potentially reducing fat deposition in the liver. Recent developments in GLP-1RAs include various formulations with different administration and dosing options, expanding their therapeutic use. SUMMARY GLP-1RAs have become central to the management of T2DM, obesity, and possibly MASLD due to their ability to lower HbA1c, aid in weight reduction, and provide cardiovascular protection. As research continues, dual and triple hormonal agonists are emerging as the next evolution of incretin-based therapies, offering promising new strategies for addressing MASLD in the future.
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Affiliation(s)
- Eda Kaya
- Department of Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
| | - Wing-Kin Syn
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA
- Department of Physiology, Faculty of Medicine and Nursing, University of Basque Coubtry UPV/EHU, Viscaya, Spain
| | - Paul Manka
- Department of Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany
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John S, Bhowmick K, Park A, Huang H, Yang X, Mishra L. Recent advances in targeting obesity, with a focus on TGF-β signaling and vagus nerve innervation. Bioelectron Med 2025; 11:10. [PMID: 40301996 PMCID: PMC12042417 DOI: 10.1186/s42234-025-00172-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/31/2025] [Indexed: 05/01/2025] Open
Abstract
Over a third of the global population is affected by obesity, fatty liver disease (Metabolic Dysfunction-Associated Steatotic Liver Disease, MASLD), and its severe form, MASH (Metabolic Dysfunction-Associated Steatohepatitis), which can ultimately progress to hepatocellular carcinoma (HCC). Recent advancements include therapeutics such as glucagon-like peptide 1 (GLP-1) agonists and neural/vagal modulation strategies for these disorders. Among the many pathways regulating these conditions, emerging insights into transforming growth factor-β (TGF-β) signaling highlight potential future targets through its role in pathophysiological processes such as adipogenesis, inflammation, and fibrosis. Vagus nerve innervation in the gastrointestinal tract is involved in satiety regulation and energy homeostasis, and vagus nerve stimulation has been applied in weight loss and diabetes. This review explores clinical trials in obesity, novel therapeutic targets, and the role of TGF-β signaling and vagus nerve modulation in obesity-related liver diseases and HCC.
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Affiliation(s)
- Sahara John
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Krishanu Bhowmick
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA
| | - Andrew Park
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Hai Huang
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Xiaochun Yang
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
| | - Lopa Mishra
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
- Department of Surgery, George Washington University, Washington, DC, 20037, USA.
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Drucker DJ. GLP-1-based therapies for diabetes, obesity and beyond. Nat Rev Drug Discov 2025:10.1038/s41573-025-01183-8. [PMID: 40281304 DOI: 10.1038/s41573-025-01183-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2025] [Indexed: 04/29/2025]
Abstract
Glucagon-like peptide 1 (GLP-1)-based therapies, such as semaglutide and tirzepatide, represent highly effective treatment options for people with type 2 diabetes and obesity, enabling effective control of glucose and weight loss, while reducing cardiovascular and renal morbidity and mortality. The success of these medicines has spurred development of next-generation GLP-1-based drugs, promising greater weight loss, improved tolerability and additional options for the route and frequency of dosing. This Review profiles established and emerging GLP-1-based medicines, discussing optimization of pharmacokinetics and tolerability, engagement of new therapeutically useful pathways and safety aspects. Structurally unique GLP-1-based medicines that achieve substantially greater and rapid weight loss may impact musculoskeletal health, providing a rationale for therapeutics that more selectively target adipose tissue loss while preserving muscle mass and strength. Ongoing clinical trials in peripheral vascular disease, neuropsychiatric and substance use disorders, metabolic liver disease, arthritis, hypertension and neurodegenerative disorders may broaden indications for GLP-1-based therapeutics.
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Affiliation(s)
- Daniel J Drucker
- Department of Medicine and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
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40
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Wang W, Gao X, Niu W, Yin J, He K. Targeting Metabolism: Innovative Therapies for MASLD Unveiled. Int J Mol Sci 2025; 26:4077. [PMID: 40362316 PMCID: PMC12071536 DOI: 10.3390/ijms26094077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/01/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.
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Affiliation(s)
- Weixin Wang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Xin Gao
- School of Public Health, Jilin University, Changchun 130021, China;
| | - Wentong Niu
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Jinping Yin
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130041, China;
| | - Kan He
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
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Makam AN, Bailey L, Anderson N, Bellitti K, Skinner S, Nguyen OK. Availability of Cardioprotective Medications for Type 2 Diabetes in the Medicaid Program. Ann Intern Med 2025. [PMID: 40258281 DOI: 10.7326/annals-24-01449] [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: 04/23/2025] Open
Abstract
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the only type 2 diabetes medications that reduce cardiovascular disease and death, yet their availability in Medicaid is unclear. OBJECTIVE To assess the unrestricted availability of SGLT2is and GLP-1 RAs, using dipeptidyl peptidase-4 inhibitors (DPP4is) as a benchmark. DESIGN National cross-sectional study using publicly available data. SETTING All 50 state Medicaid fee-for-service (FFS) plans and 273 nonelderly adult managed care organization (MCO) plans with comprehensive coverage in March 2024. PARTICIPANTS Medicaid plans and enrollees with diabetes in those plans as of March 2024. MEASUREMENTS Unrestricted availability was defined as having at least 1 medication in each class listed on the preferred drug list without prior authorization or step therapy. RESULTS Of 50 FFS plans (including Washington, DC, and excluding 1 state, which had 5 MCO plans), 40 (80%) had unrestricted availability of SGLT2is, 30 (60%) of GLP-1 RAs, 41 (82%) of either, 29 (58%) of both, and 42 (84%) of DPP4is. Among 273 MCO plans (39 states; median, 6 plans [range, 2 to 24 plans]), 182 (67%) had availability of SGLT2is, 131 (48%) of GLP-1 RAs, 184 (67%) of either, 129 (47%) of both, and 204 (75%) of DPP4is. The proportion of MCO enrollees with availability varied markedly among states (SGLT2i range, 24% to 100%; GLP-1 RA range, 0% to 99%; DPP4i range, 41% to 100%). Primarily because of more MCO restrictions, 1.7 million enrollees (lower to upper bound, 1.33 million to 2.17 million enrollees; 25%) had restricted SGLT2i availability, 2.72 million (lower to upper bound, 2.12 million to 3.45 million; 40%) had restricted GLP-1 RA availability, and 1.5 million (lower to upper bound, 1.17 million to 1.90 million; 22%) had restricted DPP4i availability. Availability increased from 2020 to 2024, especially in FFS, but MCO GLP-1 RA availability has plateaued at below 60% since 2022. Tirzepatide was almost entirely restricted. LIMITATIONS Diabetes enrollment was estimated using plan size and state and national prevalence data. The appropriateness of prior authorization restrictions was unknown. CONCLUSION Many Medicaid enrollees have restricted access to cardioprotective medications, particularly in MCO plans for GLP-1 RA medications, with substantial state variation. Formulary coverage is a potential lever to increase availability of these medications while balancing pharmaceutical costs. PRIMARY FUNDING SOURCE University of California, San Francisco, Action Research Center for Health Equity.
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Affiliation(s)
- Anil N Makam
- Division of Hospital Medicine, UCSF at San Francisco General Hospital; UCSF Philip R. Lee Institute for Health Policy Studies; and UCSF Action Research Center for Health Equity, San Francisco, California (A.N.M.)
| | - Logan Bailey
- School of Medicine, UCSF, San Francisco, and Departments of Graduate Medical Education and Emergency Medicine, Sutter Roseville Medical Center, Roseville, California (L.B.)
| | - Nigel Anderson
- School of Medicine, UCSF, San Francisco, California (N.A.)
| | - Kathy Bellitti
- Fingertip Formulary, Clarivate Analytics, Chandler, Arizona (K.B.)
| | - Sasha Skinner
- Division of Hospital Medicine, UCSF at San Francisco General Hospital, San Francisco, California (S.S.)
| | - Oanh Kieu Nguyen
- Division of Hospital Medicine, UCSF at San Francisco General Hospital; UCSF Philip R. Lee Institute for Health Policy Studies; UCSF Action Research Center for Health Equity; and Chan Zuckerberg Biohub, San Francisco, California (O.K.N.)
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Bansal B, Lajeunesse-Trempe F, Keshvani N, Lavie CJ, Pandey A. Impact of Metabolic Dysfunction-associated Steatotic Liver Disease on Cardiovascular Structure, Function, and the Risk of Heart Failure. Can J Cardiol 2025:S0828-282X(25)00315-0. [PMID: 40258400 DOI: 10.1016/j.cjca.2025.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 04/01/2025] [Accepted: 04/10/2025] [Indexed: 04/23/2025] Open
Abstract
Mounting evidence has established metabolic dysfunction-associated steatotic liver disease (MASLD) as an independent risk factor for heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). In this narrative review we explore the impact of MASLD on cardiovascular structure and function. We summarize findings from multiple cohort studies demonstrating that MASLD is associated with distinct patterns of adverse cardiac remodeling, including increased left ventricular concentricity and impaired diastolic function. These subclinical changes in cardiac structure and function often precede overt HF development and appear to occur in the context of multiple interconnected pathways involving metabolic dysfunction, systemic inflammation, adipose tissue dysregulation, vascular dysfunction, and altered hepatic hemodynamics. Early identification of cardiac structural and functional abnormalities through systematic screening may enable timely intervention in this high-risk population. Lifestyle modifications remain foundational, but achieving and maintaining significant weight loss is challenging. Recent clinical trials have shown promising results with cardiometabolic agents, particularly glucagon-like protein 1 receptor agonists, which demonstrate significant weight loss and hepatic and cardiovascular benefits. Despite these advances, key knowledge gaps remain regarding optimal screening strategies, mechanisms linking MASLD to HF, and targeted therapeutic approaches. Addressing these gaps will be essential for developing effective prevention and treatment strategies in this high-risk population.
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Affiliation(s)
- Bhavik Bansal
- All India Institute of Medical Sciences, New Delhi, India; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Fannie Lajeunesse-Trempe
- Department of Internal Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, Québec, Canada
| | - Neil Keshvani
- Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Baylor Scott and White Research Institute, Dallas, Texas, USA; Baylor Scott & White The Heart Hospital, Plano, Texas, USA
| | - Carl J Lavie
- Department of Cardiovascular Diseases and Internal Medicine, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
| | - Ambarish Pandey
- Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
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Iakovleva V, de Jong YP. Gene-based therapies for steatotic liver disease. Mol Ther 2025:S1525-0016(25)00298-9. [PMID: 40254880 DOI: 10.1016/j.ymthe.2025.04.024] [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: 01/06/2025] [Revised: 03/26/2025] [Accepted: 04/16/2025] [Indexed: 04/22/2025] Open
Abstract
Advances in nucleic acid delivery have positioned the liver as a key target for gene therapy, with adeno-associated virus vectors showing long-term effectiveness in treating hemophilia. Steatotic liver disease (SLD), the most common liver condition globally, primarily results from metabolic dysfunction-associated and alcohol-associated liver diseases. In some individuals, SLD progresses from simple steatosis to steatohepatitis, cirrhosis, and eventually hepatocellular carcinoma, driven by a complex interplay of genetic, metabolic, and environmental factors. Genetic variations in various lipid metabolism-related genes, such as patatin-like phospholipase domain-containing protein 3 (PNPLA3), 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13), and mitochondrial amidoxime-reducing component 1 (MTARC1), impact the progression of SLD and offer promising therapeutic targets. This review largely focuses on genes identified through clinical association studies, as they are more likely to be effective and safe for therapeutic intervention. While preclinical research continues to deepen our understanding of genetic factors, early-stage clinical trials involving gene-based SLD therapies, including transient antisense and small-molecule approaches, are helping prioritize therapeutic targets. Meanwhile, hepatocyte gene editing technologies are advancing rapidly, offering alternatives to transient methods. As such, gene-based therapies show significant potential for preventing the progression of SLD and enhancing long-term liver health.
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Affiliation(s)
- Viktoriia Iakovleva
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Ype P de Jong
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10021, USA.
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Pecani M, Andreozzi P, Cangemi R, Corica B, Miglionico M, Romiti GF, Stefanini L, Raparelli V, Basili S. Metabolic Syndrome and Liver Disease: Re-Appraisal of Screening, Diagnosis, and Treatment Through the Paradigm Shift from NAFLD to MASLD. J Clin Med 2025; 14:2750. [PMID: 40283580 PMCID: PMC12028215 DOI: 10.3390/jcm14082750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/11/2025] [Accepted: 04/12/2025] [Indexed: 04/29/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), encompasses a spectrum of liver diseases characterized by hepatic steatosis, the presence of at least one cardiometabolic risk factor, and no other apparent cause. Metabolic syndrome (MetS) is a cluster of clinical conditions associated with increased risk of cardiovascular disease, type 2 diabetes, and overall morbidity and mortality. This narrative review summarizes the changes in the management of people with MetS and NAFLD/MASLD from screening to therapeutic strategies that have occurred in the last decades. Specifically, we underline the clinical importance of considering the different impacts of simple steatosis and advanced fibrosis and provide an up-to-date overview on non-invasive diagnostic tests (i.e., imaging and serum biomarkers), which now offer acceptable accuracy and are globally more accessible. Early detection of MetS and MASLD is a top priority as it allows for timely interventions, primarily through lifestyle modification. The liver and cardiovascular benefits of a global and multidimensional approach are not negligible. Therefore, a holistic approach to both conditions, MetS and related chronic liver disease, should be applied to improve overall health and longevity.
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Affiliation(s)
- Marin Pecani
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Paola Andreozzi
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Roberto Cangemi
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Bernadette Corica
- Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Polyclinic of Modena, 41121 Modena, Italy
| | - Marzia Miglionico
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Giulio Francesco Romiti
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Lucia Stefanini
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Valeria Raparelli
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Stefania Basili
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
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Kamrul-Hasan ABM, Pappachan JM, Dutta D, Nagendra L, Kuchay MS, Kapoor N. Reasons for discontinuing tirzepatide in randomized controlled trials: A systematic review and meta-analysis. World J Diabetes 2025; 16:101731. [PMID: 40236848 PMCID: PMC11947928 DOI: 10.4239/wjd.v16.i4.101731] [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: 09/24/2024] [Revised: 12/21/2024] [Accepted: 01/14/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND Despite therapeutic benefits, discontinuation of tirzepatide is common in randomized controlled trials (RCTs) due to adverse events (AEs) and other causes. No previous systematic reviews have explored the reasons for discontinuing tirzepatide in the RCTs. AIM To explore the reasons for permanent discontinuation of tirzepatide vs controls [placebo, insulin, and glucagon-like peptide-1 receptor agonists (GLP-1Ras)] in RCTs. METHODS Relevant RCTs were systematically searched using related terms through multiple databases such as MEDLINE (via PubMed), Scopus, Cochrane Central Register, and ClinicalTrials.gov from their inception until June 20, 2024. RevMan web was used to conduct meta-analysis using random-effects models. Outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI). RESULTS Seventeen RCTs (n = 14645), mostly having low risks of bias, were analyzed. Compared to placebo, the risk of permanent discontinuation of the study drug was substantially lower with tirzepatide 10 mg (RR: 0.69, 95%CI: 0.51-0.93, P = 0.02) and similar with tirzepatide 5 mg (RR: 0.74, 95%CI: 0.47-1.17, P = 0.20) and 15 mg (RR: 0.94, 95%CI: 0.68-1.31, P = 0.71). Tirzepatide had identical discontinuation risks when compared to insulin at 5 mg (RR: 0.96, 95%CI: 0.75-1.24, P = 0.77) and 10 mg (RR: 1.19, 95%CI: 0.77-1.82, P = 0.44) doses, whereas such risk was higher with tirzepatide 15 mg than insulin (RR: 1.31, 95%CI: 1.03-1.67, P = 0.03). Compared to GLP-1RA, the permanent discontinuation risk was similar with tirzepatide 5 mg (RR: 0.98, 95%CI: 0.70-1.37, P = 0.90) but was higher with tirzepatide 10 mg (RR: 1.40, 95%CI: 1.03-1.90, P = 0.03) and 15 mg (RR: 1.70, 95%CI: 1.27-2.27, P = 0.0004). Tirzepatide, at all doses, had higher risks of AE-related discontinuation than insulin; such risks were only greater with higher doses of tirzepatide than with placebo or GLP-1RA. Discontinuation risk due to withdrawal by the study subjects was lower with tirzepatide than with placebo or insulin. Compared to the placebo, tirzepatide (all doses) conferred a lower risk of study drug discontinuation due to other causes not specifically mentioned. CONCLUSION The discontinuation risk is not higher in tirzepatide group than in the placebo arm. Many factors other than AEs led to drug discontinuation in the included RCTs.
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Affiliation(s)
| | - Joseph M Pappachan
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Department of Endocrinology, KMC Medical College, Manipal University, Manipal 576104, India
| | - Deep Dutta
- Department of Endocrinology, CEDAR Superspeciality Healthcare, Dwarka, New Delhi 110075, India
| | - Lakshmi Nagendra
- Department of Endocrinology, JSS Medical College, JSS Academy of Higher Education & Research, Mysore 570015, India
| | - Mohammad Shafi Kuchay
- Department of Endocrinology and Diabetes, Medanta the Medicity Hospital, Gurugram 122001, Haryana, India
| | - Nitin Kapoor
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
- Non-Communicable Disease Unit, Melbourne School of Population and Global Health, University of Melbourne, Carlton 3053, Victoria, Australia
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Anastasiou IΑ, Argyrakopoulou G, Dalamaga M, Kokkinos A. Dual and Triple Gut Peptide Agonists on the Horizon for the Treatment of Type 2 Diabetes and Obesity. An Overview of Preclinical and Clinical Data. Curr Obes Rep 2025; 14:34. [PMID: 40210807 PMCID: PMC11985575 DOI: 10.1007/s13679-025-00623-1] [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] [Accepted: 03/21/2025] [Indexed: 04/12/2025]
Abstract
PURPOSE OF REVIEW The development of long-acting incretin receptor agonists represents a significant advance in the fight against the concurrent epidemics of type 2 diabetes mellitus (T2DM) and obesity. The aim of the present review is to examine the cellular processes underlying the actions of these new, highly significant classes of peptide receptor agonists. We further explore the potential actions of multi-agonist drugs as well as the mechanisms through which gut-brain communication can be used to achieve long-term weight loss without negative side effects. RECENT FINDINGS Several unimolecular dual-receptor agonists have shown promising clinical efficacy studies when used alone or in conjunction with approved glucose-lowering medications. We also describe the development of incretin-based pharmacotherapy, starting with exendin- 4 and ending with the identification of multi-incretin hormone receptor agonists, which appear to be the next major step in the fight against T2DM and obesity. We discuss the multi-agonists currently in clinical trials and how each new generation of these drugs improves their effectiveness. Since most glucose-dependent insulinotropic polypeptide (GIP) receptor: glucagon-like peptide- 1 receptor (GLP- 1) receptor: glucagon receptor triagonists compete in efficacy with bariatric surgery, the success of these agents in preclinical models and clinical trials suggests a bright future for multi-agonists in the treatment of metabolic diseases. To fully understand how these treatments affect body weight, further research is needed.
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Affiliation(s)
- Ioanna Α Anastasiou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
- Department of Pharmacology, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | | | - Maria Dalamaga
- Department of Biological Chemistry, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Alexander Kokkinos
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece.
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Romero-Gómez M, Escalada J, Noguerol M, Pérez A, Carretero J, Crespo J, Mascort JJ, Aguilar I, Tinahones F, Cañones P, Gómez-Huelgas R, de Luis D, Genúa Trullos I, Aller R, Rubio MA. Multidisciplinary clinical practice guideline on the management of metabolic hepatic steatosis. GASTROENTEROLOGIA Y HEPATOLOGIA 2025:502442. [PMID: 40221023 DOI: 10.1016/j.gastrohep.2025.502442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/26/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025]
Abstract
Metabolic hepatic steatosis (MetHS) is a clinically heterogeneous, multisystemic, dynamic, and complex disease, whose progression is one of the main causes of cirrhosis and hepatocarcinoma. This clinical practice guideline aims to respond to its main challenges, both in terms of disease burden and complexity. To this end, recommendations have been proposed to experts through the Delphi method. The consensus was optimal in recommendations regarding type 2 diabetes as a risk factor (1.5.1, 4.5.1), in which cases early detection of MetHS should be carried out (4.5.2). Its results also emphasize the importance of the use of non-invasive tests (FIB-4, NFS, HFS) for the exclusion of significant fibrosis in patients with suspected MetHS (2.3.1, 2.3.3). Diagnosis should be carried out through the sequential combination of non-invasive indices and transient elastography by FibroScan® for its risk stratification (2.3.3). A nearly unanimous consensus was reached regarding the role of early prevention in the impact on the quality of life and survival of patients (5.1.2), as well as on the effectiveness of the Mediterranean diet and physical exercise in relation to the improvement of steatosis, steatohepatitis and fibrosis in MetHS patients (5.2.2) and on the positive results offered by resmiterom and semaglutide in promoting fibrosis regression (5.4.1). Finally, a great consensus has been reached regarding the importance of multidisciplinary management in MetHS, for which it is essential to agree on multidisciplinary protocols for referral between levels in each health area (6.2.1), as well as ensuring that referrals to Hepatology/Digestive and Endocrinology or Internal Medicine services are effective and beneficial to prevent the risk of disease progression (6.2.3, 6.3.1).
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Affiliation(s)
- Manuel Romero-Gómez
- UGC Aparato Digestivo, Hospital Universitario Virgen del Rocío, Sevilla, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Departamento de Medicina, Universidad de Sevilla, Sevilla, España; Asociación España para el Estudio del Hígado, España.
| | - Javier Escalada
- Clínica Universidad de Navarra, Pamplona, España; Sociedad Española de Endocrinología y Nutrición, España; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, España; Instituto de Investigación en la Salud de Navarra (IdiSNA), Pamplona, España.
| | - Mar Noguerol
- Centro de Salud Universitario Cuzco de Fuenlabrada, Madrid, España; Sociedad Española de Medicina de Familia y Comunitaria, España
| | - Antonio Pérez
- Servicio de Endocrinología y Nutrición, Hospital de la Santa Creu i Sant Pau, Barcelona, España; CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), España; Sociedad Española de Diabetes, España
| | - Juana Carretero
- Hospital Universitario de Badajoz, Badajoz, España; Sociedad Española de Medicina Interna (SEMI), España
| | - Javier Crespo
- Hospital Universitario Marqués de Valdecilla, Santander, España; Sociedad Española de Patología Digestiva, España; Grupo de Investigación Clínica y Traslacional en Enfermedades Digestivas, España; Instituto de Investigación Valdecilla (IDIVAL), Santander, España
| | - Juan J Mascort
- Sociedad Española de Medicina de Familia y Comunitaria, España; Centro de Salud Florida Sud, Institut Català de la Salut, Hospitalet de Llobregat, España
| | - Ignacio Aguilar
- Clínica Universidad de Navarra, Pamplona, España; Sociedad Española de Endocrinología y Nutrición, España; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, España; Instituto de Investigación en la Salud de Navarra (IdiSNA), Pamplona, España
| | - Francisco Tinahones
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, España; Departamento de Endocrinología y Nutrición, Hospital Virgen de la Victoria, Málaga, España; Sociedad Española de Obesidad, España; Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma Bionard, Universidad de Málaga, Málaga, España
| | - Pedro Cañones
- Sociedad Española de Médicos Generales y de Familia, España
| | - Ricardo Gómez-Huelgas
- Sociedad Española de Medicina Interna (SEMI), España; Servicio de Medicina Interna, Hospital Regional Universitario de Málaga, Málaga, España; Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga (UMA), Málaga, España
| | - Daniel de Luis
- Sociedad Española de Endocrinología y Nutrición, España; Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valladolid, Valladolid, España; Centro de Investigación de Endocrinología y Nutrición, Universidad de Valladolidad, Valladolid, España
| | - Idoia Genúa Trullos
- Servicio de Endocrinología y Nutrición, Hospital de la Santa Creu i Sant Pau, Barcelona, España; CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), España; Sociedad Española de Diabetes, España
| | - Rocío Aller
- Servicio de Endocrinología y Nutrición, Hospital de la Santa Creu i Sant Pau, Barcelona, España; CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), España; Sociedad Española de Diabetes, España; Servicio de Aparato Digestivo, Hospital Clínico Universitario de Valladolid, Universidad de Valladolid, Valladolid, España; Ciber Enfermedades infecciosas (CIBERINFEC), España
| | - Miguel A Rubio
- Sociedad Española de Endocrinología y Nutrición, España; Hospital Clínico San Carlos, Madrid, España
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Andersson A, Loomba R, Beyer C, Mouchti S, Vuppalanchi R, Harisinghani M, Ajaz S, Dinani A, Banerjee A, Muthiah M, Dennis A, Pansini M. Change in cT1 Following Interventions in MASLD: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2025:S1542-3565(25)00254-X. [PMID: 40220846 DOI: 10.1016/j.cgh.2025.03.003] [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: 12/11/2024] [Revised: 02/13/2025] [Accepted: 03/18/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND AND AIMS Liver corrected T1 (cT1), measured with multiparametric magnetic resonance imaging, offers an alternative to liver biopsy to monitor treatment response and liver disease activity. We aimed to perform a systematic evaluation of change in cT1 following a treatment intervention in adults with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS We searched the Cochrane Library, PubMed Central, and MEDLINE from 2014 to September 2024 for studies that examined cT1 responses following intervention in metabolic dysfunction-associated liver disease. Two authors independently screened records, assessed risk of bias, and extracted data. Meta-analyses were performed to explore the mean change in cT1 between baseline and end of study. RESULTS A total of 16 studies (n = 1134 individuals) were analyzed (13 randomized controlled trials [n = 1077]) and 3 prospective diet, lifestyle and bariatric surgery studies [n = 57]). The mean change in cT1 was -57 ms (95% confidence interval [CI], -62 to -52 ms) over a median 17 weeks (interquartile range: 12-24 weeks). By treatment type, fibroblast growth factor analogues, glucagon-like peptide-1 receptor agonists, and farnesoid X receptor agonists, cT1 had a mean change of -79 ms (95% CI, -90 to -68 ms) to -68 ms (95% CI, -77 to -58 ms) and -62 ms (95% CI, -74 to -49 ms), respectively. In contrast, the placebo arms showed a mean change in cT1 of 0 ms (95% CI, -8 to 8 ms). CONCLUSIONS Evidence to date supports a significant treatment-induced reduction in cT1 as compared with minimal changes in the placebo group. Our findings could inform study designs for investigational therapies and support monitoring of treatment response in individuals with metabolic dysfunction-associated liver disease in clinical trials and clinical practice.
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Affiliation(s)
| | - Rohit Loomba
- MASLD Research Center, University of California at San Diego, La Jolla, California
| | | | | | - Raj Vuppalanchi
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Saima Ajaz
- Institute of Liver Studies, Kings College Hospital, London, United Kingdom
| | - Amreen Dinani
- Division of Gastroenterology and Hepatology, Duke University Health System, Durham, North Carolina
| | - Amitava Banerjee
- Institute of Health Informatics, University College London, London, United Kingdom; Department of Cardiology, University College London Hospitals NHS Foundation Trust, London, United Kingdom; Department of Cardiology, Barts Health NHS Trust, London, United Kingdom
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Michele Pansini
- Clinica Di Radiologia EOC, Istituto Di Imaging Della Svizzera Italiana, Lugano, Switzerland; Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
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Colagiuri S, Ceriello A. 7. Management of metabolic dysfunction-associated steatotic liver disease (MASLD) in type 2 diabetes. Diabetes Res Clin Pract 2025:112151. [PMID: 40209901 DOI: 10.1016/j.diabres.2025.112151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/12/2025]
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50
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Boulos M, Mousa RS, Jeries N, Simaan E, Alam K, Bulus B, Assy N. Hidden in the Fat: Unpacking the Metabolic Tango Between Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Syndrome. Int J Mol Sci 2025; 26:3448. [PMID: 40244398 PMCID: PMC11989262 DOI: 10.3390/ijms26073448] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/25/2025] [Accepted: 03/30/2025] [Indexed: 04/18/2025] Open
Abstract
Metabolic syndrome (MetS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related, with rapidly increasing prevalence globally, driving significant public health concerns. Both conditions share common pathophysiological mechanisms such as insulin resistance (IR), adipose tissue dysfunction, oxidative stress, and gut microbiota dysbiosis, which contribute to their co-occurrence and progression. While the clinical implications of this overlap, including increased cardiovascular, renal, and hepatic risk, are well recognized, current diagnostic and therapeutic approaches remain insufficient due to the clinical and individuals' heterogeneity and complexity of these diseases. This review aims to provide an in-depth exploration of the molecular mechanisms linking MetS and MASLD, identify critical gaps in our understanding, and highlight existing challenges in early detection and treatment. Despite advancements in biomarkers and therapeutic interventions, the need for a comprehensive, integrated approach remains. The review also discusses emerging therapies targeting specific pathways, the potential of precision medicine, and the growing role of artificial intelligence in enhancing research and clinical management. Future research is urgently needed to combine multi-omics data, precision medicine, and novel biomarkers to better understand the complex interactions between MetS and MASLD. Collaborative, multidisciplinary efforts are essential to develop more effective diagnostic tools and therapies to address these diseases on a global scale.
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Affiliation(s)
- Mariana Boulos
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Rabia S. Mousa
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Nizar Jeries
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Elias Simaan
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Klode Alam
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Bulus Bulus
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
| | - Nimer Assy
- Internal Medicine Department, Galilee Medical Centre, Nahariya 221001, Israel; (R.S.M.); (N.J.); (E.S.); (K.A.); (B.B.); (N.A.)
- The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
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