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Zambrano-Vásquez OR, Cortés-Camacho F, Castañeda-Sánchez JI, Aréchaga-Ocampo E, Valle-Velázquez E, Cabrera-Angeles JC, Sánchez-Gloria JL, Sánchez-Muñoz F, Arellano-Buendia AS, Sánchez-Lozada LG, Osorio-Alonso H. Update in non-alcoholic fatty liver disease management: role of sodium-glucose cotransporter 2 inhibitors. Life Sci 2025; 372:123638. [PMID: 40246191 DOI: 10.1016/j.lfs.2025.123638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 03/28/2025] [Accepted: 04/09/2025] [Indexed: 04/19/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes without significant alcohol consumption. It is closely associated with sedentarism, hypercaloric diets, obesity, dyslipidemia, insulin resistance, type 2 diabetes mellitus, and genetic predisposition. NAFLD comprises a spectrum of liver disorders, from simple steatosis to non-alcoholic (NASH) and liver cirrhosis. The complex etiological mechanisms include oxidative stress, inflammation, apoptosis, and fibrosis; therefore, its management is challenging. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i), a class of antidiabetic drugs, have emerged as promising therapeutic agents due to their ability to improve key metabolic parameters, including obesity, dyslipidemia, insulin resistance, and hyperglycemia. This review explores the cellular mechanisms by which SGLT2i, either as monotherapy or combined with other treatments, modulate signaling pathways involved in lipid and carbohydrate metabolism. Additionally, we examine their effects on oxidative stress, inflammation, fibrosis, and apoptosis, which are critical drivers of NAFLD progression. This review is intended to summarize the multiple benefits of SGLT2 inhibitors and to educate healthcare providers on the therapeutic potential of these drugs in order to foster their incorporation into effective NAFLD management plans.
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Affiliation(s)
- Oscar R Zambrano-Vásquez
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Ciudad de México 04960, Mexico; Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Fernando Cortés-Camacho
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Ciudad de México 04960, Mexico; Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Jorge I Castañeda-Sánchez
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, México City 04960, Mexico
| | - Elena Aréchaga-Ocampo
- Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Unidad Cuajimalpa, México City 05348, Mexico
| | - Estefanía Valle-Velázquez
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Juan C Cabrera-Angeles
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México City, Mexico
| | - José L Sánchez-Gloria
- Department of Internal Medicine, Division of Nephrology, Rush University Medical Center, Chicago, IL 60612, USA
| | - Fausto Sánchez-Muñoz
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Abraham S Arellano-Buendia
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Laura G Sánchez-Lozada
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Horacio Osorio-Alonso
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico.
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Luo JC, Jin LH, Zhong YS, Xu XY, Zhang ZY, Chen J, Chen ZX, Li S, Zhang XD, Qian JC. Sotagliflozin provides additional benefits for high-fat diet-induced cardiac inflammatory injury by extra inhibiting P38MAPK and JNK. Int Immunopharmacol 2025; 155:114631. [PMID: 40215771 DOI: 10.1016/j.intimp.2025.114631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 04/06/2025] [Accepted: 04/06/2025] [Indexed: 04/29/2025]
Abstract
SGLT1/2 dual-target inhibitors have demonstrated significant benefits for diabetic patients, particularly those with cardiovascular complications. However, pharmacological mechanisms beyond SGLT1/2 inhibition remain incompletely understood. The current study investigated the effects of sotagliflozin, a representative SGLT1/2 inhibitor, on obesity-related cardiomyopathy and explored the underlying molecular mechanisms. A high-fat diet-induced obese mouse model was employed to evaluate cardiac function and biochemical parameters, complemented by transcriptomic analysis and network pharmacology to identify potential therapeutic targets. Results demonstrated that sotagliflozin effectively ameliorated hyperglycemia, hyperlipidemia, and hypertension in obese mice while significantly improving obesity-induced cardiac dysfunction through suppression of myocardial inflammatory responses. Transcriptomic analysis revealed enrichment of differentially expressed genes in the MAPK pathway, which was further corroborated by network pharmacology. Both in vivo and in vitro validation confirmed direct binding of sotagliflozin to P38MAPK and JNK, leading to significant inhibition of their activation induced by palmitic acid or high-fat diet. These findings suggest that the cardioprotective effects of sotagliflozin against obesity-related cardiomyopathy are mediated through multi-target inhibition of P38MAPK and JNK pathways. Targeting inflammatory signaling pathways while managing cardiovascular risk factors may represent a promising therapeutic strategy for obesity-associated cardiovascular diseases.
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Affiliation(s)
- Jian-Chao Luo
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Le-Hao Jin
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yun-Shan Zhong
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiao-Yu Xu
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhe-Yan Zhang
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jing Chen
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhong-Xi Chen
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Sen Li
- School of Basic Medicine, Wenzhou Medical University, Wenzhou 325035, China.
| | - Xiao-Dan Zhang
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Jian-Chang Qian
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
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3
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Bhattacharya I, Maity DK, Kumar A, Sarkar S, Bhattacharya T, Sahu A, Sreedhar R, Arumugam S. Beyond obesity: lean metabolic dysfunction-associated steatohepatitis from unveiling molecular pathogenesis to therapeutic advancement. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04257-x. [PMID: 40366398 DOI: 10.1007/s00210-025-04257-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 05/01/2025] [Indexed: 05/15/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD), now known by the name of metabolic dysfunction-associated fatty liver disease (MAFLD), with increased global incidence, has been recognized as a significant metabolic disorder. NAFLD includes a spectrum liver disease from hepatocellular fat accumulation (isolated steatosis) to an advanced form of liver injury known as nonalcoholic steatohepatitis (NASH), which refers to distinct histologic features, including hepatocellular steatosis and injury, necroinflammation, and eventually fibrosis. Nonobese or lean individuals associated with metabolic dysregulation usually demonstrated diverse risk factors compared to obese MAFLD. The presence of normal range body mass index (BMI) and excess visceral adiposity with increased cardiometabolic and renal comorbidities, along with sarcopenia, has been evidenced to be associated with lean MASH. Genetic predispositions accompanying lifestyle and environmental factors contribute to disease initiation and progression. The genetic influence in pathophysiology indicated the significant contributions of the following genes: PNPLA3, TM6SF2, APOB, LIPA, MBOAT7, and HSD17B13, and the impact of their disease-specific variants in the development of obesity-independent MASH. The epigenetic modifications exhibited differential DNA methylation patterns in the genes involved in lipid metabolism, particularly hypomethylation of PEMT. Diet-induced and genetic animal models of lean MASH, including Slc: Wistar/ST rats, PPAR-α, PTEN, and MAT1A knockout mice models, are indicated to be pivotal in the exploration of disease progression and observing the effect of therapeutic interventions. This comprehensive review comprises the molecular and genetic pathophysiology, molecular diagnostics, and therapeutic aspects of lean MASH to enunciate a diagnostic approach that combines detailed clinical phenotyping regarding genomic analysis.
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Affiliation(s)
- Indrajit Bhattacharya
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India
| | - Deep Kumar Maity
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India
| | - Amit Kumar
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India
| | - Sampriti Sarkar
- School of Biosciences & Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632014, India
| | - Teeshyo Bhattacharya
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India
| | - Amrita Sahu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India
| | - Remya Sreedhar
- School of Pharmacy, Sister Nivedita University, DG Block, Action Area I, 1/2, Newtown, Kolkata, 700156, West Bengal, India
| | - Somasundaram Arumugam
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054, West Bengal, India.
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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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5
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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: 0] [Impact Index Per Article: 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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6
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Eslam M, Fan JG, Yu ML, Wong VWS, Cua IH, Liu CJ, Tanwandee T, Gani R, Seto WK, Alam S, Young DY, Hamid S, Zheng MH, Kawaguchi T, Chan WK, Payawal D, Tan SS, Goh GBB, Strasser SI, Viet HD, Kao JH, Kim W, Kim SU, Keating SE, Yilmaz Y, Kamani L, Wang CC, Fouad Y, Abbas Z, Treeprasertsuk S, Thanapirom K, Al Mahtab M, Lkhagvaa U, Baatarkhuu O, Choudhury AK, Stedman CAM, Chowdhury A, Dokmeci AK, Wang FS, Lin HC, Huang JF, Howell J, Jia J, Alboraie M, Roberts SK, Yoneda M, Ghazinian H, Mirijanyan A, Nan Y, Lesmana CRA, Adams LA, Shiha G, Kumar M, Örmeci N, Wei L, Lau G, Omata M, Sarin SK, George J. The Asian Pacific association for the study of the liver clinical practice guidelines for the diagnosis and management of metabolic dysfunction-associated fatty liver disease. Hepatol Int 2025; 19:261-301. [PMID: 40016576 DOI: 10.1007/s12072-024-10774-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 12/28/2024] [Indexed: 03/01/2025]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over one-fourth of the global adult population and is the leading cause of liver disease worldwide. To address this, the Asian Pacific Association for the Study of the Liver (APASL) has created clinical practice guidelines focused on MAFLD. The guidelines cover various aspects of the disease, such as its epidemiology, diagnosis, screening, assessment, and treatment. The guidelines aim to advance clinical practice, knowledge, and research on MAFLD, particularly in special groups. The guidelines are designed to advance clinical practice, to provide evidence-based recommendations to assist healthcare stakeholders in decision-making and to improve patient care and disease awareness. The guidelines take into account the burden of clinical management for the healthcare sector.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, 2145, Australia.
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal MedicineCollege of Medicine and Center for Liquid Biopsy and Cohort ResearchFaculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of MedicineSchool of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, Kaohsiung Medical University, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
| | - Ian Homer Cua
- Institute of Digestive and Liver Diseases, St. Luke's Medical Center, Global City, Philippines
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal MedicineHepatitis Research CenterGraduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tawesak Tanwandee
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rino Gani
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Pangeran Diponegoro Road No. 71St, Central Jakarta, 10430, Indonesia
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Shahinul Alam
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Dan Yock Young
- Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Saeed Hamid
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Diana Payawal
- Department of Medicine, Cardinal Santos Medical Center, Mandaluyong, Philippines
| | - Soek-Siam Tan
- Department of Hepatology, Selayang Hospital, Batu Caves, Malaysia
| | - George Boon-Bee Goh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
- Medicine Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore
| | - Simone I Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Hang Dao Viet
- Internal Medicine Faculty, Hanoi Medical University, Hanoi, Vietnam
| | - Jia-Horng Kao
- Graduate Institute of Clinical MedicineDepartment of Internal MedicineHepatitis Research CenterDepartment of Medical Research, National Taiwan University College of Medicine, National Taiwan University, National Taiwan University Hospital, 1 Chang-Te Street, 10002, Taipei, Taiwan
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, 50-1, Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, Republic of Korea
| | - Shelley E Keating
- School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | | | - Chia-Chi Wang
- Buddhist Tzu Chi Medical Foundation and School of Medicine, Taipei Tzu Chi Hospital, Tzu Chi University, Taipei, Taiwan
| | - Yasser Fouad
- Department of Gastroenterology, Hepatology and Endemic Medicine, Faculty of Medicine, Minia University, Cairo, Egypt
| | - Zaigham Abbas
- Department of Hepatogastroenterology, Dr.Ziauddin University Hospital, Clifton, Karachi, Pakistan
| | | | | | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Undram Lkhagvaa
- Department of Health Policy, School of Public Health, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Oidov Baatarkhuu
- Department of Infectious Diseases, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Ashok Kumar Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - A Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Fu-Sheng Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, 100039, China
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Institute of Clinical Medicine, School of Medicine, Taipei Veterans General Hospital, National Yang-Ming Chiao Tung University, No. 201, Section 2, Shipai RdNo. 155, Section 2, Linong St, Beitou District, Taipei City, 112, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal MedicineCollege of Medicine and Center for Liquid Biopsy and Cohort ResearchFaculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jess Howell
- Burnet Institute, Melbourne, VIC, 3004, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Clayton, VIC, 3008, Australia
- Department of Medicine, The University of Melbourne, Parkville, VIC, 3050, Australia
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC, 3165, Australia
| | - Jidong Jia
- Liver Research Center, Beijing Key Laboratory of Translational Medicine On Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Mohamed Alboraie
- Department of Internal Medicine, Al-Azhar University, Cairo, 11884, Egypt
| | - Stuart K Roberts
- Department of Gastroenterology and Hepatology, Central Clinical School, The Alfred, Monash University, Melbourne, Australia
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Hasmik Ghazinian
- Gastroenterology and Hepatology Department, Yerevan Medical Scientific Center, Yerevan, Armenia
| | - Aram Mirijanyan
- Gastroenterology and Hepatology Department, Yerevan Medical Scientific Center, Yerevan, Armenia
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China
| | | | - Leon A Adams
- Medical School, Faculty of Medicine and Health Sciences, The University of Western Australia, Nedlands, WA, Australia
| | - Gamal Shiha
- Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Necati Örmeci
- Department of Gastroenterohepatology, Istanbul Health and Technology University, Istanbul, Turkey
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - George Lau
- Humanity and Health Medical Group, Humanity and Health Clinical Trial Center, Hong Kong SAR, China
- The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Tokyo, Japan
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, 2145, Australia
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7
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Konings LAM, Miguelañez‐Matute L, Boeren AMP, van de Luitgaarden IAT, Dirksmeier F, de Knegt RJ, Tushuizen ME, Grobbee DE, Holleboom AG, Cabezas MC. Pharmacological treatment options for metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus: A systematic review. Eur J Clin Invest 2025; 55:e70003. [PMID: 39937036 PMCID: PMC11891831 DOI: 10.1111/eci.70003] [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: 11/07/2024] [Accepted: 01/24/2025] [Indexed: 02/13/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to type 2 diabetes mellitus (T2DM) through a common root in insulin resistance. The more severe stage, metabolic dysfunction-associated steatohepatitis (MASH), increases the risk for cardiovascular complications, liver cirrhosis and hepatocellular carcinoma. Several trials investigating established antidiabetic-drugs in patients with T2DM and MASLD have yielded promising results. Therefore, we aimed to systematically review the effect of T2DM-drug treatment on MALSD parameters. METHODS Medical databases were searched until January 2025 for controlled trials in patients with T2DM and MASLD/MASH. Studies that evaluated the effect of T2DM-medication on the severity of MASLD/MASH in T2DM patients were included. The quality of the studies was assessed by three independent reviewers using a set of Cochrane risk-of-bias tools. RESULTS Of 1748 references, 117 studies fulfilled the inclusion-criteria and were assessed for eligibility in full-text. Fifty-two articles were included. Data included a total of 64.708 patients and study populations ranged from 9 to 50.742. Heterogeneity in study-design and analysis hampered the comparability of the results. Most evidence was present for GLP-1 receptor agonists, SGLT2-inhibitors and PPAR-γ-agonists for regression of liver fibrosis and MASH. CONCLUSION Studies on the value of T2DM-drug treatment in the improvement of MASLD vary significantly in study design, size and quality. GLP-1 receptor agonists, PPAR-γ-agonists, SGLT2-inhibitors may all be preferred pharmacological interventions for patients with MASLD/MASH and T2DM. Newer agents like dual GLP-1/GIP or triple GLP-1/GIP/Glucagon agonists will likely play an important role in the treatment of MASLD/MASH in the near future.
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Affiliation(s)
- Laura A. M. Konings
- Department of Internal MedicineFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
- Department of Internal Medicine and EndocrinologyErasmus MCRotterdamthe Netherlands
| | | | - Anna M. P. Boeren
- Department of Internal MedicineFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
| | | | - Femme Dirksmeier
- Department of Gastroenterology and HepatologyFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
| | - Rob J. de Knegt
- Department of Gastroenterology and HepatologyErasmus MCRotterdamthe Netherlands
| | | | | | | | - Manuel Castro Cabezas
- Department of Internal MedicineFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
- Department of Internal Medicine and EndocrinologyErasmus MCRotterdamthe Netherlands
- Julius ClinicalZeistthe Netherlands
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Uchinuma H, Matsushita M, Tanahashi M, Suganami H, Utsunomiya K, Kaku K, Tsuchiya K. Post-hoc analysis of the tofogliflozin post-marketing surveillance study (J-STEP/LT): Tofogliflozin improves liver function in type 2 diabetes patients regardless of BMI. J Diabetes Investig 2025; 16:615-628. [PMID: 39823131 PMCID: PMC11970296 DOI: 10.1111/jdi.14402] [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: 08/25/2024] [Revised: 12/05/2024] [Accepted: 12/27/2024] [Indexed: 01/19/2025] Open
Abstract
AIMS/INTRODUCTION Patients with type 2 diabetes are at high risk of developing steatotic liver disease (SLD). Weight loss has proven effective in treating metabolic dysfunction-associated steatotic liver disease (MASLD) in obese patients with type 2 diabetes, with sodium-glucose cotransporter 2 (SGLT2) inhibitors showing promising results. However, lean MASLD is more prevalent in Japan, necessitating alternative approaches to body weight reduction. MATERIALS AND METHODS We used the J-STEP/LT dataset including up to 3-year treatment data to analyze the effects of the SGLT2 inhibitor tofogliflozin on liver function and treatment safety and conducted a subgroup analysis based on body mass index (BMI; kg/m2, <20, 20-<23, 23-<25, 25-<30, and ≥30). RESULTS This study included 4,208 participants. Tofogliflozin significantly reduced alanine aminotransferase (ALT) levels in participants with baseline ALT levels >30 U/L across all BMI groups, with median changes of -12, -16, -13, -15, and -15 U/L, respectively (P = 0.9291 for trends). However, median changes in body weight with tofogliflozin were -2.00, -2.75, -2.00, -3.00, and -3.80 kg, respectively (P < 0.0001 for trends), with no significant weight loss observed in the BMI <20 group. ALT levels were also significantly decreased in participants who did not lose weight. Safety assessments according to BMI and age categories revealed no clear differences in the frequency of adverse events. CONCLUSIONS Tofogliflozin reduced ALT levels without substantial body weight reduction among lean participants. These findings suggest that SGLT2 inhibitors may be a viable treatment option for non-obese patients with type 2 diabetes and SLD.
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Affiliation(s)
- Hiroyuki Uchinuma
- Department of Diabetes and EndocrinologyUniversity of Yamanashi HospitalYamanashiJapan
| | | | | | | | | | - Kohei Kaku
- Division of Diabetes, Metabolism and EndocrinologyKawasaki Medical SchoolOkayamaJapan
| | - Kyoichiro Tsuchiya
- Department of Diabetes and EndocrinologyUniversity of Yamanashi HospitalYamanashiJapan
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9
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Xu R, Liu B, Zhou X. Comparison of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter Protein-2 Inhibitors on Treating Metabolic Dysfunction-Associated Steatotic Liver Disease or Metabolic Dysfunction-Associated Steatohepatitis: Systematic Review and Network Meta-Analysis of Randomised Controlled Trials. Endocr Pract 2025; 31:521-535. [PMID: 39701283 DOI: 10.1016/j.eprac.2024.11.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/11/2024] [Accepted: 11/24/2024] [Indexed: 12/21/2024]
Abstract
OBJECTIVE To assess glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) and sodium-glucose cotransporter protein-2 inhibitors (SGLT-2 inhibitors) in patients with metabolic dysfunction-associated steatotic liver disease or metabolic dysfunction-associated steatohepatitis (previously known as nonalcoholic fatty liver disease [NAFLD] and nonalcoholic steatohepatitis [NASH]), we performed a systematic review and network meta-analysis of randomized controlled trials. METHODS The study searched Pubmed, Embase, the Cochrane Library, and Web of Science databases up to November 26, 2023. Two reviewers independently selected the studies, extracted the data, and assessed the risk of bias. RESULTS Thirty-seven studies were included in the analysis. GLP-1 receptor agonists were found to be more effective than placebo in resolving NASH (relative risk: 2.48, 95% CI:1.86 to 3.30). Both drugs were superior to placebo in reducing liver fat content, as well as decreasing levels of liver enzyme. Network meta-analysis indicated that SGLT-2 inhibitors were more effective than GLP-1 receptor agonists in reducing alanine aminotransferase and aspartate aminotransferase levels. According to the surface under the cumulative probability ranking curve values, GLP-1 receptor agonists and SGLT-2 inhibitors consistently ranked among the top 2 in terms of reducing anthropometric data compared to other included drugs. CONCLUSIONS GLP-1 receptor agonists and SGLT-2 inhibitors have significant effects on reducing liver fat content and liver enzymes in NAFLD or NASH patients compared to placebo. GLP-1 receptor agonists were found to be superior to placebo in resolving NASH. SGLT-2 inhibitors were more effective than GLP-1 receptor agonists in reducing alanine aminotransferase and aspartate aminotransferase levels.
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Affiliation(s)
- Ruhan Xu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Bo Liu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xianghai Zhou
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
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10
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Amin MA, Sadik NA, Saad HA, Fawzy M, Elsheimy HA. The effect of SGLT2 inhibitors on hepatic steatosis detected by MRI-PDFF in patients with type 2 Diabetes mellitus and metabolic-associated steatotic liver disease. Intern Emerg Med 2025:10.1007/s11739-025-03902-w. [PMID: 40085410 DOI: 10.1007/s11739-025-03902-w] [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: 10/04/2024] [Accepted: 02/12/2025] [Indexed: 03/16/2025]
Abstract
Sodium-glucose co-transporter type-2 (SGLT2) inhibitors have been identified to have a crucial hepatoprotective role in patients with type 2 diabetes (T2DM) and metabolic-associated steatotic liver disease (MASLD). Thus, we aimed to assess the effect of SGLT2 inhibitors on hepatic steatosis in patients with T2DM and MASLD added to the standard of care (SOC) treatment. Our study was a single-arm clinical trial with trial no ISRCTN85961860. Thirty T2DM patients with MASLD were recruited from the outpatient endocrinology and diabetes clinic of the Internal Medicine Department at Kasr Al-Aini Hospital, Cairo University, Egypt. Our Patients received Empagliflozin 10 mg daily which was added to SOC treatment and followed up for 24 weeks. Magnetic resonance imaging proton density fat fraction (MRI-PDFF) was done at baseline and after 24 weeks to assess the percentage change in hepatic fat mass. Also changes in Fib-4 and NAFLD fibrosis scores were calculated. Our study showed a statistically significant decrease in the mean MRI-PDFF measurement of hepatic steatosis after 24 weeks of adding empagliflozin to SOC treatment (13.297 ± 7.15) compared to the mean at baseline (15.288 ± 8.72), P = 0.006 with overall percentage decrease about 13.16% of liver steatosis. There were significant decreases in BMI, fasting blood glucose, and Alanine transaminase, (P < 0.001, 0.03, 0.01) respectively. There were no significant differences in Fib-4 or NAFLD fibrosis scores. Adding empagliflozin 10 mg to the standard treatment in patients with diabetes and MASLD could reduce hepatic fat mass significantly after 24 weeks of treatment. Thus, adding SGLT2 inhibitors to the clinical practice guidelines could be a therapeutic agent for patients with MASLD and T2DM.
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Affiliation(s)
- Mona Ahmed Amin
- Faculty of Medicine, Internal Medicine Department, Hepatology and Gastroenterology, Endocrinology and Diabetes Division, Cairo University, Cairo, Egypt
| | - Noha Adly Sadik
- Faculty of Medicine, Internal Medicine Department, Hepatology and Gastroenterology, Endocrinology and Diabetes Division, Cairo University, Cairo, Egypt.
| | - Hala Ahmed Saad
- Faculty of Medicine, Internal Medicine Department, Hepatology and Gastroenterology, Endocrinology and Diabetes Division, Cairo University, Cairo, Egypt
| | - Mohammed Fawzy
- Department of Diagnostic Radiology, National Hepatology and Tropical Research Institute, Cairo, Egypt
| | - Hend Abdallah Elsheimy
- Faculty of Medicine, Internal Medicine Department, Hepatology and Gastroenterology, Endocrinology and Diabetes Division, Cairo University, Cairo, Egypt
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11
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Misra A, Kumar A, Kuchay MS, Ghosh A, Gulati S, Choudhary NS, Dutta D, Sharma P, Vikram NK. Consensus guidelines for the diagnosis and management of metabolic dysfunction-associated steatotic liver disease in adult Asian Indians with type 2 diabetes. Diabetes Metab Syndr 2025; 19:103209. [PMID: 40222341 DOI: 10.1016/j.dsx.2025.103209] [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] [Revised: 02/14/2025] [Accepted: 02/17/2025] [Indexed: 04/15/2025]
Affiliation(s)
- Anoop Misra
- Fortis CDOC Center of Excellence for Diabetes, Metabolic Diseases and Endocrinology, New Delhi, India; National Diabetes Obesity and Cholesterol Foundation (N-DOC), New Delhi, India; Diabetes Foundation India, New Delhi, India.
| | - Ashish Kumar
- Gastroenterology & Hepatology,Sir Ganga Ram Hospital, Rajinder Nagar New Delhi, India
| | - Mohammad Shafi Kuchay
- Division of Endocrinology and Diabetes, Medanta, The Medicity, Gurugram, 122001, Haryana, India
| | - Amerta Ghosh
- Fortis CDOC Center of Excellence for Diabetes, Metabolic Diseases and Endocrinology, New Delhi, India; National Diabetes Obesity and Cholesterol Foundation (N-DOC), New Delhi, India
| | - Seema Gulati
- National Diabetes Obesity and Cholesterol Foundation (N-DOC), New Delhi, India; Diabetes Foundation India, New Delhi, India
| | | | - Deep Dutta
- Department of Endocrinology, Center for Endocrinology, Diabetes, Arthritis & Rheumatism (CEDAR) Super speciality Clinics, New Delhi, India
| | - Praveen Sharma
- Gastroenterology & Hepatology,Sir Ganga Ram Hospital, Rajinder Nagar New Delhi, India
| | - Naval K Vikram
- Department of Internal Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
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12
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Hupa-Breier KL, Schenk H, Campos-Murguia A, Wellhöner F, Heidrich B, Dywicki J, Hartleben B, Böker C, Mall J, Terkamp C, Wilkens L, Becker F, Rudolph KL, Manns MP, Mederacke YS, Marhenke S, Redeker H, Lieber M, Iordanidis K, Taubert R, Wedemeyer H, Noyan F, Hardtke-Wolenski M, Jaeckel E. Novel translational mouse models of metabolic dysfunction-associated steatotic liver disease comparable to human MASLD with severe obesity. Mol Metab 2025; 93:102104. [PMID: 39855563 PMCID: PMC11815970 DOI: 10.1016/j.molmet.2025.102104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 01/27/2025] Open
Abstract
OBJECTIVE Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease, especially in patients with severe obesity. However, current mouse models for MASLD do not reflect the polygenetic background nor the metabolic changes in this population. Therefore, we investigated two novel mouse models of MASLD with a polygenetic background for the metabolic syndrome. METHODS TALLYHO/JngJ mice and NONcNZO10/LtJ mice were fed a high-fat- high-carbohydrate (HF-HC) diet with a surplus of cholesterol diet. A second group of TH mice was additional treated with empagliflozin. RESULTS After sixteen weeks of feeding, both strains developed metabolic syndrome with severe obesity and histological manifestation of steatohepatitis, which was associated with significantly increased intrahepatic CD8+cells, CD4+cells and Tregs, contributing to a significant increase in pro-inflammatory and pro-fibrotic gene activation as well as ER stress and oxidative stress. In comparison with the human transcriptomic signature, we could demonstrate a good metabolic similarity, especially for the TH mouse model. Furthermore, TH mice also developed signs of kidney injury as an extrahepatic comorbidity of MASLD. Additional treatment with empagliflozin in TH mice attenuates hepatic steatosis and improves histological manifestation of MASH. CONCLUSIONS Overall, we have developed two promising new mouse models that are suitable for preclinical studies of MASLD as they recapitulate most of the key features of MASLD.
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Affiliation(s)
- Katharina L Hupa-Breier
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Heiko Schenk
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Alejandro Campos-Murguia
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Freya Wellhöner
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Janine Dywicki
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Clara Böker
- Department of General, Visceral, Vascular and Bariatric Surgery, Klinikum Nordstadt, 30167, Hannover, Germany
| | - Julian Mall
- Department of General, Visceral, Vascular and Bariatric Surgery, Klinikum Nordstadt, 30167, Hannover, Germany
| | - Christoph Terkamp
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ludwig Wilkens
- Department of Pathology, Nordstadt Hospital Hannover, 30167, Hannover, Germany
| | - Friedrich Becker
- Research Group on Stem Cell and Metabolism Aging, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745, Jena, Germany
| | - Karl Lenhard Rudolph
- Research Group on Stem Cell and Metabolism Aging, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745, Jena, Germany
| | - Michael Peter Manns
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Young-Seon Mederacke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Silke Marhenke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Hanna Redeker
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Maren Lieber
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Konstantinos Iordanidis
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Fatih Noyan
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; Ajmera Transplant Centre, Toronto General Hospital, United Health Network, University of Toronto, Toronto, Canada
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13
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Ng HY, Zhang L, Tan JT, Hui RWH, Yuen MF, Seto WK, Leung WK, Cheung KS. Gut Microbiota Predicts Treatment Response to Empagliflozin Among MASLD Patients Without Diabetes Mellitus. Liver Int 2025; 45:e70023. [PMID: 39950834 PMCID: PMC11827547 DOI: 10.1111/liv.70023] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/11/2025] [Accepted: 01/30/2025] [Indexed: 02/17/2025]
Abstract
BACKGROUND AND AIM We aimed to investigate whether gut microbiota could predict the treatment response to pharmacological agents among metabolic dysfunction-associated steatotic liver disease (MASLD) patients without diabetes mellitus (DM), as data are lacking. METHODS We prospectively followed up non-diabetic MASLD patients who used empagliflozin. Clinical, anthropometric, laboratory assessments and magnetic resonance imaging-proton density fat fraction (MRI-PDFF) were performed from baseline to week 52 (EOT). Baseline stool samples were collected, and shotgun DNA metagenomic sequencing was performed to profile microbiome. The primary outcome was treatment response to empagliflozin at EOT, defined as MRI-PDFF decline ≥ 30% at EOT from baseline. Linear discriminant analysis [LDA] effect size was used to identify putative bacterial species. Multivariable logistic regression was used to derive adjusted odds ratio (aOR) of outcome with bacterial species by adjusting for clinical factors. RESULTS Twenty-two (48.9%) of 45 patients (median age: 56.9 years [IQR: 51.0-63.2]; male: 23 [51.1%]) achieved treatment response at EOT. There was difference in alpha diversity (Shannon index: p < 0.001; Simpson index: p = 0.001) and beta diversity (p = 0.048) in baseline microbiome between treatment response and non-response groups. Faecalibacterium prausnitzii (log10LDAscore = 4.27), Lachnospira pectinoschiza (log10LDAscore = 3.99), Anaerostipes hadrus (log10LDAscore = 3.98), Roseburia faecis (log10LDAscore = 3.97), Roseburia inulinivorans (log10LDAscore = 3.58) and Agathobaculum butyriciproducens (log10LDAscore = 2.77) were enriched in the treatment response group. L. pectinoschiza (aOR: 34.1; p = 0.015), A. hadrus (aOR:35.0; p = 0.032) and A. butyriciproducens (aOR:22.3; p = 0.023) independently predicted treatment response but not clinical factors. These three species collectively predicted treatment response with AUROC of 0.89 (95% CI: 0.80-0.99). CONCLUSIONS Certain gut bacterial species, particularly the combination of A. hadrus, L. pectinoschiza and A. butyriciproducens, may predict treatment response to empagliflozin in MAFLD patients without DM.
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Affiliation(s)
- Ho Yu Ng
- Li Ka Shing Faculty of MedicineThe University of Hong Kong, Queen Mary HospitalHong Kong
| | - Lina Zhang
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong Kong, Queen Mary HospitalHong Kong
| | - Jing Tong Tan
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong Kong, Queen Mary HospitalHong Kong
| | - Rex Wan Hin Hui
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong Kong, Queen Mary HospitalHong Kong
| | - Man Fung Yuen
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong Kong, Queen Mary HospitalHong Kong
- State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Wai Kay Seto
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong Kong, Queen Mary HospitalHong Kong
- State Key Laboratory of Liver ResearchThe University of Hong KongHong Kong
| | - Wai K. Leung
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong Kong, Queen Mary HospitalHong Kong
| | - Ka Shing Cheung
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong Kong, Queen Mary HospitalHong Kong
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Li H, Hou Y, Xin W, Ding L, Yang Y, Zhang Y, Wu W, Wang Z, Ding W. The efficacy of sodium-glucose transporter 2 inhibitors in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis. Pharmacol Res 2025; 213:107647. [PMID: 39929274 DOI: 10.1016/j.phrs.2025.107647] [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: 07/19/2024] [Revised: 02/05/2025] [Accepted: 02/05/2025] [Indexed: 02/13/2025]
Abstract
The efficacy of sodium-glucose transporter 2 (SGLT-2) inhibitors for nonalcoholic fatty liver disease (NAFLD) is unclear. Therefore, we conducted a systematic review and meta-analysis to evaluate SGLT-2 inhibitors efficacy for NAFLD treatment. We systematically searched major electronic databases (PubMed, Cochrane Library, Web of Science, Embase) from inception until 11/2023, identifying randomized controlled trials (RCTs) of SGLT-2 inhibitors treatment for patients with NAFLD. The mean differences (MD or SMD) and 95 % confidence intervals (CIs) were calculated via random-effects models. Eleven articles (n = 805 patients with NAFLD) were included in this study. Of these, 408 participants received SGLT-2 inhibitors, while 397 participants were in the control group. SGLT-2 inhibitors significantly reduced liver enzyme levels, including aspartate alanine aminotransferase (ALT) (MD [95 % CI]; -9.31 U/L [-13.41, -5.21], p < 0.00001), aspartate aminotransferase (AST) (MD [95 % CI]; -6.06 U/L [-10.98, -1.15], p = 0.02), and gamma-glutamyltransferase (GGT) (MD [95 % CI]; -11.72 U/L [-15.65, -7.80], p < 0.00001). SGLT-2 inhibitors intervention was also associated with significant reductions in body weight (MD [95 % CI]; -2.72 kg [-3.49, -1.95], p < 0.00001) and BMI (MD [95 % CI]; -1.11 kg/m2 [-1.39, -0.82], p < 0.00001) and improvements in glycaemic indices, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C). However, no significant changes in total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) were observed. The meta-analysis revealed a beneficial effect of SGLT-2 inhibitors on liver functions and body weight, BMI, TG, HDL-C, and glucose homeostasis in patients with NAFLD, indicating that SGLT-2 inhibitors might be a clinical therapeutic strategy for these patients, especially individuals with concurrent type 2 diabetes mellitus (T2DM).
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Affiliation(s)
- Hongsheng Li
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Yanli Hou
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Wenyong Xin
- Department of Retirement Affairs, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China
| | - Lina Ding
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Ying Yang
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Yikun Zhang
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Wenqi Wu
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Zhibin Wang
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China.
| | - Wenyu Ding
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China.
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Guiraud V, Sauce D, Bittar R, Fernandez J, Thévenet H, Teyssou E, Alkouri R, Bonnefont-Rousselot D, Marcelin AG, Calvez V, Pourcher V. Clinical, biological, metabolic, and immune changes associated with the use of sodium-glucose cotransporter 2 inhibitors in people living with HIV. Infect Dis Now 2025; 55:105040. [PMID: 39961547 DOI: 10.1016/j.idnow.2025.105040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 02/04/2025] [Accepted: 02/13/2025] [Indexed: 02/23/2025]
Abstract
INTRODUCTION Positive cardiovascular and renal outcomes associated with the sodium-glucose cotransporter 2 inhibitor (SGLT2i) use are attributed to their anti-inflammatory properties. Persistent immune activation accounts for part of the elevated cardiovascular risk of people living with HIV (PWH), but SGLT2i impact on this population has been poorly described. METHODS All PWH with a history of SGLT2i treatment from May 2020 to April 2023 receiving care at Pitié-Salpêtrière Hospital (Paris, France) and with available pre- and post-treatment blood samples were included. Clinical and biological data were extracted from medical records, metabolic and immune biomarkers from cryopreserved plasma samples. RESULTS Most of the 20 patients with SGLT2i treatment were men (75 %), with a median [IQR] age of 59 years [55;68], receiving antiretroviral therapy for a median of 21.5 years [15.3;26.5]. Most had type 2 diabetes (95 %), chronic kidney disease (90 %), dyslipidemia (80 %), and hypertension (75 %). SGLT2i treatment was associated with a median weight loss of 3 kg, an increase in hematocrit, and decreased AST levels. LDL, HDL, oxLDL, and Lp-PLA2 levels were unaffected. SGLT2i was associated with inflammasome inhibition and with decreased circulating levels of IL-1β and IL-8. We also observed a decrease in cytokines associated with the recruitment and activation of monocytes-macrophages MCP-1, MIP-1α, MIP-1β, Eotaxin, RANTES, IL-8, and their positive feedback, IL-13/IL-4. Decreased IL-6, CRP, and sCD14 levels were not significant. CONCLUSION SGLT2i was associated with weight loss and a significant impact on innate immunity in PWH, with inhibition of inflammasome and monocyte-macrophage activation.
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Affiliation(s)
- Vincent Guiraud
- Sorbonne Université, INSERM, Institut Pierre Louis D'Epidémiologie Et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Laboratoire de Virologie, F-75013 Paris, France.
| | - Delphine Sauce
- Sorbonne Université, Inserm, Centre D'Immunologie Et Des Maladies Infectieuses, Cimi-Paris F-75013 Paris, France
| | - Randa Bittar
- Service de Biochimie Métabolique, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix , AP-HP Paris, France; INSERM, UMR_S1166 ICAN, Sorbonne Université, Paris, France
| | - José Fernandez
- Sorbonne Université, INSERM, Institut Pierre Louis D'Epidémiologie Et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Laboratoire de Virologie, F-75013 Paris, France
| | - Henri Thévenet
- Sorbonne Université, INSERM, Institut Pierre Louis D'Epidémiologie Et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Laboratoire de Virologie, F-75013 Paris, France
| | - Elisa Teyssou
- Sorbonne Université, INSERM, Institut Pierre Louis D'Epidémiologie Et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Laboratoire de Virologie, F-75013 Paris, France
| | - Rana Alkouri
- Service de Biochimie Métabolique, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix , AP-HP Paris, France
| | - Dominique Bonnefont-Rousselot
- Service de Biochimie Métabolique, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix , AP-HP Paris, France; Université Paris Cité, UTCBS, CNRS, INSERM, Paris, France
| | - Anne-Geneviève Marcelin
- Sorbonne Université, INSERM, Institut Pierre Louis D'Epidémiologie Et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Laboratoire de Virologie, F-75013 Paris, France
| | - Vincent Calvez
- Sorbonne Université, INSERM, Institut Pierre Louis D'Epidémiologie Et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Laboratoire de Virologie, F-75013 Paris, France
| | - Valérie Pourcher
- Service Des Maladies Infectieuses Et Tropicales, Hôpital Pitié-Salpêtrière, AP-HP Paris, France; INSERM UMR-S 1136, Pierre Louis Institute of Epidemiology and Public Health, Sorbonne Université, Paris, France
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Knezović E, Hefer M, Blažanović S, Petrović A, Tomičić V, Srb N, Kirner D, Smolić R, Smolić M. Drug Pipeline for MASLD: What Can Be Learned from the Successful Story of Resmetirom. Curr Issues Mol Biol 2025; 47:154. [PMID: 40136408 PMCID: PMC11941580 DOI: 10.3390/cimb47030154] [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: 02/02/2025] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 03/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing global health problem linked to obesity, insulin resistance, and dyslipidemia. MASLD often leads to fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, therapeutic options are limited, emphasizing the need for novel, targeted pharmacological interventions. Resmetirom, a selective thyroid hormone receptor beta (THR-β) agonist, offers a promising approach by specifically enhancing hepatic metabolism while minimizing systemic effects. Clinical trials have demonstrated its capacity to reduce hepatic triglyceride accumulation and improve lipid profiles. Early- and advanced-phase studies, including the MAESTRO program, highlight significant reductions in hepatic fat content and favorable impacts on noninvasive biomarkers of fibrosis with minimal side effects. This review highlights evidence from pivotal studies, explores resmetirom's mechanism of action, and compares its efficacy and safety with other emerging therapeutic agents. While resmetirom marks a breakthrough in non-cirrhotic MASH management, further long-term studies are essential to fully evaluate its clinical benefits and potential regulatory approval for broader use in MASLD and MASH.
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Affiliation(s)
- Elizabeta Knezović
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (E.K.); (M.H.); (S.B.); (A.P.); (V.T.); (N.S.); (D.K.); (R.S.)
- Clinical Institute of Translational Medicine, University Hospital Osijek, 31000 Osijek, Croatia
| | - Marija Hefer
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (E.K.); (M.H.); (S.B.); (A.P.); (V.T.); (N.S.); (D.K.); (R.S.)
| | - Suzana Blažanović
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (E.K.); (M.H.); (S.B.); (A.P.); (V.T.); (N.S.); (D.K.); (R.S.)
| | - Ana Petrović
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (E.K.); (M.H.); (S.B.); (A.P.); (V.T.); (N.S.); (D.K.); (R.S.)
| | - Vice Tomičić
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (E.K.); (M.H.); (S.B.); (A.P.); (V.T.); (N.S.); (D.K.); (R.S.)
| | - Nika Srb
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (E.K.); (M.H.); (S.B.); (A.P.); (V.T.); (N.S.); (D.K.); (R.S.)
| | - Damir Kirner
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (E.K.); (M.H.); (S.B.); (A.P.); (V.T.); (N.S.); (D.K.); (R.S.)
| | - Robert Smolić
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (E.K.); (M.H.); (S.B.); (A.P.); (V.T.); (N.S.); (D.K.); (R.S.)
| | - Martina Smolić
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (E.K.); (M.H.); (S.B.); (A.P.); (V.T.); (N.S.); (D.K.); (R.S.)
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Shojaei F, Erfanifar A, Kalbasi S, Nikpour S, Gachkar L. The effect of empagliflozin on non-alcoholic fatty liver disease-related parameters in patients with type 2 diabetes mellitus: a randomized controlled trial. BMC Endocr Disord 2025; 25:52. [PMID: 40011855 PMCID: PMC11863618 DOI: 10.1186/s12902-025-01882-8] [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: 12/24/2024] [Accepted: 02/14/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND AND OBJECTIVE The effects of Empagliflozin on liver health in patients with Type 2 Diabetes Mellitus (T2DM) have not been fully elucidated. This study aimed to assess the impact of Empagliflozin on liver steatosis and related biomarkers in T2DM patients. METHODS A before-after clinical trial was conducted with 119 T2DM patients aged 20 to 70 with fatty liver, recruited from Laghman Hakim Hospital, Tehran, Iran. Participants were administered Empagliflozin for 6 months, with clinical and laboratory assessments conducted at baseline, 3 months, and 6 months. Liver function was evaluated through blood tests and imaging, including ultrasound and Magnetic resonance imaging (MRI), to assess hepatic steatosis. Biomarkers such as HbA1c, fasting blood glucose, insulin, lipid profile, and liver enzymes were measured. Insulin resistance was estimated using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) formula. Data were analyzed using SPSS 26 and STATA 14. RESULTS A total of 119 patients (Intervention (N = 69), Control (N = 50)) were participated. The intervention group demonstrated a significant reduction in liver fat grade compared to the control group, with 17.5% of patients showing a reduction from grade 3 to grade 1 on MRI and 6% in the control group. The odds of worsening fatty liver in the control group were 48 times higher (95% CI: 15.5, 148.5) on MRI and 52 times higher (95% CI: 15.2, 178.1) on ultrasound, compared to the intervention group (NNT = 2). After 6 months, the intervention group showed significantly lower risks for ALT (RR: 0.72, 95% CI: 0.62-0.84), AST, and alkaline phosphatase (Alkp) abnormalities. Liver enzyme levels (ALT, AST, GGT) and systolic blood pressure (SBP) decreased significantly in the Empagliflozin group, with mean differences of -15.33 (95% CI: -18.8, -11.88) for ALT, -12.82 (95% CI: -15.5, -10.13) for AST, and - 6.31 (95% CI: -8.65, -3.97) for systolic blood pressure (SBP). CONCLUSION These findings suggest that Empagliflozin could be an effective adjunctive therapy for managing liver dysfunction in T2DM patients with NAFLD. TRIAL REGISTRATION Registered retrospectively in the Iranian Registry of Clinical Trials (IRCT20210811052150N1) on April 16,2023 Access at https://irct.behdasht.gov.ir/search/result?query=IRCT20210811052150N1 .
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Affiliation(s)
- Fatemeh Shojaei
- Internal Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Azam Erfanifar
- Department of Endocrinology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeid Kalbasi
- Department of Clinical Endocrinology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahriar Nikpour
- Gastroenterology and Hepatology, Department of Adult Gastroenterology and Hepatology, School of Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Latif Gachkar
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Gao X, Zhu C, Zhu W, Wang L. Dapagliflozin treatment alleviates fatty liver in patients with type 2 diabetes. Biomed Rep 2025; 22:26. [PMID: 39720302 PMCID: PMC11668134 DOI: 10.3892/br.2024.1904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/11/2024] [Indexed: 12/26/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is common in patients with type 2 diabetes mellitus (T2DM). The present study evaluated the effect of dapagliflozin on the liver fat content in patients with T2DM and NAFLD. The changes in biochemical data and metabolic parameters were analyzed. Clinical data of patients with T2DM and NAFLD treated by dapagliflozin were retrospectively collected between June 2022 and December 2022. A total of 35 patients, with a mean age of 45.8±2.2 years, consisting of 60.0% male patients, were included in the final analysis. After 20 weeks of dapagliflozin treatment, the parameters of diabetes improved. Plasma glucose and hemoglobin A1C levels significantly decreased (P<0.01), and insulin resistance improved. The change in liver fat content was evaluated by quantitative computed tomography, which revealed a decrease from 16.1±2.2 to 11.2±1.3% after treatment (P<0.01). Liver function (alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase levels) also improved. Visceral and subcutaneous fat areas showed a significant decrease after treatment, and there was a more significant reduction in visceral fat area. The factors associated with liver fat content were determined by Pearson's correlation and regression analyses. Pearson's correlation analysis indicated that the post-treatment decrease in liver fat content was positively correlated with the change in body weight (r=0.642, P=0.033), index of homeostasis model assessment-insulin resistance (r=0.670, P=0.048), triglycerides (r=0.627, P=0.039), high sensitivity C-reactive protein (r=0.608, P=0.047) and interleukin (IL)-6 (r=0.604, P=0.049). Linear regression analysis revealed that body weight (β=0.416, P=0.001), IL-6 (β=0.284, P=0.009), triglycerides (β=0.262, P=0.011) and total cholesterol (β=0.388, P=0.001) were independent factors related to liver fat content. In conclusion, dapagliflozin can reduce liver fat in patients with T2DM and NAFLD. The reduction in liver fat is associated with improvement of metabolic parameters and inflammatory cytokines.
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Affiliation(s)
- Xiuying Gao
- Department of Endocrinology, Beijing Aerospace General Hospital, Beijing 100076, P.R. China
| | - Chuanming Zhu
- Department of Radiology, Beijing Aerospace General Hospital, Beijing 100076, P.R. China
| | - Wei Zhu
- Department of Endocrinology, Beijing Aerospace General Hospital, Beijing 100076, P.R. China
| | - Lin Wang
- Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, P.R. China
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Nomura K, Takata T, Muramae N, Takahashi H, Abe K, Matsuda T. Comprehensive treatment with dapagliflozin in elderly chronic kidney disease patients: Clinical efficacy and impact on body composition. J Diabetes Complications 2025; 39:108951. [PMID: 39813896 DOI: 10.1016/j.jdiacomp.2025.108951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/18/2025]
Abstract
BACKGROUND Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is widely used for treating heart failure and chronic kidney disease (CKD). While its renoprotective effects are well established, concerns remain regarding its impact on muscle mass and function, especially in elderly patients. OBJECTIVE To assess the effects of dapagliflozin on renal function, body composition, and muscle strength in elderly CKD patients. METHODS Twelve elderly CKD patients (75.6 ± 1.4 years) were treated with dapagliflozin for 12 months. Body composition, serum parameters, and muscle function were evaluated at baseline, 6 months, and 12 months. Measurements included changes in eGFR, liver function, HbA1c, and muscle strength. RESULTS Dapagliflozin treatment stabilized eGFR without significant improvement, but proteinuria was notably reduced in most patients, indicating a positive renal effect. AST and ALT levels showed significant reduction after 12 months, suggesting improved liver function. No significant changes were observed in body weight, BMI, or muscle mass. Muscle function, as measured by the 5-sit-to-stand test, improved significantly, while grip strength remained stable. No serious adverse events were reported. CONCLUSION Dapagliflozin is a safe and effective treatment for CKD in elderly patients, demonstrating renal protection and improved liver function without adversely affecting muscle mass or strength. The study supports the use of dapagliflozin as part of a comprehensive approach, combining pharmacotherapy, lifestyle modification, and exercise to optimize patient outcomes in CKD management.
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Affiliation(s)
- Kazuhiro Nomura
- Matsuda Diabetes Clinic, Kobe, Japan; Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
| | - Toshiyuki Takata
- Department of Internal Medicine and Physical Medicine, Rehabilitation, Hyogo Prefectural Rehabilitation Center Hospital, Kobe, Japan
| | - Naokazu Muramae
- Matsuda Diabetes Clinic, Kobe, Japan; Muramae Diabetes Clinic, Akashi, Japan
| | | | - Kozue Abe
- Matsuda Diabetes Clinic, Kobe, Japan
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Ao N, Du J, Jin S, Suo L, Yang J. The cellular and molecular mechanisms mediating the protective effects of sodium-glucose linked transporter 2 inhibitors against metabolic dysfunction-associated fatty liver disease. Diabetes Obes Metab 2025; 27:457-467. [PMID: 39508115 DOI: 10.1111/dom.16043] [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: 09/10/2024] [Revised: 10/16/2024] [Accepted: 10/16/2024] [Indexed: 11/08/2024]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a common, highly heterogeneous condition that affects about a quarter of the world's population, with no approved drug therapy. Current evidence from preclinical research and a number of small clinical trials indicates that SGLT2 inhibitors could also be effective for MAFLD. MAFLD is associated with a higher risk of chronic liver disease and multiple extrahepatic events, especially cardiovascular disease (CVD) and chronic kidney disease (CKD). MAFLD is considered a more appropriate terminology than NAFLD because it captures the complex bidirectional interplay between fatty liver and metabolic dysfunctions associated with disease progression, such as obesity and type 2 diabetes mellitus (T2DM). SGLT2 inhibitors are antidiabetic drugs that block glucose reabsorption in the kidney proximal tubule. In this article, we reviewed current clinical evidence supporting the potential use of SGLT2 inhibitors as a drug therapy for MAFLD and discussed the possible cellular and molecular mechanisms involved. We also reviewed the clinical benefits of SGLT2 inhibitors against MAFLD-related comorbidities, especially CVD, CKD and cardiovascular-kidney-metabolic syndrome (CKM). The broad beneficial effects of SGLT2 inhibitors support their use, likely in combination with other drugs, as a therapy for MAFLD.
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Affiliation(s)
- Na Ao
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jian Du
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Shi Jin
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Linna Suo
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jing Yang
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
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Pandey A, Alcaraz M, Saggese P, Soto A, Gomez E, Jaldu S, Yanagawa J, Scafoglio C. Exploring the Role of SGLT2 Inhibitors in Cancer: Mechanisms of Action and Therapeutic Opportunities. Cancers (Basel) 2025; 17:466. [PMID: 39941833 PMCID: PMC11815934 DOI: 10.3390/cancers17030466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 01/23/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Cancer cells utilize larger amounts of glucose than their normal counterparts, and the expression of GLUT transporters is a known diagnostic target and a prognostic factor for many cancers. Recent evidence has shown that sodium-glucose transporters are also expressed in different types of cancer, and SGLT2 has raised particular interest because of the current availability of anti-diabetic drugs that block SGLT2 in the kidney, which could be readily re-purposed for the treatment of cancer. The aim of this article is to perform a narrative review of the existing literature and a critical appraisal of the evidence for a role of SGLT2 inhibitors for the treatment and prevention of cancer. SGLT2 inhibitors block Na-dependent glucose uptake in the proximal kidney tubules, leading to glycosuria and the improvement of blood glucose levels and insulin sensitivity in diabetic patients. They also have a series of systemic effects, including reduced blood pressure, weight loss, and reduced inflammation, which also make them effective for heart failure and kidney disease. Epidemiological evidence in diabetic patients suggests that individuals treated with SGLT2 inhibitors may have a lower incidence and better outcomes of cancer. These studies are confirmed by pre-clinical evidence of an effect of SGLT2 inhibitors against cancer in xenograft and genetically engineered models, as well as by in vitro mechanistic studies. The action of SGLT2 inhibitors in cancer can be mediated by the direct inhibition of glucose uptake in cancer cells, as well as by systemic effects. In conclusion, there is evidence suggesting a potential role of SGLT2 inhibitors against different types of cancer. The most convincing evidence exists for lung and breast adenocarcinomas, hepatocellular carcinoma, and pancreatic cancer. Several ongoing clinical trials will provide more information on the efficacy of SGLT2 inhibitors against cancer.
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Affiliation(s)
- Aparamita Pandey
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
| | - Martín Alcaraz
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
| | - Pasquale Saggese
- Department of Biology and Biotechnologies Charles Darwin, University of Rome “Sapienza”, Piazzale Aldo Moro 5, 00185 Rome, Italy;
| | - Adriana Soto
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
| | - Estefany Gomez
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
| | - Shreya Jaldu
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
| | - Jane Yanagawa
- Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA;
| | - Claudio Scafoglio
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA 90095, USA; (A.P.); (A.S.); (E.G.); (S.J.)
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Bea S, Ko HY, Bae JH, Cho YM, Chang Y, Ryu S, Byrne CD, Shin JY. Risk of hepatic events associated with use of sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists, and thiazolidinediones among patients with metabolic dysfunction-associated steatotic liver disease. Gut 2025; 74:284-294. [PMID: 39242193 PMCID: PMC11874371 DOI: 10.1136/gutjnl-2024-332687] [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: 04/18/2024] [Accepted: 08/21/2024] [Indexed: 09/09/2024]
Abstract
OBJECTIVE To examine the hepatic effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) through a head-to-head comparison with glucagon-like peptide-1 receptor agonists (GLP-1RA) or thiazolidinediones (TZD) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). DESIGN This population-based cohort study was conducted using a nationwide healthcare claims database (2014-2022) of Korea. We included individuals with MASLD (aged ≥40 years) who initiated SGLT-2i or comparator drugs (GLP-1RA or TZD). Primary outcome was a composite of hepatic decompensation events, including ascites, oesophageal varices with bleeding, hepatic failure or liver transplant. Liver-cause death and all-cause death were also assessed as secondary outcomes. Cox proportional hazards models were used to estimated HRs with 95% CIs. RESULTS After 1:1 propensity score matching, we included 22 550 patients who initiated SGLT-2i and GLP-1RA (median age=57 years, 60% male), and 191 628 patients who initiated SGLT-2i and TZD (median age=57 years, 72% male). Compared with GLP-1RA, SGLT-2i showed a similar risk of hepatic decompensation events (HR 0.93, 95% CI 0.76 to 1.14). Compared with TZD, SGLT-2i demonstrated a reduced risk of hepatic decompensation events (HR 0.77, 95% CI 0.72 to 0.82). As compared with TZD, the results of secondary analyses showed significantly lower hepatic decompensation event risks with SGLT-2i when stratified by sex (male: HR 0.87 (95% CI 0.80-0.94); female: HR 0.62 (95% CI 0.55-0.69)). CONCLUSIONS In this nationwide cohort study, SGLT-2i was associated with a lower risk of hepatic decompensation events in patients with MASLD compared with TZD, while demonstrating similar effectiveness to GLP-1RA.
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Affiliation(s)
- Sungho Bea
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- School of Pharmacy, Sungkyunkwan University, Suwon, Korea (the Republic of)
| | - Hwa Yeon Ko
- School of Pharmacy, Sungkyunkwan University, Suwon, Korea (the Republic of)
| | - Jae Hyun Bae
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea (the Republic of)
| | - Young Min Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
| | - Yoosoo Chang
- Kangbuk Samsung Hospital, Seoul, Korea (the Republic of)
| | - Seungho Ryu
- Center for Cohort Study, Kangbuk Samsung Hospital, Seoul, Korea (the Republic of)
| | | | - Ju-Young Shin
- School of Pharmacy, Sungkyunkwan University, Suwon, Korea (the Republic of)
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23
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Bril F, Berg G, Barchuk M, Nogueira JP. Practical Approaches to Managing Dyslipidemia in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease. J Lipid Atheroscler 2025; 14:5-29. [PMID: 39911965 PMCID: PMC11791423 DOI: 10.12997/jla.2025.14.1.5] [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: 12/25/2023] [Revised: 02/15/2024] [Accepted: 03/10/2024] [Indexed: 02/07/2025] Open
Abstract
Dyslipidemia is a major risk factor for cardiovascular disease, and its impact may be exacerbated when accompanied by metabolic dysfunction-associated steatotic liver disease (MASLD). The simultaneous management of these conditions poses multiple challenges for healthcare providers. Insulin resistance has been implicated in the pathogenesis of both dyslipidemia and MASLD, necessitating a holistic approach to managing dyslipidemia, glucose levels, body weight, and MASLD. This review explores the intricate pathophysiological relationship between MASLD and dyslipidemia. It also examines current guidance regarding the use of lipid-lowering agents (including statins, ezetimibe, fibrates, omega-3 polyunsaturated fatty acids, and proprotein convertase subtilisin/kexin type 9 inhibitors) as well as glucose-lowering medications (such as pioglitazone, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors) in patients with MASLD, with or without metabolic dysfunction-associated steatohepatitis (MASH), and dyslipidemia. Additionally, the review addresses the potential of emerging drugs to concurrently target both MASLD/MASH and dyslipidemia. Our hope is that a deeper understanding of the mechanisms underlying MASLD and dyslipidemia may assist clinicians in the management of these complex cases.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gabriela Berg
- Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Cátedra de Bioquímica Clínica I, Laboratorio de Lípidos y Aterosclerosis, Universidad de Buenos Aires, Buenos Aires, Argentina
- CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Magali Barchuk
- Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Cátedra de Bioquímica Clínica I, Laboratorio de Lípidos y Aterosclerosis, Universidad de Buenos Aires, Buenos Aires, Argentina
- CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Juan Patricio Nogueira
- Centro de Investigación en Endocrinología, Nutrición y Metabolismo (CIENM), Facultad de Ciencias de la Salud, Universidad Nacional de Formosa, Formosa, Argentina
- Universidad Internacional de las Américas, San José, Costa Rica
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24
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Koullias E, Papavdi M, Koskinas J, Deutsch M, Thanopoulou A. Targeting Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Available and Future Pharmaceutical Options. Cureus 2025; 17:e76716. [PMID: 39897209 PMCID: PMC11783198 DOI: 10.7759/cureus.76716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/31/2024] [Indexed: 02/04/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects an ever-increasing part of the global population, affecting millions of individuals worldwide. Despite the progress in the treatment of other liver diseases, there is a scarcity of liver-specific drugs targeting MASLD. In light of that, research has focused both on pipeline drugs targeting multiple different receptors implicated in the pathogenesis of the disease, as well as medications already approved for other indications, that might exert beneficial effects on MASLD. The fact that MASLD is associated with an increased prevalence of obesity and type 2 diabetes mellitus (T2DM) establishes a possible pathway with respect to already available pharmaceutical interventions for this group of patients, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT2-is). Thus, the hitherto at hand, along with the upcoming members of these families, provide much-needed options for our arsenal. This review attempts to explore old and novel dimensions of the pharmaceutical treatment of MASLD in the continuous effort of the medical society to improve patient outcomes.
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Affiliation(s)
- Emmanouil Koullias
- Second Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, GRC
| | - Maria Papavdi
- Second Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, GRC
| | - John Koskinas
- Second Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, GRC
| | - Melanie Deutsch
- Second Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, GRC
| | - Anastasia Thanopoulou
- Second Department of Internal Medicine, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, GRC
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25
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Misceo D, Mocciaro G, D'Amore S, Vacca M. Diverting hepatic lipid fluxes with lifestyles revision and pharmacological interventions as a strategy to tackle steatotic liver disease (SLD) and hepatocellular carcinoma (HCC). Nutr Metab (Lond) 2024; 21:112. [PMID: 39716321 DOI: 10.1186/s12986-024-00871-3] [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: 08/22/2024] [Accepted: 11/13/2024] [Indexed: 12/25/2024] Open
Abstract
Steatotic liver disease (SLD) and Hepatocellular Carcinoma (HCC) are characterised by a substantial rewiring of lipid fluxes caused by systemic metabolic unbalances and/or disrupted intracellular metabolic pathways. SLD is a direct consequence of the interaction between genetic predisposition and a chronic positive energy balance affecting whole-body energy homeostasis and the function of metabolically-competent organs. In this review, we discuss how the impairment of the cross-talk between peripheral organs and the liver stalls glucose and lipid metabolism, leading to unbalances in hepatic lipid fluxes that promote hepatic fat accumulation. We also describe how prolonged metabolic stress builds up toxic lipid species in the liver, and how lipotoxicity and metabolic disturbances drive disease progression by promoting a chronic activation of wound healing, leading to fibrosis and HCC. Last, we provide a critical overview of current state of the art (pre-clinical and clinical evidence) regarding mechanisms of action and therapeutic efficacy of candidate SLD treatment options, and their potential to interfere with SLD/HCC pathophysiology by diverting lipids away from the liver therefore improving metabolic health.
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Affiliation(s)
- Davide Misceo
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Gabriele Mocciaro
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK
| | - Simona D'Amore
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Clinica Medica "G. Baccelli", "Aldo Moro" University of Bari, 70124, Bari, Italy.
| | - Michele Vacca
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK.
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26
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Karagiannakis DS, Stefanaki K, Paschou SA, Papatheodoridi M, Tsiodras S, Papanas N. Addressing the essentials of the recent guidelines for managing patients with metabolic dysfunction-associated steatotic liver disease. Hormones (Athens) 2024:10.1007/s42000-024-00625-z. [PMID: 39695010 DOI: 10.1007/s42000-024-00625-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 12/16/2024] [Indexed: 12/20/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of end-stage liver disease and liver transplantation in the Western world, with an approximate prevalence of 30% worldwide which is continuously rising. It is characterized by intrahepatic fat deposition along with at least one cardiometabolic risk factor, such as diabetes mellitus, obesity, hypertriglyceridemia, and hypertension. MASLD consists of a spectrum of liver diseases ranging from simple liver steatosis to steatohepatitis, liver fibrosis, and cirrhosis. Recently, the European Association for the Study of the Liver (EASL), the European Association for the Study of Diabetes (EASD), and the European Association for the Study of Obesity (EASO) released the latest guidelines regarding the management of patients with MASLD. This article highlights the critical points of these guidelines and emphasizes problematic issues that need further evaluation.
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Affiliation(s)
- Dimitrios S Karagiannakis
- Academic Department of Gastroenterology, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
| | - Katerina Stefanaki
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, School of Medicine, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavroula A Paschou
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, School of Medicine, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Margarita Papatheodoridi
- Academic Department of Gastroenterology, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Sotirios Tsiodras
- 4th Department of Internal Medicine, School of Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Papanas
- Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, Thrace, Alexandroupolis, Greece
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27
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Lin XF, Cui XN, Yang J, Jiang YF, Wei TJ, Xia L, Liao XY, Li F, Wang DD, Li J, Wu Q, Yin DS, Le YY, Yang K, Wei R, Hong TP. SGLT2 inhibitors ameliorate NAFLD in mice via downregulating PFKFB3, suppressing glycolysis and modulating macrophage polarization. Acta Pharmacol Sin 2024; 45:2579-2597. [PMID: 39294445 PMCID: PMC11579449 DOI: 10.1038/s41401-024-01389-3] [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: 04/15/2024] [Accepted: 08/30/2024] [Indexed: 09/20/2024]
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitor (SGLT2i) is a novel class of anti-diabetic drug, which has displayed a promising benefit for non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the protective effects of SGLT2i against NAFLD and the underlying mechanisms. The db/db mice and western diet-induced NAFLD mice were treated with dapagliflozin (1 mg·kg-1·d-1, i.g.) or canagliflozin (10 mg·kg-1·d-1, i.g.) for 8 weeks. We showed that the SGLT2i significantly improved NAFLD-associated metabolic indexes, and attenuated hepatic steatosis and fibrosis. Notably, SGLT2i reduced the levels of pro-inflammatory cytokines and chemokines, downregulated M1 macrophage marker expression and upregulated M2 macrophage marker expression in liver tissues. In cultured mouse bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages, the SGLT2i (10, 20 and 40 μmol/L) significantly promoted macrophage polarization from M1 to M2 phenotype. RNA sequencing, Seahorse analysis and liquid chromatography-tandem mass spectrometry analysis revealed that the SGLT2i suppressed glycolysis and triggered metabolic reprogramming in macrophages. By using genetic manipulation and pharmacological inhibition, we identified that the SGLT2i targeted PFKFB3, a key enzyme of glycolysis, to modulate the macrophage polarization of M1 to M2 phenotype. Using a co-culture of macrophages with hepatocytes, we demonstrated that the SGLT2i inhibited lipogenesis in hepatocytes via crosstalk with macrophages. In conclusion, this study highlights a potential therapeutic application for repurposing SGLT2i and identifying a potential target PFKFB3 for NAFLD treatment.
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Affiliation(s)
- Xia-Fang Lin
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Xiao-Na Cui
- State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, 100191, China
| | - Jin Yang
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Ya-Fei Jiang
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Tian-Jiao Wei
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Li Xia
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Xin-Yue Liao
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Fei Li
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Dan-Dan Wang
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Jian Li
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Qi Wu
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - De-Shan Yin
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Yun-Yi Le
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Kun Yang
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China
| | - Rui Wei
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China.
| | - Tian-Pei Hong
- Department of Endocrinology and Metabolism, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, 100191, China.
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28
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Xu X, Hu J, Pang X, Wang X, Xu H, Yan X, Zhang J, Pan S, Wei W, Li Y. Association between plant and animal protein and biological aging: findings from the UK Biobank. Eur J Nutr 2024; 63:3119-3132. [PMID: 39292264 PMCID: PMC11519226 DOI: 10.1007/s00394-024-03494-9] [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: 03/04/2024] [Accepted: 08/21/2024] [Indexed: 09/19/2024]
Abstract
PURPOSE This study aimed to evaluate the relationship between plant protein, animal protein and biological aging through different dimensions of biological aging indices. Then explore the effects of substitution of plant protein, animal protein, and their food sources on biological aging. METHODS The data came from 79,294 participants in the UK Biobank who completed at least two 24-h dietary assessments. Higher Klemera-Doubal Method Biological Age (HKDM-BA), higher PhenoAge (HPA), higher allostatic load (HAL), and longer telomere length (LTL) were estimated to assess biological aging. Logistic regression was used to estimate protein-biological aging associations. Substitution model was performed to assess the effect of dietary protein substitutions. RESULTS Plant protein intake was inversely associated with HKDM-BA, HPA, HAL, and positively associated with LTL (odds ratios after fully adjusting and comparing the highest to the lowest quartile: 0.83 (0.79-0.88) for HKDM-BA, 0.86 (0.72-0.94) for HPA, 0.90 (0.85-0.95) for HAL, 1.06 (1.01-1.12) for LTL), while animal protein was not correlated with the four indices. Substituting 5% of energy intake from animal protein with plant protein, replacing red meat or poultry with whole grains, and replacing red or processed meat with nuts, were negatively associated with HKDM-BA, HPA, HAL and positively associated with LTL. However, an inverse association was found when legumes were substituted for yogurt. Gamma glutamyltransferase, alanine aminotransferase, and aspartate aminotransferase mediated the relationship between plant protein and HKDM-BA, HPA, HAL, and LTL (mediation proportion 11.5-24.5%; 1.9-6.7%; 2.8-4.5%, respectively). CONCLUSION Higher plant protein intake is inversely associated with biological aging. Although there is no association with animal protein, food with animal proteins displayed a varied correlation.
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Affiliation(s)
- Xiaoqing Xu
- Department of Nutrition and Food Hygiene, School of Public Health, The National Key Discipline, Harbin Medical University, Harbin, 150081, China
| | - Jinxia Hu
- Department of Nutrition and Food Hygiene, School of Public Health, The National Key Discipline, Harbin Medical University, Harbin, 150081, China
| | - Xibo Pang
- Department of Nutrition and Food Hygiene, School of Public Health, The National Key Discipline, Harbin Medical University, Harbin, 150081, China
| | - Xuanyang Wang
- Department of Nutrition and Food Hygiene, School of Public Health, The National Key Discipline, Harbin Medical University, Harbin, 150081, China
| | - Huan Xu
- Department of Nutrition and Food Hygiene, School of Public Health, The National Key Discipline, Harbin Medical University, Harbin, 150081, China
- The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Xuemin Yan
- Department of Nutrition and Food Hygiene, School of Public Health, The National Key Discipline, Harbin Medical University, Harbin, 150081, China
| | - Jia Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, The National Key Discipline, Harbin Medical University, Harbin, 150081, China
| | - Sijia Pan
- Department of Nutrition and Food Hygiene, School of Public Health, The National Key Discipline, Harbin Medical University, Harbin, 150081, China
| | - Wei Wei
- Department of Nutrition and Food Hygiene, School of Public Health, The National Key Discipline, Harbin Medical University, Harbin, 150081, China
| | - Ying Li
- Department of Nutrition and Food Hygiene, School of Public Health, The National Key Discipline, Harbin Medical University, Harbin, 150081, China.
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29
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Kitsios K, Trakatelli CM, Antza C, Triantafyllou A, Sarigianni M, Kotsis V. Treatment of Metabolic (Dysfunction)-Associated Fatty Liver Disease: Evidence from Randomized Controlled Trials-A Short Review. Metab Syndr Relat Disord 2024; 22:703-708. [PMID: 39088384 DOI: 10.1089/met.2024.0059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/03/2024] Open
Abstract
Metabolic-associated fatty liver disease (MALFD) is a highly prevalent and progressive disease, strongly related to obesity, metabolic syndrome, and cardiovascular disease. It comprises a spectrum of liver pathology from steatosis (fat accumulation in the hepatocytes) to steatosis with inflammation (metabolic-associated steatohepatitis, MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. There is currently only one medication, resmetirom, US Food and Drug Administration approved for the treatment of MALFD. Evidence from randomized trials supports the efficacy of hypocaloric diets and exercise in MASH resolution. Moreover, substantial weight loss after bariatric surgery can lead to significant and longitudinally sustained MASH resolution, improvement in liver fibrosis, and decrease in the risk of major cardiovascular adverse events. Pioglitazone, an insulin sensitizer, initiated at the early stages, before the progression to fibrosis, may be effective in resolution of MASH in patients with or without type 2 diabetes. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), semaglutide and liraglutide, may also be effective in resolution of MASH but not of fibrosis. Preliminary data from interventions with tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide RA, and sodium-glucose cotransporter 2 inhibitors are encouraging, but more data based on liver biopsy are needed.
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Affiliation(s)
- Konstantinos Kitsios
- Third Department of Internal Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece
| | - Christina-Maria Trakatelli
- Third Department of Internal Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece
| | - Christina Antza
- Third Department of Internal Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece
| | - Areti Triantafyllou
- Third Department of Internal Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece
| | - Maria Sarigianni
- Third Department of Internal Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece
| | - Vasilios Kotsis
- Third Department of Internal Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece
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30
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Lee HA, Lee HA, Kim HY. Evolution of characteristics of MASLD with and without diabetes: a meta-analysis of placebo arms. Sci Rep 2024; 14:28951. [PMID: 39578601 PMCID: PMC11584620 DOI: 10.1038/s41598-024-79428-6] [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: 01/09/2024] [Accepted: 11/08/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND We explored the changes in metabolic dysfunction-associated steatotic liver disease (MASLD) severity over time by analyzing data from the placebo arms of randomized controlled trials (RCTs), focusing on the presence of diabetes. METHODS RCTs on MASLD that included a placebo arm were identified using a systematic search of the literature. Primary outcomes were changes in hepatic steatosis and fibrosis. RESULTS The meta-analysis included 8 RCTs involving 386 patients without diabetes and 24 RCTs involving 637 patients with diabetes. The pooled estimate of mean change in steatosis grade was - 0.1 in patients without diabetes, and - 0.37 in patients with diabetes (P = 0.066). The mean change in fibrosis stage was 0.05 in patients without diabetes, and - 0.03 in patients with diabetes (P = 0.359). The mean change in nonalcoholic fatty liver disease activity score was - 0.55 in patients without diabetes, and - 1.50 in patients with diabetes (P = 0.100). The mean change in ALT and AST were significantly larger in patients without diabetes compared to those with diabetes (P < 0.05). CONCLUSION Placebo treatment had a greater effect in improving liver steatosis in patients with diabetes compared to those without. These findings highlight the importance of tailored treatment strategies in MASLD, particularly considering diabetes status.
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Affiliation(s)
- Han Ah Lee
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Hye Ah Lee
- Clinical Trial Center, Ewha Womans University College of Medicine, Seoul, Korea
| | - Hwi Young Kim
- Department of Internal Medicine, College of Medicine, Ewha Womans University, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul, 07985, Korea.
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31
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Zhou D, Fan J. Drug treatment for metabolic dysfunction-associated steatotic liver disease: Progress and direction. Chin Med J (Engl) 2024; 137:2687-2696. [PMID: 39470028 PMCID: PMC11611247 DOI: 10.1097/cm9.0000000000003355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Indexed: 10/30/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), also called non-alcoholic fatty liver disease, is the most epidemic chronic liver disease worldwide. Metabolic dysfunction-associated steatohepatitis (MASH) is the critical stage of MASLD, and early diagnosis and treatment of MASH are crucial for reducing the incidence of intrahepatic and extrahepatic complications. So far, pharmacotherapeutics for the treatment of MASH are still a major challenge, because of the complexity of the pathogenesis and heterogeneity of MASH. Many agents under investigation have shown impressive therapeutic effects by targeting different key pathways, including the attenuation of steatohepatitis or fibrosis or both. It is notable that thyroid hormone receptor-β agonist, resmetirom has become the first officially approved drug for treating MASH with fibrosis. Other agents such as peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 analogs, and fibroblast growth factor 21 analogs are awaiting approval. This review focuses on the current status of drug therapy for MASH and summarizes the latest results of new medications that have completed phase 2 or 3 clinical trials, and presents the future directions and difficulties of new drug research for MASH.
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Affiliation(s)
- Da Zhou
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
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32
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Mao X, Zhang X, Kam L, Chien N, Lai R, Cheung KS, Yuen MF, Cheung R, Seto WK, Nguyen MH. Synergistic association of sodium-glucose cotransporter-2 inhibitor and metformin on liver and non-liver complications in patients with type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease. Gut 2024; 73:2054-2061. [PMID: 39122360 DOI: 10.1136/gutjnl-2024-332481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 07/28/2024] [Indexed: 08/12/2024]
Abstract
OBJECTIVE Type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease (diabetic MASLD) frequently coexist and worsen liver and non-liver outcomes, but effective pharmacological therapies are limited. We aimed to evaluate the long-term effect of sodium-glucose cotransporter-2 inhibitor (SGLT-2i) on liver and non-liver outcomes among patients with diabetic MASLD. DESIGN This population-based cohort study retrieved patients with diabetic MASLD from Merative Marketscan Research Databases (April 2013 and December 2021). The active comparator was other glucose-lowering drugs (oGLDs). Primary outcomes were liver complications including hepatocellular carcinoma (HCC) and liver cirrhosis, as well as non-liver complications including cardiovascular disease (CVD), chronic kidney disease (CKD) and non-liver cancer. Propensity score matching was applied and Cox regression models were conducted. RESULTS Compared with oGLD, SGLT-2i users had significantly lower risk of HCC (HR 0.76, 95% CI 0.62 to 0.93), liver cirrhosis (HR 0.80, 95% CI 0.76 to 0.84), CVD (HR 0.82, 95% CI 0.79 to 0.85) and CKD (HR 0.66, 95% CI 0.62 to 0.70), non-liver cancer (HR 0.81, 95% CI 0.76 to 0.86). Compared with patients without metformin and SGLT-2i, a stepwise decreasing risk was observed in users of either metformin or SGLT-2i (HRs 0.76-0.97) and in users of both medications (HRs 0.58-0.79). The lower risk also was shown in liver decompensation, compensated cirrhosis, major CVD, end-stage renal disease and specific common cancers (HRs 0.61-0.84). CONCLUSION In a nationwide cohort, SGLT-2i users were associated with a substantially lower risk of liver and non-liver complications than oGLD users among patients with diabetic MASLD. The risk was further reduced with concomitant metformin use.
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Affiliation(s)
- Xianhua Mao
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
- Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xinrong Zhang
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
| | - Leslie Kam
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
| | - Nicholas Chien
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
| | - Rongtao Lai
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
- Department of Infectious Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ka-Shing Cheung
- Department of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Ramsey Cheung
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
- Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong, China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
- Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California, USA
- Stanford Cancer Institute, Stanford University Medical Center, Palo Alto, California, USA
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Abdel-Samiee M, Ibrahim ES, Kohla M, Abdelsameea E, Salama M. Regression of hepatic fibrosis after pharmacological therapy for nonalcoholic steatohepatitis. World J Gastrointest Pharmacol Ther 2024; 15:97381. [PMID: 39534523 PMCID: PMC11551621 DOI: 10.4292/wjgpt.v15.i6.97381] [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: 05/29/2024] [Revised: 08/28/2024] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
The global incidence of nonalcoholic fatty liver disease (NAFLD) is escalating considerably. NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis, which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix, leading to fibrosis. Hepatocyte ballooning is a key catalyst for fibrosis progression, potentially advancing to cirrhosis and its decompensated state. Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD; therefore, those with substantial fibrosis require timely intervention. Although liver biopsy is the most reliable method for fibrosis detection, it is associated with certain risks and limitations, particularly in routine screening. Consequently, various noninvasive diagnostic techniques have been introduced. This review examines the increasing prevalence of NAFLD, evaluates the noninvasive diagnostic techniques for fibrosis, and assesses their efficacy in staging the disease. In addition, it critically appraises current and emerging antifibrotic therapies, focusing on their mechanisms, efficacy, and potential in reversing fibrosis. This review underscores the urgent need for effective therapeutic strategies, given the dire consequences of advanced fibrosis.
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Affiliation(s)
- Mohamed Abdel-Samiee
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Essam Salah Ibrahim
- Department of Medicine, RCSI Medical University of Bahrain, Adliya 15503, Bahrain
| | - Mohamed Kohla
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Eman Abdelsameea
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Mohsen Salama
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
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Ayesh H, Beran A, Suhail S, Ayesh S, Niswender K. Comparative Analysis of Resmetirom vs. FGF21 Analogs vs. GLP-1 Agonists in MASLD and MASH: Network Meta-Analysis of Clinical Trials. Biomedicines 2024; 12:2328. [PMID: 39457640 PMCID: PMC11505228 DOI: 10.3390/biomedicines12102328] [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: 09/10/2024] [Revised: 10/06/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
INTRODUCTION Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic-Dysfunction Associated Steatohepatitis (MASH) are linked to obesity, type 2 diabetes, and metabolic syndrome, increasing liver-related morbidity and cardiovascular risk. Recent therapies, including Resmetirom, FGF21 analogs, and GLP-1 agonists, have shown promise. This network meta-analysis evaluates their comparative efficacy and safety. METHODS A literature search was conducted across PubMed, Scopus, Web of Science, and Cochrane Library. Included clinical trials addressed MASLD or MASH with Resmetirom, FGF21 analogs, or GLP-1 agonists. Statistical analyses used a random-effects model, calculating mean differences (MD) and relative risks (RR), with heterogeneity assessed using τ2, I2, and Q statistics. RESULTS MASH resolution was significantly higher for FGF21 (RR 4.84, 95% CI: 2.59 to 9.03), Resmetirom showed the most significant reduction in MRI-PDFF (MD -18.41, 95% CI: -23.60 to -13.22) and >30% fat reduction (RR 3.56, 95% CI: 2.41 to 5.26). Resmetirom significantly reduced ALT (MD -15.71, 95% CI: -23.30 to -8.13), AST (MD -12.28, 95% CI: -21.07 to -3.49), and GGT (MD -19.56, 95% CI: -34.68 to -4.44). FGF21 and GLP-1 also reduced these markers. Adverse events were significantly higher with Resmetirom (RR 1.47, 95% CI: 1.24 to 1.74), while GLP-1 and FGF21 showed non-significant trends towards increased risk. CONCLUSIONS Resmetirom and FGF21 show promise in treating MASLD and MASH, with Resmetirom particularly effective in reducing liver fat and improving liver enzymes. GLP-1 agonists also show benefits but to a lesser extent. Further long-term studies are needed to validate these findings and assess cost-effectiveness.
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Affiliation(s)
- Hazem Ayesh
- Deaconess Health System, Evansville, IN 47708, USA
| | - Azizullah Beran
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | | | | | - Kevin Niswender
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Bandyopadhyay S, Samajdar SS, Chaudhuri S, Das S. An insight into the updated pharmacotherapy of metabolic-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatohepatitis (MASH) in lean individuals: a review. Hosp Pract (1995) 2024:1-7. [PMID: 39356238 DOI: 10.1080/21548331.2024.2412513] [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: 04/30/2024] [Revised: 09/22/2024] [Accepted: 10/01/2024] [Indexed: 10/03/2024]
Abstract
Metabolic-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatohepatitis (MASH) in lean individuals represents a distinctive subset of MASH. Current pharmacotherapies, for MASH as demonstrated in clinical trials, predominantly target obese patients with limited consideration for lean MASH. We aimed to systematically review the literature on the pharmacotherapy of lean MASH. We searched standard medical databases, such as PubMed, Embase, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov to identify eligible studies published in English up to 31 December 2023 regarding the effect of pharmacological interventions in individuals with lean MASH. We have summarized the role of various drug classes including peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, vitamin E, farnesoid X receptor agonists, selective thyroid hormone receptor-β agonists, and selective cholesterol absorption inhibitors. Consequently, lifestyle interventions, encompassing dietary modifications, exercise, and weight loss particularly directed at visceral obesity or achieving a reduction in body weight are recommended for all non-obese individuals with MASH. A highlight on the only available treatment recommendation for lean MASH is also presented. The available evidence regarding the efficacy of various drugs for the treatment of lean MASH is limited. Conclusive evidence is warranted from clinical trials exclusively involving lean individuals with MASH.
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Affiliation(s)
| | - Shambo Samrat Samajdar
- Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, India
| | | | - Saibal Das
- Indian Council of Medical Research - Centre for Ageing and Mental Health, Kolkata, India
- Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden
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Luo S, Zheng MH, Wong VWS, Au Yeung SL. Drug-target Mendelian randomisation applied to metabolic dysfunction-associated steatotic liver disease: opportunities and challenges. EGASTROENTEROLOGY 2024; 2:e100114. [PMID: 39944268 PMCID: PMC11770435 DOI: 10.1136/egastro-2024-100114] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 09/13/2024] [Indexed: 03/19/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent cause of chronic liver disease worldwide affecting over one-third of the adult population. Despite the recent evolution of new nomenclature and diagnostic criteria for MASLD, progress in drug development for this condition remains limited. This review highlights the potential of drug-target Mendelian randomisation (MR), a study design that leverages human genetics and genomics, for the discovery, repositioning and safety assessment of drug targets in MASLD. We summarised key aspects of designing and appraising a drug-target MR study, discussing its inherent assumptions and considerations for instrument selection. Furthermore, we presented real-world examples from studies in MASLD which focused on opportunities and challenges in identifying novel drug targets, repositing existing drug targets, informing adjunctive treatments and addressing issues in paediatric MASLD.
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Affiliation(s)
- Shan Luo
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease, Zhejiang, China
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Shiu Lun Au Yeung
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Liu W, You D, Lin J, Zou H, Zhang L, Luo S, Yuan Y, Wang Z, Qi J, Wang W, Ye X, Yang X, Deng Y, Teng F, Zheng X, Lin Y, Huang Z, Huang Y, Yang Z, Zhou X, Zhang Y, Chen R, Xu L, Li J, Yang W, Zhang H. SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8 + T cell activation. Cell Metab 2024; 36:2245-2261.e6. [PMID: 39243758 DOI: 10.1016/j.cmet.2024.08.005] [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: 01/23/2023] [Revised: 02/26/2024] [Accepted: 08/09/2024] [Indexed: 09/09/2024]
Abstract
During the progression of metabolic dysfunction-associated steatohepatitis (MASH), the accumulation of auto-aggressive CD8+ T cells significantly contributes to liver injury and inflammation. Empagliflozin (EMPA), a highly selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), exhibits potential therapeutic benefits for liver steatosis; however, the underlying mechanism remains incompletely elucidated. Here, we found that EMPA significantly reduced the hepatic accumulation of auto-aggressive CD8+ T cells and lowered granzyme B levels in mice with MASH. Mechanistically, EMPA increased β-hydroxybutyric acid by promoting the ketogenesis of CD8+ T cells via elevating 3-hydroxybutyrate dehydrogenase 1 (Bdh1) expression. The β-hydroxybutyric acid subsequently inhibited interferon regulatory factor 4 (Irf4), which is crucial for CD8+ T cell activation. Furthermore, the ablation of Bdh1 in T cells aggravated the manifestation of MASH and hindered the therapeutic efficacy of EMPA. Moreover, a case-control study also showed that SGLT2 inhibitor treatment repressed CD8+ T cell infiltration and improved liver injury in patients with MASH. In summary, our study indicates that SGLT2 inhibitors can target CD8+ T cells and may be an effective strategy for treating MASH.
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Affiliation(s)
- Wenhui Liu
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Endocrinology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Danming You
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiayang Lin
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huren Zou
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shenjian Luo
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Youwen Yuan
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiyi Wang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jingwen Qi
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weiwei Wang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xueru Ye
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyu Yang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yajuan Deng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fei Teng
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaojun Zheng
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yuhao Lin
- Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhiwei Huang
- Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yan Huang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhi Yang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuan Zhou
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanan Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruxin Chen
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lingling Xu
- Department of Endocrinology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jin Li
- Division of Endocrinology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, China.
| | - Wei Yang
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
| | - Huijie Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Key Laboratory of Cell Metabolic Homeostasis and Major Chronic Diseases, Guangzhou, China.
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Cheung KS, Ng HY, Hui RWH, Lam LK, Mak LY, Ho YC, Tan JT, Chan EW, Seto WK, Yuen MF, Leung WK. Effects of empagliflozin on liver fat in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus: A randomized, double-blind, placebo-controlled trial. Hepatology 2024; 80:916-927. [PMID: 38536017 DOI: 10.1097/hep.0000000000000855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 02/19/2024] [Indexed: 05/03/2024]
Abstract
BACKGROUND AND AIMS We investigated whether empagliflozin reduces hepatic steatosis in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus. APPROACH AND RESULTS This was an investigator-initiated, double-blind, randomized, placebo-controlled trial recruiting adult subjects from the community. Eligible subjects without diabetes mellitus (fasting plasma glucose < 7 mmol/L and HbA1c < 6.5%) who had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 5% were randomly allocated to receive empagliflozin 10 mg daily or placebo (1:1 ratio) for 52 weeks (end of treatment, EOT). MRI-PDFF was conducted at baseline and EOT. The primary outcome was the difference in change of MRI-PDFF between the 2 groups at EOT. Secondary outcomes were hepatic steatosis resolution (MRI-PDFF < 5%), alanine aminotransferase drop ≥ 17 U/L, MRI-PDFF decline ≥ 30%, a combination of both, and changes of anthropometric and laboratory parameters at EOT. All outcomes were based on intention-to-treat analysis. Of 98 recruited subjects (median age: 55.7 y [IQR:49.5-63.4]; male:54 [55.1%]), 97 (empagliflozin:49, placebo:48; median MRI-PDFF:9.7% vs 9.0%) had MRI-PDFF repeated at EOT. The Empagliflozin group had a greater reduction in median MRI-PDFF compared to the placebo group (-2.49% vs. -1.43%; p = 0.025), with a nonsignificant trend of resolution of hepatic steatosis (44.9% vs. 28.6%; p = 0.094). There was no significant difference in alanine aminotransferase drop ≥ 17 U/L (16.3% vs. 12.2%; p = 0.564), MRI-PDFF drop ≥ 30% (49.0% vs. 40.8%; p = 0.417), and composite outcome (8.2% vs. 8.2%; p = 1.000). Empagliflozin group had a greater drop in body weight (-2.7 vs. -0.2 kg), waist circumference (-2.0 vs. 0 cm), fasting glucose (-0.3 vs. 0 mmol/L), and ferritin (-126 vs. -22 pmol/L) (all p < 0.05). CONCLUSIONS Empagliflozin for 52 weeks reduces hepatic fat content in subjects with nondiabetic metabolic dysfunction-associated steatotic liver disease. (ClinicalTrials.gov Identifier: NCT04642261).
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Affiliation(s)
- Ka Shing Cheung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Ho Yu Ng
- School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Rex Wan Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Lok Ka Lam
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Lung Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
- Department of Medicine, Surgery, Pathology, Clinical Oncology and School of Biomedical Sciences, State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Yuen Chi Ho
- Department of Radiology, Queen Mary Hospital, Hong Kong
| | - Jing Tong Tan
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Esther W Chan
- Department of Pharmacology and Pharmacy, Centre for Safe Medication Practice and Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong
| | - Wai Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
- Department of Medicine, Surgery, Pathology, Clinical Oncology and School of Biomedical Sciences, State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Man Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
- Department of Medicine, Surgery, Pathology, Clinical Oncology and School of Biomedical Sciences, State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Wai K Leung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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Ren L, Ju F, Liu S, Cai Y, Gang X, Wang G. New Perspectives on Obesity-Associated Nephropathy from Pathophysiology to Therapeutics: Revealing the Promise of GLP-1 RA Therapy. Drug Des Devel Ther 2024; 18:4257-4272. [PMID: 39347536 PMCID: PMC11437658 DOI: 10.2147/dddt.s476815] [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: 07/04/2024] [Accepted: 09/10/2024] [Indexed: 10/01/2024] Open
Abstract
Obesity represents a substantial risk factor for a multitude of metabolic disorders, which seriously threatens human life and health. As the global obesity epidemic intensifies, obesity-related nephropathy (ORN) has attracted great attention. ORN arises from both physical/mechanical and non-physical insults to the glomerular and tubular structures precipitated by obesity, culminating in structural impairments and functional aberrations within the kidneys. Physical injury factors include changes in renal hemodynamics, renal compression, and mechanical stretching of podocytes. Non-physical injury factors include overactivation of the RAAS system, insulin resistance, lipotoxicity, inflammation, and dysregulation of bile acid metabolism. Exploring molecules that target modulation of physical or nonphysical injury factors is a potential approach to ORN treatment. ORN is characterized clinically by microproteinuria and pathologically by glomerulomegaly, which is atypical and makes early diagnosis difficult. Investigating early diagnostic markers for ORN thus emerges as a critical direction for future research. Additionally, there is no specific drug for ORN in clinical treatment, which mainly focuses on weight reduction, mitigating proteinuria, and preserving renal function. In our review, we delineate a progressive therapeutic approach involving enhancements in lifestyle, pharmacotherapy, and bariatric surgery. Our emphasis underscores glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as poised to emerge as pivotal therapeutic modalities for ORN in forthcoming clinical avenues.
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Affiliation(s)
- Linan Ren
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
- Institute of Translational Medicine, First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
| | - Feng Ju
- Department of Orthopedics, Yuci District People’s Hospital, Yuci, Shanxi, 030600, People’s Republic of China
| | - Siyuan Liu
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
- Institute of Translational Medicine, First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
| | - Yunjia Cai
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
- Institute of Translational Medicine, First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
| | - Xiaokun Gang
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
| | - Guixia Wang
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
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Ishikawa T, Terai N, Sato R, Jimbo R, Kobayashi Y, Sato T, Iwanaga A, Sano T, Yokoyama J, Honma T. Clinical Efficacy and Body Composition Changes with Sodium Glucose Cotransporter 2 Inhibitor/Glucagon-like Peptide-1 Antagonist Combination Therapy in Patients with Type 2 Diabetes Mellitus-associated Nonalcoholic Fatty Liver Disease. Intern Med 2024; 63:2491-2497. [PMID: 38346734 PMCID: PMC11473285 DOI: 10.2169/internalmedicine.3259-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 12/14/2023] [Indexed: 09/18/2024] Open
Abstract
Objective Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) treatment guidelines recommend sodium glucose cotransporter 2 inhibitor (SGLT2I) and glucagon-like peptide-1 agonist (GLP-1A) therapy in patients with type 2 diabetes mellitus (T2DM). SGLT2I improves the pathological condition of NAFLD/NASH in T2DM patients. However, cases of rebound during long-term SGLT2I treatment have been reported. This study investigated the efficacy of SGLT2I and GLP-1A combination therapy in diabetic patients with NAFLD by examining changes in computed tomography (CT)-based body composition and clinical outcomes. Methods Fifteen patients (5 men/10 women) with T2DM-associated NAFLD who had not responded to SGLT2I treatment and were being treated with GLP-1A combination therapy were included. Changes in the liver function, visceral adipose tissue index (VATI), and subcutaneous adipose tissue index (SATI) were compared using CT to evaluate the body composition. Results SGLT2I significantly improved alanine aminotransferase (28.0 to 13.0 IU/L), alkaline phosphatase (250.0 to 77.0 IU/L), and gamma glutamyl transpeptidase (23.0 to 12.0 IU/L) levels. The body mass index (BMI) decreased from 25.7 to 25.2 kg/m2. A CT-based analysis showed a significant improvement in SATI (80.9 to 66.1, p=0.002), with no significant change in VATI (53.2 to 51.5). GLP-1A addition improved the BMI (25.2 to 23.5 kg/m2) and hemoglobin A1c (6.5% to 6.2%, p=0.001). A further analysis revealed additional improvement in SATI (66.1 to 56.6, p=0.007) and a significant decrease in VATI (51.5 to 48.3, p=0.001). Conclusion SGLT2I and GLP-1A combination therapy improved the liver function, body composition, and glycemic control in diabetic patients with NAFLD/NASH, as well as SATI and VATI. The optimal timing of combination therapy remains to be determined.
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Affiliation(s)
- Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Nanako Terai
- Department of Radiographer, Saiseikai Niigata Hospital, Japan
| | - Ryo Sato
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Ryo Jimbo
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Yuji Kobayashi
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Toshifumi Sato
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Akito Iwanaga
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Tomoe Sano
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Junji Yokoyama
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
| | - Terasu Honma
- Department of Gastroenterology, Saiseikai Niigata Hospital, Japan
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Yadav M, Verma S, Tiwari P, Mugale MN. Unraveling the mechanisms of hepatogenous diabetes and its therapeutic perspectives. Life Sci 2024; 353:122934. [PMID: 39089644 DOI: 10.1016/j.lfs.2024.122934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/26/2024] [Accepted: 07/25/2024] [Indexed: 08/04/2024]
Abstract
The review focused mainly on the pathogenesis of hepatogenous diabetes (HD) in liver cirrhosis (LC). This review reveals parallels between the mechanisms of metabolic dysfunction observed in LC and type II diabetes (T2DM), suggesting a shared pathway leading to HD. It underscores the role of insulin in HD pathogenesis, highlighting key factors such as insulin signaling, glucose metabolism, insulin resistance (IR), and the influence of adipocytes. Furthermore, the impact of adipose tissue accumulation, fatty acid metabolism, and pro-inflammatory cytokines like Tumor necrosis factor-α (TNF-α) on IR are discussed in the context of HD. Altered signaling pathways, disruptions in the endocrine system, liver inflammation, changes in muscle mass and composition, and modifications to the gut microbiota collectively contribute to the complex interplay linking cirrhosis and HD. This study highlights how important it is to identify and treat this complex condition in cirrhotic patients by thoroughly analyzing the link between cirrhosis, IR, and HD. It also emphasizes the vitality of targeted interventions. Cellular and molecular investigations into IR have revealed potential therapeutic targets for managing and preventing HD.
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Affiliation(s)
- Manisha Yadav
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Smriti Verma
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Purnima Tiwari
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India
| | - Madhav Nilakanth Mugale
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Procyk G, Jaworski J, Gąsecka A, Filipiak KJ, Borovac JA. Metabolic dysfunction-associated steatotic liver disease - A new indication for sodium-glucose Co-transporter-2 inhibitors. Adv Med Sci 2024; 69:407-415. [PMID: 39260740 DOI: 10.1016/j.advms.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 07/09/2024] [Accepted: 09/09/2024] [Indexed: 09/13/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed as a new name for the previous non-alcoholic fatty liver disease (NAFLD). There are some differences between MASLD and NAFLD, e.g., diagnostic criteria. MASLD is a hepatic steatosis without harmful alcohol consumption and is caused by metabolic factors. The prevalence of MASLD varies amongst different populations. The change in lifestyle plays a fundamental role in MASLD management, while there is no registered pharmacotherapy in this indication. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to have a beneficial effect on hepatic steatosis, hence, they have been widely investigated as potential therapeutics in MASLD. In this review, we aimed to thoroughly summarize current evidence from original research about the effects of SGLT2i use on MASLD. Almost all discussed studies advocate using SGLT2i in MASLD because of their beneficial effects. It includes the loss of body weight, which is beneficial per se, and the improvement in hepatic parameters. Most importantly, steatosis reduction has been observed in patients using SGLT2i. We highly recommend further research in this field, which we believe will eventually lead to a new indication for SGLT2i, i.e., MASLD.
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Affiliation(s)
- Grzegorz Procyk
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland; Doctoral School, Medical University of Warsaw, Warsaw, Poland.
| | - Jakub Jaworski
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Aleksandra Gąsecka
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof J Filipiak
- Institute of Clinical Science, Maria Sklodowska-Curie Medical Academy, Warsaw, Poland; Department of Hypertension, Angiology and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Josip A Borovac
- Cardiovascular Diseases Department, University Hospital of Split, Split, Croatia
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Ibraheem A, Al Tameemi WF. Impact of Empagliflozin on the Outcomes of β-Thalassemia Major in Patients With Type 2 Diabetes Mellitus: The THALEMPA Observational Study. Cureus 2024; 16:e69837. [PMID: 39435207 PMCID: PMC11492160 DOI: 10.7759/cureus.69837] [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] [Accepted: 09/21/2024] [Indexed: 10/23/2024] Open
Abstract
OBJECTIVE Beta-thalassemia major (β-TM) is a genetic disorder characterized by ineffective erythropoiesis and chronic hemolytic anemia, necessitating lifelong blood transfusions and leading to severe complications. This study, termed THALEMPA by the authors, investigated the effect of empagliflozin (EMPA) on β-TM outcomes in patients with type 2 diabetes mellitus (T2DM), focusing on disease severity and associated complications of iron overload and hyperuricemia. METHODOLOGY This study conducted a single-center prospective observational investigation involving adults diagnosed with β-TM and T2DM. A total of 20 carefully selected patients were stratified into two groups based on their medical condition: the EMPA group, receiving 10 mg of empagliflozin, and a control group, receiving standard care. This focused cohort size was chosen to ensure a detailed, in-depth analysis of the treatment effects within this specific patient population. Over three months, both groups were closely monitored for β-TM outcomes. The study assessed β-TM severity parameters such as hemoglobin levels, blood transfusion frequency, aspartate aminotransferase (AST), alanine aminotransferase (ALT), left ventricular ejection fraction percentage, and spleen size. Additionally, β-TM complications were evaluated through serum ferritin and uric acid levels. RESULTS Our analysis revealed that EMPA increased hemoglobin levels by up to 0.56 g/dL compared to baseline (P < 0.05). Liver enzyme levels significantly improved with EMPA by the third month. AST and ALT decreased by 36.22% and 33.36%, respectively, from baseline levels (P < 0.05), highlighting EMPA's potential benefits for β-TM severity. Serum ferritin and uric acid levels decreased by 27.93% and 21.29%, respectively, over three months on EMPA (P < 0.05). However, other parameters did not show significant changes post-EMPA. CONCLUSIONS This study demonstrates the significant impact of EMPA treatment over three months on β-TM patients with T2DM, evidenced by notable improvements in hemoglobin levels and reductions in liver enzymes, as well as in complications related to iron overload and hyperuricemia. Future research should confirm these benefits over longer durations and assess broader patient outcomes such as quality of life.
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Affiliation(s)
- Anas Ibraheem
- Department of Hematology, King's College Hospital, London, GBR
| | - Waseem F Al Tameemi
- Department of Internal Medicine, Section of Hematology, Al-Nahrain University College of Medicine, Baghdad, IRQ
- Department of Internal Medicine, Section of Hematology, Al-Immamain Al-Kadhumein Medical City, Baghdad, IRQ
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Tacke F, Horn P, Wai-Sun Wong V, Ratziu V, Bugianesi E, Francque S, Zelber-Sagi S, Valenti L, Roden M, Schick F, Yki-Järvinen H, Gastaldelli A, Vettor R, Frühbeck G, Dicker D. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024; 81:492-542. [PMID: 38851997 DOI: 10.1016/j.jhep.2024.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 04/30/2024] [Indexed: 06/10/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.
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Agrinier AL, Morissette A, Daoust L, Gignac T, Marois J, Varin TV, Pilon G, Larose É, Gagnon C, Desjardins Y, Anhê FF, Carreau AM, Vohl MC, Marette A. Camu-camu decreases hepatic steatosis and liver injury markers in overweight, hypertriglyceridemic individuals: A randomized crossover trial. Cell Rep Med 2024; 5:101682. [PMID: 39168095 PMCID: PMC11384942 DOI: 10.1016/j.xcrm.2024.101682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/16/2024] [Accepted: 07/18/2024] [Indexed: 08/23/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects 25% of the adult population with no effective drug treatments available. Previous animal studies reported that a polyphenol-rich extract from the Amazonian berry camu-camu (CC) prevented hepatic steatosis in a mouse model of diet-induced obesity. This study aims to determine the impact of CC on hepatic steatosis (primary outcome) and evaluate changes in metabolic and gut microbiota profiles (exploratory outcomes). A randomized, double-blind, placebo-controlled crossover trial is conducted on 30 adults with overweight and hypertriglyceridemia, who consume 1.5 g of CC capsules or placebo daily for 12 weeks. CC treatment decreases liver fat by 7.43%, while it increases by 8.42% during the placebo intervention, showing a significant difference of 15.85%. CC decreases plasma aspartate and alanine aminotransferases levels and promotes changes in gut microbiota composition. These findings support that polyphenol-rich prebiotic may reduce liver fat in adults with overweight, reducing the risk of developing NAFLD.
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Affiliation(s)
- Anne-Laure Agrinier
- Department of Medicine, Faculty of Medicine, Québec Heart and Lung Institute (IUCPQ), Université Laval, Quebec City, QC, Canada; Centre Nutrition, santé et société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec City, QC, Canada
| | - Arianne Morissette
- Department of Medicine, Faculty of Medicine, Québec Heart and Lung Institute (IUCPQ), Université Laval, Quebec City, QC, Canada; Centre Nutrition, santé et société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec City, QC, Canada
| | - Laurence Daoust
- Department of Medicine, Faculty of Medicine, Québec Heart and Lung Institute (IUCPQ), Université Laval, Quebec City, QC, Canada; Centre Nutrition, santé et société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec City, QC, Canada
| | - Théo Gignac
- Department of Medicine, Faculty of Medicine, Centre de Recherche CHU de Québec-Université Laval, Université Laval, Quebec City, QC, Canada
| | - Julie Marois
- Centre Nutrition, santé et société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec City, QC, Canada
| | - Thibault V Varin
- Centre Nutrition, santé et société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec City, QC, Canada
| | - Geneviève Pilon
- Department of Medicine, Faculty of Medicine, Québec Heart and Lung Institute (IUCPQ), Université Laval, Quebec City, QC, Canada; Centre Nutrition, santé et société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec City, QC, Canada
| | - Éric Larose
- Department of Medicine, Faculty of Medicine, Québec Heart and Lung Institute (IUCPQ), Université Laval, Quebec City, QC, Canada
| | - Claudia Gagnon
- Department of Medicine, Faculty of Medicine, Québec Heart and Lung Institute (IUCPQ), Université Laval, Quebec City, QC, Canada; Department of Medicine, Faculty of Medicine, Centre de Recherche CHU de Québec-Université Laval, Université Laval, Quebec City, QC, Canada
| | - Yves Desjardins
- Centre Nutrition, santé et société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec City, QC, Canada; Department of Plant Science, Faculty of Agriculture and Food sciences, Université Laval, Quebec City, QC, Canada
| | - Fernando F Anhê
- Department of Medicine, Faculty of Medicine, Québec Heart and Lung Institute (IUCPQ), Université Laval, Quebec City, QC, Canada; Centre Nutrition, santé et société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec City, QC, Canada
| | - Anne-Marie Carreau
- Department of Medicine, Faculty of Medicine, Centre de Recherche CHU de Québec-Université Laval, Université Laval, Quebec City, QC, Canada
| | - Marie-Claude Vohl
- Centre Nutrition, santé et société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec City, QC, Canada; School of Nutrition, Université Laval, Quebec City, QC, Canada
| | - André Marette
- Department of Medicine, Faculty of Medicine, Québec Heart and Lung Institute (IUCPQ), Université Laval, Quebec City, QC, Canada; Centre Nutrition, santé et société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec City, QC, Canada.
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Suzuki A, Hayashi A, Oda S, Fujishima R, Shimizu N, Matoba K, Taguchi T, Toki T, Miyatsuka T. Prolonged impacts of sodium glucose cotransporter-2 inhibitors on metabolic dysfunction-associated steatotic liver disease in type 2 diabetes: a retrospective analysis through magnetic resonance imaging. Endocr J 2024; 71:767-775. [PMID: 38811192 DOI: 10.1507/endocrj.ej24-0005] [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: 05/31/2024] Open
Abstract
The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in people with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) have been suggested in several reports based on serological markers, imaging data, and histopathology associated with steatotic liver disease. However, evidence regarding their long-term effects is currently insufficient. In this retrospective observational study, 34 people with T2D and MASLD, treated with SGLT2 inhibitors, were examined by proton density fat fraction derived by magnetic resonance imaging (MRI-PDFF) and other clinical data before, one year after the treatment. Furthermore, 22 of 34 participants underwent MRI-PDFF five years after SGLT2 inhibitors were initiated. HbA1c decreased from 8.9 ± 1.8% to 7.8 ± 1.0% at 1 year (p = 0.006) and 8.0 ± 1.1% at 5 years (p = 0.122). Body weight and fat mass significantly reduced from baseline to 1 and 5 year(s), respectively. MRI-PDFF significantly decreased from 15.3 ± 7.8% at baseline to 11.9 ± 7.6% (p = 0.001) at 1 year and further decreased to 11.3 ± 5.7% (p = 0.013) at 5 years. Thus, a 5-year observation demonstrated that SGLT2 inhibitors have beneficial effects on liver steatosis in people with T2D and MASLD.
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Affiliation(s)
- Agena Suzuki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Akinori Hayashi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Satoshi Oda
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Rei Fujishima
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Naoya Shimizu
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Kenta Matoba
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Tomomi Taguchi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Takuya Toki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Takeshi Miyatsuka
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
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Huttasch M, Roden M, Kahl S. Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? Metabolism 2024; 157:155937. [PMID: 38782182 DOI: 10.1016/j.metabol.2024.155937] [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: 08/29/2023] [Revised: 04/25/2024] [Accepted: 05/12/2024] [Indexed: 05/25/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) closely associates with obesity and type 2 diabetes. Lifestyle intervention and bariatric surgery aiming at substantial weight loss are cornerstones of MASLD treatment by improving histological outcomes and reducing risks of comorbidities. Originally developed as antihyperglycemic drugs, incretin (co-)agonists and SGLT2 inhibitors also reduce steatosis and cardiorenovascular events. Certain incretin agonists effectively improve histological features of MASLD, but not fibrosis. Of note, beneficial effects on MASLD may not necessarily require weight loss. Despite moderate weight gain, one PPARγ agonist improved adipose tissue and MASLD with certain benefit on fibrosis in post-hoc analyses. Likewise, the first THRβ-agonist was recently provisionally approved because of significant improvements of MASLD and fibrosis. We here discuss liver-related and metabolic effects induced by different MASLD treatments and their association with weight loss. Therefore, we compare results from clinical trials on drugs acting via weight loss (incretin (co)agonists, SGLT2 inhibitors) with those exerting no weight loss (pioglitazone; resmetirom). Furthermore, other drugs in development directly targeting hepatic lipid metabolism (lipogenesis inhibitors, FGF21 analogs) are addressed. Although THRβ-agonism may effectively improve hepatic outcomes, MASLD treatment concepts should consider all cardiometabolic risk factors for effective reduction of morbidity and mortality in the affected people.
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Affiliation(s)
- Maximilian Huttasch
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany.
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Sabine Kahl
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany.
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Zhang J, Li Y, Yang L, Ma N, Qian S, Chen Y, Duan Y, Xiang X, He Y. New advances in drug development for metabolic dysfunction-associated diseases and alcohol-associated liver disease. Cell Biosci 2024; 14:90. [PMID: 38971765 PMCID: PMC11227172 DOI: 10.1186/s13578-024-01267-9] [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: 03/14/2024] [Accepted: 06/19/2024] [Indexed: 07/08/2024] Open
Abstract
Metabolic disorders are currently threatening public health worldwide. Discovering new targets and developing promising drugs will reduce the global metabolic-related disease burden. Metabolic disorders primarily consist of lipid and glucose metabolic disorders. Specifically, metabolic dysfunction-associated steatosis liver disease (MASLD) and alcohol-associated liver disease (ALD) are two representative lipid metabolism disorders, while diabetes mellitus is a typical glucose metabolism disorder. In this review, we aimed to summarize the new drug candidates with promising efficacy identified in clinical trials for these diseases. These drug candidates may provide alternatives for patients with metabolic disorders and advance the progress of drug discovery for the large disease burden.
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Affiliation(s)
- Jinming Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yixin Li
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, 230001, Anhui, China
| | - Liu Yang
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ningning Ma
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Shengying Qian
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yingfen Chen
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yajun Duan
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, 230001, Anhui, China.
| | - Xiaogang Xiang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Yong He
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, China.
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Katakami N, Mita T, Sato Y, Watada H, Shimomura I. Changes in serum levels of liver-related parameters, uric acid, and hemoglobin in patients with type 2 diabetes mellitus under treatment with tofogliflozin-a post-hoc analysis of the UTOPIA study. Diabetol Int 2024; 15:379-388. [PMID: 39101158 PMCID: PMC11291786 DOI: 10.1007/s13340-024-00693-x] [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: 09/26/2023] [Accepted: 01/08/2024] [Indexed: 08/06/2024]
Abstract
Aims/Introduction The aim of the study was to evaluate the effects of tofogliflozin, a selective sodium-glucose cotransporter 2 inhibitor, on circulating levels of hepatic enzymes, uric acid and hemoglobin levels in patients with type 2 diabetes mellitus (T2DM). Materials and methods We evaluated longitudinal changes in circulating aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), uric acid, and hemoglobin levels in tofogliflozin (n = 169) and conventional treatment groups (n = 170) using data obtained from the UTOPIA trial, a randomized prospective study conducted to evaluate the efficacy of tofogliflozin in preventing atherosclerosis. Results Within 104 weeks, tofogliflozin treatment, but not conventional treatment, significantly reduced AST, ALT, and γ-GTP levels. This reduction was significantly greater in the tofogliflozin group than in the conventional group. Stratified analysis showed that, in patients with obesity (defined as body mass index (BMI) ≥ 25.0 kg/m2), significant differences were observed in AST, ALT, and γ-GTP changes from baseline to 104 weeks between treatment groups. However, in patients without obesity, there were no significant differences in AST and γ-GTP changes from baseline to 104 weeks between treatment groups. Multivariable regression analysis showed that changes in BMI and HbA1c levels were independently associated with changes in AST, ALT, and γ-GTP levels. The reduction of uric acid and the increase of hemoglobin from baseline to 104 weeks were significantly greater in the tofogliflozin group than in the conventional group. Conclusions The beneficial effects of tofogliflozin on circulating levels of hepatic enzymes, uric acid, and Hb lasted for 2 years in patients with T2DM. Clinical trial registration UMIN000017607 (https://www.umin.ac.jp/icdr/index.html). Supplementary Information The online version contains supplementary material available at 10.1007/s13340-024-00693-x.
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Affiliation(s)
- Naoto Katakami
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871 Japan
| | - Tomoya Mita
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-Ku, Tokyo 113-8421 Japan
| | - Yasunori Sato
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, 45 Shinanomachi, Shinjuku-Ku, Tokyo 160-8582 Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-Ku, Tokyo 113-8421 Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871 Japan
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50
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Malandris K, Papandreou S, Vasilakou D, Kakotrichi P, Sarakapina A, Kalopitas G, Karagiannis T, Giouleme O, Bekiari E, Liakos A, Iatridi F, Paschos P, Sinakos E, Tsapas A. Efficacy of pharmacologic interventions on magnetic resonance imaging biomarkers in patients with nonalcoholic fatty liver disease: systematic review and network meta-analysis. J Gastroenterol Hepatol 2024; 39:1219-1229. [PMID: 38627972 DOI: 10.1111/jgh.16559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 03/14/2024] [Accepted: 03/25/2024] [Indexed: 07/13/2024]
Abstract
BACKGROUND AND AIM Several agents are under investigation for nonalcoholic fatty liver disease (NAFLD). We assessed the comparative efficacy of pharmacologic interventions for patients with NAFLD focusing on magnetic resonance imaging (MRI) biomarkers. METHODS We searched Medline, Embase, and CENTRAL. We included randomized controlled trials of more than 12 weeks of intervention that recruited patients with biopsy-confirmed or MRI-confirmed NAFLD and assessed the efficacy of interventions on liver fat content (LFC) and fibrosis by means of MRI. We performed random-effects frequentist network meta-analyses and assessed confidence in our estimates using the CINeMA (Confidence in Network Meta-Analysis) approach. RESULTS We included 47 trials (8583 patients). Versus placebo, thiazolidinediones were the most efficacious for the absolute change in LFC, followed by vitamin E, fibroblast growth factor (FGF) analogs, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with mean differences ranging from -7.46% (95% confidence interval [-11.0, -3.9]) to -4.36% (-7.2, -1.5). No differences between drug classes were evident. Patients receiving GLP-1 RAs or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs were more likely to achieve ≥30% relative reduction in LFC. Among agents, efruxifermin produced the largest reduction in LFC compared to placebo [-13.5% (-18.5, -8.5)], followed by pioglitazone, while being superior to most interventions. The effect of interventions on magnetic resonance elastography assessed fibrosis was small and insignificant. The confidence in our estimates was low to very low. CONCLUSIONS Several drug classes may reduce LFC in patients with NAFLD without a significant effect on fibrosis; nevertheless, trial duration was small, and confidence in the effect estimates was low.
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Affiliation(s)
- Konstantinos Malandris
- Clinical Research and Evidence-Based Medicine Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stylianos Papandreou
- Clinical Research and Evidence-Based Medicine Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Despoina Vasilakou
- Clinical Research and Evidence-Based Medicine Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Panagiota Kakotrichi
- Clinical Research and Evidence-Based Medicine Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Anna Sarakapina
- First Medical Department, Papageorgiou Hospital, Thessaloniki, Greece
| | - Georgios Kalopitas
- First Medical Department, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Thomas Karagiannis
- Clinical Research and Evidence-Based Medicine Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Olga Giouleme
- Second Propaedeutic Medical Department, Hippokration General Hospital of Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleni Bekiari
- Clinical Research and Evidence-Based Medicine Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Aris Liakos
- Clinical Research and Evidence-Based Medicine Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Fotini Iatridi
- First Department of Nephrology, Hippokration General Hospital of Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paschalis Paschos
- First Medical Department, Papageorgiou Hospital, Thessaloniki, Greece
| | - Emmanouil Sinakos
- Fourth Medical Department, Hippokration General Hospital of Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Apostolos Tsapas
- Clinical Research and Evidence-Based Medicine Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Harris Manchester College, University of Oxford, Oxford, UK
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