1
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Sun X. Dapagliflozin ameliorates metabolic and hepatic outcomes in a mouse model of metabolic dysfunction-associated steatotic liver disease and diabetes. Acta Diabetol 2025:10.1007/s00592-025-02488-1. [PMID: 40353918 DOI: 10.1007/s00592-025-02488-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 03/04/2025] [Indexed: 05/14/2025]
Abstract
AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (NAFLD), has become a great public healthcare burden and is closely associated with type 2 diabetes (T2D) and insulin resistance. However, there is no specific treatment for MASLD. Recent clinical findings have indicated a possible beneficial effect of sodium-glucose cotransporter 2 (SGLT2) on MASLD. This study aimed to investigate the effects of dapagliflozin (Dapa) on MASLD in T2D mice. METHODS Four-week-old ob/ob mice were fed with a high-fat diet (HFD) for 8 weeks and then randomly divided into two groups supplemented with Dapa or vehicle for another 12 weeks. C57BL/6J mice fed with a standard chow diet (CD) were used as the control group. Metabolic outcomes, liver pathology, lipidomics and insulin signaling were assessed. RESULTS We showed that Dapa reduced body weight and ameliorated hyperglycemia and fatty liver in obese diabetic ob/ob mice. Compared with vehicle, dapa improved the NAFLD activity score mainly by attenuating fat deposition. Importantly, Dapa decreased the expression levels of mRNAs and proteins related to fatty acid synthesis and increased the expression levels of β-oxidation-related factors. We also found that Dapa treatment improved insulin signaling by increasing PI3K and Akt phosphorylation. CONCLUSIONS Dapa protects mice from diet-induced weight gain and improves hepatic lipotoxicity and insulin resistance in diabetic MASLD mice. Our results revealed that Dapa has a therapeutic effect on MASLD and could be a potential drug candidate for the treatment of MASLD.
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Affiliation(s)
- Xiaoya Sun
- Department of Geriatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
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2
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Stefanakis K, George J, Mantzoros CS. Non-invasive diagnosis and prognosis of MASH with fibrosis F2-F3: In need for a tailored, accessible, and affordable solution for the 21st century public health epidemic. Metabolism 2025:156296. [PMID: 40355078 DOI: 10.1016/j.metabol.2025.156296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Affiliation(s)
- Konstantinos Stefanakis
- Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, and Department of Gastroenterology & Hepatology, Westmead Hospital and Sydney West Local Health District, Sydney Medical School, Australia
| | - Christos S Mantzoros
- Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Boston VA Healthcare System, Harvard Medical School, Boston, MA 02115, USA.
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3
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Deshmukh NJ, Kalshetti MS, Patil M, Nandanwar M, Sangle GV. Therapeutic Potential of Sotagliflozin in Animal Models of Non-alcoholic Fatty Liver Disease with and without Diabetes. Drug Res (Stuttg) 2025. [PMID: 40228542 DOI: 10.1055/a-2557-8927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025]
Abstract
Sotagliflozin, a dual SGLT1/2 inhibitor, enhances glucagon like peptide-1 (GLP-1) levels and GLP-1 receptor agonists are used to manage non-alcoholic fatty liver disease (NAFLD). Study investigates the effects of sotagliflozin on NAFLD, alone and combined with linagliptin, comparing outcomes in normoglycemic and hyperglycemic animal models.Obese fatty liver disease (FLD) model was induced by high-fat diet (HFD) feeding, while a diabetic non-alcoholic steatohepatitis (NASH) model was developed by administering a single dose of streptozotocin to neonatal mice, followed by HFD feeding post-weaning. At termination of the study, parameters including biochemical markers, inflammatory cytokines, hepatic lipid content, and histopathology were assessed.In NASH mice, sotagliflozin and linagliptin reduced hepatic triglycerides by 60% and 44%, respectively, and cholesterol by 46% and 49%. Their combination further decreased triglycerides by 68.5% and cholesterol by 83.9%. In FLD mice, sotagliflozin and linagliptin reduced triglycerides by 33% and 17%, respectively, and cholesterol by 46% and 21%. Combination treatment offered no benefit, reducing triglycerides by 38% and cholesterol by 27%. Both the treatments improved plasma fibroblast growth factor 21, hepatic interlukin-6, glucose tolerance, steatosis and mitigated fat pad weight, but their combination did not show additional benefit. However, combination treatment demonstrated added benefit in modulating NAFLD activity score, liver enzymes, glycogenated hepatic nuclei, plasma glucose and active GLP-1 levels.Study underscores sotagliflozin's potential to mitigate NAFLD and highlights the benefit of combining it with linagliptin in hyperglycemic NASH model, which showed limited efficacy in normoglycemic FLD mice.
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Affiliation(s)
- Nitin J Deshmukh
- D.S.T.S. Mandal's Collage of Pharmacy, Solapur, Maharashtra, India
- Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India
| | - M S Kalshetti
- D.S.T.S. Mandal's Collage of Pharmacy, Solapur, Maharashtra, India
| | - Mohan Patil
- Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia
| | - Manohar Nandanwar
- Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India
| | - Ganesh V Sangle
- Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India
- Kashiv BioSciences Private Limited, Ahmedabad, Gujarat
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4
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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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5
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Bogdan RG, Boicean A, Anderco P, Ichim C, Iliescu-Glaja M, Todor SB, Leonte E, Bloanca VA, Crainiceanu ZP, Popa ML. From Liver to Kidney: The Overlooked Burden of Nonalcoholic Fatty Liver Disease in Chronic Kidney Disease. J Clin Med 2025; 14:2486. [PMID: 40217935 PMCID: PMC11989420 DOI: 10.3390/jcm14072486] [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: 03/18/2025] [Revised: 03/30/2025] [Accepted: 04/03/2025] [Indexed: 04/14/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a contributor to chronic kidney disease (CKD), yet its impact remains underappreciated in clinical practice. Recent studies reveal a strong association between NAFLD and CKD progression, with evidence linking hepatic dysfunction to renal impairment through metabolic and inflammatory pathways. NAFLD not only increases the risk of CKD but also accelerates its progression, leading to worse cardiovascular outcomes and higher mortality, particularly in patients with advanced fibrosis. Despite this growing evidence, NAFLD often goes undiagnosed in CKD patients and routine hepatic evaluation is rarely integrated into nephrology care. Emerging diagnostic tools, including noninvasive biomarkers and imaging techniques, offer potential for earlier detection, yet their clinical implementation remains inconsistent. Although lifestyle modifications remain the foundation of treatment, pharmacotherapeutic strategies, including SGLT2 inhibitors and GLP-1 receptor agonists, have demonstrated potential in mitigating both hepatic and renal impairment. Recognizing the interplay between NAFLD and CKD is essential for improving patient outcomes. A multidisciplinary approach, integrating hepatology and nephrology expertise, is crucial to refining screening strategies, optimizing treatment, and reducing the long-term burden of these coexisting conditions.
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Affiliation(s)
- Razvan George Bogdan
- Plastic Surgery Department, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.G.B.); (M.I.-G.); (E.L.); (V.A.B.); (Z.P.C.)
| | - Adrian Boicean
- Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550024 Sibiu, Romania; (C.I.); (S.B.T.); (M.L.P.)
| | - Paula Anderco
- Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550024 Sibiu, Romania; (C.I.); (S.B.T.); (M.L.P.)
| | - Cristian Ichim
- Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550024 Sibiu, Romania; (C.I.); (S.B.T.); (M.L.P.)
| | - Mihai Iliescu-Glaja
- Plastic Surgery Department, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.G.B.); (M.I.-G.); (E.L.); (V.A.B.); (Z.P.C.)
| | - Samuel Bogdan Todor
- Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550024 Sibiu, Romania; (C.I.); (S.B.T.); (M.L.P.)
| | - Elisa Leonte
- Plastic Surgery Department, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.G.B.); (M.I.-G.); (E.L.); (V.A.B.); (Z.P.C.)
| | - Vlad Adam Bloanca
- Plastic Surgery Department, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.G.B.); (M.I.-G.); (E.L.); (V.A.B.); (Z.P.C.)
| | - Zorin Petrisor Crainiceanu
- Plastic Surgery Department, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (R.G.B.); (M.I.-G.); (E.L.); (V.A.B.); (Z.P.C.)
| | - Mirela Livia Popa
- Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550024 Sibiu, Romania; (C.I.); (S.B.T.); (M.L.P.)
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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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Weng MT, Yang PJ, Liu PF, Chang CH, Lee HS, Sheu JC, Nien HC. Effects of dapagliflozin on liver steatosis in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Hepatol Int 2025; 19:405-414. [PMID: 39625600 DOI: 10.1007/s12072-024-10758-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 11/15/2024] [Indexed: 04/17/2025]
Abstract
BACKGROUND/AIMS Nonalcoholic fatty liver disease (NAFLD) is a common liver comorbidity with considerable global consequences. This study explores the efficacy of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor primarily used to manage type 2 diabetes, in reducing liver steatosis among NAFLD patients. METHODS This randomized, open-label, two-arm, parallel-group trial enrolled patients with NAFLD and a controlled attenuation parameter (CAP) score of ≥ 252 dB/m. Participants were randomized (1:1) into either the control or dapagliflozin groups. The primary outcome was the change in CAP scores, measured with FibroScan after 24 weeks. RESULTS The trial included 150 patients, 20 of whom (13%) had type 2 diabetes. In week 24, the dapagliflozin group had significantly lower CAP score and fatty liver grade than did the control group (266.3 ± 57.8 50 vs 298.6 ± 59.0 dB/m, respectively [p = 0.002]; 1.7 ± 0.7 vs 2.2 ± 0.8, respectively [p < 0.001]). Liver stiffness, waist circumference, and alanine transaminase levels decreased in both the dapagliflozin and control groups, but the between-group differences were nonsignificant (1.0 ± 0.3 vs 1.1 ± 0.3 [p = 0.678], 94.2 ± 12.7 vs 92.4 ± 11.1 [p = 0.382], and 28.8 ± 18.3 vs 28.3 ± 14.2 U/L [p = 0.856], respectively). In the multivariate analysis, a reduction in CAP was associated with dapagliflozin treatment (p = 0.01) and changes in BMI (p = 0.007). No adverse events were observed. CONCLUSION Dapagliflozin can reduce CAP score and fatty liver grade in patients with moderate to severe NAFLD, regardless of their diabetes status.
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Affiliation(s)
- Meng-Tzu Weng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan
| | - Po-Jen Yang
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | | | - Chin-Hao Chang
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsuan-Shu Lee
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan
| | - Jin-Chuan Sheu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan
| | - Hsiao-Ching Nien
- Department of Family Medicine, National Taiwan University Hospital and College of Medicine, No. 7 Chung-Shan South Road, Taipei, Taiwan.
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan.
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8
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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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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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Feng Q, Wu M, Mai Z. Emerging horizons: clinical applications and multifaceted benefits of SGLT-2 inhibitors beyond diabetes. Front Cardiovasc Med 2025; 12:1482918. [PMID: 40182430 PMCID: PMC11965600 DOI: 10.3389/fcvm.2025.1482918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 03/10/2025] [Indexed: 04/05/2025] Open
Abstract
SGLT-2 inhibitors, initially developed for type 2 diabetes, demonstrate profound cardiorenal and metabolic benefits. This review synthesizes evidence from clinical trials and mechanistic studies to elucidate their roles in cardiovascular diseases, chronic kidney disease, and non-alcoholic fatty liver disease. Key findings include a notable reduction in cardiovascular death/heart failure hospitalization, a marked decrease in heart failure hospitalization risk, and significant improvements in renal and hepatic outcomes. Emerging mechanisms, such as autophagy induction, ketone utilization, and anti-inflammatory effects, underpin these benefits. Ongoing trials explore their potential in non-diabetic populations, positioning SGLT-2 inhibitors as transformative agents in multisystem disease management.
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Affiliation(s)
- Qing Feng
- Department of Cardiology, Kaiping Central Hospital, Kaiping, China
| | - Miaoqiong Wu
- Department of Endocrinology, Kaiping Central Hospital, Kaiping, China
| | - Zizhao Mai
- School of Stomatology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China
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11
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Fan X, Wang Y, Wang Y, Duan H, Du Y, Pan T, Zhong X. Dapagliflozin attenuates metabolic dysfunction-associated steatotic liver disease by inhibiting lipid accumulation, inflammation and liver fibrosis. BMC Pharmacol Toxicol 2025; 26:59. [PMID: 40075451 PMCID: PMC11905655 DOI: 10.1186/s40360-025-00898-z] [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: 12/15/2024] [Accepted: 03/07/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a globally prevalent liver disease, closely linked to the rising incidence of obesity, diabetes, and metabolic syndrome. Dapagliflozin (DaPa), a sodium-glucose cotransporter-2 inhibitor, is primarily prescribed for diabetes management. It has shown potential efficacy in managing MASLD in clinical settings. However, the molecular mechanisms underlying the effects of DaPa on MASLD remain poorly understood. Hence, we aimed to investigate the role of and mechanisms underlying DaPa in MASLD. METHODS Male diet-induced obese (DIO) C57BL/6J mice were injected with streptozotocin (STZ), followed by a high-fat diet regimen to stimulate metabolic dysfunction. Subsequently, they received DaPa via gavage for 5 weeks. Hepatic lipid accumulation, pathological alterations, inflammatory markers, and liver fibrosis were assessed. RESULTS DaPa administration reduced liver fat accumulation in DIO mice. Additionally, it decreased oxidative stress and lipid peroxide levels, which was attributed to the upregulation of glutathione and the downregulation of malondialdehyde and reactive oxygen species levels. Notably, DaPa downregulated the inflammatory response and reduced liver fibrosis. CONCLUSIONS DaPa protects against MASLD by inhibiting lipid accumulation, inflammation, oxidative stress, and liver fibrosis.
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Affiliation(s)
- Xingyu Fan
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China
| | - Yueyue Wang
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China
| | - Yue Wang
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China
| | - Hao Duan
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China
| | - Yijun Du
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China
| | - Tianrong Pan
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China.
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China.
| | - Xing Zhong
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China.
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, Anhui Province, 230601, China.
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12
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Afsar B, Afsar RE, Caliskan Y, Lentine KL. Sodium-glucose co-transporter inhibitors for APOL1 kidney disease: A call for studies. Int Urol Nephrol 2025:10.1007/s11255-025-04443-z. [PMID: 40038200 DOI: 10.1007/s11255-025-04443-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 02/27/2025] [Indexed: 03/06/2025]
Abstract
Renal risk variants in the apolipoprotein L1 (APOL1) gene confer protection against trypanosomiasis, but these risk variants (G1 and G2 variants) also predispose to kidney disease among individuals, especially from Sub-SaharanAfrica. Currently, the mechanisms of how these renal risk variants induce kidney damage are not precisely defined, but lysosomal and mitochondrial dysfunction, altered ion channel activity, altered autophagy, and disordered immunity are suggested. Currently, there is no specific treatment for APOL1 kidney disease (APOL1-KD) although several potential disease-specific therapeutic agents are being evaluated in clinical trials. Non-specific interventions include proteinuria screening, salt restriction, and renin-angiotensin-aldosterone system inhibition but are not sufficient to prevent kidney disease progression in APOL1-KD. Given the lack of specific treatment options, more efforts are necessary to reduce kidney disease progression. Sodium glucose co-transport-2 (SGLT2) inhibitors (SGLT2i) are gaining attention for benefits in proteinuric kidney diseases and exert many beneficial effects which theoretically may be beneficial in the context of APOL1-KD. These beneficial effects include but are not limited to increased natriuresis, decreased proteinuria/albuminuria, and mitochondrial dysfunction. SGLT2i have antioxidant, anti-inflammatory and anti-fibrotic effects. In the current review, we highlight the potential reasons for exploring the use of SGLT2i in APOL1-KD. Future studies are warranted to explore if SGLT2i use can provide protection in APOL1-KD.
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Affiliation(s)
- Baris Afsar
- Department of Nephrology, Saint Louis University, School of Medicine, SSM Health Saint Louis University Hospital, Saint Louis, MO, USA.
| | - Rengin Elsurer Afsar
- Department of Nephrology, Saint Louis University, School of Medicine, SSM Health Saint Louis University Hospital, Saint Louis, MO, USA
| | - Yasar Caliskan
- Department of Nephrology, Saint Louis University, School of Medicine, SSM Health Saint Louis University Hospital, Saint Louis, MO, USA
- Center for Transplantation, Saint Louis University, School of Medicine, SSM Health Saint Louis University Hospital, Saint Louis, MO, USA
| | - Krista L Lentine
- Department of Nephrology, Saint Louis University, School of Medicine, SSM Health Saint Louis University Hospital, Saint Louis, MO, USA
- Center for Transplantation, Saint Louis University, School of Medicine, SSM Health Saint Louis University Hospital, Saint Louis, MO, USA
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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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14
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Abdel Monem MS, Adel A, Abbassi MM, Abdelaziz DH, Hassany M, Raziky ME, Sabry NA. Efficacy and safety of dapagliflozin compared to pioglitazone in diabetic and non-diabetic patients with non-alcoholic steatohepatitis: A randomized clinical trial. Clin Res Hepatol Gastroenterol 2025; 49:102543. [PMID: 39884573 DOI: 10.1016/j.clinre.2025.102543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/21/2025] [Accepted: 01/26/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) is a serious end-stage spectrum of non-alcoholic fatty liver disease (NAFLD) with associated high risk of hepatic and extrahepatic complications. Several studies showed the significant beneficial effect of dapagliflozin on body composition, hepatic and metabolic parameters on NAFLD/NASH patients. The study aimed to investigate the efficacy and safety of dapagliflozin in both diabetic and non-diabetic biopsy-proven NASH patients; compared to pioglitazone. METHODS This was a four-group, prospective, randomized, parallel, open label study in which 100 biopsy-proven NASH patients were selected, stratified to diabetics and non-diabetics and randomized with 1:1 allocation to either 30 mg pioglitazone or 10 mg dapagliflozin, once daily for 24 weeks. Histological evaluation, anthropometric measures, hepatic, metabolic biochemical markers, fibrosis non-invasive markers, quality of life (QOL) and medications adverse events were examined. RESULTS Dapagliflozin showed a comparable histological effect to pioglitazone in both diabetic and non-diabetic patients (P>0.05). As assessed by transient elastography, it also showed a comparable effect on liver fibrosis grade improvement from baseline in diabetics (P=0.287) versus a significant superiority in non-diabetics (P=0.018). Dapagliflozin showed a significant superiority in all anthropometric measures (P<0.001) and QOL (P<0.05) among both diabetics and non-diabetics. There was a significant interaction between interventions and diabetes status on change from baseline of hepatic and metabolic panel collectively (P=0.023) in favor to dapagliflozin among diabetics. CONCLUSION Compared to pioglitazone, dapagliflozin had a comparable effect histologically, superior effect biochemically among diabetics and superior effect on liver fibrosis, steatosis and insulin resistance among non-diabetics. TRIAL REGISTRATION The study was registered on clinicaltrials.gov, identifier number NCT05254626.
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Affiliation(s)
- Mona S Abdel Monem
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Egypt.
| | - Abdulmoneim Adel
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt.
| | - Maggie M Abbassi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Egypt.
| | - Doaa H Abdelaziz
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Baha University, Al-Baha, Saudi Arabia/Department of Clinical Pharmacy, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt.
| | - Mohamed Hassany
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt.
| | - Maissa El Raziky
- Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Egypt.
| | - Nirmeen A Sabry
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Egypt.
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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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Hu W, Gong W, Yang F, Cheng R, Zhang G, Gan L, Zhu Y, Qin W, Gao Y, Li X, Liu J. Dual GIP and GLP-1 receptor agonist tirzepatide alleviates hepatic steatosis and modulates gut microbiota and bile acid metabolism in diabetic mice. Int Immunopharmacol 2025; 147:113937. [PMID: 39752752 DOI: 10.1016/j.intimp.2024.113937] [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: 10/29/2024] [Revised: 12/14/2024] [Accepted: 12/21/2024] [Indexed: 01/29/2025]
Abstract
Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors and is a promising therapeutic option for type 2 diabetes mellitus (T2DM). Nevertheless, its effect and underlying mechanism on hepatic steatosis remain ambiguous. Herein, we explored the impact of tirzepatide on improving hepatic steatosis in diabetic mice, with a particular focus on the gut microbiota and bile acids (BAs) using animal models. The tirzepatide effectively reduced body weight, improved insulin resistance, decreased serum and hepatic lipid levels, and mitigated liver injury. Compared to semaglutide, tirzepatide exhibited superior efficacy in reducing hepatic lipid accumulation. 16S rRNA gene sequencing and targeted metabolomics of BAs revealed that tirzepatide ameliorated gut microbiota dysbiosis and BAs metabolism in diabetic mice. Notably, tirzepatide observably increased the abundance of beneficial genera such as Akkermansia, elevated the ratio of farnesoid X receptor (FXR) antagonists (glycoursodeoxycholic acid: GUDCA, β-muricholic acid: β-MCA, hyodeoxycholic acid: HDCA, ursodeoxycholic acid: UDCA) to natural agonists (cholic acid: CA, lithocholic acid: LCA, chenodeoxycholic acid: CDCA, glycocholic acid: GCA, taurodeoxycholic acid: TDCA), and reduced FXR expression in intestinal tissues. In conclusion, tirzepatide attenuated hepatic steatosis in diabetic mice and regulated the gut microbiota and BAs metabolism, which may help to provide a novel therapeutic approach and therapeutic target for metabolic dysfunction-associated steatotic liver disease (MASLD).
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Affiliation(s)
- Weiting Hu
- Department of Clinical Medicine, The Second Clinical Medical College, Shanxi Medical University, Taiyuan 030000, China; Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan 030000, China
| | - Wenyu Gong
- Department of Clinical Medicine, The Second Clinical Medical College, Shanxi Medical University, Taiyuan 030000, China
| | - Fan Yang
- The First Clinical Medical College, Shanxi Medical University, Taiyuan 030000, China
| | - Rui Cheng
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan 030000, China
| | - Gerong Zhang
- Department of Clinical Medicine, The Second Clinical Medical College, Shanxi Medical University, Taiyuan 030000, China
| | - Lu Gan
- Department of Emergency Medicine and National Clinical Research Center for Geriatrics, Laboratory of Emergency Medicine, West China Hospital, Sichuan University, Chengdu 610000, China
| | - Yikun Zhu
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan 030000, China
| | - Weiwei Qin
- Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan 030000, China
| | - Ying Gao
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan 030000, China
| | - Xing Li
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan 030000, China.
| | - Jing Liu
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan 030000, China.
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Wan Z, Yuan M, Liu Z, Cai Y, He H, Hao K. Impact of Dapagliflozin on Hepatic Lipid Metabolism and a Dynamic Model of Ketone Body Levels. AAPS J 2025; 27:38. [PMID: 39900889 DOI: 10.1208/s12248-025-01024-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 01/15/2025] [Indexed: 02/05/2025] Open
Abstract
The rising prevalence of metabolic-associated steatotic liver disease emphasizes the need to understand its lipid metabolism. Dapagliflozin may improve hepatic steatosis but could also increase the risk of ketoacidosis by elevating β-hydroxybutyrate (KB) levels. This study investigates dapagliflozin's effects on hepatic lipid metabolism and quantifies KB levels in vivo. Male Sprague-Dawley rats were fed either a normal diet or a high-fat diet (HFD) for 12 weeks. The HFD rats were then divided into four subgroups to receive vehicle, 0.5 mg/kg, 1 mg/kg, and 3 mg/kg of dapagliflozin for four weeks. Free fatty acids (FFA) and KB levels were monitored, while protein and gene expression were analyzed. And a dynamic model of KB was developed for humans based on preclinical data. Dapagliflozin decreased body weight and visceral fat in HFD rats, increasing KB by upregulating CPT1a, HMGCS2, and HMGCL, and downregulating ACC. These changes correlated with reduced liver/fat index, liver pathology score, and oil-red staining area. A pharmacokinetic/pharmacodynamic (PK/PD) model was created from preclinical data to quantify KB levels in rats and validated in humans. Dapagliflozin reduces hepatic steatosis by enhancing fatty acid β-oxidation and ketogenesis and inhibiting fat synthesis. A dynamic model accurately predicts ketone body levels in treated individuals.
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Affiliation(s)
- Zhijie Wan
- State Key Laboratory of Natural Medicine, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Ming Yuan
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Ziao Liu
- State Key Laboratory of Natural Medicine, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Yuan Cai
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Hua He
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China.
| | - Kun Hao
- State Key Laboratory of Natural Medicine, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China.
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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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19
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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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Wan X, Ma J, Bai H, Hu X, Ma Y, Zhao M, Liu J, Duan Z. Drug Advances in NAFLD: Individual and Combination Treatment Strategies of Natural Products and Small-Synthetic-Molecule Drugs. Biomolecules 2025; 15:140. [PMID: 39858534 PMCID: PMC11764138 DOI: 10.3390/biom15010140] [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: 12/15/2024] [Revised: 01/07/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease and is closely associated with metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. However, effective treatment strategies for NAFLD are still lacking. In recent years, progress has been made in understanding the pathogenesis of NAFLD, identifying multiple therapeutic targets and providing new directions for drug development. This review summarizes the recent advances in the treatment of NAFLD, focusing on the mechanisms of action of natural products, small-synthetic-molecule drugs, and combination therapy strategies. This review aims to provide new insights and strategies in treating NAFLD.
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Affiliation(s)
- Xing Wan
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
- Institute of Integrated Traditional Chinese and Western Medicine, Dalian Medical University, Dalian 116051, China
| | - Jingyuan Ma
- The First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang 110033, China; (J.M.); (Y.M.)
| | - He Bai
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
| | - Xuyang Hu
- The Second Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang 110033, China;
| | - Yanna Ma
- The First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang 110033, China; (J.M.); (Y.M.)
| | - Mingjian Zhao
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
| | - Jifeng Liu
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
| | - Zhijun Duan
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
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Vargas-Ramírez CU, Posadas-Posadas V, Ochoa-Précoma R, Porchia LM, Pérez-Fuentes R, Gonzalez-Mejia ME. Dapagliflozin treatment decreases visceral and subcutaneous adipose tissue: a systematic review and meta-analysis. Diabetol Int 2025; 16:65-77. [PMID: 39877433 PMCID: PMC11769893 DOI: 10.1007/s13340-024-00765-y] [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: 04/24/2024] [Accepted: 09/24/2024] [Indexed: 01/31/2025]
Abstract
Aims Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have been shown to reduce visceral (VAT) and subcutaneous (SAT) adipose tissue. Although many systematic reviews have examined SGLT2i's effect on VAT and SAT, a focus analysis of dapagliflozin, one of the more commonly prescribe SGLT2i, has yet to been done. This study aims to determine the effect of dapagliflozin on reducing VAT and SAT in patients with chronic disease. Methods SCOPUS, PubMed, EBSCO, and LILACS databases were searched until December 26, 2023. Heterogeneity was determined using Cochran's Q test and quantified using the inconsistency index. The random-effects model was used to calculate the pooled standardize difference in means (SDM) and 95% confidence intervals (95% CI). Duval and Tweedie trim and fill (DT), Egger's test, and Beggs-Muzamar's test were used to assess publication bias. PROSPERO: CRD42023426208. Results Twelve reports were included (treated = 299 and controls = 301). Overall, dapagliflozin treatment reduced VAT (SDM = - 0.406, 95% CI: - 0.526 to - 0.286, p < 0.001) and SAT (SDM = - 0.439, 95% CI: - 0.601 to - 0.278, p < 0.001). These results were stable as determined with a sensitivity analysis; however, there was potential publication bias. Two and three imputed studies were determined by the DT method for VAT and SAT, respectively. When stratified by pathology (obesity, T2D, and T2D/NAFLD), dapagliflozin treatment decreased VAT and SAT for all conditions. However, for specifically SAT, only when compared between T2D and T2D/NAFLD, T2D/NAFLD was associated with a twofold decrease (p = 0.003). Conclusion Treatment with dapagliflozin resulted in a significant reduction in VAT and SAT in patients with obesity, T2D, or T2D/NAFLD. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-024-00765-y.
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Affiliation(s)
- Carlos U. Vargas-Ramírez
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, 13 Sur 2901 Colonia Volcanes, 72420 Puebla, Puebla México
| | - Víctor Posadas-Posadas
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, 13 Sur 2901 Colonia Volcanes, 72420 Puebla, Puebla México
| | - Renata Ochoa-Précoma
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, 13 Sur 2901 Colonia Volcanes, 72420 Puebla, Puebla México
| | - Leonardo M. Porchia
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, 13 Sur 2901 Colonia Volcanes, 72420 Puebla, Puebla México
| | - Ricardo Pérez-Fuentes
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, 13 Sur 2901 Colonia Volcanes, 72420 Puebla, Puebla México
| | - M. Elba Gonzalez-Mejia
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, 13 Sur 2901 Colonia Volcanes, 72420 Puebla, Puebla México
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22
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Katsarou A, Tsioulos G, Kassi E, Chatzigeorgiou A. Current and experimental pharmacotherapy for the management of non-alcoholic fatty liver disease. Hormones (Athens) 2024; 23:621-636. [PMID: 39112786 DOI: 10.1007/s42000-024-00588-1] [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: 03/08/2024] [Accepted: 07/17/2024] [Indexed: 10/29/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with its incidence increasing in parallel with the global prevalence of obesity and type 2 diabetes mellitus. Despite our steadily increasing knowledge of its pathogenesis, there is as yet no available pharmacotherapy specifically tailored for NAFLD. To define the appropriate management, it is important to clarify the context in which the disease appears. In the case of concurrent metabolic comorbidities, NAFLD patients are treated by targeting these comorbidities, such as diabetes and obesity. Thus, GLP-1 analogs, PPAR, and SGLT2 inhibitors have recently become central to the treatment of NAFLD. In parallel, randomized trials are being conducted to explore new agents targeting known pathways involved in NAFLD progression. However, there is an imperative need to intensify the effort to design new, safe drugs with biopsy-proven efficacy. Of note, the main target of the pharmacotherapy should be directed to the regression of fibrotic NASH, as this histologic stage has been correlated with increased overall as well as liver-related morbidity and mortality. Herein we discuss the drugs currently at the forefront of NAFLD treatment.
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Affiliation(s)
- Angeliki Katsarou
- 251 Hellenic Airforce General Hospital, 1 P.Kanellopoulou Str, Athens, 11525, Greece.
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str, Athens, 11527, Greece.
| | - Georgios Tsioulos
- 4th Department of Internal Medicine, Medical School, University General Hospital Attikon, National and Kapodistrian University of Athens, 1 Rimini Str, Athens, 12462, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str, Athens, 11527, Greece
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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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Khaliq A, Badshah H, Shah Y, Rehman IU, Khan KU, Ming LC, Cheng MH. The effect of ertugliflozin in patients with nonalcoholic fatty liver disease associated with type 2 diabetes mellitus: A randomized controlled trial. Medicine (Baltimore) 2024; 103:e40356. [PMID: 39533572 PMCID: PMC11556963 DOI: 10.1097/md.0000000000040356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with liver inflammation, fibrosis, and cirrhosis and is associated with a greater risk of hepatocarcinoma. Nonalcoholic steatohepatitis (NASH) is a persistent and progressive form of NAFLD. Recent evidence suggested that ertugliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2), suppresses NAFLD development in patients with type 2 diabetes mellitus (T2DM). The objective of this study was to determine the impact of ertugliflozin on improving NAFLD in patients with T2DM and the function of liver enzymes. METHODS This prospective, randomized, double-blind, placebo-controlled, interventional study aimed to determine the effectiveness of 15 mg of ertugliflozin versus 30 mg of the standard therapy pioglitazone versus placebo in NAFLD patients with T2DM. The study was established based on patient randomization in three groups: ertugliflozin, pioglitazone, and a placebo. This study was registered under the Australian New Zealand Clinical Trial Registry (Trial ID: ACTRN12624000032550). RESULTS The impact of therapy was determined in the treatment groups by utilizing liver ultrasonography and biochemical parameters. After 24 weeks of clinical study, the results revealed significant improvement in the grades of fatty liver, especially in the ertugliflozin group. The number of patients with hepatic steatosis significantly decreased among the respective groups classified according to fatty liver grade. Among patients in the ertugliflozin and pioglitazone groups, 45% to 23.4% and 41.7% to 26.6%, respectively, decreased in the Grade 2 group. The aspartate aminotransferase and alanine aminotransferase levels were significantly lower in all the study groups, especially in the ertugliflozin group (P ≤ .001). CONCLUSION The present study revealed that the concomitant use of ertugliflozin has favorable effects on liver enzymes, as it decreases liver fat intake and reduces complications in patients with NAFLD-associated T2DM. However, more in-depth studies will be required to observe every aspect of ertugliflozin.
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Affiliation(s)
- Adil Khaliq
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Haroon Badshah
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Yasar Shah
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Inayat Ur Rehman
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Universiti Malaya, Malaysia
| | - Kashif Ullah Khan
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Universiti Malaya, Malaysia
| | - Long Chiau Ming
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, Malaysia
| | - Maong Hui Cheng
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, Malaysia
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25
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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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Khawaja T, Nied M, Wilgor A, Neeland IJ. Impact of Visceral and Hepatic Fat on Cardiometabolic Health. Curr Cardiol Rep 2024; 26:1297-1307. [PMID: 39235730 PMCID: PMC11538208 DOI: 10.1007/s11886-024-02127-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/22/2024] [Indexed: 09/06/2024]
Abstract
PURPOSE OF REVIEW Body fat distribution plays a significant role in the cardiometabolic consequences of obesity. We review the impact of visceral and hepatic fat and highlight important interventions. RECENT FINDINGS Several epidemiologic studies have established a clear association between visceral fat and cardiovascular disease. The association between hepatic fat and cardiovascular disease is less clear with discordant results. Novel evidence demonstrates sodium glucose co-transporter-2 (SGLT2) inhibitors facilitate modest weight loss and reductions in ectopic fat depots in patient with type 2 diabetes. Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with decreased visceral/hepatic fat and reductions in MACE in populations with type 2 diabetes and with overweight/obesity. Clear associations between visceral fat and cardiometabolic outcomes have been established, whereas the impact of hepatic fat remains less clear. Lifestyle modification and pharmacologic interventions remain the initial therapies, while surgical intervention is associated with improved long-term outcomes. Emerging therapies have demonstrated a profound impact on body fat distribution and cardiometabolic risk.
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Affiliation(s)
- Tasveer Khawaja
- Harrington Heart and Vascular Institute, University Hospitals Cleveland and Case Western Reserve University, Cleveland, OH, USA
- Department of Medicine, University Hospitals Cleveland and Case Western Reserve University, 11100 Euclid Ave. Mailstop Lakeside, Cleveland, OH, USA
| | - Matthew Nied
- Department of Medicine, University Hospitals Cleveland and Case Western Reserve University, 11100 Euclid Ave. Mailstop Lakeside, Cleveland, OH, USA
| | - Abigail Wilgor
- Department of Medicine, University Hospitals Cleveland and Case Western Reserve University, 11100 Euclid Ave. Mailstop Lakeside, Cleveland, OH, USA
| | - Ian J Neeland
- Harrington Heart and Vascular Institute, University Hospitals Cleveland and Case Western Reserve University, Cleveland, OH, USA.
- Department of Medicine, University Hospitals Cleveland and Case Western Reserve University, 11100 Euclid Ave. Mailstop Lakeside, Cleveland, OH, USA.
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Gancheva S, Roden M, Castera L. Diabetes as a risk factor for MASH progression. Diabetes Res Clin Pract 2024; 217:111846. [PMID: 39245423 DOI: 10.1016/j.diabres.2024.111846] [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: 07/24/2024] [Revised: 08/28/2024] [Accepted: 09/03/2024] [Indexed: 09/10/2024]
Abstract
Non-alcoholic (now: metabolic) steatohepatitis (MASH) is the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD), which often coexists and mutually interacts with type 2 diabetes (T2D), resulting in worse hepatic and cardiovascular outcomes. Understanding the intricate mechanisms of diabetes-related MASH progression is crucial for effective therapeutic strategies. This review delineates the multifaceted pathways involved in this interplay and explores potential therapeutic implications. The synergy between adipose tissue, gut microbiota, and hepatic alterations plays a pivotal role in disease progression. Adipose tissue dysfunction, particularly in the visceral depot, coupled with dysbiosis in the gut microbiota, exacerbates hepatic injury and insulin resistance. Hepatic lipid accumulation, oxidative stress, and endoplasmic reticulum stress further potentiate inflammation and fibrosis, contributing to disease severity. Dietary modification with weight reduction and exercise prove crucial in managing T2D-related MASH. Additionally, various well-known but also novel anti-hyperglycemic medications exhibit potential in reducing liver lipid content and, in some cases, improving MASH histology. Therapies targeting incretin receptors show promise in managing T2D-related MASH, while thyroid hormone receptor-β agonism has proven effective as a treatment of MASH and fibrosis.
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Affiliation(s)
- Sofiya Gancheva
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München-Neuherberg, Germany
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München-Neuherberg, Germany.
| | - Laurent Castera
- Department of Hepatology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France; Université Paris-Cité, INSERM UMR 1149, Centre de Recherche sur l'Inflammation Paris, Montmartre, Paris, France.
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Zheng H, Guo T, Zhao X, Wang K, Shan S, Xie S, Xu Y, Liu C, Lu W. Helicobacter pylori Infection Is Not Associated with Nonalcoholic Fatty Liver Disease: A Two-Year Cohort Study. Dig Dis 2024; 43:75-83. [PMID: 39496224 DOI: 10.1159/000542180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 10/06/2024] [Indexed: 11/06/2024]
Abstract
INTRODUCTION Previous studies reported inconsistent results of the association between Helicobacter pylori infection and nonalcoholic fatty liver disease (NAFLD). METHODS A cohort study of 2,063 adults without NAFLD at baseline, who participated in a repeated health checkup including a 13C-urea breath test and abdominal ultrasonography, was conducted to evaluate the link between H. pylori infection and NAFLD development. RESULTS During a mean follow-up period of 1.7 years, we did not find a significant association between H. pylori infection and NAFLD (hazard ratio = 1.10 (0.86, 1.40), p = 0.4689). We also found that higher age, body mass index (BMI), systolic blood pressure (systolic BP), diastolic blood pressure (diastolic BP), fasting blood glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were risk factors, and high-density lipoprotein cholesterol (HDL-C) was a protective factor for NAFLD development. CONCLUSION H. pylori infection might not be positively related to NAFLD development.
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Affiliation(s)
- Huabo Zheng
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Tangmeng Guo
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaofang Zhao
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Wang
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shengshuai Shan
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia, USA
| | - Songpu Xie
- Laboratory of Experimental Cardiology, Department Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Yichen Xu
- Department of Histology and Embryology, Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Chengyun Liu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weilin Lu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Mollace R, Longo S, Nardin M, Tavernese A, Musolino V, Cardamone A, Federici M. Role of MASLD in CVD: A review of emerging treatment options. Diabetes Res Clin Pract 2024; 217:111891. [PMID: 39414088 DOI: 10.1016/j.diabres.2024.111891] [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: 08/20/2024] [Revised: 10/03/2024] [Accepted: 10/13/2024] [Indexed: 10/18/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), represents a growing health concern due to its strong association with metabolic syndrome, obesity, and type 2 diabetes mellitus (T2DM). This condition, characterized by excessive fat accumulation in the liver not attributed to alcohol consumption, has emerged as a leading cause of chronic liver disease globally. MASLD significantly elevates the risk of major adverse cardiovascular events (MACE) through mechanisms like increased oxidative stress, insulin resistance, and chronic inflammation, all of which contribute to the development of atherosclerosis and endothelial dysfunction. Effective management of MASLD is crucial not only for liver health but also for cardiovascular disease (CVD) prevention. Lifestyle modifications, particularly weight loss achieved through dietary changes and increased physical activity, are the cornerstone of MASLD treatment. Additionally, pharmacological interventions, especially antihyperglycemic agents, play a pivotal role in treating MASLD in patients with T2DM. Novel therapeutic agents targeting various pathways of metabolic and liver dysfunction are under investigation, offering hope for more effective management strategies. This review explores the interconnectedness of MASLD and CVD, highlighting current and emerging therapeutic approaches.
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Affiliation(s)
- Rocco Mollace
- Department of Experimental Medicine, Tor Vergata University, 00133 Rome, Italy; Cardiology Unit, Humanitas Gavazzeni, 24125 Bergamo, Italy
| | - Susanna Longo
- Center for Atherosclerosis and Internal Medicine Unit, Policlinico Tor Vergata University Hospital, Via Oxford 81, Rome 00133, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome 00133, Italy
| | - Matteo Nardin
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090 Milan, Italy; Internal Medicine, Department of Medicine, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Annamaria Tavernese
- Cardiovascular Imaging Unit, Cardio-Thoracic-Vascular Department IRCCS San Raffaele Scientific Institute Milan Italy, Italy
| | - Vincenzo Musolino
- IRC-FSH Center, Department of Health Sciences, University "Magna Græcia" of Catanzaro, Germaneto, 88100 Catanzaro, Italy
| | - Antonio Cardamone
- IRC-FSH Center, Department of Health Sciences, University "Magna Græcia" of Catanzaro, Germaneto, 88100 Catanzaro, Italy
| | - Massimo Federici
- Center for Atherosclerosis and Internal Medicine Unit, Policlinico Tor Vergata University Hospital, Via Oxford 81, Rome 00133, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome 00133, Italy.
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Jeong IK, Choi KM, Han KA, Kim KA, Kim IJ, Han SJ, Lee WY, Yoo SJ. Efficacy and safety of dapagliflozin add-on to evogliptin plus metformin therapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2024; 26:5065-5077. [PMID: 39223856 DOI: 10.1111/dom.15838] [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: 04/20/2024] [Revised: 07/09/2024] [Accepted: 07/11/2024] [Indexed: 09/04/2024]
Abstract
AIM To evaluate the efficacy and safety of dapagliflozin versus placebo as an add-on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination. PATIENTS AND METHODS In this multicentre, randomized, double-blind, placebo-controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable-dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level. RESULTS In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was -0.70% (-7.7 mmol/mol) (p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol) was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2-h postprandial plasma glucose, fasting insulin, uric acid and gamma-glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups. CONCLUSION Dapagliflozin add-on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients.
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Affiliation(s)
- In-Kyung Jeong
- Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Korea
| | - Kyung Mook Choi
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea
| | - Kyung Ah Han
- Department of Internal Medicine, Nowon Eulgi Medical Center, Seoul, Korea
| | - Kyoung-Ah Kim
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Korea
| | - In Joo Kim
- Department of Internal Medicine, Pusan National University Hospital, Busan, Korea
| | - Seung Jin Han
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea
| | - Won Young Lee
- Department of Internal Medicine, Kangbuk Samsung Hospital, Seoul, Korea
| | - Soon Jib Yoo
- Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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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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Ito D, Shimizu S, Haisa A, Yanagisawa S, Inoue K, Saito D, Sumita T, Yanagisawa M, Uchida Y, Inukai K, Shimada A. Long-term effects of ipragliflozin and pioglitazone on metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes: 5 year observational follow-up of a randomized, 24 week, active-controlled trial: Effect of ipragliflozin in MASLD. J Diabetes Investig 2024; 15:1220-1230. [PMID: 38775319 PMCID: PMC11363141 DOI: 10.1111/jdi.14246] [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: 01/22/2024] [Revised: 04/23/2024] [Accepted: 05/06/2024] [Indexed: 08/31/2024] Open
Abstract
AIMS/INTRODUCTION We conducted a 5 year post-trial monitoring study of our previous randomized 24 week, open-label, active-controlled trial that showed beneficial effects of ipragliflozin on metabolic dysfunction-associated steatotic liver disease (MASLD), identical to those of pioglitazone. MATERIALS AND METHODS In our previous trial, 66 patients with MASLD and type 2 diabetes were randomly assigned to receive either ipragliflozin (n = 32) or pioglitazone (n = 34). Upon its conclusion, 61 patients were monitored for 5 years for outcome measures of MASLD, glycemic, and metabolic parameters. Differences between the two groups were analyzed at baseline, 24 weeks, and 5 years; changes in outcome measures from baseline were also evaluated. RESULTS At 5 years, the mean liver-to-spleen attenuation ratio increased by 0.20 (from 0.78 ± 0.24 to 0.98 ± 0.20) in the ipragliflozin group and by 0.26 (from 0.76 ± 0.26 to 1.02 ± 0.20) in the pioglitazone group (P = 0.363). Similarly, ipragliflozin and pioglitazone significantly improved serum aminotransferase, HbA1c, and fasting plasma glucose levels over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat area observed at 24 weeks were sustained throughout the 5 years (-4.0%, P = 0.0075 and -7.6%, P = 0.045, respectively). Moreover, ipragliflozin significantly reduced the values of fibrosis markers (serum ferritin and FIB-4 index), was well tolerated, and had a higher continuation rate for 5 years compared with pioglitazone. CONCLUSIONS Ipragliflozin and pioglitazone improved MASLD and glycemic parameters over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat mass persisted for 5 years.
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Affiliation(s)
- Daisuke Ito
- Department of Endocrinology and DiabetesSaitama Medical UniversitySaitamaJapan
- Department of Internal MedicineOgawa Red Cross HospitalSaitamaJapan
| | - Satoshi Shimizu
- Department of Internal MedicineOgawa Red Cross HospitalSaitamaJapan
| | - Akifumi Haisa
- Department of Endocrinology and DiabetesSaitama Medical UniversitySaitamaJapan
- Department of Internal MedicineOgawa Red Cross HospitalSaitamaJapan
| | - Shinnosuke Yanagisawa
- Department of Endocrinology and DiabetesSaitama Medical UniversitySaitamaJapan
- Department of Internal MedicineOgawa Red Cross HospitalSaitamaJapan
- Satsuki Medical ClinicSaitamaJapan
| | - Kazuyuki Inoue
- Department of Endocrinology and DiabetesSaitama Medical UniversitySaitamaJapan
- Department of Internal MedicineOgawa Red Cross HospitalSaitamaJapan
| | - Daigo Saito
- Department of Endocrinology and DiabetesSaitama Medical UniversitySaitamaJapan
- Department of Internal MedicineOgawa Red Cross HospitalSaitamaJapan
| | - Takashi Sumita
- Department of Endocrinology and DiabetesSaitama Medical UniversitySaitamaJapan
- Department of Internal MedicineOgawa Red Cross HospitalSaitamaJapan
| | | | - Yoshihito Uchida
- Department of Gastroenterology and HepatologySaitama Medical UniversitySaitamaJapan
| | - Kouichi Inukai
- Department of Diabetes and EndocrinologyHigashiyamato HospitalTokyoJapan
| | - Akira Shimada
- Department of Endocrinology and DiabetesSaitama Medical UniversitySaitamaJapan
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Kawaguchi T, Murotani K, Kajiyama H, Obara H, Yamaguchi H, Toyofuku Y, Kaneko F, Seino Y, Uchida S. Effects of luseogliflozin on suspected MASLD in patients with diabetes: a pooled meta-analysis of phase III clinical trials. J Gastroenterol 2024; 59:836-848. [PMID: 39060520 PMCID: PMC11338969 DOI: 10.1007/s00535-024-02122-x] [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: 02/25/2024] [Accepted: 05/29/2024] [Indexed: 07/28/2024]
Abstract
BACKGROUND Luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, potentially exerts pleiotropic effects on the liver. However, the sufficient evidence is still lacking. We aimed to investigate the effects of luseogliflozin on hepatic steatosis, fibrosis, and cardiometabolic risk factors in diabetic patients by a pooled meta-analysis. METHODS In this pooled meta-analysis, we enrolled diabetic patients who participated in phase III clinical trials of luseogliflozin (luseogliflozin group n = 302, placebo group n = 191). The primary outcomes were changes in fatty liver index (FLI) and Hepamet fibrosis score (HFS) after 24 weeks. The secondary outcomes were changes in cardiometabolic risk factors after 24 weeks. Statistical analysis was performed using propensity scoring analysis by the inverse probability of treatment weighting method. RESULTS Primary outcomes: Luseogliflozin significantly decreased FLI compared to placebo after 24 weeks (adjusted coefficient - 5.423, 95%CI - 8.760 to - 2.086, P = 0.0016). There was no significant difference in changes in HFS between the two groups. However, luseogliflozin significantly decreased HFS compared to placebo in diabetic patients with ALT > 30 U/L (adjusted coefficient - 0.039, 95%CI - 0.077 to - 0.001, P = 0.0438) and with FIB-4 index > 1.3 (adjusted coefficient - 0.0453, 95%CI - 0.075 to - 0.016, P = 0.0026). Secondary outcom8es: Luseogliflozin significantly decreased HbA1c level, HOMA-IR value, BMI, and uric acids level, and increased HDL cholesterol level compared to placebo. CONCLUSIONS This pooled meta-analysis demonstrated that 24-week treatment with luseogliflozin improved hepatic steatosis and fibrosis indexes in diabetic patients, especially those with liver injury. Furthermore, luseogliflozin improved various cardiometabolic risk factors. Thus, luseogliflozin may be useful for improving MASLD in diabetic patients.
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Affiliation(s)
- Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-Machi, Kurume, 830-0011, Japan.
- Clinical Research Center, Kurume University Hospital, Kurume, Japan.
| | - Kenta Murotani
- Clinical Research Center, Kurume University Hospital, Kurume, Japan
- Biostatistics Center, Kurume University, Kurume, Japan
- School of Medical Technology, Kurume University, Kurume, Japan
| | | | - Hitoshi Obara
- Clinical Research Center, Kurume University Hospital, Kurume, Japan
- Biostatistics Center, Kurume University, Kurume, Japan
| | | | - Yuko Toyofuku
- Clinical Research Center, Kurume University Hospital, Kurume, Japan
| | - Fumi Kaneko
- Clinical Research Center, Kurume University Hospital, Kurume, Japan
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Fardman A, Kodesh A, Siegel AJ, Segev A, Regev E, Maor E, Berkovitch A, Kuperstein R, Morgan A, Nahum E, Peled Y, Grupper A. The safety of sodium glucose transporter 2 inhibitors and trends in clinical and hemodynamic parameters in patients with left ventricular assist devices. Artif Organs 2024; 48:902-911. [PMID: 38409872 DOI: 10.1111/aor.14733] [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: 10/21/2023] [Revised: 12/14/2023] [Accepted: 02/12/2024] [Indexed: 02/28/2024]
Abstract
BACKGROUND The safety and impact of sodium glucose transporter 2 inhibitors (SGLT2-I) in patients with left ventricular assist devices (LVAD) are unknown. METHODS A retrospective analysis of all consecutive patients who underwent LVAD Heart Mate 3 (HM3) implantation at a single medical center and received SGLT2-I therapy following surgery was conducted. LVAD parameters, medical therapy, laboratory tests, echocardiography, and right heart catheterization (RHC) study results were recorded and compared before and after initiation of SGLT2-I. RESULTS SGLT2-I medications were initiated in 29 (21%) of 138 patients following HM3 implantation (23 (79%) received Empagliflozin and 6 (21%) Dapagliflozin). The mean age at the time of LVAD implantation was 62 ± 6.7 years, 25 (86%) were male, and 23 (79%) had diabetes mellitus. The median time from HM3 implantation to SGLT2-I initiation was 108 days, IQR (26-477). Following SGLT2-I therapy, the daily dose of furosemide decreased from 47 to 23.5 mg/day (mean difference = 23.5 mg/d, 95% CI 8.2-38.7, p = 0.004) and significant weight reduction was observed (mean difference 2.5 kg, 95% CI 0.7-4.3, p = 0.008). Moreover, a significant 5.6 mm Hg reduction in systolic pulmonary artery pressure (sPAP) was measured during RHC (95% CI 0.23-11, p = 0.042) in a subgroup of 11 (38%) patients. LVAD parameters were similar before and after SGLT2-I initiation (p > 0.2 for all). No adverse events were recorded during median follow-up of 354 days, IQR (206-786). CONCLUSION SGLT2-I treatment is safe in LVAD patients and might contribute to reduction in patients sPAP.
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Affiliation(s)
- Alexander Fardman
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Afek Kodesh
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
- Department of Internal Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA
| | | | - Amitai Segev
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Ehud Regev
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Elad Maor
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Anat Berkovitch
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Rafael Kuperstein
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Avi Morgan
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Eyal Nahum
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Yael Peled
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Avishay Grupper
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
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Chen H, Zhou Y, Hao H, Xiong J. Emerging mechanisms of non-alcoholic steatohepatitis and novel drug therapies. Chin J Nat Med 2024; 22:724-745. [PMID: 39197963 DOI: 10.1016/s1875-5364(24)60690-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Indexed: 09/01/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver disease globally. It initiates with simple steatosis (NAFL) and can progress to the more severe condition of non-alcoholic steatohepatitis (NASH). NASH often advances to end-stage liver diseases such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Notably, the transition from NASH to end-stage liver diseases is irreversible, and the precise mechanisms driving this progression are not yet fully understood. Consequently, there is a critical need for the development of effective therapies to arrest or reverse this progression. This review provides a comprehensive overview of the pathogenesis of NASH, examines the current therapeutic targets and pharmacological treatments, and offers insights for future drug discovery and development strategies for NASH therapy.
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Affiliation(s)
- Hao Chen
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yang Zhou
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Haiping Hao
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
| | - Jing Xiong
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
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Beygi M, Ahi S, Zolghadri S, Stanek A. Management of Metabolic-Associated Fatty Liver Disease/Metabolic Dysfunction-Associated Steatotic Liver Disease: From Medication Therapy to Nutritional Interventions. Nutrients 2024; 16:2220. [PMID: 39064665 PMCID: PMC11279539 DOI: 10.3390/nu16142220] [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: 06/03/2024] [Revised: 06/30/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common long-lasting liver disease that affects millions of people around the world. It is best identified with a hepatic fat build-up that ultimately leads to inflammation and damage. The classification and nomenclature of NAFLD have long been a controversial topic, until 2020 when a group of international experts recommended substituting NAFLD with MAFLD (metabolic dysfunction-associated FLD). MAFLD was then terminologically complemented in 2023 by altering it to MASLD, i.e., metabolic dysfunction-associated steatotic liver disease (MASLD). Both the MAFLD and the MASLD terminologies comprise the metabolic element of the disorder, as they offer diagnostic benchmarks that are embedded in the metabolic risk factors that underlie the disease. MASLD (as a multisystemic disease) provides a comprehensive definition that includes a larger population of patients who are at risk of liver morbidity and mortality, as well as adverse cardiovascular and diabetes outcomes. MASLD highlights metabolic risks in lean or normal weight individuals, a factor that has not been accentuated or discussed in previous guidelines. Novel antihyperglycemic agents, anti-hyperlipidemic drugs, lifestyle modifications, nutritional interventions, and exercise therapies have not been extensively studied in MAFLD and MASLD. Nutrition plays a vital role in managing both conditions, where centralizing on a diet rich in whole vegetables, fruits, foods, healthy fats, lean proteins, and specific nutrients (e.g., omega-3 fatty acids and fibers) can improve insulin resistance and reduce inflammation. Thus, it is essential to understand the role of nutrition in managing these conditions and to work with patients to develop an individualized plan for optimal health. This review discusses prevention strategies for NAFLD/MAFLD/MASLD management, with particular attention to nutrition and lifestyle correction.
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Affiliation(s)
- Mohammad Beygi
- Department of Agricultural Biotechnology, College of Agriculture, Isfahan University of Technology (IUT), Isfahan 8415683111, Iran;
| | - Salma Ahi
- Research Center for Noncommunicable Diseases, Jahrom University of Medical Sciences, Jahrom 7414846199, Iran;
| | - Samaneh Zolghadri
- Department of Biology, Jahrom Branch, Islamic Azad University, Jahrom 7414785318, Iran
| | - Agata Stanek
- Department of Internal Medicine, Angiology and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland
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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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Iordan L, Gaita L, Timar R, Avram V, Sturza A, Timar B. The Renoprotective Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i)-A Narrative Review. Int J Mol Sci 2024; 25:7057. [PMID: 39000165 PMCID: PMC11241663 DOI: 10.3390/ijms25137057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Chronic kidney disease (CKD) is a noncommunicable condition that has become a major healthcare burden across the globe, often underdiagnosed and associated with low awareness. The main cause that leads to the development of renal impairment is diabetes mellitus and, in contrast to other chronic complications such as retinopathy or neuropathy, it has been suggested that intensive glycemic control is not sufficient in preventing the development of diabetic kidney disease. Nevertheless, a novel class of antidiabetic agents, the sodium-glucose cotransporter-2 inhibitors (SGLT2i), have shown multiple renoprotective properties that range from metabolic and hemodynamic to direct renal effects, with a major impact on reducing the risk of occurrence and progression of CKD. Thus, this review aims to summarize current knowledge regarding the renoprotective mechanisms of SGLT2i and to offer a new perspective on this innovative class of antihyperglycemic drugs with proven pleiotropic beneficial effects that, after decades of no significant progress in the prevention and in delaying the decline of renal function, start a new era in the management of patients with CKD.
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Affiliation(s)
- Liana Iordan
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Laura Gaita
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Romulus Timar
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Vlad Avram
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Adrian Sturza
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Bogdan Timar
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
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Stefan N, Hartleb M, Popovic B, Varona R. Effect of essential phospholipids on hepatic steatosis in metabolic dysfunction-associated steatotic liver disease associated with type 2 diabetes mellitus and/or hyperlipidemia and/or obesity: study protocol of a randomized, double-blind, phase IV clinical trial. Trials 2024; 25:374. [PMID: 38858768 PMCID: PMC11165850 DOI: 10.1186/s13063-024-08208-4] [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: 12/15/2023] [Accepted: 05/29/2024] [Indexed: 06/12/2024] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a predominant chronic liver condition globally and is strongly associated with obesity, diabetes mellitus, and dyslipidemia. Essential phospholipids (EPL) are recommended as supportive treatment for managing liver conditions, including MASLD or metabolic dysfunction-associated steatohepatitis, cirrhosis, and viral hepatitis. While efficacy of EPL as an adjunctive therapy in MASLD treatment has been established earlier, certain aspects of its usage such as the impact of standard-of-care parameters, effect of EPL on quality of life (QoL) and change in symptoms evaluation in patients with MASLD remain unexplored. The proposed trial aims to assess the efficacy and safety of EPL and the subsequent QoL of patients with MASLD associated with type 2 diabetes mellitus (T2DM) and/or hyperlipidemia and/or obesity. METHODS This is a multicenter, multinational, double-blind, randomized, two-arm, placebo-controlled, parallel-group, phase IV clinical trial. The trial is being conducted in approximately 190 patients who are randomized on a 1:1 basis either to the EPL arm (Essentiale® 1800 mg/day orally + standard of care) or placebo arm (placebo + standard of care). The primary outcome is to assess the efficacy of EPL on hepatic steatosis, as measured by transient elastography, from baseline to 6 months. The secondary outcomes include change in QoL parameters, as measured by the Chronic Liver Disease Questionnaire-metabolic dysfunction-associated steatotic liver disease/ metabolic dysfunction-associated steatohepatitis and change in symptom evaluation (using the Global Overall Symptom scale) from baseline to 6 months for symptoms, including asthenia, feeling depressed, abdominal pain/discomfort, or fatigue. DISCUSSION The current protocol design will allow to comprehensively explore the efficacy of EPL added to the standard of care on hepatic steatosis and QoL and its safety in patients with MASLD associated with T2DM and/or hyperlipidemia and/or obesity by assessing various outcome measures. TRIAL REGISTRATION European Union Clinical Trials Register, EudraCT, 2021-006069-39. Registered on March 13, 2022.
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Affiliation(s)
- Norbert Stefan
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany.
| | - Marek Hartleb
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Medical University of Silesia, Katowice, Poland
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Wang H, Ma Q, Chen Y, Luo L, Ye J, Zhong B. Optimized strategy among diet, exercise, and pharmacological interventions for nonalcoholic fatty liver disease: A network meta-analysis of randomized controlled trials. Obes Rev 2024; 25:e13727. [PMID: 38509775 DOI: 10.1111/obr.13727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 01/23/2024] [Accepted: 01/30/2024] [Indexed: 03/22/2024]
Abstract
BACKGROUND Emerging treatment methods, including exercise, diet, and drugs, for nonalcoholic fatty liver disease have been proposed. However, the differences in their efficacy have not been determined. We aimed to compare the effects of these treatments excluding surgery via a systematic review and network meta-analysis of randomized controlled trials. DATA SOURCE The data sources included PubMed, Embase, Web of Science and Cochrane up to February 1st, 2023. The endpoints consisted of body mass index (BMI), serum markers of metabolism and liver injury markers, liver fat content, and stiffness. RESULTS A total of 174 studies with 10,183 patients were included in this meta-analysis. In terms of improving BMI, Pan-agonist of peroxisome proliferator-activated receptors (PPAR) is the best treatment with the highest SUCRA (surface under the cumulative ranking) of 84.8% (mean = -3.40, 95% CI -5.55, -1.24) by the comparative effectiveness ranking. GLP-1 (glucagon-like peptide-1) has the best effect in improving the liver fat content based on the MRI-PDFF, steatosis score (SUCRA 99.7%, mean = -2.19, 95% CI -2.90, -1.48) and ballooning score (SUCRA 61.2%, mean = -0.82, 95% CI -4.46, 2.83). CONCLUSIONS Pan-agonist of PPAR was the most efficacious regimen in lowering BMIs, whereas GLP-1R agonists achieved the highest efficacy of steatosis improvement in this network meta-analysis.
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Affiliation(s)
- Hao Wang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Qianqian Ma
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Infectious Diseases, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Youpeng Chen
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Ling Luo
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Junzhao Ye
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bihui Zhong
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Kokkorakis M, Muzurović E, Volčanšek Š, Chakhtoura M, Hill MA, Mikhailidis DP, Mantzoros CS. Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies. Pharmacol Rev 2024; 76:454-499. [PMID: 38697855 DOI: 10.1124/pharmrev.123.001087] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/22/2023] [Accepted: 01/25/2024] [Indexed: 05/05/2024] Open
Abstract
Steatotic liver disease (SLD) displays a dynamic and complex disease phenotype. Consequently, the metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) therapeutic pipeline is expanding rapidly and in multiple directions. In parallel, noninvasive tools for diagnosing and monitoring responses to therapeutic interventions are being studied, and clinically feasible findings are being explored as primary outcomes in interventional trials. The realization that distinct subgroups exist under the umbrella of SLD should guide more precise and personalized treatment recommendations and facilitate advancements in pharmacotherapeutics. This review summarizes recent updates of pathophysiology-based nomenclature and outlines both effective pharmacotherapeutics and those in the pipeline for MASLD/MASH, detailing their mode of action and the current status of phase 2 and 3 clinical trials. Of the extensive arsenal of pharmacotherapeutics in the MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, have shown only marginal benefits and are now being tested as part of combination therapies, yet others are still in development as monotherapies. Although the Food and Drug Administration (FDA) has recently approved resmetirom, additional therapeutic approaches in development will ideally target MASH and fibrosis while improving cardiometabolic risk factors. Due to the urgent need for the development of novel therapeutic strategies and the potential availability of safety and tolerability data, repurposing existing and approved drugs is an appealing option. Finally, it is essential to highlight that SLD and, by extension, MASLD should be recognized and approached as a systemic disease affecting multiple organs, with the vigorous implementation of interdisciplinary and coordinated action plans. SIGNIFICANCE STATEMENT: Steatotic liver disease (SLD), including metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, is the most prevalent chronic liver condition, affecting more than one-fourth of the global population. This review aims to provide the most recent information regarding SLD pathophysiology, diagnosis, and management according to the latest advancements in the guidelines and clinical trials. Collectively, it is hoped that the information provided furthers the understanding of the current state of SLD with direct clinical implications and stimulates research initiatives.
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Affiliation(s)
- Michail Kokkorakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Emir Muzurović
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Špela Volčanšek
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Marlene Chakhtoura
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Michael A Hill
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Dimitri P Mikhailidis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
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Jin Z, Yin R, Yuan Y, Zheng C, Zhang P, Wang Y, Weng H. Dapagliflozin ameliorates hepatic steatosis via suppressing LXRα-mediated synthesis of lipids and bile acids. Biochem Pharmacol 2024; 223:116167. [PMID: 38527558 DOI: 10.1016/j.bcp.2024.116167] [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: 01/16/2024] [Revised: 03/20/2024] [Accepted: 03/22/2024] [Indexed: 03/27/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) prevalence is rising globally with no pharmacotherapies approved. Hepatic steatosis is closely associated with progression and prognosis of NAFLD. Dapagliflozin, kind of sodium-glucose cotransporter 2 (SGLT2) inhibitor, was found to improve NAFLD in clinical trials, while the underlying mechanism remains poorly elucidated. Here, we reported that dapagliflozin effectively mitigated liver injury and relieved lipid metabolism disorders in vivo. Further investigation showed that dapagliflozin markedly suppressed Liver X Receptor α (LXRα)-mediated synthesis of de novo lipids and bile acids (BAs). In AML12 cells, our results proved dapagliflozin decreased lipid contents via inhibiting the expression of LXRα and downstream liposynthesis genes. Proteosome inhibitor MG132 eliminated the effect of dapagliflozin on LXRα-mediated signaling pathway, which suggested that dapagliflozin downregulated LXRα expression through increasing LXRα degradation. Knockdown of LXRα with siRNA abolished the reduction of lipogenesis from dapagliflozin treatment, indicating that LXRα might be the pivotal target for dapagliflozin to exhibit the aforementioned benefits. Furthermore, the data showed that dapagliflozin reversed gut dysbiosis induced by BAs disruption and altered gut microbiota profile to reduce intestinal lipids absorption. Together, our study deciphered a novel mechanism by which dapagliflozin relieved hepatic steatosis and highlighted the potential benefit of dapagliflozin in treating NAFLD.
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Affiliation(s)
- Zijie Jin
- Fudan University School of Pharmacy, Shanghai 201203, China.
| | - Ruotong Yin
- Fudan University School of Pharmacy, Shanghai 201203, China
| | - Yan Yuan
- Fudan University School of Pharmacy, Shanghai 201203, China
| | - Chen Zheng
- Fudan University School of Pharmacy, Shanghai 201203, China
| | - Peng Zhang
- Fudan University School of Pharmacy, Shanghai 201203, China
| | - Yalin Wang
- Fudan University School of Pharmacy, Shanghai 201203, China
| | - Hongbo Weng
- Fudan University School of Pharmacy, Shanghai 201203, China.
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Jojima T, Sakurai S, Kishi H, Kato K, Iijima T, Tomaru T, Usui I, Aso Y. Empagliflozin increases plasma levels of citrulline, histidine, and α-aminobutyric acid in patients with type 2 diabetes: effects of a sodium-glucose co-transporter 2 inhibitor on the plasma amino acid profile. Expert Opin Pharmacother 2024; 25:937-944. [PMID: 38809611 DOI: 10.1080/14656566.2024.2362265] [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: 04/10/2024] [Accepted: 05/28/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND To investigate effects of empagliflozin on plasma amino acids in people with type 2 diabetes. RESEARCH DESIGN AND METHODS In a randomized, active-controlled, open-label trial, 58 patients with type 2 diabetes were randomized to 10 mg/day empagliflozin (n = 29) or standard treatment without empagliflozin (control group, n = 29) and treated for 12 weeks. We obtained blood samples at baseline and 12 weeks and assessed the plasma amino acid profile by liquid chromatography-mass spectrometry liquid chromatography. We also calculated the Fischer ratio (the ratio of branched-chain to aromatic amino acids). RESULTS In the empagliflozin group but not in the control group, plasma levels of citrulline, histidine, and α-aminobutyric acid (AABA), the Fischer ratio, and serum high-molecular weight (HMW) adiponectin increased significantly (p = 0.0099, 0.0277, 0.0318, 0.0135, and 0.0304, respectively) and plasma plasminogen activator inhibitor-1 (PAI-1) decreased significantly (p = 0.0014). In the empagliflozin group, the change in plasma citrulline was positively correlated with the changes in HMW adiponectin (r = 0.488, p = 0.0084) and the Fischer ratio (r = 0.393, p = 0.0353) but negatively correlated with the change in ferritin (r= -0.533,p = 0.0051); the change in plasma histidine was negatively correlated with the change in PAI-1 (r= -0.398, p = 0.0397) and urinary albumin creatinine ratio (r= -0.478, p = 0.0088). CONCLUSION Empagliflozin significantly increases plasma citrulline, histidine, and AABA in people with type 2 diabetes. CLINICAL TRIAL REGISTRATION www.umin.ac.jp identifier is UMIN000025418.
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Affiliation(s)
- Teruo Jojima
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Japan
| | - Shintaro Sakurai
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Japan
| | - Haruka Kishi
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Japan
| | - Kananko Kato
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Japan
| | - Toshie Iijima
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Japan
| | - Takuya Tomaru
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Japan
| | - Isao Usui
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Japan
| | - Yoshimasa Aso
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Japan
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Hu J, Teng J, Hui S, Liang L. SGLT-2 inhibitors as novel treatments of multiple organ fibrosis. Heliyon 2024; 10:e29486. [PMID: 38644817 PMCID: PMC11031788 DOI: 10.1016/j.heliyon.2024.e29486] [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: 12/26/2023] [Revised: 04/08/2024] [Accepted: 04/08/2024] [Indexed: 04/23/2024] Open
Abstract
Fibrosis, a significant health issue linked to chronic inflammatory diseases, affects various organs and can lead to serious damage and loss of function. Despite the availability of some treatments, their limitations necessitate the development of new therapeutic options. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), known for their glucose-lowering ability, have shown promise in offering protective effects against fibrosis in multiple organs through glucose-independent mechanisms. This review explores the anti-fibrotic potential of SGLT2i across different tissues, providing insights into their underlying mechanisms and highlighting recent research advancements. The evidence positions SGLT2i as a potential future treatments for fibrotic diseases.
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Affiliation(s)
- Junpei Hu
- Department of Geriatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, China
| | - Jianhui Teng
- Department of Geriatrics, Hunan Provincial People's Hospital, China
| | - Shan Hui
- Department of Geriatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, China
| | - Lihui Liang
- Department of Geriatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, China
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Luo W, Xiao Z, Yang X, Wu R, Li J, Yu Z, Guo S, Nie B, Liu D. Liver fat as a dietary target by Chinese Medical Nutrition Therapy (CMNT) diet for treating type 2 diabetes with non-alcoholic fatty liver disease: study protocol for a randomised controlled trial. BMJ Open 2024; 14:e081263. [PMID: 38684277 PMCID: PMC11086286 DOI: 10.1136/bmjopen-2023-081263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 04/10/2024] [Indexed: 05/02/2024] Open
Abstract
INTRODUCTION Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) often coexist and increase risk for developing liver fibrosis and diabetes complications if no effective measures are taken. Dietary intervention is known to be able to achieve diabetes remission, while evidence regarding the long-term effect on liver fat is limited for comorbidity management of type 2 diabetes and NAFLD. This study aims to investigate the long-term effect of a Chinese Medical Nutrition Therapy (CMNT) diet accompanied by intermittent energy restriction on reducing liver fat and glycated haemoglobin (HbA1c) in patients with type 2 diabetes and NAFLD. METHODS AND ANALYSIS This is a multicentre two-armed parallel randomised controlled trial study. 120 participants with type 2 diabetes and NAFLD will be recruited from the physical examination centres of multiple hospitals in China. Participants will be randomly allocated 1:1 to either the CMNT group or the usual care group. The CMNT group will be instructed to consume the provided specific meal replacement Chinese medicinal foods consisting of 6 cycles of 5 consecutive days followed by 10 days of regular food intake. The usual care group will be given standard dietary advice. Primary outcomes are changes in the controlled attenuation parameter value by transient elastography and HbA1c level. Secondary outcomes include differences in anthropometrics, clinical blood markers, questionnaires, gut microbiota and metabolomics. Further follow-up will be performed at 6 months, 1 year and 2 years. ETHICS AND DISSEMINATION The study protocol was approved by the Biomedical Research Ethics Committee of Hunan Agricultural University (BRECHAU20200235).The results will be disseminated via relevant peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER NCT05439226.
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Affiliation(s)
- Wu Luo
- College of Biology, Hunan University, Changsha, Hunan, China
- Horticulture College, Hunan Agricultural University, Changsha, Hunan, China
| | - Zhiyong Xiao
- Horticulture College, Hunan Agricultural University, Changsha, Hunan, China
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xiao Yang
- Horticulture College, Hunan Agricultural University, Changsha, Hunan, China
- Hunan Provincial Engineering Research Center of Medical Nutrition Intervention Technology for Metabolic Diseases, Changsha, Hunan, China
| | - Ruiyu Wu
- Horticulture College, Hunan Agricultural University, Changsha, Hunan, China
- Hunan Provincial Engineering Research Center of Medical Nutrition Intervention Technology for Metabolic Diseases, Changsha, Hunan, China
| | - Jian Li
- Hunan Provincial Engineering Research Center of Medical Nutrition Intervention Technology for Metabolic Diseases, Changsha, Hunan, China
- Clinical Research Centre, State Key Laboratory of Subhealth Intervention Technology, Changsha, Hunan, China
| | - Zhen Yu
- Horticulture College, Hunan Agricultural University, Changsha, Hunan, China
| | - Shengxiang Guo
- Horticulture College, Hunan Agricultural University, Changsha, Hunan, China
| | - Beibei Nie
- Horticulture College, Hunan Agricultural University, Changsha, Hunan, China
| | - Dongbo Liu
- Horticulture College, Hunan Agricultural University, Changsha, Hunan, China
- Clinical Research Centre, State Key Laboratory of Subhealth Intervention Technology, Changsha, Hunan, China
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Akhtar A, Ijaz H, Waseem M, Khan MI, Saif Y, Iqbal H, Batool SA, Kumari U, Surani S, Khan A. The interplay between diabetes and non-alcoholic fatty liver disease: a cross-sectional study from Pakistan. Ann Med Surg (Lond) 2024; 86:1929-1932. [PMID: 38576946 PMCID: PMC10990318 DOI: 10.1097/ms9.0000000000001875] [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: 08/10/2023] [Accepted: 02/19/2024] [Indexed: 04/06/2024] Open
Abstract
Background and objectives Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic deposition of fat in the liver, in the absence of other secondary causes of fat buildup. The relationship between NAFLD, including alanine aminotransferase (ALT), and glycated haemoglobin (HbA1c), is important for predicting the severity of disease and prognosis. This study aims to investigate the association of HbA1c in type 2 diabetes mellitus (T2DM) patients with NAFLD via measuring the ALT levels. Materials and methods This retrospective cross-sectional study enroled 130 patients with T2DM and NAFLD. The association between levels of HbA1c and ALT in patients of NAFLD with controlled and uncontrolled T2DM, respectively, was investigated. Stratification was done based on gender and diabetic control, using HbA1c levels as a marker of glycemic control. Serum ALT levels were also compared in both groups. Results The mean age of the participants was 50.2±5.7 years. The total participants were 130, of which 77 (59.3%) were females and 53 (40.7%) were males. The numbers of patients having uncontrolled T2DM (HbA1c>7%), and controlled T2DM (HbA1c <7%) were 78 (60%) and 52 (40%), respectively. Moreover, 46 (35.3%) females and 32 (24.7%) males had uncontrolled T2DM, and 31 (23.8%) females and 21 (16.2%) males had controlled T2DM. The mean ALT level for uncontrolled and controlled T2DM in female patients was found to be 24.6±3.4 and 13.5±2.4, respectively, (P <0.05). For male patients, it was found to be 54.0±4.9 and 29.1±5.4, respectively (P=0.008). Conclusion There is a positive association between elevated HbA1c and ALT levels in T2DM patients with NAFLD.
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Affiliation(s)
- Ayesha Akhtar
- Internal Medicine, Khyber Teaching Hospital, Peshawar
| | - Huda Ijaz
- Internal Medicine, Allama Iqbal Medical College
| | | | | | - Yasir Saif
- Internal Medicine, University Hospital Kerry, Kerry, Ireland
| | | | | | - Usha Kumari
- Medicine, Dow University of Health Sciences, Karachi
| | - Salim Surani
- Texas A&M University, College Station, TX
- Research Collaborator, Mayo Clinic, Rochester, MN
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Lombardi R, Mantovani A, Cespiati A, Francione P, Maffi G, Del Zanna E, Maffeis C, Colecchia A, Passigato N, Ferrarese A, Cusumanu CD, Villani R, Orsi E, Grancini V, Airaghi L, Bignamini D, Serviddio G, Targher G, Dongiovanni P, Fargion S, Fracanzani AL. Evolution of liver fibrosis in diabetic patients with NAFLD in a follow-up study: Hepatoprotective effects of sodium-glucose co-transporter-2 inhibitors. Dig Liver Dis 2024; 56:551-558. [PMID: 37845152 DOI: 10.1016/j.dld.2023.09.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/29/2023] [Accepted: 09/27/2023] [Indexed: 10/18/2023]
Abstract
BACKGROUND AND AIMS Patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are at high risk of hepatic fibrosis. To prospectively evaluate changes in fibrosis in diabetic patients with NAFLD, predisposing factors and sodium glucose cotransporter 2 inhibitors (SGLT2i) influence. METHODS 237 T2DM outpatients (mean age 67 ± 9 years, 54% male) were enrolled and re-evaluated after 52 ± 10 months. At baseline and follow-up NAFLD and liver fibrosis (LSM) were detected by ultrasonography and Fibroscan®. RESULTS During follow-up an increase in LSM (6.0 ± 2.8 vs 5.8 ± 2.7 kPa, p = 0.02) and in the prescription of SGLT2i (20% vs 6%, p<0.001) was registered, despite stability of diabetic control. LSM worsened in 133(56%) subjects, 92 (39%) with worsening >10% from baseline. Patients with worsening versus non worsening of LSM had higher prevalence of increase in BMI during follow-up (45% vs 32%, p = 0.06) and lower SGLT2i prescription (15% vs 27%, p = 0.034). In multivariate analysis use of SGLT2-inhibitors at follow-up reduced the risk of LSM worsening (HR 0.34, 95% CI 0.13-0.88), even when considered>10% from baseline. CONCLUSIONS A high prevalence of fibrosis progression was observed in diabetic subjects with NAFLD over a nearly 5-years follow up and SGLT2-inhibitors seem to reduce the risk of worsening of liver stiffness.
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Affiliation(s)
- Rosa Lombardi
- SC- Medicina-Indirizzo Metabolico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Annalisa Cespiati
- SC- Medicina-Indirizzo Metabolico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Paolo Francione
- UO di Medicina, Azienda Ospedaliera "Card. G. Panico" di Tricase, Italy
| | - Gabriele Maffi
- SC- Medicina-Indirizzo Metabolico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Elena Del Zanna
- SC- Medicina-Indirizzo Metabolico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Claudio Maffeis
- Pediatric Diabetes and Metabolic Disorders Unit, Department of Surgical Sciences, Dentistry, and Pediatrics, and Gynaecology, University Hospital of Verona, Verona, Italy
| | - Antonio Colecchia
- Gastroenterology Unit, Department of Medical Specialities, University Hospital of Modena, University of Modena & Reggio Emilia, Modena, Italy
| | - Nicola Passigato
- Gastroenterology Unit, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Alberto Ferrarese
- Gastroenterology Unit, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Caterina Daniela Cusumanu
- Gastroenterology Unit, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Rosanna Villani
- Centro C.U.R.E, Dept. of Medical and Surgical Sciences, University of Foggia, Italy
| | - Emanuela Orsi
- Department of Medical Science, Endocrinology and Diabetes Unit, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan Italy
| | - Valeria Grancini
- Department of Medical Science, Endocrinology and Diabetes Unit, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan Italy
| | - Lorena Airaghi
- SC- Medicina-Indirizzo Metabolico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
| | - Daniela Bignamini
- SC- Medicina-Indirizzo Metabolico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
| | - Gaetano Serviddio
- Centro C.U.R.E, Dept. of Medical and Surgical Sciences, University of Foggia, Italy
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy; Metabolic Diseases Research Unit, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Italy
| | - Paola Dongiovanni
- SC- Medicina-Indirizzo Metabolico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Anna Ludovica Fracanzani
- SC- Medicina-Indirizzo Metabolico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Abdelgani S, Khattab A, Adams J, Baskoy G, Brown M, Clarke G, Larvenenko O, DeFronzo RA, Abdul-Ghani M. Empagliflozin Reduces Liver Fat in Individuals With and Without Diabetes. Diabetes Care 2024; 47:668-675. [PMID: 38295394 PMCID: PMC10973912 DOI: 10.2337/dc23-1646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 12/22/2023] [Indexed: 02/02/2024]
Abstract
OBJECTIVE To examine the effect of empagliflozin on liver fat content in individuals with and without type 2 diabetes (T2D) and the relationship between the decrease in liver fat and other metabolic actions of empagliflozin. RESEARCH DESIGN AND METHODS Thirty individuals with T2D and 27 without were randomly assigned to receive in double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks. Participants underwent 75-g oral glucose tolerance testing and measurement of liver fat content with MRS before therapy and at study end. Hepatic glucose production before the start of therapy was measured with 3-3H-glucose. RESULTS Empagliflozin caused an absolute reduction of 2.39% ± 0.79% in liver fat content compared with an increase of 0.91% ± 0.64% in participants receiving placebo (P < 0.007 with ANOVA). The decrease in liver fat was comparable in both individuals with diabetes and those without (2.75% ± 0.81% and 1.93% ± 0.78%, respectively; P = NS). The decrease in hepatic fat content caused by empagliflozin was strongly correlated with baseline liver fat content (r = -0.62; P < 0.001), decrease in body weight (r = 0.53; P < 0.001), and improvement in insulin sensitivity (r = -0.51; P < 0.001) but was not related to the decrease in fasting plasma glucose or HbA1c or the increase in hepatic glucose production. CONCLUSIONS Empagliflozin is effective in reducing liver fat content in individuals with and without T2D. The decrease in liver fat content is independent of the decrease in plasma glucose concentration and is strongly related to the decrease in body weight and improvement in insulin sensitivity.
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Affiliation(s)
- Siham Abdelgani
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX
| | - Ahmed Khattab
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX
| | - John Adams
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX
| | - Gozde Baskoy
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX
| | - Marissa Brown
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX
| | - Geoff Clarke
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX
| | - Olga Larvenenko
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX
| | - Ralph A. DeFronzo
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX
| | - Muhammad Abdul-Ghani
- Division of Diabetes, University of Texas Health Science Center, San Antonio, TX
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50
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Wei S, Wang L, Evans PC, Xu S. NAFLD and NASH: etiology, targets and emerging therapies. Drug Discov Today 2024; 29:103910. [PMID: 38301798 DOI: 10.1016/j.drudis.2024.103910] [Citation(s) in RCA: 45] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 01/22/2024] [Accepted: 01/26/2024] [Indexed: 02/03/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) pose a significant threat to human health and cause a tremendous socioeconomic burden. Currently, the molecular mechanisms of NAFLD and NASH remain incompletely understood, and no effective pharmacotherapies have been approved. In the past five years, significant advances have been achieved in our understanding of the pathomechanisms and potential pharmacotherapies of NAFLD and NASH. Research advances include the investigation of the effects of the fibroblast growth factor 21 (FGF21) analog pegozafermin and the thyroid hormone receptor-β (THRβ) agonist resmetriom on hepatic fat content, NASH resolution and/or fibrosis regression. Future directions of NAFLD and NASH research (including combination therapy, organoids and humanized mouse models) are also discussed in this state-of-the-art review.
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Affiliation(s)
- Shulin Wei
- School of Life Sciences, Jilin University, Changchun, China; Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China
| | - Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, China
| | - Paul C Evans
- Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ, UK
| | - Suowen Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China.
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