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Moolla A, Poolman T, Othonos N, Dong J, Smith K, Cornfield T, White S, Ray DW, Mouchti S, Mózes FE, Thomaides-Brears H, Neubauer S, Cobbold JF, Hodson L, Tomlinson JW. Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD. JHEP Rep 2025; 7:101363. [PMID: 40342635 PMCID: PMC12060445 DOI: 10.1016/j.jhepr.2025.101363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 02/06/2025] [Accepted: 02/11/2025] [Indexed: 05/11/2025] Open
Abstract
Background & Aims Glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies deliver histological benefit in people with metabolic dysfunction-associated steatotic liver disease (MASLD). Multiple mechanisms may be important including weight loss, improved glycaemic control and putative direct tissue-specific actions. Following cessation of GLP1-RA therapy, weight regain is common. To dissect the mechanisms underpinning their benefits, we conducted a prospective, randomised, experimental medicine study in people with MASLD, comparing GLP-1RA treatment (liraglutide) to matched lifestyle-induced weight loss and assessed the impact of treatment withdrawal. Methods Twenty-nine participants with MASLD, without type 2 diabetes underwent metabolic phenotyping including measurement de novo lipogenesis (DNL), liver magnetic resonance imaging, body composition, adipose tissue RNA sequencing, circulating proteome, and stool microbiome analysis. Participants were randomised to lifestyle (∼500 kcal energy deficit) or GLP1-RA treatment for 12 weeks, after which investigations were repeated, and treatment stopped; investigations were also repeated 12 weeks after treatment withdrawal. Results Matched weight loss was achieved in both arms. Body composition changes, reductions in alanine aminotransferase, liver steatosis, and disease activity were similar following both treatments. GLP-1RA treatment, but not lifestyle, improved glucose handling, fasting lipids, and significantly deceased DNL. The subcutaneous adipose transcriptome, circulating proteome profile and stool microbiome were not different between groups after treatment. However, 12 weeks after GLP1-RA (but not lifestyle) withdrawal, circulating MMP-10, IL10RB, FGF-23, and Flt3L were elevated, alongside dysregulated adipose gene expression. Conclusions Although matched weight loss through lifestyle or GLP-1RA have comparable effects on hepatic steatosis, GLP-1RA treatment had additional metabolic benefits on glucose homeostasis, lipid profiles, and DNL. However, GLP-1RA withdrawal may adversely impact the circulating proteome, adipose tissue gene expression, and the stool microbiome, predisposing to weight regain. Impact and implications Weight loss, through either lifestyle intervention or pharmacotherapy with GLP-1RA has an equally beneficial impact on the liver, and both strategies should be considered in the management of people with MASLD. GLP-1RA therapy may have additional benefits to improve glucose homeostasis even in the absence of pre-existing type 2 diabetes. Further research is needed to explore the differential impact of treatment withdrawal and the resultant metabolic consequences. Clinical Trials Registration This study is registered at EudraCT (2016-002045-36).
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Affiliation(s)
- Ahmad Moolla
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Toryn Poolman
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
- Structural and Molecular Biology, Faculty of Life Sciences, University College London, London, UK
| | - Nantia Othonos
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Jiawen Dong
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Kieran Smith
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Thomas Cornfield
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Sarah White
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - David W. Ray
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
- NIHR Oxford Health Biomedical Research Centre, University of Oxford, Oxford, UK
- Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
| | | | - Ferenc E. Mózes
- Oxford Centre for Clinical Magnetic Resonance Research (OCMR), John Radcliffe Hospital, University of Oxford, Oxford, UK
| | | | - Stefan Neubauer
- Oxford Centre for Clinical Magnetic Resonance Research (OCMR), John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Jeremy F. Cobbold
- Department of Gastroenterology and Hepatology, Oxford University Hospitals, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Jeremy W. Tomlinson
- Oxford Centre for Diabetes Endocrinology & Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
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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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Wang MW, Lu LG. Current Status of Glucagon-like Peptide-1 Receptor Agonists in Metabolic Dysfunction-associated Steatotic Liver Disease: A Clinical Perspective. J Clin Transl Hepatol 2025; 13:47-61. [PMID: 39801787 PMCID: PMC11712088 DOI: 10.14218/jcth.2024.00271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 10/13/2024] [Accepted: 10/24/2024] [Indexed: 01/16/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a pressing public health issue associated with adverse outcomes such as cirrhosis, malignancy, transplantation, and mortality. Lifestyle modifications constitute the most effective and fundamental management approach, but they often pose challenges in sustaining long-term clinical benefits. Hence, there is a critical need to enhance our understanding through pharmacological management, which unfortunately remains limited. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a leading treatment in the fields of diabetes and obesity, with recent preclinical and clinical studies indicating significant benefits in the management and treatment of MASLD. Our article begins by reviewing the beneficial therapeutic components of GLP-1RAs in MASLD. Subsequently, from a clinical research perspective, we concluded with the liver outcomes of current primary GLP-1RAs and co-agonists. Finally, we presented our insights on clinical concerns such as appropriate trial endpoints, management of comorbidities, and future developments. In conclusion, the benefits of GLP-1RAs in MASLD are promising, and background therapy involving metabolic modulation may represent one of the future therapeutic paradigms.
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Affiliation(s)
- Ming-Wang Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lun-Gen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Njei B, Al-Ajlouni Y, Lemos SY, Ugwendum D, Ameyaw P, Njei LP, Boateng S. Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cureus 2024; 16:e71366. [PMID: 39534801 PMCID: PMC11556413 DOI: 10.7759/cureus.71366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2024] [Indexed: 11/16/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a major global health challenge. glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential therapeutic benefits for MASLD patients, including improvements in liver function, inflammation, and fibrosis. This study aims to systematically review and meta-analyze randomized controlled trials (RCTs) to evaluate the efficacy and safety of GLP-1RAs in MASLD patients, focusing on hepatic outcomes, cardiovascular outcomes, anthropometric measurements, and mortality. Following PRISMA guidelines, a comprehensive database search was conducted to include RCTs assessing GLP-1RAs' effects on MASLD. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool. Our meta-analysis used a random-effects model, calculating standardized mean differences for continuous outcomes to determine the agents' efficacy and safety. Additionally, funnel plots were generated to assess publication bias, ensuring the integrity of our meta-analytical findings. The review included 27 trials, revealing GLP-1RAs significantly improved hepatic function markers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and liver fat content) and cardiovascular risk factors (fasting blood sugar, HbA1c levels, lipid profiles). Additionally, GLP-1RAs were associated with significant reductions in body weight, BMI, subcutaneous fat, and waist circumference. GLP-1RAs demonstrate a promising therapeutic role in managing MASLD, offering benefits that extend to improving liver function, mitigating cardiovascular risk, and promoting weight loss. Further research is needed to confirm these findings and optimize GLP-1RAs' usage in MASLD treatment.
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Affiliation(s)
- Basile Njei
- Department of Medicine, Yale School of Medicine, New Haven, USA
| | | | - Samira Y Lemos
- Department of Diabetes and Endocrinology, Yaoundé General Hospital, Yaoundé, CMR
| | - Derek Ugwendum
- Department of Internal Medicine, Richmond University Medical Center Affiliated with Mount Sinai Health System and Icahn School of Medicine at Mount Sinai, Staten Island, USA
| | - Prince Ameyaw
- Department of Internal Medicine, Bridgeport Hospital, Yale New Haven Health, Bridgeport, USA
| | - Lea-Pearl Njei
- Department of Biological Science, University of Maryland Baltimore County, Baltimore, USA
| | - Sarpong Boateng
- Department of Medicine, Bridgeport Hospital, Bridgeport, USA
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Deng Y, Dong Y, Zhang S, Feng Y. Targeting mitochondrial homeostasis in the treatment of non-alcoholic fatty liver disease: a review. Front Pharmacol 2024; 15:1463187. [PMID: 39290869 PMCID: PMC11405192 DOI: 10.3389/fphar.2024.1463187] [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: 07/11/2024] [Accepted: 08/20/2024] [Indexed: 09/19/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and its prevalence is rapidly increasing. Antioxidants, lipid-lowering medications, and lifestyle interventions are the most commonly used treatment options for NAFLD, but their efficacy in inhibiting steatosis progression is limited and their long-term ineffectiveness and adverse effects have been widely reported. Therefore, it is important to gain a deeper understanding of the pathogenesis of NAFLD and to identify more effective therapeutic approaches. Mitochondrial homeostasis governs cellular redox biology, lipid metabolism, and cell death, all of which are crucial to control hepatic function. Recent findings have indicated that disruption of mitochondrial homeostasis occurs in the early stage of NAFLD and mitochondrial dysfunction reinforces disease progression. In this review, we summarize the physical roles of the mitochondria and describe their response and dysfunction in the context of NAFLD. We also discuss the drug targets associated with the mitochondria that are currently in the clinical trial phase of exploration. From our findings, we hope that the mitochondria may be a promising therapeutic target for the treatment of NAFLD.
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Affiliation(s)
- Yalan Deng
- Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yuan Dong
- Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
| | - Sitian Zhang
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yingmei Feng
- Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, 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: 15] [Impact Index Per Article: 15.0] [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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Rochoń J, Kalinowski P, Szymanek-Majchrzak K, Grąt M. Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease. World J Gastroenterol 2024; 30:2964-2980. [PMID: 38946874 PMCID: PMC11212696 DOI: 10.3748/wjg.v30.i23.2964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/08/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.
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Affiliation(s)
- Jakub Rochoń
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland
| | - Piotr Kalinowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland
| | | | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland
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Pramanik S, Pal P, Ray S. Non-alcoholic fatty liver disease in type 2 diabetes: Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies. World J Methodol 2024; 14:91319. [PMID: 38983664 PMCID: PMC11229880 DOI: 10.5662/wjm.v14.i2.91319] [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: 12/27/2023] [Revised: 01/20/2024] [Accepted: 02/27/2024] [Indexed: 06/13/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, affecting more than half of the people living with type 2 diabetes (T2D). The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other, which significantly increases the hepatic as well as extrahepatic complications. Until recently, there was no approved pharmacological treatment for NAFLD/ nonalcoholic steatohepatitits (NASH). However, there is evidence that drugs used for diabetes may have beneficial effects on NAFLD. Insulin sensitizers acting through peroxisome proliferator-activated receptor (PPAR) modulation act on multiple levels of NAFLD pathogenesis. Pioglitazone (PPARγ agonist) and saroglitazar (PPARα/γ agonist) are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D, although data on biopsy-proven NASH are lacking with the latter. Initial data on elafibanor (PPAR α/δ agonist) and Lanifibranor (pan PPAR agonist) are promising. On the other hand, incretin therapies based on glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and dual- and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties. GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual- and triple-agonists are required. Furthermore, the long-term safety of these therapies in NAFLD needs to be established. Collaborative efforts among healthcare providers such as primary care doctors, hepatologists, and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.
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Affiliation(s)
- Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Multispecialty Hospital, Siliguri 734010, West Bengal, India
| | - Partha Pal
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 500082, India
| | - Sayantan Ray
- Department of Endocrinology, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar 751019, Odisha, India
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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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10
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Brouwers B, Rao G, Tang Y, Rodríguez Á, Glass LC, Hartman ML. Incretin-based investigational therapies for the treatment of MASLD/MASH. Diabetes Res Clin Pract 2024; 211:111675. [PMID: 38636848 DOI: 10.1016/j.diabres.2024.111675] [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: 08/30/2023] [Revised: 04/15/2024] [Accepted: 04/15/2024] [Indexed: 04/20/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common form of chronic liver disease. It exists as either simple steatosis or its more progressive form, metabolic dysfunction-associated steatohepatitis (MASH), formerly, non-alcoholic steatohepatitis (NASH). The global prevalence of MASLD is estimated to be 32% among adults and is projected to continue to rise with increasing rates of obesity, type 2 diabetes, and metabolic syndrome. While simple steatosis is often considered benign and reversible, MASH is progressive, potentially leading to the development of cirrhosis, liver failure, and hepatocellular carcinoma. Treatment of MASH is therefore directed at slowing, stopping, or reversing the progression of disease. Evidence points to improved liver histology with therapies that result in sustained body weight reduction. Incretin-based molecules, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), alone or in combination with glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptor agonists, have shown benefit here, and several are under investigation for MASLD/MASH treatment. In this review, we discuss current published data on GLP-1, GIP/GLP-1, GLP-1/glucagon, and GLP-1/GIP/glucagon RAs in MASLD/MASH, focusing on their efficacy on liver histology, liver fat, and MASH biomarkers.
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Affiliation(s)
| | - Girish Rao
- Eli Lilly and Company, Indianapolis, IN, USA
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11
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Mi A, Hu Q, Liu Y, Zhao Y, Shen F, Lan J, Lv K, Wang B, Gao R, Yu X. Hepatoprotective efficacy and interventional mechanism of the panaxadiol saponin component in high-fat diet-induced NAFLD mice. Food Funct 2024; 15:794-808. [PMID: 38131276 DOI: 10.1039/d3fo03572g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
Dietary administration is a promising strategy for intervention in non-alcoholic fatty liver disease (NAFLD). Our research team has identified a biologically active component, the panaxadiol saponin component (PDS-C) isolated from total saponins of panax ginseng, which has various pharmacological and therapeutic functions. However, the efficacy and mechanism of PDS-C in NAFLD were unclear. This study aimed to elucidate the hepatoprotective effects and underlying action mechanism of PDS-C in NAFLD. Mice were fed a high-fat diet (HFD) for 8 weeks to induce NAFLD and treated with PDS-C and metformin as the positive control for 12 weeks. PDS-C significantly alleviated liver function, hepatic steatosis and blood lipid levels, reduced oxidative stress and inflammation in NAFLD mice. In vitro, PDS-C has been shown to reduce lipotoxicity and ROS levels while enhancing the antioxidant and anti-inflammatory capabilities in HepG2 cells induced by palmitic acid. PDS-C induced AMPK phosphorylation, leading to upregulation of the Nrf2/HO1 pathway expression and downregulation of the NFκB protein level. Furthermore, our observations indicate that PDS-C supplementation improves insulin resistance and glucose homeostasis in NAFLD mice, although its efficacy is not as pronounced as metformin. In conclusion, these results demonstrate the hepatoprotective efficacy of PDS-C in NAFLD and provide potential opportunities for developing functional products containing PDS-C.
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Affiliation(s)
- Ai Mi
- Institute of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Qinxue Hu
- Institute of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Ying Liu
- Institute of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Yanna Zhao
- Institute of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Fenglin Shen
- Institute of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Jinjian Lan
- Institute of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Keren Lv
- Institute of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Bolin Wang
- Institute of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Ruilan Gao
- Institute of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Xiaoling Yu
- Institute of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
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12
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Zachou M, Flevari P, Nasiri-Ansari N, Varytimiadis C, Kalaitzakis E, Kassi E, Androutsakos T. The role of anti-diabetic drugs in NAFLD. Have we found the Holy Grail? A narrative review. Eur J Clin Pharmacol 2024; 80:127-150. [PMID: 37938366 PMCID: PMC10781828 DOI: 10.1007/s00228-023-03586-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 10/19/2023] [Indexed: 11/09/2023]
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease, affecting 30% of the global population. NAFLD prevalence is particularly high in obese individuals and patients with type 2 diabetes mellitus (T2DM). NAFLD ranges from simple fat deposition in the liver to necroinflammation and fibrosis (non-alcoholic steatohepatitis (NASH)), NASH-cirrhosis, and/or hepatocellular carcinoma. Insulin resistance plays a key role in NAFLD pathogenesis, alongside dysregulation of adipocytes, mitochondrial dysfunction, genetic factors, and changes in gut microbiota. Since insulin resistance is also a major predisposing factor of T2DM, the administration of anti-diabetic drugs for the management of NAFLD seems reasonable. METHODS In this review we provide the NAFLD-associated mechanisms of action of some of the most widely used anti-diabetic drugs, namely metformin, pioglitazone, sodium-glucose transport protein-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor analogs (GLP1 RAs), and dipeptyl-peptidase-4 inhibitors (DPP4i) and present available data regarding their use in patients with NAFLD, with and without T2DM. RESULTS Both metformin and DPP4i have shown rather contradictory results, while pioglitazone seems to benefit patients with NASH and is thus the only drug approved for NASH with concomitant significant liver fibrosis by all major liver societies. On the other hand, SGLT2i and GLP1 RAs seem to be beneficiary in patients with NAFLD, showing both remarkable results, with SGLT2i proving to be more efficient in the only head-to-head study so far. CONCLUSION In patients with NAFLD and diabetes, pioglitazone, GLP1 RAs, and SGLT2i seem to be logical treatment options. Larger studies are needed before these drugs can be recommended for non-diabetic individuals.
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Affiliation(s)
- Maria Zachou
- Gastroenterology Department, "Sismanoglio" General Hospital, 151 26, Athens, Greece
| | - Pagona Flevari
- Expertise Center in Rare Haematological Diseases-Haemoglobinopathies, "Laiko" General Hospital, 115 27, Athens, Greece
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | | | - Evangelos Kalaitzakis
- Department of Gastroenterology, University Hospital of Heraklion, University of Crete, 715 00, Heraklion, Greece
| | - Eva Kassi
- Unit of Molecular Endocrinology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, "Laiko" Hospital, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27, Athens, Greece.
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Beiriger J, Chauhan K, Khan A, Shahzad T, Parra NS, Zhang P, Chen S, Nguyen A, Yan B, Bruckbauer J, Halegoua-DeMarzio D. Advancements in Understanding and Treating NAFLD: A Comprehensive Review of Metabolic-Associated Fatty Liver Disease and Emerging Therapies. LIVERS 2023; 3:637-656. [DOI: 10.3390/livers3040042] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
This paper provides a comprehensive review of the current understanding of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH), focusing on key factors influencing its pathogenesis and emerging therapeutic strategies. This review highlights the growing prevalence of NAFLD and NASH, emphasizing their multifactorial nature. The manuscript identifies various contributors to NAFLD development, including genetic, dietary, and environmental factors, while examining the intricate interplay between these factors and their impact on hepatic lipid metabolism, inflammation, and insulin resistance. Genetic predisposition, dietary fat intake, and excessive fructose consumption are discussed as significant contributors to NAFLD progression. The article emphasizes the lack of a single therapeutic approach and underscores the need for combination strategies. Lifestyle interventions, particularly weight loss through diet and exercise, remain crucial, while pharmacological options like GLP-1 receptor agonists, obeticholic acid, lanifibranor, and resmetirom show promise but require further validation. Bariatric surgery and emerging endoscopic procedures offer potential in eligible patients. In sum, this article underscores the complexity of NAFLD and NASH, addresses key factors influencing pathogenesis, and discusses emerging therapies advocating for a multifaceted approach to this increasingly prevalent and clinically relevant condition.
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Affiliation(s)
- Jacob Beiriger
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Kashyap Chauhan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Adnan Khan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Taha Shahzad
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Natalia Salinas Parra
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Peter Zhang
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Sarah Chen
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Anh Nguyen
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Brian Yan
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - John Bruckbauer
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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14
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Liu Y, Ruan B, Jiang H, Le S, Liu Y, Ao X, Huang Y, Shi X, Xue R, Fu X, Wang S. The Weight-loss Effect of GLP-1RAs Glucagon-Like Peptide-1 Receptor Agonists in Non-diabetic Individuals with Overweight or Obesity: A Systematic Review with Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials. Am J Clin Nutr 2023; 118:614-626. [PMID: 37661106 DOI: 10.1016/j.ajcnut.2023.04.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/07/2023] [Accepted: 04/12/2023] [Indexed: 09/05/2023] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new drugs for the treatment of obesity. OBJECTIVE To assess the weight-loss effects of GLP-1RAs in the treatment of patients with overweight or obesity without diabetes. METHODS This is a systematic review with meta-analysis and trial sequential analysis. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched from their inception to January 1, 2022. Eligible trials report on outcomes including body weight (BW), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), or total body fat (TBF). Mean differences (MDs) and standardized mean differences (SMDs) were summarized using random-effects models. RESULTS Forty-one trials involving 15,135 participants were included. Compared with controls, GLP-1RAs significantly reduced BW (MD -5.319 kg, 95% CI: -6.465, -4.174), BMI (MD -2.373 kg/m2, 95% CI: -2.821, -1.924), WC (MD -4.302 cm, CI:-5.185 to -3.419), WHR (MD -0.011, CI -0.015 to -0.007), but not TBF (MD -0.320%, CI -1.420 to -0.780). Trial sequential analysis (TSA) supported conclusive evidence of the effects of GLP-1RAs on BW, BMI, and WC for weight loss. GLP-1RAs had nonlinear dose-response relationships with weight loss. Extensive sensitivity analyses demonstrated the robustness of the results, though the GRADE certainty of the evidence ranged from high to very low. High to moderate GRADE certainty of evidence suggested semaglutide as the most effective GLP-1RA agent, with the best efficacy and low to moderate risk of adverse effects. CONCLUSIONS The present study provides conclusive evidence for the effect of GLP-1RAs on weight loss in a nonlinear dose-response manner in patients with obesity or overweight without diabetes. In terms of changes in BW, BMI, and WC, there is firm evidence for the overall weight-loss effects of GLP-1RAs. Of the GLP-1RAs, semaglutide might be the most effective agent.
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Affiliation(s)
- Yupeng Liu
- Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Binye Ruan
- Department of Nutrition and Food Hygiene, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Huinan Jiang
- Department of Nutrition and Food Hygiene, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Siyu Le
- Department of Nutrition and Food Hygiene, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Yi Liu
- Department of Nutrition and Food Hygiene, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Xuemei Ao
- Department of Nutrition and Food Hygiene, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Yufeng Huang
- Department of Nutrition and Food Hygiene, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Xudong Shi
- Department of Nutrition and Food Hygiene, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Ru Xue
- Department of Nutrition and Food Hygiene, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Xiaoyi Fu
- Department of Nutrition and Food Hygiene, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
| | - Shuran Wang
- Department of Nutrition and Food Hygiene, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
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15
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Kongmalai T, Srinonprasert V, Anothaisintawee T, Kongmalai P, McKay G, Attia J, Thakkinstian A. New anti-diabetic agents for the treatment of non-alcoholic fatty liver disease: a systematic review and network meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne) 2023; 14:1182037. [PMID: 37441498 PMCID: PMC10335801 DOI: 10.3389/fendo.2023.1182037] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/14/2023] [Indexed: 07/15/2023] Open
Abstract
Objectives This network meta-analysis aims to compare the efficacy and safety of new anti-diabetic medications for the treatment of non-alcoholic fatty liver disease (NAFLD). Materials and methods PubMed and Scopus were searched from inception to 27th March 2022 to identify all randomized controlled trials (RCTs) in NAFLD patients. Outcomes included reductions in intrahepatic steatosis (IHS) and liver enzyme levels. The efficacy and safety of DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, and other therapies were indirectly compared using a NMA approach. Unstandardized mean difference (USMD) with 95% confidence intervals (CI) were calculated. Results 2,252 patients from 31 RCTs were included. "Add-on" GLP-1 agonists with standard of care (SoC) treatment showed significantly reduced IHS compared to SoC alone [USMD (95%CI) -3.93% (-6.54%, -1.33%)]. Surface under the cumulative ranking curve (SUCRA) identified GLP-1 receptor agonists with the highest probability to reduce IHS (SUCRA 88.5%), followed by DPP-4 inhibitors (SUCRA 69.6%) and pioglitazone (SUCRA 62.2%). "Add-on" GLP-1 receptor agonists were also the most effective treatment for reducing liver enzyme levels; AST [USMD of -5.04 (-8.46, -1.62)], ALT [USMD of -9.84 (-16.84, -2.85)] and GGT [USMD of -15.53 (-22.09, -8.97)] compared to SoC alone. However, GLP-1 agonists were most likely to be associated with an adverse event compared to other interventions. Conclusion GLP-1 agonists may represent the most promising anti-diabetic treatment to reduce hepatic steatosis and liver enzyme activity in T2DM and NAFLD patients. Nevertheless, longer-term studies are required to determine whether this delays progression of liver cirrhosis in patients with NAFLD and T2DM. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42021259336.1.
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Affiliation(s)
- Tanawan Kongmalai
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Varalak Srinonprasert
- Siriraj Health Policy Unit, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Division of Geriatric Medicine, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Mahidol University Health Technology Assessment Graduate Program, Mahidol University, Bangkok, Thailand
| | - Thunyarat Anothaisintawee
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Pinkawas Kongmalai
- Department of Orthopaedics, Faculty of Medicine, Srinakharinwirot University, Ongkharak, Nakhon Nayok, Thailand
| | - Gareth McKay
- Centre for Public Health, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University, Belfast, Ireland
| | - John Attia
- School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia
| | - Ammarin Thakkinstian
- Mahidol University Health Technology Assessment Graduate Program, Mahidol University, Bangkok, Thailand
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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16
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Wibawa IDN, Mariadi IK, Somayana G, Krisnawardani Kumbara CIY, Sindhughosa DA. Diabetes and fatty liver: Involvement of incretin and its benefit for fatty liver management. World J Diabetes 2023; 14:549-559. [PMID: 37273247 PMCID: PMC10237000 DOI: 10.4239/wjd.v14.i5.549] [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: 12/03/2022] [Revised: 02/02/2023] [Accepted: 04/11/2023] [Indexed: 05/15/2023] Open
Abstract
Fatty liver disease is defined as liver condition characterized by hepatic steatosis, closely related to pathological conditions in type 2 diabetes and obesity. The high prevalence of fatty liver disease in obese patients with type 2 diabetes reached 70%, reflecting the importance of these conditions with fatty liver. Although the exact pathological mechanism of fatty liver disease, specifically non-alcoholic fatty liver disease (NAFLD) remains not completely revealed, insulin resistance is suggested as the major mechanism that bridged the development of NAFLD. Indeed, loss of the incretin effect leads to insulin resistance. Since incretin is closely related to insulin resistance and the resistance of insulin associated with the development of fatty liver disease, this pathway suggested a potential me-chanism that explains the association between type 2 diabetes and NAFLD. Furthermore, recent studies indicated that NAFLD is associated with impaired glucagon-like peptide-1, resulting in decreased incretin effect. Nevertheless, improving the incretin effect becomes a reasonable approach to manage fatty liver disease. This review elucidates the involvement of incretin in fatty liver disease and recent studies of incretin as the management for fatty liver disease.
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Affiliation(s)
- I Dewa Nyoman Wibawa
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | - I Ketut Mariadi
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | - Gde Somayana
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | | | - Dwijo Anargha Sindhughosa
- Internal Medicine Resident, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
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17
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Ong J, Alswat K, Hamid S, El-Kassas M. Nonalcoholic Fatty Liver Disease in Asia, Africa, and Middle East Region. Clin Liver Dis 2023; 27:287-299. [PMID: 37024208 DOI: 10.1016/j.cld.2023.01.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. The global prevalence of the disease varies according to the geographical region. Despite having distinct models for the western patterns of NAFLD, Africa, Asia, and the Middle East regions exhibited varying prevalence rates of NAFLD. The disease burden is anticipated to significantly increase in these areas. Furthermore, with an increase in NAFLD risk factors in these regions, the disease burden is expected to rise even more. Policies at the regional and international levels are required to address such growing burden of NAFLD consequences.
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Affiliation(s)
- Janus Ong
- College of Medicine, University of the Philippines, Manila, Philippines
| | - Khalid Alswat
- Department of Medicine, Liver Disease Research Centre, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Saeed Hamid
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Ain Helwan, Cairo 11795, Egypt.
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18
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Walmsley R, Sumithran P. Current and emerging medications for the management of obesity in adults. Med J Aust 2023; 218:276-283. [PMID: 36934408 PMCID: PMC10952877 DOI: 10.5694/mja2.51871] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/31/2023] [Accepted: 02/06/2023] [Indexed: 03/20/2023]
Affiliation(s)
| | - Priya Sumithran
- University of MelbourneMelbourneVIC
- Austin HealthMelbourneVIC
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19
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Gu Y, Sun L, Zhang W, Kong T, Zhou R, He Y, Deng C, Yang L, Kong J, Chen Y, Shi J, Hu Y. Comparative efficacy of 5 sodium-glucose cotransporter protein-2 (SGLT-2) inhibitor and 4 glucagon-like peptide-1 (GLP-1) receptor agonist drugs in non-alcoholic fatty liver disease: A GRADE-assessed systematic review and network meta-analysis of randomized controlled trials. Front Pharmacol 2023; 14:1102792. [PMID: 36992825 PMCID: PMC10040540 DOI: 10.3389/fphar.2023.1102792] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 02/28/2023] [Indexed: 03/14/2023] Open
Abstract
Background: The relative efficacy of 5 sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and 4 glucagon-like peptide-1 (GLP-1) receptor agonists for non-alcoholic fatty liver disease (NAFLD) therapy has not been sufficiently investigated. Methods: Randomized controlled trials (RCTs) in which patients with NAFLD were treated with SGLT-2 inhibitors or GLP-1 receptor agonists were included. Primary outcomes were improvements in liver enzymes and liver fat parameters, while secondary outcomes included anthropometric measures, blood lipids and glycemic parameters. The frequentist method was used to perform a network meta-analysis. Evidence certainty was assessed using the grading of recommendations assessment, development, and evaluation (GRADE). Results: The criteria were satisfied by 37 RCTs with 9 interventions (5 SGLT-2 inhibitors and 4 GLP-1 receptor agonists). Based on high certainty evidence, in patients with NAFLD (or comorbid with type 2 diabetes), semaglutide could lower alanine aminotransferase as well as aspartate aminotransferase, γ-glutamyl transferase, controlled attenuation parameter, liver stiffness measurement, body weight, systolic blood pressure, triglycerides, high-density lipoprotein-cholesterol, glycosylated hemoglobin. Liraglutide could lower alanine aminotransferase as well as subcutaneous adipose tissue, body mass index, fasting blood glucose, glycosylated hemoglobin, glucose and homeostasis model assessment, while dapagliflozin could lower alanine aminotransferase as well as body weight, fasting blood glucose, postprandial blood glucose, glycosylated hemoglobin, glucose and homeostasis model assessment. Conclusion: Semaglutide, liraglutide, and dapagliflozin all have a certain effect on NAFLD (or comorbid with type 2 diabetes) based on high confidence evidence from indirect comparisons, and semaglutide appears to have a therapeutic advantage over the other included medicines. Head-to-head studies are needed to provide more confidence in clinical decision-making.
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Affiliation(s)
- Yunpeng Gu
- School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Lei Sun
- Medical School, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Wei Zhang
- School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Tingting Kong
- School of Nursing, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Run Zhou
- School of Nursing, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yining He
- Medical School, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Chaohua Deng
- Medical School, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Luping Yang
- Medical School, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jianing Kong
- Medical School, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yutong Chen
- School of Nursing, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Junping Shi
- The Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yanli Hu
- School of Nursing, Guangzhou Medical University, Guangzhou, Guangdong, China
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20
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A Bidirectional Association Between Obstructive Sleep Apnea and Metabolic-Associated Fatty Liver Disease. Endocrinol Metab Clin North Am 2023. [PMID: 37495341 DOI: 10.1016/j.ecl.2023.01.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2023]
Abstract
Obesity is considered a twentieth-century epidemic and is a growing concern among health professionals. Obesity and its complications contribute to multiple chronic illnesses, such as type 2 diabetes (T2D), metabolic syndrome, obstructive sleep apnea (OSA), malignancy, and cardiovascular and liver diseases. In the last two decades, a bidirectional association between OSA and metabolic-associated fatty liver disease (MAFLD), independent of obesity, has been established. Both conditions have similar risk factors and metabolic comorbidities that may imply a common disease pathway. This review compiles the evidence and delineates the relationship between OSA and MAFLD from a clinical and diagnostic aspect.
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21
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Sheng W, Ji G, Zhang L. Management of non-alcoholic fatty liver disease patients with sleep apnea syndrome. World J Gastroenterol 2022; 28:6099-6108. [PMID: 36483151 PMCID: PMC9724487 DOI: 10.3748/wjg.v28.i43.6099] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/20/2022] [Accepted: 11/06/2022] [Indexed: 11/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is strongly associated with sleep apnea syndrome (SAS). Many NAFLD patients have SAS, and obstructive sleep apnea hypopnea syndrome is also considered to be an independent risk factor for NAFLD, as it contributes to the progression of NAFLD via oxidative stress, lipid peroxidation, inflammation, and insulin resistance. This review aims to provide some recommendations for the management of NAFLD patients with SAS, including diet, exercise, weight loss, and continuous positive airway pressure. This review also highlights the importance of effective strategies in NAFLD prevention and treatment.
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Affiliation(s)
- Wei Sheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Li Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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22
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Barron M, Hayes H, Fernando DG, Geurts AM, Kindel TL. Sleeve Gastrectomy Improves High-Fat Diet-Associated Hepatic Steatosis Independent of the Glucagon-like-Petpide-1 Receptor in Rats. J Gastrointest Surg 2022; 26:1607-1618. [PMID: 35618993 PMCID: PMC9444920 DOI: 10.1007/s11605-022-05361-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 05/14/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is increased after sleeve gastrectomy (SG). Rat and clinical studies support, while mouse studies refute, a role for GLP-1R signaling after SG. Therefore, we developed a global GLP-1R knockout (KO) rat to test the hypothesis that a functional GLP-1R is critical to induce weight loss and metabolic disease improvement after SG. METHODOLOGY A 4 bp deletion was created in exon 2 of the GLP-1R gene on a Lewis strain background to create a global GLP-1R KO rat. KO and Lewis rats were placed on a high-fat or low-fat diet and phenotyped followed by SG or Sham surgery and assessed for the effect of GLP-1R KO on surgical and metabolic efficacy. RESULTS Loss of the GLP-1R created an obesity-prone rodent without changes in energy expenditure. Both male and female KO rats had significantly greater insulin concentrations after an oral glucose gavage, augmented by a high-fat diet, compared to Lewis rats despite similar glucose concentrations. GLP-1R KO caused hepatomegaly and increased triglyceride deposition compared to Lewis rats. We found no difference between SG GLP-1R KO and Lewis groups when considering efficacy on body weight, glucose tolerance, and a robustly preserved improvement in fatty liver disease. CONCLUSIONS Loss of the GLP-1R in rats resulted in increased adiposity, insulin resistance, and severe steatosis. A functional GLP-1R is not critical to the metabolic efficacy of SG in Lewis rats, similar to mouse studies, but importantly including steatosis, supporting a GLP-1R-independent mechanism for the improvement in fatty liver disease after SG.
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Affiliation(s)
- Matthew Barron
- Department of Surgery, Division of Gastrointestinal and Minimally Invasive Surgery, Medical College of Wisconsin, 8900 W. Doyne Avenue, Milwaukee, WI, 53226, USA
| | - Hailey Hayes
- Medical College of Wisconsin School of Medicine, Medical College of Wisconsin, 8900 W. Doyne Avenue, Milwaukee, WI, 53226, USA
| | - Deemantha G Fernando
- Department of Surgery, Division of Gastrointestinal and Minimally Invasive Surgery, Medical College of Wisconsin, 8900 W. Doyne Avenue, Milwaukee, WI, 53226, USA
| | - Aron M Geurts
- Department of Physiology, Medical College of Wisconsin, 8900 W. Doyne Avenue, Milwaukee, WI, 53226, USA
| | - Tammy L Kindel
- Department of Surgery, Division of Gastrointestinal and Minimally Invasive Surgery, Medical College of Wisconsin, 8900 W. Doyne Avenue, Milwaukee, WI, 53226, USA.
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23
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Ding C, Tang Y, Zhu W, Huang P, Lian P, Ran J, Huang X. Sodium-glucose cotransporter protein-2 inhibitors and glucagon-like peptide-1 receptor agonists versus thiazolidinediones for non-alcoholic fatty liver disease: A network meta-analysis. Acta Diabetol 2022; 59:519-533. [PMID: 34988690 DOI: 10.1007/s00592-021-01830-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023]
Abstract
AIMS Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disorders worldwide. Some hypoglycemic drugs can improve NAFLD. However, it is unclear which of these types of hypoglycemic drugs are more effective for NAFLD. Therefore, we conducted a network meta-analysis to determine the effect of thiazolidinediones (TZDs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists on NAFLD patients. METHODS A literature search of PubMed, EMBASE, the Cochrane Library, and Medline was conducted, and the literature from database inception up to April 30, 2021 was obtained. Liver function tests, lipid profiles, body mass index (BMI) and glycemic parameters were obtained from randomized controlled trials. Weighted mean differences (WMDs), relative risks and 95% confidence intervals (CIs) were calculated for continuous outcomes, and the I2 statistic was used to evaluate the heterogeneity of the studies. RESULTS In total, 22 trials, including 1361 patients, were selected. In direct meta-analysis, GLP-1 receptor agonists were superior to TZDs in decreasing alanine aminotransferase (WMD, -0.40, 95% CI: -0.60 to -0.20), γ-glutamyl transferase (WMD, -5.00, 95% CI: -6.47 to -3.53), BMI (WMD, -4.10, 95%CI: -6.55 to -1.65) and triglycerides (WMD, - 0.50, 95% CI: -0.68 to -0.32). Based on Bayesian network meta-analysis, the effect of SGLT-2 inhibitors on weight loss was superior to that of TZDs (WMD, -1.80, 95%CI: -3.30 to -0.41). CONCLUSIONS GLP-1 receptor agonists and SGLT-2 inhibitors improved liver enzymes, BMI, blood lipid, blood glucose and insulin resistance in NAFLD patients.
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Affiliation(s)
- Chen Ding
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yaxin Tang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Wenqiang Zhu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Piaopiao Huang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Pingan Lian
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Juanli Ran
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Xiansheng Huang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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24
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Koo BK, Lim S. Metabolic Syndrome and Metabolic Dysfunction‐Associated Fatty Liver Disease. CLINICAL OBESITY IN ADULTS AND CHILDREN 2022:159-177. [DOI: 10.1002/9781119695257.ch13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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25
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Sun Q, Xin X, An Z, Hu Y, Feng Q. Therapeutic Potential of Natural Plants Against Non-Alcoholic Fatty Liver Disease: Targeting the Interplay Between Gut Microbiota and Bile Acids. Front Cell Infect Microbiol 2022; 12:854879. [PMID: 35356532 PMCID: PMC8959594 DOI: 10.3389/fcimb.2022.854879] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/16/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) remains a common disease with a significant health and economic burden worldwide. The gut microbiota (GM) and bile acids (BAs), which play important roles in the gut-liver axis, have been confirmed to jointly participate in the development of NAFLD. GM not only regulate bile acids’ synthesis, transport, and reabsorption by regulating other metabolites (such as trimetlyl amine oxide, butyrate), but also regulate dehydrogenation, dehydroxylation and desulfurization of bile acids. Meanwhile, disordered bile acids influence the gut microbiota mainly through promoting the bacterial death and lowering the microbial diversity. Although weight loss and lifestyle changes are effective in the treatment of NAFLD, the acceptability and compliance of patients are poor. Recently, increasing natural plants and their active ingredients have been proved to alleviate NAFLD by modulating the joint action of gut microbiota and bile acids, and considered to be promising potential candidates. In this review, we discuss the efficacy of natural plants in treating NAFLD in the context of their regulation of the complex interplay between the gut microbiota and bile acids, the crosstalk of which has been shown to significantly promote the progression of NAFLD. Herein, we summarize the prior work on this topic and further suggest future research directions in the field.
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Affiliation(s)
- QinMei Sun
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xin Xin
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - ZiMing An
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - YiYang Hu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, China
- *Correspondence: YiYang Hu, ; Qin Feng,
| | - Qin Feng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, China
- *Correspondence: YiYang Hu, ; Qin Feng,
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26
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Brodosi L, Petta S, Petroni ML, Marchesini G, Morelli MC. Management of Diabetes in Candidates for Liver Transplantation and in Transplant Recipients. Transplantation 2022; 106:462-478. [PMID: 34172646 PMCID: PMC9904447 DOI: 10.1097/tp.0000000000003867] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 11/25/2022]
Abstract
Diabetes is common in patients waitlisted for liver transplantation because of end-stage liver disease or hepatocellular cancer as well as in posttransplant phase (posttransplantation diabetes mellitus). In both conditions, the presence of diabetes severely affects disease burden and long-term clinical outcomes; careful monitoring and appropriate treatment are pivotal to reduce cardiovascular events and graft and recipients' death. We thoroughly reviewed the epidemiology of diabetes in the transplant setting and the different therapeutic options, from lifestyle intervention to antidiabetic drug use-including the most recent drug classes available-and to the inclusion of bariatric surgery in the treatment cascade. In waitlisted patients, the old paradigm that insulin should be the treatment of choice in the presence of severe liver dysfunction is no longer valid; novel antidiabetic agents may provide adequate glucose control without the risk of hypoglycemia, also offering cardiovascular protection. The same evidence applies to the posttransplant phase, where oral or injectable noninsulin agents should be considered to treat patients to target, limiting the impact of disease on daily living, without interaction with immunosuppressive regimens. The increasing prevalence of liver disease of metabolic origin (nonalcoholic fatty liver) among liver transplant candidates, also having a higher risk of noncirrhotic hepatocellular cancer, is likely to accelerate the acceptance of new drugs and invasive procedures, as suggested by international guidelines. Intensive lifestyle intervention programs remain however mandatory, both before and after transplantation. Achievement of adequate control is mandatory to increase candidacy, to prevent delisting, and to improve long-term outcomes.
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Affiliation(s)
- Lucia Brodosi
- IRCCS – Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, Alma Mater University, Bologna, Italy
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Maria L. Petroni
- IRCCS – Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, Alma Mater University, Bologna, Italy
| | - Giulio Marchesini
- IRCCS – Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, Alma Mater University, Bologna, Italy
| | - Maria C. Morelli
- IRCCS – Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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27
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Pulipati VP, Pannain S. Pharmacotherapy of obesity in complex diseases. Clin Obes 2022; 12:e12497. [PMID: 34889046 DOI: 10.1111/cob.12497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 10/09/2021] [Accepted: 10/26/2021] [Indexed: 12/16/2022]
Abstract
More than 40% of adults in the United States suffer from obesity. Obesity is inextricably linked to many chronic illnesses like type-2 diabetes mellitus, hypertension, hyperlipidemia, heart disease, sleep apnea, stroke, and cancers. When used in combination with lifestyle modifications, pharmacotherapy has a vital role in treating obesity and improves short-term and long-term outcomes. A growing number of physicians are now interested in obesity medicine, and many of them are seeking guidance on how to treat complex patients with co-morbidities. This review provides a practical guide to the use of anti-obesity medications across various obesity-related comorbidities. It provides a general review of the currently approved anti-obesity medications and effective combinations. It discusses the highlights of the major trials and recent studies assessing the benefits of anti-obesity medications in comorbid conditions such as type-2 diabetes mellitus, psychiatric disorders, cardiovascular diseases, hypertension, renal diseases, and liver diseases. This review briefly examines the aspects of recognizing and addressing iatrogenic weight gain; discusses the precautions and prescribing considerations of anti-obesity medications, including side effects and possible dose adjustments in various comorbid conditions; and provides an expert opinion on an individualized choice of the best anti-obesity medication.
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Affiliation(s)
| | - Silvana Pannain
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Chicago, Chicago, Illinois, USA
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28
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Laurindo LF, Barbalho SM, Guiguer EL, da Silva Soares de Souza M, de Souza GA, Fidalgo TM, Araújo AC, de Souza Gonzaga HF, de Bortoli Teixeira D, de Oliveira Silva Ullmann T, Sloan KP, Sloan LA. GLP-1a: Going beyond Traditional Use. Int J Mol Sci 2022; 23:739. [PMID: 35054924 PMCID: PMC8775408 DOI: 10.3390/ijms23020739] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 02/07/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a human incretin hormone derived from the proglucagon molecule. GLP-1 receptor agonists are frequently used to treat type 2 diabetes mellitus and obesity. However, the hormone affects the liver, pancreas, brain, fat cells, heart, and gastrointestinal tract. The objective of this study was to perform a systematic review on the use of GLP-1 other than in treating diabetes. PubMed, Cochrane, and Embase were searched, and the PRISMA guidelines were followed. Nineteen clinical studies were selected. The results showed that GLP-1 agonists can benefit defined off-medication motor scores in Parkinson's Disease and improve emotional well-being. In Alzheimer's disease, GLP-1 analogs can improve the brain's glucose metabolism by improving glucose transport across the blood-brain barrier. In depression, the analogs can improve quality of life and depression scales. GLP-1 analogs can also have a role in treating chemical dependency, inhibiting dopaminergic release in the brain's reward centers, decreasing withdrawal effects and relapses. These medications can also improve lipotoxicity by reducing visceral adiposity and decreasing liver fat deposition, reducing insulin resistance and the development of non-alcoholic fatty liver diseases. The adverse effects are primarily gastrointestinal. Therefore, GLP-1 analogs can benefit other conditions besides traditional diabetes and obesity uses.
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Affiliation(s)
- Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marília 17500-000, SP, Brazil
| | - Elen Landgraf Guiguer
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marília 17500-000, SP, Brazil
| | - Maricelma da Silva Soares de Souza
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Gabriela Achete de Souza
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Thiago Marques Fidalgo
- Department of Psychiatry, Federal University of São Paulo, R. Sena Madureira 04021-001, SP, Brazil;
| | - Adriano Cressoni Araújo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
| | - Heron F. de Souza Gonzaga
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
| | - Daniel de Bortoli Teixeira
- Postgraduate Program in Animal Health, Production and Environment, University of Marilia, Marília 17525-902, SP, Brazil;
| | - Thais de Oliveira Silva Ullmann
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Katia Portero Sloan
- Texas Institute for Kidney and Endocrine Disorders, Lufkin, TX 75904, USA; (K.P.S.); (L.A.S.)
| | - Lance Alan Sloan
- Texas Institute for Kidney and Endocrine Disorders, Lufkin, TX 75904, USA; (K.P.S.); (L.A.S.)
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
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Rezaei S, Tabrizi R, Nowrouzi-Sohrabi P, Jalali M, Atkin SL, Al-Rasadi K, Jamialahmadi T, Sahebkar A. GLP-1 Receptor Agonist Effects on Lipid and Liver Profiles in Patients with Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis. Can J Gastroenterol Hepatol 2021; 2021:8936865. [PMID: 34805029 PMCID: PMC8604595 DOI: 10.1155/2021/8936865] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/04/2021] [Accepted: 10/25/2021] [Indexed: 12/13/2022] Open
Abstract
AIMS This meta-analysis of randomized placebo-controlled clinical trials assessed the effect of glucose-like peptide-1-receptor agonists (GLP-1RA) on the lipid profile and liver enzymes in patients with nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS Randomized placebo-controlled trials investigating GLP-1RA on the lipid profile and liver enzymes in patients with NAFLD were searched in PubMed-Medline, Scopus, Web of Science, and Google Scholar databases (from inception to January 2020). A random-effects model and a generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted. Weighted random-effects meta-regression was performed on potential confounders on lipid profile and liver enzyme concentrations. RESULTS 12 studies were identified (12 GLP-1RA arms; 677 subjects) that showed treatment with GLP-1RA reduced alanine transaminase (ALT) concentrations (WMD = -10.14, 95%CI = [-15.84, -0.44], P < 0.001), gamma-glutamyl transferase (GGT) (WMD = -11.53, 95%CI = [-15.21,-7.85], P < 0.001), and alaline phosphatase (ALP) (WMD = -8.29, 95%CI = [-11.34, -5.24], P < 0.001). Aspartate aminotransferase (AST) (WMD = -2.95, 95% CI = [-7.26, 1.37], P=0.18) was unchanged. GLP-1 therapy did not alter triglycerides (TC) (WMD = -7.07, 95%CI = [-17.51, 3.37], P=0.18), total cholesterol (TC) (WMD = -1.17 (-5.25, 2.91), P=0.57), high-density lipoprotein (HDL-C) (WMD = 0.97, 95%CI = [-1.63, 3.58], P=0.46), or low-density lipoprotein (LDL-C) (WMD = -1.67, 95%CI = [-10.08, 6.74], P=0.69) in comparison with controls. CONCLUSION The results of this meta-analysis suggest that GLP-1RA treatment significantly reduces liver enzymes in patients with NAFLD, but the lipid profile is unaffected.
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Affiliation(s)
- Shahla Rezaei
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Clinical Nutrition, School of Health & Nutrition, Shiraz University of Medical Sciences, Shiraz, Iran
- Nutrition Research Center, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Tabrizi
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Peyman Nowrouzi-Sohrabi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Jalali
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Nutrition Research Center, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | | | - Tannaz Jamialahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Francque SM, Marchesini G, Kautz A, Walmsley M, Dorner R, Lazarus JV, Zelber-Sagi S, Hallsworth K, Busetto L, Frühbeck G, Dicker D, Woodward E, Korenjak M, Willemse J, Koek GH, Vinker S, Ungan M, Mendive JM, Lionis C. Non-alcoholic fatty liver disease: A patient guideline. JHEP Rep 2021; 3:100322. [PMID: 34693236 PMCID: PMC8514420 DOI: 10.1016/j.jhepr.2021.100322] [Citation(s) in RCA: 137] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 06/08/2021] [Indexed: 02/07/2023] Open
Abstract
This patient guideline is intended for all patients at risk of or living with non-alcoholic fatty liver disease (NAFLD). NAFLD is the most frequent chronic liver disease worldwide and comes with a high disease burden. Yet, there is a lot of unawareness. Furthermore, many aspects of the disease are still to be unravelled, which has an important impact on the information that is given (or not) to patients. Its management requires a close interaction between patients and their many healthcare providers. It is important for patients to develop a full understanding of NAFLD in order to enable them to take an active role in their disease management. This guide summarises the current knowledge relevant to NAFLD and its management. It has been developed by patients, patient representatives, clinicians and scientists and is based on current scientific recommendations, intended to support patients in making informed decisions.
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Key Words
- ALD, alcohol-related or alcoholic liver disease
- ASH, alcoholic steatohepatitis
- BMI, body mass index
- CAP, controlled attenuation parameter
- CT, computed tomography
- CVD, cardiovascular disease
- EASD, European Association for the Study of Diabetes
- EASL, European Association for the Study of the Liver
- EASO, European Association for the Study of Obesity
- FIB-4, fibrosis-4 index
- FXR, farnesoid X receptor
- GLP-1 RAs, glucagon-like receptor 1 agonists
- GP, general practitioner
- HCC, hepatocellular carcinoma
- HDL, high-density lipoprotein
- LDL, low-density lipoproteins
- MRE, magnetic resonance elastography
- MRI, magnetic resonance imaging
- NAFL, non-alcoholic fatty liver
- NAFLD, non-alcoholic fatty liver disease
- NASH CRN, NASH Clinical Research Network
- NASH, non-alcoholic steatohepatitis
- NIT, non-invasive test
- SMART, specific, measurable, achievable, relevant, timely
- T1D, type 1 diabetes
- T2D, type 2 diabetes
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Affiliation(s)
- Sven M. Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
- Laboratory of Experimental Medicine and Paediatrics (LEMP), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- InflaMed Centre of Excellence, University of Antwerp, Antwerp, Belgium
- Translational Sciences in Inflammation and Immunology, University of Antwerp, Antwerp, Belgium
| | - Giulio Marchesini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
- Department of Medical and Surgical Sciences, “Alma Mater” University, Bologna, Italy
| | | | | | | | - Jeffrey V. Lazarus
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Spain
| | - Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
- Department of Gastroenterology and Hepatology, The Tel-Aviv Medical Center, Tel-Aviv, Israel
| | - Kate Hallsworth
- Newcastle NIHR Biomedical Research Centre, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Luca Busetto
- Department of Medicine, University of Padova, Italy
- European Association for the Study of Obesity
| | - Gema Frühbeck
- Department of Endocrinology & Nutrition, University of Navarra Clinic, IdiSNA, CIBEROBN, Pamplona, Spain
- European Association for the Study of Obesity
| | - Dror Dicker
- Department of Internal Medicine, Rabin Medical Center Hasharon Hospital, Tikva, Israel
- European Association for the Study of Obesity
| | | | | | | | - Gerardus H. Koek
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Shlomo Vinker
- Department of Family Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- World Organization of Family Doctors (WONCA)
- European General Practice Research Network (EGPRN)
- Israel Association of Family Physicians, Israel
- Leumit Health Services, Tel Aviv, Israel
| | | | - Juan M. Mendive
- Training Unit of Family Medicine, Catalan Institute of Health, Barcelona, Spain
- European Society for Primary Care Gastroenterology
| | - Christos Lionis
- European Society for Primary Care Gastroenterology
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, Heraklion, Greece
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Osorio-Conles Ó, Vega-Beyhart A, Ibarzabal A, Balibrea JM, Graupera I, Rimola J, Vidal J, de Hollanda A. A Distinctive NAFLD Signature in Adipose Tissue from Women with Severe Obesity. Int J Mol Sci 2021; 22:ijms221910541. [PMID: 34638880 PMCID: PMC8509058 DOI: 10.3390/ijms221910541] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/20/2021] [Accepted: 09/24/2021] [Indexed: 02/06/2023] Open
Abstract
Development and severity of nonalcoholic fatty liver disease (NAFLD) have been linked to obesity and white adipose tissue (WAT) dysfunction plays a key role in this relation. We compared the main features of subcutaneous (SAT) and visceral WAT (VAT) tissue dysfunction in 48 obese women without (Ob) and with NAFLD (Ob-NAFLD) undergoing bariatric surgery and matched for age, BMI and T2D status. Fat cell area, adipocyte size distribution, the degree of histological fibrosis and the mRNA expression of adipokines and genes implicated in inflammation, adipogenesis, angiogenesis, metabolism and extracellular matrix remodeling were measured by RT-qPCR in both fat depots. Ob-NAFLD group showed higher TG and lower HDL circulating levels, increased VAT fat cell area and similar WAT fibrosis in comparison with Ob group. A sPLS-DA was performed in order to identify the set of genes that better characterize the presence of NAFLD. Finally, we build a multinomial logistic model including seven genes that explained 100% of the variance in NAFLD and correctly predicted 100% of cases. Our data support the existence of distinctive NAFLD signatures in WAT from women with severe obesity. A better understanding of these pathways may help in future strategies for the prevention and treatment of NAFLD.
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Affiliation(s)
- Óscar Osorio-Conles
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló Street 149, 08036 Barcelona, Spain;
- Correspondence: ; Tel.: +34-932-275-707 (ext. 2910)
| | - Arturo Vega-Beyhart
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.V.-B.); (J.R.); (A.d.H.)
| | - Ainitze Ibarzabal
- Gastrointestinal Surgery Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; (A.I.); (J.M.B.)
| | - José María Balibrea
- Gastrointestinal Surgery Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; (A.I.); (J.M.B.)
| | - Isabel Graupera
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Hospital Clínic de Barcelona, 08036 Barcelona, Spain;
| | - Jordi Rimola
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.V.-B.); (J.R.); (A.d.H.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Hospital Clínic de Barcelona, 08036 Barcelona, Spain;
| | - Josep Vidal
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló Street 149, 08036 Barcelona, Spain;
- Obesity Unit, Endocrinology and Nutrition Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
| | - Ana de Hollanda
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.V.-B.); (J.R.); (A.d.H.)
- Obesity Unit, Endocrinology and Nutrition Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red Fisiopatologia de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
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Perakakis N, Stefanakis K, Feigh M, Veidal SS, Mantzoros CS. Elafibranor and liraglutide improve differentially liver health and metabolism in a mouse model of non-alcoholic steatohepatitis. Liver Int 2021; 41:1853-1866. [PMID: 33788377 DOI: 10.1111/liv.14888] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 03/16/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS This study aimed to assess and compare the effects of the GLP-1 analog liraglutide and the PPARα/δ agonist elafibranor on liver histology and their impact on hepatic lipidome, metabolome, Kupffer and hepatic stellate cell activation in a model of advanced non-alcoholic fatty liver disease (NAFLD). METHODS Male C57BL/6JRj mice with biopsy-confirmed hepatosteatosis and fibrosis induced by 36-week Amylin liver NASH (AMLN) diet (high-fat, fructose and cholesterol) were randomized to receive for 12 weeks: (a) liraglutide (0.4 mg/kg/day s.c.), (b) elafibranor (30 mg/kg/day p.o.) and (c) vehicle. Metabolic status, liver pathology, markers of inflammation, Kupffer and stellate cell activation, and metabolomics/lipidomics were assessed at study completion. RESULTS Elafibranor and liraglutide improved weight, insulin sensitivity, glucose homeostasis and NAFLD activity score (pre-to-post biopsy). Elafibranor had a profound effect on hepatic lipidome, demonstrated by reductions in glycerides, increases in phospholipids, and by beneficial regulation of mediators of fatty acid oxidation, inflammation and oxidative stress. Liraglutide had a major impact on inflammatory and fibrogenic markers of Kupffer and hepatic stellate cell activation (Galectin-3, Collagen type I alpha 1, alpha-smooth muscle actin). Liraglutide exerted beneficial effects on bile acid and carbohydrate metabolism, demonstrated by restorations of the concentrations of bile acids, glycogen metabolism by-products and pentoses, thus facilitating glycogen utilization turnover and nucleic acid formation. CONCLUSIONS Liraglutide and elafibranor robustly but through different pathways improve overall metabolic health and liver status in NAFLD. These data indicate important differences in the respective mechanisms of action and support the notion for their evaluation as combination therapies in the future.
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Affiliation(s)
- Nikolaos Perakakis
- Department of Medicine, Boston VA Healthcare System and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Konstantinos Stefanakis
- Department of Medicine, Boston VA Healthcare System and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | | | | | - Christos S Mantzoros
- Department of Medicine, Boston VA Healthcare System and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Jianping W, Xuelian Z, Anjiang W, Haiying X. Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Metabolic Associated Fatty Liver Disease: A Systematic Review and Meta-analysis. J Clin Gastroenterol 2021; 55:586-593. [PMID: 34039937 DOI: 10.1097/mcg.0000000000001556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Clinical trials examining the therapeutic benefits of glucagon-like peptide-1 receptor agonists (GLP-1RA) on patients with metabolic associated fatty liver disease (MAFLD) have reported inconsistent results. The aim of this meta-analysis was to verify the role of GLP-1RA in the treatment of MAFLD patients. MATERIALS AND METHODS We searched PubMed, Embase, Medline, and the Cochrane Library for randomized controlled trials published that compared GLP-1RA with the control treatment in patients with MAFLD till to July 30, 2020. The effects of GLP-1RA on liver histology, body mass index, waist circumference (WC), aspartate aminotransferase, total cholesterol, triglycerides (TG), low-density lipoprotein and high-density lipoprotein were evaluated. RESULTS Thirteen trials involving 704 patients were included in the meta-analysis. Compared with the control treatment, GLP-1RA treatment induced a greater resolution of steatohepatitis [RR=2.87; 95% confidence interval (CI): 0.89 to 9.23], delayed the progression of liver fibrosis (RR=3.83, 95% CI: 0.91 to 16.07) and reduced liver fat deposition (MD: -1.40; 95% CI: -2.75 to -0.05). In addition, it reduced the body mass index (MD: -1.15; 95% CI: -2.26 to -0.04), WC (MD: -3.33; 95% CI: -6.31 to -0.35) and improved serum aspartate aminotransferase (MD: -3.04; 95% CI: -5.93 to -0.16) and total cholesterol (MD: -0.20; 95% CI: -0.28 to -0.13). CONCLUSION GLP-1RA improves liver steatosis and fibrosis. It is also beneficial to metabolic syndrome as it reduces BMI, WC, and hyperlipidemia.
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Affiliation(s)
- Wu Jianping
- Departments of Gastroenterology
- Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zheng Xuelian
- Pharmacy, The First Affiliated Hospital of Nanchang University
| | | | - Xiao Haiying
- Department of Gastroenterology, Nanchang Third Hospital, Nanchang, Jiangxi
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Fan S, Shi X, Yao J, Zhong M, Feng P. The efficacy of glucagon-like peptide 1 receptor agonists in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 112:627-635. [PMID: 32496108 DOI: 10.17235/reed.2020.6392/2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND non-alcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome and is highly prevalent all over the world. New drugs are urgently needed for the treatment of NAFLD. The aim of this meta-analysis was to assess the efficacy of glucagon-like peptide 1 receptor agonists (GLP-1RAs) in patients with NAFLD. METHOD English language publications in the PubMed, Cochrane Library, Embase and Web of Science databases were searched from inception to October 2019. All randomized controlled trials (RCTs) of GLP-1RAs treatment for NAFLD were considered. Standardized mean difference (SMD) with 95 % confidence intervals (CIs) were pooled using the fixed-effects or random-effects model. RESULTS six RCTs, involving 406 patients, were included in the analysis. A significant improvement was found in liver fat fraction (LFF) (SMD = -0.33, 95 % CI, -0.64 to -0.03, p = 0.034), body mass index (BMI) (SMD: -0.89, 95 % CI: -1.60 to -0.19, p = 0.012) and adiponectin (SMD: 0.66, 95 % CI: 0.37 to 0.95, p = 0.000) with GLP-1RAs treatment. There were no significant differences in serum alanine aminotransferase (ALT) (SMD: -0.52, 95 % CI: -1.04 to 0.01, p = 0.054) and aspartate transaminase (AST) (SMD: -0.20, 95 % CI: -0.54 to 0.15, p = 0.134) reduction between the GLP-1RAs and control groups. In the subgroup analysis, exenatide was associated with an improvement in serum ALT (SMD = -1.25, 95 % CI: -1.68 to -0.82, p = 0.000) and AST (SMD = -0.62, 95 % CI: -1.16 to -0.08, p = 0.024). Liraglutide was associated with a reduction in BMI (SMD = -0.44, 95 % CI: -0.77 to -0.11, p = 0.010) and an increase in adiponectin (SMD = -0.33, 95 % CI, -0.64 to -0.03, p = 0.034). CONCLUSION our study suggested that GLP-1RAs may improve LFF, BMI and adiponectin in patients with NAFLD. Furthermore, the potential efficacy to treat NAFLD was also shown. More high-quality RCTs are needed to validate our findings.
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Affiliation(s)
- Simin Fan
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Xiaoyan Shi
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Jia Yao
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Min Zhong
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
| | - Peimin Feng
- Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, China
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Tchang BG, Tarazi MS, Aras M, Shukla AP. An update on pharmacotherapeutic strategies for obesity. Expert Opin Pharmacother 2021; 22:1305-1318. [PMID: 33599159 DOI: 10.1080/14656566.2021.1888927] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The field of obesity medicine has evolved over the past several years. With greater understanding of its pathophysiology, obesity is regarded more as a chronic disease than a lifestyle choice. However, it is difficult to treat with lifestyle modifications alone due to the complexity of energy dysregulation. The availability of anti-obesity medications (AOMs) provides practitioners with more effective and sustainable ways to treat obesity. AREAS COVERED This review briefly summarizes the weight loss efficacy of AOMs currently approved for long-term use and expands on their therapeutic potential beyond weight loss with particular focus on obesity-related comorbidities. Possible future AOMs with promising phase II or III data are also covered. EXPERT OPINION The future of obesity medicine is in recognizing obesity as a disease and approaching treatment similarly to other chronic diseases. Lifestyle interventions alone are rarely sufficient in the treatment of chronic diseases, and pharmacotherapy often plays a necessary role in changing the course of disease. Current AOMs have proven efficacy in weight management and emerging therapeutic uses in obesity-related comorbidities, such as non-alcoholic fatty liver disease, obstructive sleep apnea, and polycystic ovarian syndrome. The development of new AOMs will further empower providers to deliver effective obesity management.
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Affiliation(s)
- Beverly G Tchang
- Assistant Professor of Clinical Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Mohamad Sirri Tarazi
- Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Fellow of Obesity Medicine, New York, NY, USA
| | - Mohini Aras
- Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Fellow of Obesity Medicine, New York, NY, USA
| | - Alpana P Shukla
- Assistant Professor of Research New York, Weill Cornell Medicine, New York, NY, USA
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Dai Y, He H, Li S, Yang L, Wang X, Liu Z, An Z. Comparison of the Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Metabolic Associated Fatty Liver Disease: Updated Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2021; 11:622589. [PMID: 33664710 PMCID: PMC7924308 DOI: 10.3389/fendo.2020.622589] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/28/2020] [Indexed: 02/05/2023] Open
Abstract
AIMS Metabolic associated fatty liver disease (MAFLD) is the most common cause of chronic liver disease and is a major health and economic burden in society. New drugs are urgently needed to treat MAFLD. This systematic review and meta-analysis was conducted to evaluate the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with MAFLD. METHOD We searched PubMed, Embase, Cochrane Library database, and Web of Science since 1977. We selected all randomized controlled trials which met the inclusion and exclusion criteria and evaluated the quality of evidence. A random-effects meta-analysis was performed to assess all the primary and second outcomes. RESULTS Eight randomized controlled trials, including 396 patients, of which 265 patients had type 2 diabetes mellitus, met the inclusion criteria. Compared with the placebo or active agents group, the GLP-RA group showed a significant reduction in the liver fat content [weight mean difference (WMD) -3.17%, 95%CI -5.30 to -1.03, P < 0.0001], body weight (WMD -4.58 kg, 95%CI -8.07 to -1.10, P = 0.010), waist circumference (WMD -3.74 cm, 95%CI -6.73 to -0.74, P = 0.010), alanine aminotransferase (WMD -10.73 U/L, 95%CI -20.94 to -0.52, P = 0.04), γ- glutamyl transferase (WMD -12.25 U/L,95% -18.85 to -5.66, P = 0.0003, with I²=23%), fasting blood glucose (MD, -0.36 mmol/L; 95%CI, -0.69 to -0.03, P = 0.030), and hemoglobin A1c (WMD -0.36%, 95%CI -0.52 to -0.19, P < 0.0001). The reported adverse events were gastrointestinal complications with no serious adverse events, and most symptoms were relieved within 1-2 weeks after dose titration. CONCLUSION GLP-RAs may improve liver injury and metabolic disorder in patients with MAFLD, regardless of the presence of type 2 diabetes mellitus. The benefits of GLP-RAs treatment outweigh the adverse effects of drugs in patients with MAFLD.
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Affiliation(s)
- Yuzhao Dai
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - He He
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Lidan Yang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xia Wang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zhi Liu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenmei An
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
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Koutoukidis DA, Koshiaris C, Henry JA, Noreik M, Morris E, Manoharan I, Tudor K, Bodenham E, Dunnigan A, Jebb SA, Aveyard P. The effect of the magnitude of weight loss on non-alcoholic fatty liver disease: A systematic review and meta-analysis. Metabolism 2021; 115:154455. [PMID: 33259835 DOI: 10.1016/j.metabol.2020.154455] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/27/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Trials show that weight loss interventions improve biomarkers of non-alcoholic fatty liver disease (NAFLD), but it is unclear if a dose-response relationship exists. OBJECTIVE We aimed to quantify the dose-response relationship between the magnitude of weight loss and improvements in NAFLD. METHODS Nine databases and trial registries were searched until October 2020. Single-arm, non-randomized comparative, or randomized trials of weight loss interventions (behavioral weight loss programs [BWLPs], pharmacotherapy, or bariatric surgery) in people with NAFLD were eligible for inclusion if they reported an association between changes in weight and changes in blood, radiological, or histological biomarkers of liver disease. The review followed Cochrane methods and the risk of bias was assessed using the Newcastle-Ottawa scale. Pooled unstandardized b coefficients were calculated using random-effect meta-analyses. RESULTS Forty-three studies (BWMPs: 26, pharmacotherapy: 9, surgery: 8) with 2809 participants were included. The median follow-up was 6 (interquartile range: 6) months. The direction of effect was generally consistent but the estimates imprecise. Every 1 kg of weight lost was associated with a 0.83-unit (95% CI: 0.53 to 1.14, p < 0.0001, I2 = 92%, n = 18) reduction in alanine aminotransferase (U/L), a 0.56-unit (95% CI: 0.32 to 0.79, p < 0.0001, I2 = 68%, n = 11) reduction in aspartate transaminase (U/L), and a 0.77 percentage point (95% CI: 0.51 to 1.03, p < 0.0001, I2 = 72%, n = 11) reduction in steatosis assessed by radiology or histology. There was evidence of a dose-response relationship with liver inflammation, ballooning, and resolution of NAFLD or NASH, but limited evidence of a dose-response relationship with fibrosis or NAFLD activity score. On average, the risk of bias for selection and outcome was medium and low, respectively. CONCLUSION Clinically significant improvements in NAFLD are achieved even with modest weight loss, but greater weight loss is associated with greater improvements. Embedding support for formal weight loss programs as part of the care pathway for the treatment of NAFLD could reduce the burden of disease. PROSPERO CRD42018093676.
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Affiliation(s)
- Dimitrios A Koutoukidis
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; NIHR Oxford Biomedical Research Centre, Oxford OX2 6GG, UK.
| | - Constantinos Koshiaris
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK.
| | - John A Henry
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK.
| | - Michaela Noreik
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; NIHR Oxford Biomedical Research Centre, Oxford OX2 6GG, UK.
| | - Elizabeth Morris
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK.
| | - Indrani Manoharan
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK.
| | - Kate Tudor
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; NIHR Oxford Biomedical Research Centre, Oxford OX2 6GG, UK.
| | - Emma Bodenham
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK
| | - Anna Dunnigan
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK
| | - Susan A Jebb
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; NIHR Oxford Biomedical Research Centre, Oxford OX2 6GG, UK.
| | - Paul Aveyard
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; NIHR Oxford Biomedical Research Centre, Oxford OX2 6GG, UK.
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Maor Y, Ergaz D, Malnick SDH, Melzer E, Neuman MG. Liraglutide-Induced Hepatotoxicity. Biomedicines 2021; 9:106. [PMID: 33498980 PMCID: PMC7911918 DOI: 10.3390/biomedicines9020106] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 12/21/2022] Open
Abstract
A 52-year-old woman with a BMI of 31.2 kg/m2 was treated with the glucagon-like peptide 1 (GLP-1) agonist liraglutide as part of her weight-reduction program. Following this, she developed an idiosyncratic drug-related liver injury (IDILI). Advances in noninvasive techniques enabled this diagnosis to be established. By employing easily quantifiable methods based on serum biomarkers, we could explore a wide variety of endpoints in assessing personalized DILI. In addition, we can test endpoints that are associated with the drug's mechanism of action. Personalized medicine and therapeutic pharmacovigilance of incretin-based hypoglycemic agents are needed to ensure the safety of patients.
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Affiliation(s)
- Yaakov Maor
- Kaplan Medical Center, Institute of Gastroenterology and Hepatology, Hebrew University Medical School of Jerusalem, Rehovot 71600, Israel; (Y.M.); (E.M.)
| | - David Ergaz
- Internal Medicine Day-Care Kaplan Medical Center, Hebrew University Medical School of Jerusalem, Rehovot 71600, Israel;
| | | | - Ehud Melzer
- Kaplan Medical Center, Institute of Gastroenterology and Hepatology, Hebrew University Medical School of Jerusalem, Rehovot 71600, Israel; (Y.M.); (E.M.)
| | - Manuela G. Neuman
- In Vitro Drug Safety and Biotechnology and Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5G 1L5, Canada
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Abstract
Non-alcoholic fatty liver disease is a very common medical condition, driven by a combination of genetic and lifestyle factors, ultimately producing a severe chronic liver disease and increased cardiovascular risk. Most people are asymptomatic for a long time, and their daily life is unaffected, leading to difficulty in identifying and managing people who slowly progress to non-alcoholic steatohepatitis (NASH), NASH-cirrhosis, and eventually hepatocellular carcinoma. Despite advances in the understanding of pathogenic mechanisms and the identification of liver fibrosis as the strongest factor in predicting disease progression, no specific treatments have been approved by regulatory agencies. Outside controlled trials, treatment is generally limited to lifestyle intervention aimed at weight loss. Pioglitazone remains the drug of choice to reduce progression of fibrosis in people with diabetes, although it is often used off-label in the absence of diabetes. Vitamin E is mainly used in children and may be considered in adults without diabetes. Several drugs are under investigation according to the agreed targets of reduced NASH activity without worsening of fibrosis or improving fibrosis without worsening of NASH. Anti-inflammatory, anti-fibrotic agents and metabolism modulators have been tested in either phase III or phase IIb randomized controlled trials; a few failed, and others have produced marginally positive results, but only a few are being tested in extension studies. The development of non-invasive, easily repeatable surrogate biomarkers and/or imaging tools is crucial to facilitate clinical studies and limit liver biopsy.
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Affiliation(s)
- Maria Letizia Petroni
- Department of Medical and Surgical Sciences, "Alma Mater" University, IRCCS Policlinico Sant'Orsola, Bologna, Italy
| | - Lucia Brodosi
- Department of Medical and Surgical Sciences, "Alma Mater" University, IRCCS Policlinico Sant'Orsola, Bologna, Italy
| | - Elisabetta Bugianesi
- Division of Gastro-Hepatology, University of Turin, Turin, Italy
- Contributed equally
| | - Giulio Marchesini
- Department of Medical and Surgical Sciences, "Alma Mater" University, IRCCS Policlinico Sant'Orsola, Bologna, Italy
- Contributed equally
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Fu ZD, Cai XL, Yang WJ, Zhao MM, Li R, Li YF. Novel glucose-lowering drugs for non-alcoholic fatty liver disease. World J Diabetes 2021; 12:84-97. [PMID: 33520110 PMCID: PMC7807257 DOI: 10.4239/wjd.v12.i1.84] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/22/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The efficacy of novel glucose-lowering drugs in treating non-alcoholic fatty liver disease (NAFLD) is unknown.
AIM To evaluate the efficacy of glucose-lowering drugs dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors in treating NAFLD and to perform a comparison between these treatments.
METHODS Electronic databases were systematically searched. The inclusion criteria were: Randomized controlled trials comparing DPP-4 inhibitors, GLP-1 RAs, or SGLT2 inhibitors against placebo or other active glucose-lowering drugs in NAFLD patients, with outcomes of changes in liver enzyme [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] from baseline.
RESULTS Nineteen studies were finally included in this meta-analysis. Compared with placebo or other active glucose-lowering drug treatment, treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors all led to a significant decrease in ALT change and AST change from baseline. The difference between the DPP-4 inhibitor and SGLT2 inhibitor groups in ALT change was significant in favor of DPP-4 inhibitor treatment (P < 0.05). The trends of reduction in magnetic resonance imaging proton density fat fraction and visceral fat area changes were also observed in all the novel glucose-lowering agent treatment groups.
CONCLUSION Treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors resulted in improvements in serum ALT and AST levels and body fat composition, indicating a beneficial effect in improving liver injury and reducing liver fat in NAFLD patients.
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Affiliation(s)
- Zuo-Di Fu
- Department of Endocrinology, Beijing Friendship Hospital Pinggu Campus, Beijing 101200, China
| | - Xiao-Ling Cai
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Wen-Jia Yang
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Ming-Ming Zhao
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100079, China
| | - Ran Li
- Sport Science School, Beijing Sport University, Beijing 100078, China
| | - Yu-Feng Li
- Department of Endocrinology, Beijing Friendship Hospital Pinggu Campus, Capital Medical University, Beijing 101200, China
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The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet. Transl Res 2021; 227:75-88. [PMID: 32711187 DOI: 10.1016/j.trsl.2020.07.008] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 07/14/2020] [Accepted: 07/16/2020] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disorder related to type 2 diabetes (T2D). The disease can evolve toward nonalcoholic steatohepatitis (NASH), a state of hepatic inflammation and fibrosis. There is presently no drug that effectively improves and/or prevents NAFLD/NASH/fibrosis. GLP-1 receptor agonists (GLP-1Ra) are effective in treating T2D. As with the endogenous gut incretins, GLP-1Ra potentiate glucose-induced insulin secretion. In addition, GLP-1Ra limit food intake and weight gain, additional beneficial properties in the context of obesity/insulin-resistance. Nevertheless, these pleiotropic effects of GLP-1Ra complicate the elucidation of their direct action on the liver. In the present study, we used the classical methionine-choline deficient (MCD) dietary model to investigate the potential direct hepatic actions of the GLP-1Ra liraglutide. A 4-week infusion of liraglutide (570 µg/kg/day) did not impact body weight, fat accretion or glycemic control in MCD-diet fed mice, confirming the suitability of this model for avoiding confounding factors. Liraglutide treatment did not prevent lipid deposition in the liver of MCD-fed mice but limited the accumulation of C16 and C24-ceramide/sphingomyelin species. In addition, liraglutide treatment alleviated hepatic inflammation (in particular accumulation of M1 pro-inflammatory macrophages) and initiation of fibrosis. Liraglutide also influenced the composition of gut microbiota induced by the MCD-diet. This included recovery of a normal Bacteroides proportion and, among the Erysipelotrichaceae family, a shift between Allobaculum and Turicibacter genera. In conclusion, liraglutide prevents accumulation of C16 and C24-ceramides/sphingomyelins species, inflammation and initiation of fibrosis in MCD-diet-fed mice liver, suggesting beneficial hepatic actions independent of weight loss and global hepatic steatosis.
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Zhu Y, Xu J, Zhang D, Mu X, Shi Y, Chen S, Wu Z, Li S. Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2021; 12:769069. [PMID: 34956080 PMCID: PMC8696030 DOI: 10.3389/fendo.2021.769069] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/23/2021] [Indexed: 02/05/2023] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) is increasing and there is an urgent need for new treatment strategy to prevent progression of hepatic steatosis and fibrosis. We have performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of hepatic steatosis and fibrosis in patients with T2DM and NAFLD. The PubMed, Web of Science, Scopus, Embase and Cochrane Central Register of Controlled Trials databases were searched for articles that met the eligibility criteria to explore the efficacy and safety of GLP-1RAs in patients with T2DM and NAFLD. We assessed pooled data using a random/fixed-effects model according to the I2 and p-values. Eight trials that included a total of 468 participants were eligible for inclusion in the review. For primary outcomes, administration of GLP-1RAs significantly decreased the content of intrahepatic adipose (IHA)[p=0.007, weight mean difference (WMD) -3.01, 95% confidence interval (CI) -4.75, -1.28], subcutaneous adipose tissue (SAT) (p<0.00001,WMD -28.53,95%CI -68.09,-26.31), and visceral adipose tissue (VAT) (p<0.0001,WMD -29.05,95%CI -42.90,-15.9). For secondary outcomes, GLP-1RAs produced a significant decrease in levels of alanine aminotransferase(ALT)(p=0.02, WMD -3.82, 95%CI -7.04, -0.60), aspartate aminotransferase (AST) (p=0.03, WMD -2.4, 95%CI -4.55,-0.25, I2 = 49%), body weight (p<0.00001,WMD -3.48,95%CI -4.58,-2.37), body mass index (p<0.00001,WMD -1.07,95%CI -1.35,-0.78), circumference waist (p=0.0002,WMD -3.87, 95%CI -5.88, -1.86) fasting blood glucose (p=0.02, WMD -0.35, 95%CI -0.06, -0.05), HbA1c (p<0.00001,WMD -0.39,95%CI -0.56,-0.22), HoMA-IR(p=0.005, WMD-1.51, 95%CI-0.87,-0.16), total cholesterol (p=0.0008, WMD -0.31, 95%CI -0.48, 0.13) and triglycerides (p=0.0008, WMD -0.27, 95%CI -0.43,-0.11) in comparison with the control regimens. The main adverse events associated with GLP-1RAs included mild-to-moderate gastrointestinal discomfort and nonsense hypoglycemia that resolved within a few weeks. GLP-1RAs were an effective treatment that improved intrahepatic visceral and subcutaneous adipose tissue, inflammatory markers, the anthropometric profiles and some metabolic indices in patients with T2DM and NAFLD, GLP-1RAs could be considered for use in these if there are no contraindications. Further studies are needed to understand the direct and indirect effects of GLP-1RAs on NAFLD and the potential mechanism via which they prevent its progression. Systematic Review Registration: PROSPERO, identifier CRD42021265806.
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Makri E, Kita M, Goulas A, Papaioannidou P, Efstathiadou ZA, Adamidou F, Polyzos SA. Comparative effectiveness of glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors on noninvasive indices of hepatic steatosis and fibrosis in patients with type 2 diabetes mellitus. Diabetes Metab Syndr 2020; 14:1913-1919. [PMID: 33011499 DOI: 10.1016/j.dsx.2020.09.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/14/2020] [Accepted: 09/24/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes mellitus (T2DM). There is currently no approved treatment for NAFLD. The main aim was the evaluation of the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) vs. dipeptidyl peptidase-4 inhibitor (DPP-4i) treatment on noninvasive indices of hepatic steatosis and fibrosis in patients with T2DM. METHODS In this retrospective study, three noninvasive indices of hepatic steatosis [HSI, NAFLD ridge score, and triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) ratio] and five of fibrosis (APRI, FIB-4, NAFLD fibrosis score, BAAT and BARD) were calculated before and after (6-18 months) the addition of a DPP-4i (n = 152) or a GLP-1 RA (n = 37) in patients with T2DM. RESULTS Regarding steatosis indices, NAFLD ridge score was significantly decreased in the GLP-1 RA group (baseline: 0.90 ± 0.34, follow-up: 0.67 ± 0.24; p = 0.001), but not in the DPP-4i group (p = 0.25); the difference for group∗time interaction was significant (p = 0.02). HSI showed a trend between groups, being significantly different at baseline and follow-up (p < 0.001) with no significant difference in group∗time interaction. Indices of fibrosis were not essentially changed within or between groups. CONCLUSIONS NAFLD ridge score was significantly decreased after the addition of GLP-1 RA in patients with T2DM. This study warrants further prospective clinical trials.
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Affiliation(s)
- Evangelia Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Marina Kita
- Department of Endocrinology, Ippokration General Hospital, Thessaloniki, Greece
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paraskevi Papaioannidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Zoe A Efstathiadou
- Department of Endocrinology, Ippokration General Hospital, Thessaloniki, Greece
| | - Fotini Adamidou
- Department of Endocrinology, Ippokration General Hospital, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Teshome G, Ambachew S, Fasil A, Abebe M. Efficacy of Glucagon-Like Peptide-1 Analogs in Nonalcoholic Fatty Liver Disease: A Systematic Review. Hepat Med 2020; 12:139-151. [PMID: 33061687 PMCID: PMC7522518 DOI: 10.2147/hmer.s265631] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/01/2020] [Indexed: 12/13/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is believed to be the hepatic manifestation of the metabolic syndrome. Many treatment approaches have been suggested so far, and several types of studies have been done to find treatment for NAFLD, the most promising of which are those with lifestyle interventions. Objective The aim of this systematic review was to evaluate the efficacy and safety of glucagon-like peptide-1 (GLP-1) analogs on the management of NAFLD. Methods The PubMed, MEDLINE, and Cochrane Central Library were searched to identify randomized controlled trials, single arm trials, and cohorts that compared GLP-1 analogs with a control treatment or baseline values with respect to efficacy and safety in patients living with NAFLD. The key outcomes were a change in serum transaminase, resolution of disease status measured by imaging or histological techniques, improvement in insulin resistance, and reduction in body weight. Results Initial searching retrieved 201 peer-reviewed articles and abstracts. Ten studies met all inclusion criteria. The review included a total of 590 participants with NAFLD. Following administration of GLP-1 analogs, a decrease in serum transaminases, improvement in liver histology and insulin resistance, and a reduction in body weight were observed. Compared with baseline, body weight, alanine aminotransferase, aspartate aminotransferase, and gamma glutamyltransferase were decreased by 5.5%, 59.5%, 52.8%, and 44.8%, respectively, due to GLP-1. Likewise, a reduction of proinflammatory cytokines and fibrosis markers and an enhancement of protective adipokines were observed in some of the studies. Conclusion The decrease in a key biochemical marker of liver injury following treatment with GLP-1 analogs, as well as improvements in imaging and histology, suggests that these agents may be effective alternatives for managing NAFLD. Registration CRD42018087262.
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Affiliation(s)
- Getnet Teshome
- University of Gondar Comprehensive Specialized Hospital, University of Gondar, Gondar, Amhara, Ethiopia
| | - Sintayehu Ambachew
- Department of Clinical Chemistry, University of Gondar, Gondar, Amhara, Ethiopia
| | - Alebachew Fasil
- Department of Clinical Chemistry, University of Gondar, Gondar, Amhara, Ethiopia
| | - Molla Abebe
- Department of Clinical Chemistry, University of Gondar, Gondar, Amhara, Ethiopia
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Khan MS, Fonarow GC, McGuire DK, Hernandez AF, Vaduganathan M, Rosenstock J, Handelsman Y, Verma S, Anker SD, McMurray JJ, Kosiborod MN, Butler J. Glucagon-Like Peptide 1 Receptor Agonists and Heart Failure. Circulation 2020; 142:1205-1218. [PMID: 32955939 DOI: 10.1161/circulationaha.120.045888] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
With worsening epidemiological trends for both the incidence and prevalence of type 2 diabetes mellitus (T2DM) and heart failure (HF) worldwide, it is critical to implement optimal prevention and treatment strategies for patients with these comorbidities, either alone or concomitantly. Several guidelines and consensus statements have recommended glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter type 2 inhibitors as add-ons to lifestyle interventions with or without metformin in those at high atherosclerotic cardiovascular disease risk. However, these recommendations are either silent about HF or fail to differentiate between the prevention of HF in those at risk versus the treatment of individuals with manifest HF. Furthermore, these documents do not differentiate among those with different HF phenotypes. This distinction, even though important, may not be critical for sodium-glucose cotransporter type 2 inhibitors in view of the consistent data for benefit for both atherosclerotic cardiovascular disease– and HF-related outcomes that have emerged from the regulatory-mandated cardiovascular outcome trials for all sodium-glucose cotransporter type 2 inhibitors and the recent DAPA-HF trial (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction)demonstrating the benefit of dapagliflozin on HF-related outcomes in patients with HF with reduced ejection fraction with or without T2DM. However, the distinction may be crucial for glucagon-like peptide-1 receptor agonists and other antihyperglycemic agents. Indeed, in several of the new statements, glucagon-like peptide-1 receptor agonists are suggested treatment not only for patients with T2DM and atherosclerotic cardiovascular disease, but also in those with manifest HF, despite a lack of evidence for the latter recommendation. Although glucagon-like peptide-1 receptor agonists may be appropriate to use in patients at risk for HF, mechanistic insights and observations from randomized trials suggest no clear benefit on HF-related outcomes and even uncertainty regarding the safety in those with HF with reduced ejection fraction. Conversely, theoretical rationales suggest that these agents may benefit patients with HF with preserved ejection fraction. Considering that millions of patients with T2DM have HF, these concerns have public health implications that necessitate the thoughtful use of these therapies. Achieving this aim will require dedicated trials with these drugs in both patients who have HF with reduced ejection fraction and HF with preserved ejection fraction with T2DM to assess their efficacy, safety, and risk-benefit profile.
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Affiliation(s)
| | - Gregg C. Fonarow
- Division of Cardiology, Ronald Reagan-UCLA Medical Center, Los Angeles, CA (G.C.F.)
| | - Darren K. McGuire
- Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (D.K.M.)
| | | | | | | | | | - Subodh Verma
- Department of Surgery, University of Toronto, Canada (S.V.)
| | - Stefan D. Anker
- Department of Cardiology (CVK); and Berlin Institute of Health Center for Regenerative Therapies (BCRT); German Centre for Cardiovascular Research (DZHK) partner site Berlin; Charité Universitätsmedizin (S.D.A.)
| | - John J.V. McMurray
- British Heart Foundation Cardiovascular Research Center, University of Glasgow, United Kingdom (J.J.V.M.)
| | - Mikhail N. Kosiborod
- Saint Luke’s Mid America Heart Institute, Kansas City, MO (M.N.K.)
- University of Missouri–Kansas City (M.N.K.)
- The George Institute for Global Health, Sydney, Australia (M.N.K.)
- University of New South Wales, Sydney, Australia (M.N.K.)
| | - Javed Butler
- Department of Medicine, University of Mississippi, Jackson (J.B.)
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Jalili R, Somi MH, Hosseinifard H, Salehnia F, Ghojazadeh M, Makhdami N, Shirmohammadi M. The Evaluation of Effective Drugs for the Treatment of Non-Alcoholic Fatty Liver Disease: A Systematic Review and Network Meta-Analysis. Adv Pharm Bull 2020; 10:542-555. [PMID: 33072533 PMCID: PMC7539311 DOI: 10.34172/apb.2020.065] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/07/2020] [Accepted: 01/27/2020] [Indexed: 12/13/2022] Open
Abstract
Purpose: Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis are two forms of fatty liver disease with benign and malignant nature, respectively. These two conditions can cause an increased risk of liver cirrhosis and hepatocellular carcinoma. Given the importance and high prevalence of NAFLD, it is necessary to investigate the results of different studies in related scope to provide a clarity guarantee of effectiveness. Therefore, this systematic review and meta-analysis aim to study the efficacy of various medications used in the treatment of NAFLD. Methods: A systematic search of medical databases identified 1963 articles. After exclusion of duplicated articles and those which did not meet our inclusion criteria, eta-analysis was performed on 84 articles. Serum levels of alanine aminotransferase (ALT), aspartate amino transferase (AST) were set as primary outcomes and body mass index (BMI), hepatic steatosis, and NAFLD activity score (NAS) were determined as secondary outcomes. Results: Based on the P-score of the therapeutic effects on the non-alcoholic steatohepatitis (NASH), we observed the highest efficacy for atorvastatin, tryptophan, orlistat, omega-3 and obeticholic acid for reduction of ALT, AST, BMI, steatosis and NAS respectively. Conclusion: This meta-analysis showed that atorvastatin. life-style modification, weight loss, and BMI reduction had a remarkable effect on NAFLD-patients by decreasing aminotransferases.
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Affiliation(s)
- Ramin Jalili
- Department of Internal Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Hosseinifard
- Research Center for Evidence Based Medicine (RCEBM), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Salehnia
- Research Center for Evidence Based Medicine (RCEBM), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Ghojazadeh
- Research Center for Evidence Based Medicine (RCEBM), Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Masoud Shirmohammadi
- Department of Gastroenterology, Liver, and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Gut-Pancreas-Liver Axis as a Target for Treatment of NAFLD/NASH. Int J Mol Sci 2020; 21:ijms21165820. [PMID: 32823659 PMCID: PMC7461212 DOI: 10.3390/ijms21165820] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/04/2020] [Accepted: 08/09/2020] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide. Due to its association with obesity and diabetes and the fall in hepatitis C virus morbidity, cirrhosis in NAFLD is becoming the most frequent indication to liver transplantation, but the pathogenetic mechanisms are still not completely understood. The so-called gut-liver axis has gained enormous interest when data showed that its alteration can lead to NAFLD development and might favor the occurrence of non-alcoholic steatohepatitis (NASH). Moreover, several therapeutic approaches targeting the gut-pancreas-liver axis, e.g., incretins, showed promising results in NASH treatment. In this review, we describe the role of incretin hormones in NAFLD/NASH pathogenesis and treatment and how metagenomic/metabolomic alterations in the gut microbiota can lead to NASH in the presence of gut barrier modifications favoring the passage of bacteria or bacterial products in the portal circulation, i.e., bacterial translocation.
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Escalada San Martín FJ. What may GLP1 receptor agonists contribute to the treatment of patients with non-alcoholic fatty liver disease? REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 112:587-589. [PMID: 32686456 DOI: 10.17235/reed.2020.7148/2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) poses a challenge to health services both in developed and developing countries, with a significant increase in incidence and prevalence that is related to the currently increased prevalence of obesity. Besides an acknowledged higher risk for advanced liver disease (cirrhosis, hepatocellular carcinoma), morbidity and mortality from cardiovascular disease both increase in people with NAFLD. As a matter of fact, NAFLD is a cardiovascular risk factor.
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Lv X, Dong Y, Hu L, Lu F, Zhou C, Qin S. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): A systematic review. Endocrinol Diabetes Metab 2020; 3:e00163. [PMID: 32704576 PMCID: PMC7375121 DOI: 10.1002/edm2.163] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/19/2020] [Accepted: 05/23/2020] [Indexed: 12/18/2022] Open
Abstract
There are no licensed drugs for nonalcoholic fatty liver disease (NAFLD), and there is a lack of consensus on the best outcome measures for controlled trials. This systematic review aimed to evaluate the efficacy of GLP-1 RAs in the management of NAFLD, the degree of heterogeneity in trial design and the robustness of conclusions drawn from these clinical trials. We searched publication databases and clinical trial registries through 2 November 2019 for clinical trials with NAFLD. We evaluated improvements in histological findings, noninvasive markers of hepatic steatosis, inflammation, and fibrosis, insulin resistance and anthropometric measures. Our final analysis included 24 clinical trials, comprising 6313 participants with a mean duration of 37 weeks. Four clinical trials, including RCT (n = 1), single-arm studies (n = 2) and case series studies (n = 1), used biopsy-confirmed liver histological change as their end-points. The remaining studies (n = 20) used surrogate end-points. GLP-1 RAs were effective for the improvement in hepatic inflammation, hepatic steatosis and fibrosis. More importantly, GLP-1 RAs showed promise in improving the histological features of NASH. In addition, 8 ongoing trials were identified. In this systematic review of published and ongoing clinical trials of the efficacy of GLP-1RAs for NAFLD, we found that GLP-1 RAs are effective for hepatic steatosis and inflammation, with the potential to reverse fibrosis. Further prospective studies of sufficient duration using histological end-points are needed to fully assess the efficacy of GLP-1 RAs in the management of NAFLD.
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Affiliation(s)
- Xiaodan Lv
- Department of EndocrinologyChina‐Japan Union Hospital of Jilin UniversityChangchunChina
| | - Yongqiang Dong
- Department of Thyroid SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Lingling Hu
- Department of EndocrinologyNingbo Medical Center Lihuili Eastern HospitalZhejiangChina
| | - Feiyu Lu
- Department of PaediatricsThe First Hospital of Jilin UniversityChangchunChina
| | - Changyu Zhou
- Department of Gastroenterology and HepatologyChina‐Japan Union Hospital of Jilin UniversityChangchunChina
| | - Shaoyou Qin
- Department of Gastroenterology and HepatologyChina‐Japan Union Hospital of Jilin UniversityChangchunChina
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Chen M, Xing J, Pan D, Peng X, Gao P. Chinese herbal medicine mixture 919 syrup alleviates nonalcoholic fatty liver disease in rats by inhibiting the NF-κB pathway. Biomed Pharmacother 2020; 128:110286. [PMID: 32521450 DOI: 10.1016/j.biopha.2020.110286] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 05/14/2020] [Accepted: 05/16/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND In many countries, nonalcoholic fatty liver disease (NAFLD) has risen to be the leading cause of liver disease, seriously threatening public health, while effective medical treatments are currently limited. 919 syrup (919 T J) is a Chinese herbal medicine, and both clinical and experimental studies have revealed that it can improve liver function. OBJECTIVE To study whether 919 T J shows a protective effect in a NAFLD rat model and explore its underlying mechanism, with a focus on the NF-κB pathway. METHODS Rats were randomly divided into three groups, including a control group, NAFLD group, and 919 T J group (n = 10 each). The control group received a standard diet, and the other two groups were fed a high-fat diet to establish the NAFLD model. From week 10, rats in the 919 T J group were intragastrically administered 919 T J for 4 weeks, and the NAFLD group was administered the same amount of saline. All rats were anesthetized at the beginning of week 14 to collect blood and liver specimens. Serum lipid levels, serum biochemical markers of liver function, and the gene expression levels of IL-1β, TNF-α, CXCL6, CXCR1, SREBP-1c, PPARγ, and NF-κB in the liver were measured. Oil Red O and hematoxylin and eosin staining of the liver was performed to observe pathological changes in the liver. RESULTS Significant abnormalities in serum lipid levels and serum biochemical markers of liver function were found in the NAFLD group relative to those in the control group. In addition, serious abnormalities were noted in the expression levels of liver inflammatory factors and lipid metabolism-related genes. Treatment of NAFLD rats with 919 T J reduced body weight and food intake and ameliorated the abnormal blood lipid levels and liver function markers. By regulating the NF-κB pathway, 919 T J downregulated the NF-κB-related proinflammatory signals, ameliorating the expression of inflammatory (IL-1β, TNF-α, CXCL6, and CXCR1) and lipid metabolism-related (SREBP-1c) factors in the liver and improving the NAFLD-induced pathological changes in the liver. CONCLUSION 919 T J reduces the liver injury, steatosis, and inflammation caused by NAFLD, thus reversing the disease process.
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Affiliation(s)
- Manman Chen
- Department of TCM, Jinshan Hospital, Fudan University, Shanghai, China
| | - Jingwei Xing
- Department of TCM, Jinshan Hospital, Fudan University, Shanghai, China
| | - Danqing Pan
- Department of TCM, Jinshan Hospital, Fudan University, Shanghai, China
| | - Xiuhua Peng
- Department of Animal Experiments, Shanghai Public Health Clinical Center, Shanghai, China
| | - Pengfei Gao
- Department of TCM, Jinshan Hospital, Fudan University, Shanghai, China.
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