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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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Raza FA, Altaf R, Bashir T, Asghar F, Altaf R, Tousif S, Goyal A, Mohammed A, Mohammad MF, Anan M, Ali S. Effect of GLP-1 receptor agonists on weight and cardiovascular outcomes: A review. Medicine (Baltimore) 2024; 103:e40364. [PMID: 39496023 PMCID: PMC11537668 DOI: 10.1097/md.0000000000040364] [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: 08/22/2024] [Accepted: 10/15/2024] [Indexed: 11/06/2024] Open
Abstract
Diet and lifestyle modifications remain the foundation of obesity treatment, but they have historically proven insufficient for significant, long-term weight loss. As a result, there is a high demand for new pharmacologic treatments to promote weight loss and prevent life-threatening diseases associated with obesity. Researchers are particularly interested in 1 type of drug, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), because of its promising potential in addressing the limitations of non-pharmacologic treatments. In addition to their role in weight loss, these drugs have shown promising early evidence of cardiovascular benefits in obese patients, further enhancing their clinical relevance. Semaglutide and liraglutide, which were initially approved for the treatment of type 2 diabetes, have since been approved by the Food and Drug Administration as weight loss medications due to their effectiveness in promoting significant and sustained weight loss. In this narrative review, we will explore the mechanism of GLP-1 RAs, their effects on weight loss, cardiovascular risk factors and outcomes, common adverse effects, and strategies for managing these effects.
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Affiliation(s)
- Fatima Ali Raza
- Department of Medicine, Karachi Medical and Dental College, Karachi, Pakistan
| | - Rafiya Altaf
- Department of Surgery, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Talha Bashir
- Department of Medicine, Karachi Institute of Medical Sciences, Combined Military Hospital Malir, Karachi City, Pakistan
| | - Fatima Asghar
- Department of Medicine, Ras Al Khaimah College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Rabiya Altaf
- Department of Medicine, Mersey and West Lancashire Teaching Hospitals NHS Trust, Prescot, United Kingdom
| | - Sohaib Tousif
- Department of Medicine, Ziauddin University, Karachi City, Pakistan
| | - Aman Goyal
- Department of Medicine, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, India
| | - Aisha Mohammed
- Department of Medicine, Comanche County Memorial Hospital, Lawton, OK
| | | | - Mahfuza Anan
- Department of Medicine, Bangladesh Medical College, Dhaka, Bangladesh
| | - Sajjad Ali
- Department of Medicine, Ziauddin University, Karachi City, Pakistan
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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: 1] [Impact Index Per Article: 1.0] [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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Alfawaz S, Burzangi A, Esmat A. Mechanisms of Non-alcoholic Fatty Liver Disease and Beneficial Effects of Semaglutide: A Review. Cureus 2024; 16:e67080. [PMID: 39286709 PMCID: PMC11404706 DOI: 10.7759/cureus.67080] [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: 08/17/2024] [Indexed: 09/19/2024] Open
Abstract
Non-alcoholic fatty liver disease stands as the predominant cause of chronic liver disease, with its prevalence and morbidity expected to escalate significantly, leading to substantial healthcare costs and diminished health-related quality of life. It comprises a range of disease manifestations that commence with basic steatosis, involving the accumulation of lipids in hepatocytes, a distinctive histological feature. If left untreated, it often advances to non-alcoholic steatohepatitis, marked by inflammatory and/or fibrotic hepatic changes, leading to the eventual development of non-alcoholic fatty liver disease-related cirrhosis and hepatocellular carcinoma. Because of the liver's vital role in body metabolism, non-alcoholic fatty liver disease is considered both a consequence and a contributor to the metabolic abnormalities observed in the metabolic syndrome. As of date, there are no authorized pharmacological agents for non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. Semaglutide, with its glycemic and weight loss advantages, could potentially offer benefits for individuals with non-alcoholic fatty liver disease. This review aims to investigate the impact of semaglutide on non-alcoholic fatty liver disease.
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Affiliation(s)
- Sultan Alfawaz
- Department of Clinical Pharmacology, King Abdulaziz University, Faculty of Medicine, Jeddah, SAU
| | - Abdulhadi Burzangi
- Department of Clinical Pharmacology, King Abdulaziz University, Faculty of Medicine, Jeddah, SAU
| | - Ahmed Esmat
- Department of Clinical Pharmacology, King Abdulaziz University, Faculty of Medicine, Jeddah, SAU
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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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Lonardo A, Ballestri S, Mantovani A, Targher G, Bril F. Endpoints in NASH Clinical Trials: Are We Blind in One Eye? Metabolites 2024; 14:40. [PMID: 38248843 PMCID: PMC10820221 DOI: 10.3390/metabo14010040] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 12/31/2023] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular-kidney-metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone.
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Affiliation(s)
- Amedeo Lonardo
- AOU—Modena—Ospedale Civile di Baggiovara, 41126 Modena, Italy;
| | | | - Alessandro Mantovani
- Section of Endocrinology and Diabetes, Department of Medicine, University of Verona, Piazzale Stefani, 37126 Verona, Italy
| | - Giovanni Targher
- Department of Medicine, University of Verona, 37126 Verona, Italy;
- Metabolic Diseases Research Unit, IRCCS Sacro Cuore—Don Calabria Hospital, 37024 Negrar di Valpolicella, Italy
| | - Fernando Bril
- Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USA;
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Bril F. Nonalcoholic fatty liver disease: What comes before and what are the consequences? CHRONIC COMPLICATIONS OF DIABETES MELLITUS 2024:185-206. [DOI: 10.1016/b978-0-323-88426-6.00017-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Malandris K, Papandreou S, Avgerinos I, Karagiannis T, Paschos P, Michailidis T, Liakos A, Bekiari E, Sinakos E, Tsapas A. Comparative efficacy of glucose-lowering drugs on liver steatosis as assessed by means of magnetic resonance imaging in patients with type 2 diabetes mellitus: systematic review and network meta-analysis. Hormones (Athens) 2023; 22:655-664. [PMID: 37770761 PMCID: PMC10651545 DOI: 10.1007/s42000-023-00493-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 09/18/2023] [Indexed: 09/30/2023]
Abstract
PURPOSE To assess the comparative efficacy of glucose-lowering drugs on liver steatosis as assessed by means of magnetic resonance imaging (MRI) in patients with T2D. METHODS We searched several databases and grey literature sources. Eligible trials had at least 12 weeks of intervention, included patients with T2D, and assessed the efficacy of glucose-lowering drugs as monotherapies. The primary outcome of interest was absolute reduction in liver fat content (LFC), assessed by means of MRI. Secondary efficacy outcomes were reduction in visceral and subcutaneous adipose tissue. We performed random effects frequentist network meta-analyses to estimate mean differences (MDs) with 95% confidence intervals (CIs). We ranked treatments based on P-scores. RESULTS We included 29 trials with 1906 patients. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors (P-score 0.84) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (0.71) were the most efficacious in terms of liver fat content reduction. Among individual agents, empagliflozin was the most efficacious (0.86) and superior to pioglitazone (MD -5.7, 95% CI -11.2 to -0.3) (very low confidence). GLP-1 RAs had also the most favorable effects on visceral and subcutaneous adipose tissue. CONCLUSIONS GLP-1 RAs and SGLT-2 inhibitors seem to be the most efficacious glucose-lowering drugs for liver steatosis in patients with T2D. Assessment of their efficacy on NAFLD in patients irrespective of presence of T2D is encouraged.
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Affiliation(s)
- Konstantinos Malandris
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Stylianos Papandreou
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Avgerinos
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642, Thessaloniki, Greece
| | - Thomas Karagiannis
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642, Thessaloniki, Greece
| | - Paschalis Paschos
- First Medical Department, "Papageorgiou" Hospital, Thessaloniki, Greece
| | - Theodoros Michailidis
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642, Thessaloniki, Greece
| | - Aris Liakos
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642, Thessaloniki, Greece
| | - Eleni Bekiari
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642, Thessaloniki, Greece
| | - Emmanouil Sinakos
- Fourth Medical Department, Hippokration General Hospital of Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Apostolos Tsapas
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54642, Thessaloniki, Greece
- Harris Manchester College, University of Oxford, Oxford, UK
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Boeriu A, Dobru D, Fofiu C. Non-Invasive Diagnostic of NAFLD in Type 2 Diabetes Mellitus and Risk Stratification: Strengths and Limitations. Life (Basel) 2023; 13:2262. [PMID: 38137863 PMCID: PMC10744403 DOI: 10.3390/life13122262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 10/26/2023] [Accepted: 11/25/2023] [Indexed: 12/24/2023] Open
Abstract
The progressive potential of liver damage in type 2 diabetes mellitus (T2DM) towards advanced fibrosis, end-stage liver disease, and hepatocarcinoma has led to increased concern for quantifying liver injury and individual risk assessment. The combination of blood-based markers and imaging techniques is recommended for the initial evaluation in NAFLD and for regular monitoring to evaluate disease progression. Continued development of ultrasonographic and magnetic resonance imaging methods for accurate quantification of liver steatosis and fibrosis, as well as promising tools for the detection of high-risk NASH, have been noted. In this review, we aim to summarize available evidence regarding the usefulness of non-invasive methods for the assessment of NAFLD in T2DM. We focus on the power and limitations of various methods for diagnosis, risk stratification, and patient monitoring that support their implementation in clinical setting or in research field.
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Affiliation(s)
- Alina Boeriu
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Gastroenterology Department, Mures County Clinical Hospital, 540103 Targu Mures, Romania
| | - Daniela Dobru
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Gastroenterology Department, Mures County Clinical Hospital, 540103 Targu Mures, Romania
| | - Crina Fofiu
- Gastroenterology Department, University of Medicine Pharmacy, Sciences, and Technology “George Emil Palade” Targu Mures, 540142 Targu Mures, Romania;
- Internal Medicine Department, Bistrita County Clinical Hospital, 420094 Bistrita, Romania
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Yu X, Bian X, Zhang H, Yang S, Cui D, Su Z. Liraglutide ameliorates hepatic steatosis via retinoic acid receptor-related orphan receptor α-mediated autophagy pathway. IUBMB Life 2023; 75:856-867. [PMID: 37310057 DOI: 10.1002/iub.2760] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/25/2023] [Indexed: 06/14/2023]
Abstract
Liraglutide, an analog of human glucagon-like peptide-1 (GLP-1), has been found to improve hepatic steatosis in clinical practice. However, the underlying mechanism remains to be fully defined. Increasing evidence suggests that retinoic acid receptor-related orphan receptor α (RORα) is involved in hepatic lipid accumulation. In the current study, we investigated whether the ameliorating impact of liraglutide on lipid-induced hepatic steatosis is dependent on RORα activity and examined the underlying mechanisms. Cre-loxP-mediated, liver-specific Rorα knockout (Rora LKO) mice, and littermate controls with a Roraloxp/loxp genotype were established. The effects of liraglutide on lipid accumulation were evaluated in mice challenged with a high-fat diet (HFD) for 12 weeks. Moreover, mouse AML12 hepatocytes expressing small interfering RNA (siRNA) of Rora were exposed to palmitic acid to explore the pharmacological mechanism of liraglutide. The results showed that liraglutide treatment significantly alleviated HFD-induced liver steatosis, marked by reduced liver weight and triglyceride accumulation, improved glucose tolerance and serum levels of lipid profiles and aminotransferase. Consistently, liraglutide also ameliorated lipid deposits in a steatotic hepatocyte model in vitro. In addition, liraglutide treatment reversed the HFD-induced downregulation of Rora expression and autophagic activity in mouse liver tissues. However, the beneficial effect of liraglutide on hepatic steatosis was not observed in Rora LKO mice. Mechanistically, the ablation of Rorα in hepatocytes diminished liraglutide-induced autophagosome formation and the fusion of autophagosomes and lysosomes, resulting in weakened autophagic flux activation. Thus, our findings suggest that RORα is essential for the beneficial impact of liraglutide on lipid deposition in hepatocytes and regulates autophagic activity in the underlying mechanism.
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Affiliation(s)
- Xiaoqian Yu
- Department of Endocrinology and Metabolism, Molecular Medicine Research Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Anaesthesiology, Affiliated Hospital of Chengdu Universtiy, Chengdu, China
| | - Xiaoqi Bian
- College of Life Science, Northeast Agricultural University, Harbin, China
| | - Hongmei Zhang
- Department of Endocrinology and Metabolism, Molecular Medicine Research Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Shanshan Yang
- Department of Endocrinology and Metabolism, Molecular Medicine Research Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Daxin Cui
- Department of Endocrinology and Metabolism, Molecular Medicine Research Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiguang Su
- Department of Endocrinology and Metabolism, Molecular Medicine Research Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Liao C, Liang X, Zhang X, Li Y. The effects of GLP-1 receptor agonists on visceral fat and liver ectopic fat in an adult population with or without diabetes and nonalcoholic fatty liver disease: A systematic review and meta-analysis. PLoS One 2023; 18:e0289616. [PMID: 37616255 PMCID: PMC10449217 DOI: 10.1371/journal.pone.0289616] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 07/22/2023] [Indexed: 08/26/2023] Open
Abstract
AIM To uncover the effect of GLP-1 receptor agonists (GLP-1 RAs) on the visceral- and hepatic fat content of adults. METHODS PubMed, EMBASE, Cochrane Library, and Web of Science were searched from inception until November 2022. Randomized controlled trials (RCTs) of GLP-1Ras was extracted, including reports of effects on visceral adipose tissue and hepatic fat content in individuals with type 2 diabetes, non-type 2 diabetes, NAFLD (non-alcoholic fatty liver disease), and non-NAFLD. Meta-analyses used random-effects models. RESULTS 1736 individuals in the 30 qualified RCTs were included, comprising 1363 people with type 2 diabetes and 318 with NFLD. GLP-1 RAs reduced visceral adipose tissue (standard mean difference [SMD] = -0.59, 95% CI [-0.83, -0.36], P<0.00001) and hepatic fat content (weighted mean difference [WMD] = -3.09, 95% CI [-4.16, -2.02], P<0.00001) compared to other control treatment. Subgroup analysis showed that GLP-1Ras dramatically decreased visceral fat in patients with type 2 diabetes (SMD = -0.49, 95% CI [-0.69, -0.29] P<0.00001), NAFLD (SMD = -0.99, 95% CI [-1.64, -0.34] P = 0.003), non-type 2 diabetes (SMD = -1.38, 95% CI [-2.44, -0.32] P = 0.01), and non-NAFLD (SMD = -0.53, 95% CI [-0.78, -0.28] P<0.0001). GLP-1Ras reduced the liver fat level of type 2 diabetes (WMD = -3.15, 95% CI [-4.14, -2.15] P<0.00001), NAFLD (WMD = -3.83, 95% CI [-6.30, -1.37] P = 0.002), and type 2 diabetes with NAFLD (WMD = -4.27, 95% CI [-6.80, -1.74] P = 0.0009), while showed no impact on the hepatic fat content in non-Type 2 diabetes (WMD = -12.48, 95% CI [-45.19, 20.24] P = 0.45). CONCLUSIONS LP-1 RAs significantly reduce visceral- and liver fat content in adults.
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Affiliation(s)
- Chao Liao
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xinyin Liang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xiao Zhang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Yao Li
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
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Vitulo M, Gnodi E, Rosini G, Meneveri R, Giovannoni R, Barisani D. Current Therapeutical Approaches Targeting Lipid Metabolism in NAFLD. Int J Mol Sci 2023; 24:12748. [PMID: 37628929 PMCID: PMC10454602 DOI: 10.3390/ijms241612748] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/07/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD, including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH)) is a high-prevalence disorder, affecting about 1 billion people, which can evolve to more severe conditions like cirrhosis or hepatocellular carcinoma. NAFLD is often concomitant with conditions of the metabolic syndrome, such as central obesity and insulin-resistance, but a specific drug able to revert NAFL and prevent its evolution towards NASH is still lacking. With the liver being a key organ in metabolic processes, the potential therapeutic strategies are many, and range from directly targeting the lipid metabolism to the prevention of tissue inflammation. However, side effects have been reported for the drugs tested up to now. In this review, different approaches to the treatment of NAFLD are presented, including newer therapies and ongoing clinical trials. Particular focus is placed on the reverse cholesterol transport system and on the agonists for nuclear factors like PPAR and FXR, but also drugs initially developed for other conditions such as incretins and thyromimetics along with validated natural compounds that have anti-inflammatory potential. This work provides an overview of the different therapeutic strategies currently being tested for NAFLD, other than, or along with, the recommendation of weight loss.
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Affiliation(s)
- Manuela Vitulo
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (M.V.); (E.G.); (R.M.)
| | - Elisa Gnodi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (M.V.); (E.G.); (R.M.)
| | - Giulia Rosini
- Department of Biology, University of Pisa, 56021 Pisa, Italy; (G.R.); (R.G.)
| | - Raffaella Meneveri
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (M.V.); (E.G.); (R.M.)
| | - Roberto Giovannoni
- Department of Biology, University of Pisa, 56021 Pisa, Italy; (G.R.); (R.G.)
| | - Donatella Barisani
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (M.V.); (E.G.); (R.M.)
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Zheng S, Huang H, Chen H, Liu Y. Glp-1 Receptor Agonists Regulate the Progression of Diabetes Mellitus Complicated with Fatty Liver by Down-regulating the Expression of Genes Related to Lipid Metabolism. Appl Biochem Biotechnol 2023; 195:5238-5251. [PMID: 37140780 DOI: 10.1007/s12010-023-04505-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2023] [Indexed: 05/05/2023]
Abstract
Non-alcoholic fatty liver disease is mostly associated with diabetes mellitus. Dulaglutide is approved in type 2 diabetes as a hypoglycemic agent. However, its effects on liver fat and pancreatic fat contents are not evaluated yet. The objectives of the study were to evaluate the effects of dulaglutide on liver fat content, pancreatic fat content, liver stiffness, and liver enzyme levels. Patients have taken 0.75 mg subcutaneous dulaglutide each week for 4 weeks, then 1.5 mg weekly for 20 weeks plus standard treatment (metformin plus sulfonylurea and/or insulin; DS group, n = 25), or patients have taken standard treatment (metformin plus sulfonylurea and/or insulin) alone (ST group, n = 46) for type 2 diabetes management. Both groups reported a decrease in liver fat content, pancreatic fat content, and liver stiffness after interventions (p < 0.001 for all). After interventions, the DS group reported a higher decrease in liver fat content, pancreatic fat content, and liver stiffness than that of the ST group (p < 0.001 for all). After interventions, the DS group reported a higher decrease in body mass index than that of the ST group (p < 0.05). There were significant improvements in liver function tests, kidney function tests, lipid profiles, and blood counts after interventions (p < 0.05 for all). Both groups reported a decrease in body mass index after interventions (p < 0.001 for both). The DS group significantly decrease body mass index after interventions (p < 0.05) than the ST group.
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Affiliation(s)
- Shuihong Zheng
- Jinhua Municipal Central Hospital, Department of Neurology, Jinhua, 321000, China.
| | - Huaying Huang
- Jinhua Municipal Central Hospital, Department of Endocrinology, Jinhua, 321000, China
| | - Heye Chen
- Jinhua Municipal Central Hospital, Department of Endocrinology, Jinhua, 321000, China
| | - Yanfen Liu
- Jinhua Municipal Central Hospital, Department of Endocrinology, Jinhua, 321000, China
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14
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Tsiampali C, Papaioannidou P, Goulas A, Polyzos SA. The role of glucagon-like peptide-1 receptor agonists in nonalcoholic fatty liver disease. Expert Rev Clin Pharmacol 2023; 16:1063-1072. [PMID: 37864548 DOI: 10.1080/17512433.2023.2274536] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/19/2023] [Indexed: 10/23/2023]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease, associated with obesity, type 2 diabetes mellitus and dyslipidemia, which can lead to liver cirrhosis and hepatocellular carcinoma in some patients. Apart from lifestyle modifications, which are the cornerstone for its management, several drugs are under evaluation, including glucagon-like peptide-1 receptor agonists (GLP-R1RAs). In this review, we summarized major clinical data concerning the effects of GLP-1RAs on NAFLD, trying to highlight existing knowledge and to elucidate areas of uncertainty, thus providing clues to potential clinical implications and research. AREAS COVERED Selected clinical studies on GLP-R1As in NAFLD are presented in this narrative review. EXPERT OPINION There is evidence that treatment with GLP-R1As in NAFLD has beneficial effects on NAFLD, i.e. improvement in liver function tests and histological improvement in hepatic steatosis and inflammation, but not fibrosis. Further research is required toward the early use of GLP-R1Αs, i.e. in NAFLD patients without fibrosis to evaluate whether they may prevent the progression to fibrosis, or in patients with advanced disease in combination with other medications, which may have additive or even synergistic effects on NAFLD.
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Affiliation(s)
- Chara Tsiampali
- 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
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
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15
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Cook JR, Hawkins MA, Pajvani UB. Liver insulinization as a driver of triglyceride dysmetabolism. Nat Metab 2023; 5:1101-1110. [PMID: 37460842 DOI: 10.1038/s42255-023-00843-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 06/13/2023] [Indexed: 07/26/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly prevalent fellow traveller with the insulin resistance that underlies type 2 diabetes mellitus. However, the mechanistic connection between MAFLD and impaired insulin action remains unclear. In this Perspective, we review data from humans to elucidate insulin's aetiological role in MAFLD. We focus particularly on the relative preservation of insulin's stimulation of triglyceride (TG) biosynthesis despite its waning ability to curb hepatic glucose production (HGP). To explain this apparent 'selective insulin resistance', we propose that hepatocellular processes that lead to TG accumulation require less insulin signal transduction, or 'insulinization,' than do those that regulate HGP. As such, mounting hyperinsulinaemia that barely compensates for aberrant HGP in insulin-resistant states more than suffices to maintain hepatic TG biosynthesis. Thus, even modestly elevated or context-inappropriate insulin levels, when sustained day and night within a heavily pro-lipogenic metabolic milieu, may translate into substantial cumulative TG biosynthesis in the insulin-resistant state.
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Affiliation(s)
- Joshua R Cook
- Naomi Berrie Diabetes Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Columbia University College of Physicians & Surgeons, New York City, NY, USA.
| | - Meredith A Hawkins
- Diabetes Research and Training Center, Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | - Utpal B Pajvani
- Naomi Berrie Diabetes Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Columbia University College of Physicians & Surgeons, New York City, NY, USA
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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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Bril F, Sanyal A, Cusi K. Metabolic Syndrome and Its Association with Nonalcoholic Steatohepatitis. Clin Liver Dis 2023; 27:187-210. [PMID: 37024202 DOI: 10.1016/j.cld.2023.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
The relationship between insulin resistance, metabolic syndrome (MetS), and nonalcoholic fatty liver disease (NAFLD) is complicated. Although insulin resistance is almost universal in people with NAFLD and MetS, NAFLD may be present without features of MetS and vice versa. While NAFLD has a strong correlation with cardiometabolic risk factors, these are not intrinsic components of this condition. Taken together, our knowledge gaps call for caution regarding the common assertion that NAFLD is the hepatic manifestation of the MetS, and for defining NAFLD in broad terms as a "metabolic dysfunction" based on a diverse and poorly understood constellation of cardiometabolic features.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Arun Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, School of Medicine Internal Medicine, Virginia Commonwealth University
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
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18
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Cazac GD, Lăcătușu CM, Ștefănescu G, Mihai C, Grigorescu ED, Onofriescu A, Mihai BM. Glucagon-like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease-Current Background, Hopes, and Perspectives. Metabolites 2023; 13:metabo13050581. [PMID: 37233622 DOI: 10.3390/metabo13050581] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/27/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease worldwide, reaching one of the highest prevalences in patients with type 2 diabetes mellitus (T2DM). For now, no specific pharmacologic therapies are approved to prevent or treat NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are currently evaluated as potential candidates for NAFLD treatment in patients with T2DM. Some representatives of this class of antihyperglycemic agents emerged as potentially beneficial in patients with NAFLD after several research studies suggested they reduce hepatic steatosis, ameliorate lesions of nonalcoholic steatohepatitis (NASH), or delay the progression of fibrosis in this population. The aim of this review is to summarize the body of evidence supporting the effectiveness of GLP-1RA therapy in the management of T2DM complicated with NAFLD, describing the studies that evaluated the effects of these glucose-lowering agents in fatty liver disease and fibrosis, their possible mechanistic justification, current evidence-based recommendations, and the next steps to be developed in the field of pharmacological innovation.
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Affiliation(s)
- Georgiana-Diana Cazac
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Cristina-Mihaela Lăcătușu
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Gabriela Ștefănescu
- Unit of Medical Semiology and Gastroenterology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Cătălina Mihai
- Unit of Medical Semiology and Gastroenterology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Elena-Daniela Grigorescu
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Alina Onofriescu
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Bogdan-Mircea Mihai
- Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, "Sf. Spiridon" County Clinical Emergency Hospital, 700111 Iași, Romania
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GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int J Mol Sci 2023; 24:ijms24021703. [PMID: 36675217 PMCID: PMC9865319 DOI: 10.3390/ijms24021703] [Citation(s) in RCA: 115] [Impact Index Per Article: 57.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.
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Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, Wei Q, Zhao C, Lin C, Yang J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther 2022; 7:287. [PMID: 35963848 PMCID: PMC9376100 DOI: 10.1038/s41392-022-01119-3] [Citation(s) in RCA: 185] [Impact Index Per Article: 61.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/15/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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Affiliation(s)
- Xiaohan Xu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Kyle L Poulsen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Lijuan Wu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shan Liu
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Qiaoling Song
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qingda Wei
- School of Medicine, Zhengzhou University, Zhengzhou, China
| | - Chenyang Zhao
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinbo Yang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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Gastaldelli A, Cusi K, Fernández Landó L, Bray R, Brouwers B, Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol 2022; 10:393-406. [PMID: 35468325 DOI: 10.1016/s2213-8587(22)00070-5] [Citation(s) in RCA: 270] [Impact Index Per Article: 90.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/28/2022] [Accepted: 02/10/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 receptor agonist under development for the treatment of type 2 diabetes. The aim of this substudy was to characterise the changes in liver fat content (LFC), volume of visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT) in response to tirzepatide or insulin degludec in a subpopulation of the SURPASS-3 study. METHODS This substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial was done at 45 medical research centres and hospitals across eight countries (Argentina, Austria, Greece, Hungary, Italy, Romania, Spain, and the USA). Eligible participants were adults with type 2 diabetes, a baseline HbA1c 7·0-10·5% (53-91 mmol/mol), a BMI of at least 25 kg/m2, stable weight, were insulin-naive, and on treatment with metformin alone or in combination with a SGLT2 inhibitor for at least 3 months before screening. In addition to the main study inclusion criteria, substudy participants had a fatty liver index of at least 60. Participants had an MRI scan and were randomised (1:1:1:1) in the main study to subcutaneous injection once per week of tirzepatide 5 mg, 10 mg, or 15 mg, or subcutaneous injection once per day of titrated insulin degludec, using an interactive web-response system, and were stratified by country, HbA1c, and concomitant oral anti-hyperglycaemic medication. The primary efficacy endpoint was the change from baseline in LFC (as measured by MRI-proton density fat fraction [MRI-PDFF]) at week 52 using pooled data from the tirzepatide 10 mg and 15 mg groups versus insulin degludec. Analyses were assessed in the enrolled MRI population, which consisted of participants in the modified intention-to-treat population of the main study who also had a valid MRI at either baseline or after baseline. This is a substudy of the trial registered with ClinicalTrials.gov, number NCT03882970, and is complete. FINDINGS From April 1, 2019, to Nov 15, 2019, 502 participants were assessed for eligibility to participate in this substudy, 296 (59%) of whom were included in the enrolled MRI population and randomly assigned to treatment (tirzepatide 5 mg, n=71; tirzepatide 10 mg, n=79; tirzepatide 15 mg, n=72; and insulin degludec, n=74). Baseline demographics and clinical characteristics were similar across all treatment groups. From an overall mean baseline LFC of 15·71% (SD 8·93), the absolute reduction in LFC at week 52 was significantly greater for the pooled tirzepatide 10 mg and 15 mg groups (-8·09%, SE 0·57) versus the insulin degludec group (-3·38%, 0·83). The estimated treatment difference versus insulin degludec was -4·71% (95% CI -6·72 to -2·70; p<0·0001). The reduction in LFC was significantly correlated (p≤0·0006) with baseline LFC (ρ=-0·71), reductions in VAT (ρ=0·29), reductions in ASAT (ρ=0·33), and reductions in body weight (ρ=0·34) in the tirzepatide groups. INTERPRETATION Tirzepatide showed a significant reduction in LFC and VAT and ASAT volumes compared with insulin degludec in this subpopulation of patients with type 2 diabetes in the SURPASS-3 study. These data provide additional evidence on the metabolic effects of this novel dual GIP and GLP-1 receptor agonist. FUNDING Eli Lilly and Company.
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Affiliation(s)
- Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes, and Metabolism, The University of Florida, Gainesville, FL, USA
| | | | - Ross Bray
- Eli Lilly and Company, Indianapolis, IN, USA
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Moon JS, Hong JH, Jung YJ, Ferrannini E, Nauck MA, Lim S. SGLT-2 inhibitors and GLP-1 receptor agonists in metabolic dysfunction-associated fatty liver disease. Trends Endocrinol Metab 2022; 33:424-442. [PMID: 35491295 DOI: 10.1016/j.tem.2022.03.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/22/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic condition that affects nearly one billion people globally, characterized by triacylglycerol accumulation in the liver as a consequence of metabolic abnormalities (obesity and impaired glucose regulation). Low-grade inflammation, oxidative stress, mitochondrial dysfunction, and dysbiosis in gut microbiota are involved in the etiology of MAFLD, and both cardiovascular events and hepatic complications are the long-term consequences. In the absence of approved therapies for this condition, sodium-glucose cotransporter 2 inhibitors (SGLT-2 Is) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have the specific advantage of lowering body weight and providing cardiovascular benefits. Here, we discuss potential roles for SGLT-2 Is and GLP-1 RAs in the prevention and treatment of intrahepatic triacylglycerol accumulation and associated inflammation and/or fibrosis.
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Affiliation(s)
- Jun Sung Moon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Jun Hwa Hong
- Department of Internal Medicine, Eulji University Hospital, School of Medicine, Daejeon, Republic of Korea
| | - Yong Jin Jung
- Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | - Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital (Ruhr-University, Bochum), Bochum, Germany.
| | - Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
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23
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Dou Z, Liu C, Feng X, Xie Y, Yue H, Dong J, Zhao Z, Chen G, Yang J. Camel whey protein (CWP) ameliorates liver injury in type 2 diabetes mellitus rats and insulin resistance (IR) in HepG2 cells via activation of the PI3K/Akt signaling pathway. Food Funct 2022; 13:255-269. [PMID: 34897341 DOI: 10.1039/d1fo01174j] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
This research investigated the effects of camel whey protein (CWP) treatment on type 2 diabetes mellitus (T2DM) rats and insulin resistance (IR) HepG2 cell models. Body weight and fasting blood glucose were observed in type 2 diabetes mellitus (T2DM) rats every week, and biochemical parameters in serum samples were evaluated after 6 weeks. Antioxidant activity in the liver was estimated, and histological examination of the liver tissues was conducted. After CWP treatment, the glucose uptake and lipid accumulation were examined in insulin-resistant HepG2 cells. Our results indicated that CWP mitigated the body weight loss, reversed dyslipidemia, and inhibited the inflammatory response, in T2DM rats. Meanwhile, it protected the liver from being injured by reducing the level of oxidative stress. In the CWP group, the pathological changes were significantly reduced, while the liver lobule structure, liver cell arrangement, as well as congestion, edema, and vacuolization were improved. Our results from quantitative real-time PCR and western blot analyses showed that CWP could up-regulate the expression levels of insulin receptor substrate-2 (IRS-2), phosphoinositide3-kinase (PI3K), protein kinase B (AKT), and glycogen synthase (GS). An active protein component CWP8 was isolated and identified, which was shown to be able to stimulate glycogen synthesis and ameliorate lipid accumulation in IR HepG2 cells. These data indicate that CWP and CWP8 might act as potential natural products regulating glucose and lipid metabolism in T2DM.
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Affiliation(s)
- Zhihua Dou
- College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, 830046, China.
| | - Chen Liu
- College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, 830046, China.
| | - Xinhuan Feng
- College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, 830046, China.
| | - Yutong Xie
- College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, 830046, China.
| | - Haitao Yue
- College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, 830046, China. .,Xinjiang Camel Industry Engineering Technology Research Center, Urumqi, Xinjiang, 830046, China
| | - Jing Dong
- Xinjiang Bactrian Camel Research Institute, Fuhai, Xinjiang, 836400, China.,Xinjiang Camel Industry Engineering Technology Research Center, Urumqi, Xinjiang, 830046, China
| | - Zhongkai Zhao
- College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, 830046, China.
| | - Gangliang Chen
- Xinjiang Bactrian Camel Research Institute, Fuhai, Xinjiang, 836400, China.,Xinjiang Camel Industry Engineering Technology Research Center, Urumqi, Xinjiang, 830046, China
| | - Jie Yang
- College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, 830046, China. .,Xinjiang Camel Industry Engineering Technology Research Center, Urumqi, Xinjiang, 830046, China
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24
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He LH, Yao DH, Wang LY, Zhang L, Bai XL. Gut Microbiome-Mediated Alteration of Immunity, Inflammation, and Metabolism Involved in the Regulation of Non-alcoholic Fatty Liver Disease. Front Microbiol 2021; 12:761836. [PMID: 34795655 PMCID: PMC8593644 DOI: 10.3389/fmicb.2021.761836] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/05/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of end-stage liver disease, leading to a rapidly growing global public health burden. The term “gut microbiome (GM)” refers to the approximately 100 trillion microbial cells that inhabit the host’s gastrointestinal tract. There is increasing evidence that GM is involved in the pathogenesis of NAFLD and may be a potential target for intervention. To explore GM-based strategies for precise diagnosis and treatment of NAFLD, great efforts have been made to develop a comprehensive and in-depth understanding of the host–microbe interaction. This review evaluates this interaction critically, mainly considering the intricate regulation of the metabolism, immunity, and inflammatory status during the evolution of the disease pathogenesis, revealing roles for the GM in NAFLD by examining advances in potential mechanisms, diagnostics, and modulation strategies. Synopsis: Considering the intricate metabolic and immune/inflammatory homeostasis regulation, we evaluate the latest understanding of the host–microbe interaction and reveal roles for the gastrointestinal microbiome in NAFLD. Strategies targeting the gastrointestinal microbiome for the diagnosis and treatment of NAFLD are proposed.
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Affiliation(s)
- Li-Hong He
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,The First Clinical Medical College, Lanzhou University, Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Dun-Han Yao
- The First Clinical Medical College, Lanzhou University, Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ling-Yun Wang
- The First Clinical Medical College, Lanzhou University, Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Lei Zhang
- The First Clinical Medical College, Lanzhou University, Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xue-Li Bai
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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25
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Ghosal S, Datta D, Sinha B. A meta-analysis of the effects of glucagon-like-peptide 1 receptor agonist (GLP1-RA) in nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes (T2D). Sci Rep 2021; 11:22063. [PMID: 34764398 PMCID: PMC8586228 DOI: 10.1038/s41598-021-01663-y] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 11/01/2021] [Indexed: 12/13/2022] Open
Abstract
Treatment options for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), two conditions which coexist, are limited though weight loss is an important strategy to improve outcomes in either disease. Glucagon-like peptide 1 receptor agonist (GLP1-RA) present a novel option to treat this dual disease by their salutary effects on glycaemic control and weight reduction. Eight randomized controlled trials on T2D and NAFLD from the Cochrane Library, Embase, and PubMed were included in this meta-analysis. The Comprehensive Meta-Analysis Software version 3 was used to calculate the effect size. In a pooled population of 615 patients-297 on GLP1-RA and 318 in the control arm, GLP1-RA produced a significant improvement in alanine aminotransferase [standardised mean difference (SDM), - 0.56, 95% CI - 0.88 to - 0.25, P < 0.01], aspartate aminotransferase (SDM, - 0.44, SE, 95% CI - 0.64 to - 0.24, P < 0.01), gamma glutaryl transaminase (SDM, - 0.60, 95% CI - 0.86 to - 0.34, P < 0.01) and reduction in liver fat content (LFC) (SDM, - 0.43, 95% CI - 0.74 to - 0.12, P < 0.01), as well as glycosylated haemoglobin (SDM, - 0.40, 95% CI, - 0.61 to - 0.19, P < 0.01) and weight (SDM, - 0.66, 95% CI, - 0.88 to - 0.44, P < 0.01), in comparison to standard of care or placebo. Significant improvement in biopsy resolution was also seen in the GLP1-RA arm (Rate Ratio, 6.60, 95% CI 2.67 to 16.29, P < 0.01). This is possibly the first meta-analysis conducted exclusively in patients with T2D and NAFLD which presents a strong signal that GLP1-RA, improve liver function and histology by improving glycaemia, reducing body weight and hepatic fat, which in turn reduces hepatic inflammation.Trial Registration: PROSPERO (ID: CRD42021228824).
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26
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van Dalem J, Driessen JHM, Burden AM, Stehouwer CDA, Klungel OH, de Vries F, Brouwers MCGJ. Thiazolidinediones and Glucagon-Like Peptide-1 Receptor Agonists and the Risk of Nonalcoholic Fatty Liver Disease: A Cohort Study. Hepatology 2021; 74:2467-2477. [PMID: 34129693 PMCID: PMC8596626 DOI: 10.1002/hep.32012] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 05/19/2021] [Accepted: 06/13/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Thiazolidinediones (TZDs) and glucagon-like peptide-1 (GLP-1) receptor agonists are potential pharmacological treatment options for patients at risk of NAFLD. Therefore, we examined the association between the risk of NAFLD and the use of TZDs and GLP-1 receptor agonists compared with the use of sulfonylureas (SUs) and insulins. Additionally, we calculated the incidence of HCC in users of TZDs and GLP-1 receptor agonists. APPROACH AND RESULTS We conducted a population-based cohort study using primary care data from the Clinical Practice Research Datalink database (2007-2018). All patients aged ≥18 with a prescription of an oral glucose-lowering agent or GLP-1 receptor agonist were included. The first prescription defined the start of follow-up. The primary outcome was a new diagnosis of NAFLD. Cox proportional hazards regression was used to estimate HRs and 95% CIs of the primary outcome. Incidence rates of HCC were determined per 1,000 person-years for all exposures. The study identified 207,367 adults with a prescription for a glucose-lowering agent. The risk of NAFLD was lower in patients prescribed a TZD than in those prescribed an SU (adjusted HR [aHR], 0.32; 95% CI, 0.20-0.51). No difference in risk of NAFLD was observed comparing GLP-1 receptor agonist use with insulin use (aHR, 1.22; 95% CI, 0.91-1.63). CONCLUSIONS Results of our study endorse the use of TZDs for selected patients at risk of NAFLD but do not support previous findings regarding the beneficial effect of GLP-1 receptor agonists. The low number of events in several subgroups may affect the generalizability of the current findings.
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Affiliation(s)
- Judith van Dalem
- Department of Clinical Pharmacy & ToxicologyMaastricht University Medical Centre+Maastrichtthe Netherlands,CARIM School for Cardiovascular DiseaseMaastricht UniversityMaastrichtthe Netherlands
| | - Johanna H. M. Driessen
- Department of Clinical Pharmacy & ToxicologyMaastricht University Medical Centre+Maastrichtthe Netherlands,CARIM School for Cardiovascular DiseaseMaastricht UniversityMaastrichtthe Netherlands,Division of Pharmacoepidemiology and Clinical PharmacologyUtrecht Institute of Pharmaceutical SciencesUtrechtthe Netherlands,NUTRIM School for Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtthe Netherlands
| | - Andrea M. Burden
- Department of Chemistry and Applied BiosciencesInstitute of Pharmaceutical SciencesETH ZurichZurichSwitzerland
| | - Coen D. A. Stehouwer
- CARIM School for Cardiovascular DiseaseMaastricht UniversityMaastrichtthe Netherlands,Department of Internal MedicineMaastricht University Medical Centre+Maastrichtthe Netherlands
| | - Olaf H. Klungel
- Division of Pharmacoepidemiology and Clinical PharmacologyUtrecht Institute of Pharmaceutical SciencesUtrechtthe Netherlands
| | - Frank de Vries
- Department of Clinical Pharmacy & ToxicologyMaastricht University Medical Centre+Maastrichtthe Netherlands,CARIM School for Cardiovascular DiseaseMaastricht UniversityMaastrichtthe Netherlands,Division of Pharmacoepidemiology and Clinical PharmacologyUtrecht Institute of Pharmaceutical SciencesUtrechtthe Netherlands
| | - Martijn C. G. J. Brouwers
- CARIM School for Cardiovascular DiseaseMaastricht UniversityMaastrichtthe Netherlands,Department of Internal MedicineDivision of Endocrinology and Metabolic DiseaseMaastricht University Medical Centre+Maastrichtthe Netherlands
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27
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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: 5] [Impact Index Per Article: 1.3] [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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28
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Almahmoud MH, Al Khawaja NM, Alkinani A, Khader Y, Ajlouni KM. Prevalence of fatty liver disease and its associated factors among Jordanian patients with type 2 diabetes mellitus: A cross-sectional study. Ann Med Surg (Lond) 2021; 68:102677. [PMID: 34401141 PMCID: PMC8358152 DOI: 10.1016/j.amsu.2021.102677] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/31/2021] [Accepted: 08/03/2021] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is a well-known risk factor for Non-alcoholic fatty liver disease (NAFLD). Patients with type 2 DM (T2DM) who have NAFLD are at a higher risk of developing advanced stages of liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma compared to non-diabetic patients. This study aimed to estimate the prevalence of NAFLD among patients with T2DM, using hepatic ultrasonographic changes combined with derangement of hepatic transaminases level. MATERIALS AND METHODS This cross-sectional study was conducted at the National Center for Diabetes, Endocrinology and Genetics (NCDEG) in Amman, Jordan. A total of 408 patients with T2DM and 90 non-diabetic subjects were included in this study. Body mass index (BMI), waist circumference, glycosylated hemoglobin (HbA1c), lipid parameters and abdominal ultrasonography were measured. RESULTS Using the ultrasonographic criteria for the diagnosis of NAFLD, the prevalence of NAFLD was 80.4 % and 53.3 % among diabetic and non-diabetic participants, respectively. Among the diabetic participants, 25 %, 40.4 %, and 15 % had mild, moderate, and severe grades of steatosis, respectively. On the other hand, 24.4 %, 21.1 %, and 7.8 % of the non-diabetic participants had mild, moderate, and severe grades of steatosis, respectively. Diabetic patients between 25 and 45 years of age, patients with overweight or obesity, patients with increased waist circumference were significantly at higher risk of having NAFLD. High TG, lower HDL, elevated AST and ALT, and using sulfonylureas and metformin versus using metformin only were significantly associated with increased odds of having NAFLD. CONCLUSIONS NAFLD is highly prevalent among patients with T2DM. Overweight or obesity, abnormal cholesterol levels and treatment with sulfonylureas were significantly associated with NAFLD.
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Affiliation(s)
- Malik H. Almahmoud
- The National Center for Diabetes, Endocrinology and Genetics, The University of Jordan, Amman, Jordan
| | | | - Arwa Alkinani
- The National Center for Diabetes, Endocrinology and Genetics, The University of Jordan, Amman, Jordan
| | - Yousef Khader
- Department of Public Health, Jordan University of Science and Technology (JUST), Irbid, Jordan
| | - Kamel M. Ajlouni
- The National Center for Diabetes, Endocrinology and Genetics, The University of Jordan, Amman, Jordan
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29
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Gastaldelli A, Stefan N, Häring HU. Liver-targeting drugs and their effect on blood glucose and hepatic lipids. Diabetologia 2021; 64:1461-1479. [PMID: 33877366 PMCID: PMC8187191 DOI: 10.1007/s00125-021-05442-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 12/18/2020] [Indexed: 12/16/2022]
Abstract
The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), fibroblast growth factor-19 and -21, single, dual or triple incretins, sodium-glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance.
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Affiliation(s)
- Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council-CNR, Pisa, Italy.
| | - Norbert Stefan
- Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany.
- Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, Tübingen, Germany.
- German Center for Diabetes Research, Neuherberg, Germany.
| | - Hans-Ulrich Häring
- Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, Tübingen, Germany
- German Center for Diabetes Research, Neuherberg, Germany
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30
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Finotti M, Romano M, Auricchio P, Scopelliti M, Brizzolari M, Grossi U, Piccino M, Benvenuti S, Morana G, Cillo U, Zanus G. Target Therapies for NASH/NAFLD: From the Molecular Aspect to the Pharmacological and Surgical Alternatives. J Pers Med 2021; 11:499. [PMID: 34199535 PMCID: PMC8229090 DOI: 10.3390/jpm11060499] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 05/25/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease represents an increasing cause of chronic hepatic disease in recent years. This condition usually arises in patients with multiple comorbidities, the so-called metabolic syndrome. The therapeutic options are multiple, ranging from lifestyle modifications, pharmacological options, to liver transplantation in selected cases. The choice of the most beneficial one and their interactions can be challenging. It is mandatory to stratify the patients according to the severity of their disease to tailor the available treatments. In our contribution, we review the most recent pharmacological target therapies, the role of bariatric surgery, and the impact of liver transplantation on the NAFLD outcome.
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Affiliation(s)
- Michele Finotti
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Maurizio Romano
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Pasquale Auricchio
- Hepatobiliary Surgery and Liver Transplantation Unit, DISCOG, University of Padua, 35121 Padua, Italy; (P.A.); (U.C.)
| | - Michele Scopelliti
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Marco Brizzolari
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Ugo Grossi
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Marco Piccino
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Stefano Benvenuti
- Gastroenterology Unit (IV), Cà Foncello Regional Hospital, 31100 Treviso, Italy;
| | - Giovanni Morana
- Division of Radiology, Treviso Regional Hospital, 31100 Treviso, Italy;
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, DISCOG, University of Padua, 35121 Padua, Italy; (P.A.); (U.C.)
| | - Giacomo Zanus
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
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31
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Song T, Jia Y, Li Z, Wang F, Ren L, Chen S. Effects of Liraglutide on Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Diabetes Ther 2021; 12:1735-1749. [PMID: 34002333 PMCID: PMC8179869 DOI: 10.1007/s13300-021-01072-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/01/2021] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity of type 2 diabetes mellitus (T2DM), and no approved therapies are currently available. A meta-analysis was performed to investigate the effects of liraglutide on NAFLD in patients with T2DM. METHODS Medline (via PubMed), Embase (via Elsevier), and the Cochrane Central Register of Controlled Trials (CENTRAL) (via Cochrane Library) from inception to April 2020 were searched. After screening the literature and extracting data, we assessed the risk of bias of the eligible studies. The Cochrane Collaboration's RevMan software program was used for the statistical analysis. RESULTS Eleven trials involving 535 patients were included for the final analysis. Compared to the placebo or control group, liraglutide decreased liver fat (LF) (insulin: mean difference MD - 2.50, 95% confidence interval [CI] - 4.30 to - 0.70), body mass index (BMI) (placebo: MD - 1.13, 95% CI - 2.03 to - 0.23; pioglitazone: MD - 4.10, 95% CI - 6.27 to - 1.93; metformin: MD - 1.07, 95% CI - 2.06 to - 0.08; insulin: MD - 1.01, 95% CI - 1.60 to - 0.43), lipoproteins, including high-density (insulin: MD - 0.10, 95% CI - 0.15 to - 0.05) and low-density lipoproteins (MD - 0.26, 95% CI - 0.43 to - 0.10), glycated hemoglobin A1c (HbA1c) (placebo: MD - 0.86; 95% CI - 1.22 to - 0.51; insulin: MD - 0.22, 95% CI - 0.41 to - 0.04), total cholesterol (placebo: MD - 0.34, 95% CI - 0.65 to - 0.03; metformin: MD 0.09, 95% CI 0.01-0.18), and triglycerides (placebo: MD - 0.29, 95% CI - 0.57 to - 0.01; insulin: MD - 0.80, 95% CI - 1.03 to - 0.57). Liraglutide may be associated with increased gastrointestinal reactions compared to pioglitazone. CONCLUSION These findings revealed that liraglutide decreased LF, BMI, lipids, or HbA1c in T2DM patients complicated with NAFLD, indicating its potential therapeutic efficacy.
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Affiliation(s)
- Tiantian Song
- Graduate School of Hebei Medical University, Shijiazhuang, China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - Yujiao Jia
- Graduate School of Hebei Medical University, Shijiazhuang, China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - Zelin Li
- Graduate School of Hebei Medical University, Shijiazhuang, China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - Fei Wang
- Graduate School of Hebei Medical University, Shijiazhuang, China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - Luping Ren
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
- Hebei Key Laboratory of Metabolic Diseases, Graduate School of Hebei Medical University, Shijiazhuang, China
| | - Shuchun Chen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China.
- Hebei Key Laboratory of Metabolic Diseases, Graduate School of Hebei Medical University, Shijiazhuang, China.
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Zhou R, Lin C, Cheng Y, Zhuo X, Li Q, Xu W, Zhao L, Yang L. Liraglutide Alleviates Hepatic Steatosis and Liver Injury in T2MD Rats via a GLP-1R Dependent AMPK Pathway. Front Pharmacol 2021; 11:600175. [PMID: 33746742 PMCID: PMC7970416 DOI: 10.3389/fphar.2020.600175] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), ranging from non-alcoholic fatty liver to non-alcoholic steatohepatitis, can be prevalent in patients with type 2 diabetes mellitus (T2DM). However, no antidiabetic drug has been approved for the treatment of NAFLD in T2DM patients. Multiple daily injections of basal-bolus insulin are often the final therapeutic option for T2DM. We found that insulin treatment aggravated hepatic steatosis and oxidative stress in Zucker diabetic fatty (ZDF) rats. In addition to glycaemic control, we demonstrated the stimulatory role of liraglutide in relieving hepatic steatosis and liver injury in ZDF rats. Interestingly, liraglutide could also alleviate insulin-aggravated hepatic fatty accumulation. The glucagon-like peptide-1 (GLP-1) agonists liraglutide and Ex-4 activated the expression of peroxisome proliferator-activated receptor alpha (PPARα) via a GLP-1 receptor-dependent 5′ AMP-activated protein kinase pathway. As a nuclear transcription factor, PPARα could mediate the effect of GLP-1 in alleviating hepatic steatosis by differentially regulating the expression of its target genes, including acetyl CoA carboxylase and carnitine palmitoyl transferase la both in vitro and in vivo. Moreover, GLP-1 could relieve liver injury by decreasing oxidative stress stimulated by hepatic steatosis. Insulin might aggravate hepatic steatosis and liver injury by inhibiting GLP-1R expression. The findings indicate the feasibility of liraglutide treatment combined with basal insulin in attenuating hepatic steatosis and liver injury in ZDF rats. This knowledge, and the evidence for the underlying mechanism, provide a theoretical basis for the combination treatment recommended by the latest clinical practice guidelines for T2DM.
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Affiliation(s)
- Rui Zhou
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Chuman Lin
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yanzhen Cheng
- Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyun Zhuo
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Qinghua Li
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Wen Xu
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liang Zhao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Li Yang
- Department of Nutrition, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Rados DV, Falcetta MRR, Pinto LC, Leitão CB, Gross JL. All-cause mortality and cardiovascular safety of basal insulin treatment in patients with type 2 diabetes mellitus: A systematic review with meta-analysis and trial sequential analysis. Diabetes Res Clin Pract 2021; 173:108688. [PMID: 33549676 DOI: 10.1016/j.diabres.2021.108688] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 09/04/2020] [Accepted: 01/24/2021] [Indexed: 11/29/2022]
Abstract
AIM To evaluate the risk of all-cause and cardiovascular mortality, acute myocardial infarction, and stroke associated with insulin treatment in patients with type 2 diabetes. METHODS A systematic review with meta-analysis of randomized clinical trials (RCTs) was performed. EMBASE, Cochrane, and PubMed databases were searched for RCTs reporting mortality or cardiovascular events and comparing basal insulin to any treatment in patients with type 2 diabetes. Data were summarized with Mantel-Haenzel relative risk (RR). Trial sequential analysis (TSA) was used to evaluate the reliability of the results considering a 20% relative risk difference between treatments. PROSPERO Registry: CRD42018087336. RESULTS In total, 2351 references were identified, and 26 studies (24348 patients) were included. Most studies evaluated glargine insulin (69%), compared insulin to GLP-1 analogs (57%), and evaluated add-on therapy with metformin (77%). Insulin was not associated with increased all-cause mortality (RR 0.99; 95% confidence interval (CI) 0.92-1.06), cardiovascular mortality (RR 1.01; 95% CI 0.91-1.13), myocardial infarction (RR 1.02; 95% CI 0.92-1.15), or stroke (RR 0.87; 95% CI 0.68-1.12). Insulin treatment increased severe hypoglycemia risk (RR 2.98; 95% CI 2.47-3.61). All analyses had low statistical heterogeneity. TSA confirmed these findings: optimal sample size (myocardial infarction), futility boundary (all-cause mortality, cardiovascular mortality, and stroke) and harm boundary (hypoglycemia) were reached. CONCLUSION Treatment with basal insulin of patients with type 2 diabetes does not increase the risk of cardiovascular events or death. Despite the increased risk of hypoglycemia, these findings reinforce that insulin is a safe option in the treatment of type 2 diabetes.
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Affiliation(s)
- Dimitris Varvaki Rados
- Division of Endocrinology, Hospital de Clínicas de Porto Alegre/Post-graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2350, Prédio 12, 4 andar, Porto Alegre, RS 90035-903, Brazil.
| | - Mariana Rangel Ribeiro Falcetta
- Division of Endocrinology, Hospital de Clínicas de Porto Alegre/Post-graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2350, Prédio 12, 4 andar, Porto Alegre, RS 90035-903, Brazil
| | - Lana Catani Pinto
- Division of Endocrinology, Hospital de Clínicas de Porto Alegre/Post-graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2350, Prédio 12, 4 andar, Porto Alegre, RS 90035-903, Brazil
| | - Cristiane Bauermann Leitão
- Division of Endocrinology, Hospital de Clínicas de Porto Alegre/Post-graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2350, Prédio 12, 4 andar, Porto Alegre, RS 90035-903, Brazil.
| | - Jorge Luiz Gross
- Division of Endocrinology, Hospital de Clínicas de Porto Alegre/Post-graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2350, Prédio 12, 4 andar, Porto Alegre, RS 90035-903, Brazil
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Jensen VS, Fledelius C, Zachodnik C, Damgaard J, Nygaard H, Tornqvist KS, Kirk RK, Viuff BM, Wulff EM, Lykkesfeldt J, Hvid H. Insulin treatment improves liver histopathology and decreases expression of inflammatory and fibrogenic genes in a hyperglycemic, dyslipidemic hamster model of NAFLD. J Transl Med 2021; 19:80. [PMID: 33596938 PMCID: PMC7890970 DOI: 10.1186/s12967-021-02729-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/29/2021] [Indexed: 11/24/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent comorbidities in patients with Type 2 diabetes. While many of these patients eventually will need treatment with insulin, little is known about the effects of insulin treatment on histopathological parameters and hepatic gene expression in diabetic patients with co-existing NAFLD and NASH. To investigate this further, we evaluated the effects of insulin treatment in NASH diet-fed hamsters with streptozotocin (STZ) -induced hyperglycemia. Methods Forty male Syrian hamsters were randomized into four groups (n = 10/group) receiving either a NASH-inducing (high fat, fructose and cholesterol) or control diet (CTRL) for four weeks, after which they were treated with STZ or sham-injected and from week five treated with either vehicle (CTRL, NASH, NASH-STZ) or human insulin (NASH-STZ-HI) for four weeks by continuous s.c. infusion via osmotic minipumps. Results NASH-STZ hamsters displayed pronounced hyperglycemia, dyslipidemia and more severe liver pathology compared to both CTRL and NASH groups. Insulin treatment attenuated dyslipidemia in NASH-STZ-HI hamsters and liver pathology was considerably improved compared to the NASH-STZ group, with prevention/reversal of hepatic steatosis, hepatic inflammation and stellate cell activation. In addition, expression of inflammatory and fibrotic genes was decreased compared to the NASH-STZ group. Conclusions These results suggest that hyperglycemia is important for development of inflammation and profibrotic processes in the liver, and that insulin administration has beneficial effects on liver pathology and expression of genes related to inflammation and fibrosis in a hyperglycemic, dyslipidemic hamster model of NAFLD.
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Affiliation(s)
- Victoria Svop Jensen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg, Denmark. .,Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark.
| | - Christian Fledelius
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | - Christina Zachodnik
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | - Jesper Damgaard
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | - Helle Nygaard
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | | | - Rikke Kaae Kirk
- Pathology & Imaging, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | | | - Erik Max Wulff
- Gubra ApS, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
| | - Jens Lykkesfeldt
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg, Denmark
| | - Henning Hvid
- Pathology & Imaging, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
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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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Li X, Wu X, Jia Y, Fu J, Zhang L, Jiang T, Liu J, Wang G. Liraglutide Decreases Liver Fat Content and Serum Fibroblast Growth Factor 21 Levels in Newly Diagnosed Overweight Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. J Diabetes Res 2021; 2021:3715026. [PMID: 34660809 PMCID: PMC8519721 DOI: 10.1155/2021/3715026] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/14/2021] [Accepted: 09/20/2021] [Indexed: 12/14/2022] Open
Abstract
PURPOSES In this study, we aimed to verify plasma fibroblast growth factor 21 (FGF21) elevation in newly diagnosed overweight patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) and to evaluate the effectiveness of liraglutide on reducing liver fat content and serum (FGF21) levels in those patients. METHODS A 12-week, single-center, prospective study was conducted. Twenty newly diagnosed overweight patients with T2DM and NAFLD were recruited. Twenty healthy age, sex, and body mass index (BMI) matched subjects were enrolled as the control group. Enzyme-linked immunosorbent assay was used to measure serum FGF21 levels. Liver fat content was determined using the 3.0 T whole-body MRI scanner. RESULTS Those newly diagnosed overweight patients with T2DM and NAFLD had a BMI of 27.6 ± 0.5 kg/m2. They had higher levels of FGF21 (159.6 ± 35.7 vs. 124.1 ± 42.9 pg/ml, P < 0.001) and increased liver fat content (19.3 ± 9.4 vs. 4.5 ± 0.6%, P < 0.001) compared to the controls. Liraglutide treatment for 12 weeks induced a significant 4.9 kg weight loss (95% confidence interval (CI): -6.1, -3.7, P < 0.001), which was equivalent to a relative reduction of 6.8% (95% CI: 5.3%, 8.3%, P < 0.001). FGF21 levels decreased after the 12-week liraglutide treatment (159.6 ± 35.7 vs. 124.2 ± 27.8 pg/ml, P = 0.006). There was a positive correlation between relative changes of liver fat content and relative change of FGF21 (r = 0.645, P = 0.002). FGF21 levels significantly decreased in patients who had a significant decrease in liver fat content (≥29%) (95% CI: -262.8, -55.1, P = 0.006); however, there was no significant change in the patients without a significant decrease in liver fat content (<29%) (95% CI: -60.0, 54.1, P = 0.899). CONCLUSIONS Liraglutide treatment reduced both liver fat content and FGF21 levels in newly diagnosed overweight patients with T2DM and NAFLD. FGF21 may be a potential biomarker for evaluating the effects of liraglutide treatment on hepatic fat and glucose metabolism.
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Affiliation(s)
- Xinyue Li
- Department of Radiology, Beijing Chao Yang Hospital, Capital Medical University, No. 8, Gong ti South Road, Chao Yang District, Beijing 100020, China
| | - Xiaojuan Wu
- Department of Endocrinology, Beijing Chao Yang Hospital, Capital Medical University, No. 8, Gong ti South Road, Chao Yang District, Beijing 100020, China
| | - Yumei Jia
- Department of Endocrinology, Beijing Chao Yang Hospital, Capital Medical University, No. 8, Gong ti South Road, Chao Yang District, Beijing 100020, China
| | - Jing Fu
- Department of Endocrinology, Beijing Chao Yang Hospital, Capital Medical University, No. 8, Gong ti South Road, Chao Yang District, Beijing 100020, China
| | - Lin Zhang
- Department of Endocrinology, Beijing Chao Yang Hospital, Capital Medical University, No. 8, Gong ti South Road, Chao Yang District, Beijing 100020, China
| | - Tao Jiang
- Department of Radiology, Beijing Chao Yang Hospital, Capital Medical University, No. 8, Gong ti South Road, Chao Yang District, Beijing 100020, China
| | - Jia Liu
- Department of Endocrinology, Beijing Chao Yang Hospital, Capital Medical University, No. 8, Gong ti South Road, Chao Yang District, Beijing 100020, China
| | - Guang Wang
- Department of Endocrinology, Beijing Chao Yang Hospital, Capital Medical University, No. 8, Gong ti South Road, Chao Yang District, Beijing 100020, China
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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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Godinez-Leiva E, Bril F. Nonalcoholic Fatty Liver Disease (NAFLD) for Primary Care Providers: Beyond the Liver. Curr Hypertens Rev 2020; 17:94-111. [DOI: 10.2174/1573402116999201209203534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 08/20/2020] [Accepted: 09/15/2020] [Indexed: 11/22/2022]
Abstract
Abstract::
Nonalcoholic fatty liver disease (NAFLD) has consolidated as a major public health problem, affecting ~25% of the global population. This percentage is significantly higher in the setting of obesity and/or type 2 diabetes. Presence of NAFLD is associated with severe liver complications, such as nonalcoholic steatohepatitis (NASH; i.e., presence of inflammation and necrosis), cirrhosis and hepatocellular carcinoma. However, the majority of these patients die of cardiovascular disease. For this reason, management of this condition requires a multidisciplinary team, where primary care providers are at center stage. However, important misconceptions remain among primary care providers, preventing them from appropriately approach these patients. Nonalcoholic fatty liver disease should be understood as part of a systemic disease, characterized for abnormal accumulation of fat in tissues other than the adipose tissue. This, in turn, produces dysfunction of those organs or tissues (process sometimes referred to as lipotoxicity). Therefore, due to the systemic nature of this condition, it should not surprise that NAFLD is closely related to other metabolic conditions. In this review, we will focus on the extrahepatic manifestations of NAFLD and its metabolic and cardiovascular implications. We believe these are the most important issues primary care providers should understand, in order to effectively manage these complicated patients. In addition, we have provided a simple and straightforward approach to the diagnosis and treatment of patients with NAFLD and/or NASH. We hope this review will serve as a guide for primary care providers to approach their patients with NAFLD.
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Affiliation(s)
- Eddison Godinez-Leiva
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL;, United States
| | - Fernando Bril
- Internal Medicine, Department of Medicine, University of Alabama in Birmingham, Birmingham, AL., United States
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Guo W, Tian W, Lin L, Xu X. Liraglutide or insulin glargine treatments improves hepatic fat in obese patients with type 2 diabetes and nonalcoholic fatty liver disease in twenty-six weeks: A randomized placebo-controlled trial. Diabetes Res Clin Pract 2020; 170:108487. [PMID: 33035599 DOI: 10.1016/j.diabres.2020.108487] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/23/2020] [Accepted: 09/24/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus is closely related to nonalcoholic fatty liver disease(NAFLD). More and more attention has been paid to the efficacy of liraglutide in the treatment of NAFLD, but the clinical evidence is still insufficient. OBJECTIVE The purpose of this study was to use proton magnetic resonance spectroscopy (H-MRS) assessment of metformin alone poor blood glucose control of obese patients type 2 diabetes with NAFLD, added with insulin glargine, liraglutide or placebo effect in improving the fatty liver. METHODS This is a 26-week, single-center, prospective, randomized placebo-controlled study. From September 2016 to July 2018, 128 patients with type 2 diabetes and NAFLD were enrolled in the China joint logistics team 900 hospital. The primary endpoints were the changes in intrahepatic content of lipid (IHCL), abdominal adiposity [subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)], from baseline to week 26 (end of treatment) and the changes in liraglutide group or insulin glargine group versus change in placebo group. Secondary endpoints included the changes in liver function (AST and ALT), glycemia (HbA1c and FPG), body weight, and BMI. RESULTS A total of 96 patients with type 2 diabetes and NAFLD under inadequate glycemic control by metformin were randomized (1:1:1) to receive add-on insulin glargine, liraglutide, or placebo. After 26 weeks of treatment, compared to the placebo group, in the liraglutide and insulin glargine groups, IHCL significantly decreased from baseline to week 26 (liraglutide 26.4% ± 3.2% to 20.6% ± 3.9%, P < 0.05; insulin glargine 25.0% ± 4.3% to 22.6% ± 5.8%, P > 0.05). SAT and VAT decreased significantly in the liraglutide group and in the insulin glargine group (P < 0.05). ΔSAT and ΔVAT were greater with liraglutide than insulin glargine, they were significantly different between the two groups (ΔSAT, -36 vs. - 24.5, P < 0.05; and ΔVAT, -47 vs. - 16.6, P > 0.05). In the liraglutide group, AST, ALT, and HOMA-IR decreased significantly from baseline. There was no significant difference in glucose-lowering among the three groups. During the treatment, the safety of the three groups performed well. CONCLUSION Compared with placebo, treatment with liraglutide plus an adequate dose of metformin (2000 g/ day) for 26 weeks is more effective in reducing IHCL, SAT and VAT in patients with type 2 diabetes and NAFLD. And it has additional advantages in weight loss, waist circumference reduction and liver function improvement.
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Affiliation(s)
- Wen Guo
- 900 Hospital of the Joint Logistics Team, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 365000, Fujian, China
| | - Wenjun Tian
- 900 Hospital of the Joint Logistics Team, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 365000, Fujian, China
| | - Lu Lin
- 900 Hospital of the Joint Logistics Team, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 365000, Fujian, China
| | - Xiangjin Xu
- 900 Hospital of the Joint Logistics Team, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou 365000, Fujian, China.
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Kuchay MS, Krishan S, Mishra SK, Choudhary NS, Singh MK, Wasir JS, Kaur P, Gill HK, Bano T, Farooqui KJ, Mithal A. Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial). Diabetologia 2020; 63:2434-2445. [PMID: 32865597 DOI: 10.1007/s00125-020-05265-7] [Citation(s) in RCA: 150] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 07/22/2020] [Indexed: 02/08/2023]
Abstract
AIMS/HYPOTHESIS Liraglutide, a daily injectable glucagon-like peptide-1 receptor (GLP-1r) agonist, has been shown to reduce liver fat content (LFC) in humans. Data regarding the effect of dulaglutide, a once-weekly GLP-1r agonist, on human LFC are scarce. This study examined the effect of dulaglutide on LFC in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). METHODS Effect of dulaglutide on liver fat (D-LIFT) was a 24 week, open-label, parallel-group, randomised controlled trial to determine the effect of dulaglutide on liver fat at a tertiary care centre in India. Adults (n = 64), who had type 2 diabetes and MRI-derived proton density fat fraction-assessed LFC of ≥6.0% at baseline, were randomly assigned to receive dulaglutide weekly for 24 weeks (add-on to usual care) or usual care, based on a predefined computer-generated number with a 1:1 allocation that was concealed using serially numbered, opaque, sealed envelopes. The primary endpoint was the difference of the change in LFC from 0 (baseline) to 24 weeks between groups. The secondary outcome measures included the difference of the change in pancreatic fat content (PFC), change in liver stiffness measurement (LSM in kPa) measured by vibration-controlled transient elastography, and change in liver enzymes. RESULTS Eighty-eight patients were screened; 32 were randomly assigned to the dulaglutide group and 32 to the control group. Overall, 52 participants were included for per-protocol analysis: those who had MRI-PDFF data at baseline and week 24. Dulaglutide treatment resulted in a control-corrected absolute change in LFC of -3.5% (95% CI -6.6, -0.4; p = 0.025) and relative change of -26.4% (-44.2, -8.6; p = 0.004), corresponding to a 2.6-fold greater reduction. Dulaglutide-treated participants also showed a significant reduction in γ-glutamyl transpeptidase (GGT) levels (mean between-group difference -13.1 U/l [95% CI -24.4, -1.8]; p = 0.025) and non-significant reductions in aspartate aminotransferase (AST) (-9.3 U/l [-19.5, 1.0]; p = 0.075) and alanine aminotransferase (ALT) levels (-13.1 U/l [-24.4, 2.5]; p = 0.10). Absolute changes in PFC (-1.4% [-3.2, 0.3]; p = 0.106) and LSM (-1.31 kPa [-2.99, 0.37]; p = 0.123) were not significant when comparing the two groups. There were no serious drug-related adverse events. CONCLUSIONS/INTERPRETATION When included in the standard treatment for type 2 diabetes, dulaglutide significantly reduces LFC and improves GGT levels in participants with NAFLD. There were non-significant reductions in PFC, liver stiffness, serum AST and serum ALT levels. Dulaglutide could be considered for the early treatment of NAFLD in patients with type 2 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT03590626 FUNDING: The current study was supported by an investigator-initiated study grant from Medanta-The Medicity's departmental research fund and a grant from the Endocrine and Diabetes Foundation (EDF), India. Graphical abstract.
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Affiliation(s)
- Mohammad S Kuchay
- Division of Endocrinology and Diabetes, Medanta-The Medicity Hospital, Haryana, India.
| | - Sonal Krishan
- Department of Radiology, Medanta-The Medicity Hospital, Haryana, India
| | - Sunil K Mishra
- Division of Endocrinology and Diabetes, Medanta-The Medicity Hospital, Haryana, India
| | - Narendra S Choudhary
- Institute of Digestive and Hepatobiliary Sciences, Medanta-The Medicity Hospital, Haryana, India
| | - Manish K Singh
- Department of Clinical Research and Studies, Medanta-The Medicity Hospital, Haryana, India
| | - Jasjeet S Wasir
- Division of Endocrinology and Diabetes, Medanta-The Medicity Hospital, Haryana, India
| | - Parjeet Kaur
- Division of Endocrinology and Diabetes, Medanta-The Medicity Hospital, Haryana, India
| | - Harmandeep K Gill
- Division of Endocrinology and Diabetes, Medanta-The Medicity Hospital, Haryana, India
| | - Tarannum Bano
- Division of Endocrinology and Diabetes, Medanta-The Medicity Hospital, Haryana, India
| | - Khalid J Farooqui
- Division of Endocrinology and Diabetes, Medanta-The Medicity Hospital, Haryana, India
| | - Ambrish Mithal
- Division of Endocrinology and Diabetes, Medanta-The Medicity Hospital, Haryana, India
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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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Abstract
Abstract
Background
Organisms show an incredibly diverse array of body and organ shapes that are both unique to their taxon and important for adapting to their environment. Achieving these specific shapes involves coordinating the many processes that transform single cells into complex organs, and regulating their growth so that they can function within a fully-formed body.
Main text
Conceptually, body and organ shape can be separated in two categories, although in practice these categories need not be mutually exclusive. Body shape results from the extent to which organs, or parts of organs, grow relative to each other. The patterns of relative organ size are characterized using allometry. Organ shape, on the other hand, is defined as the geometric features of an organ’s component parts excluding its size. Characterization of organ shape is frequently described by the relative position of homologous features, known as landmarks, distributed throughout the organ. These descriptions fall into the domain of geometric morphometrics.
Conclusion
In this review, we discuss the methods of characterizing body and organ shape, the developmental programs thought to underlie each, highlight when and how the mechanisms regulating body and organ shape might overlap, and provide our perspective on future avenues of research.
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Vedtofte L, Bahne E, Foghsgaard S, Bagger JI, Andreasen C, Strandberg C, Gørtz PM, Holst JJ, Grønbæk H, Svare JA, Clausen TD, Mathiesen ER, Damm P, Gluud LL, Knop FK, Vilsbøll T. One Year's Treatment with the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Decreases Hepatic Fat Content in Women with Nonalcoholic Fatty Liver Disease and Prior Gestational Diabetes Mellitus in a Randomized, Placebo-Controlled Trial. J Clin Med 2020; 9:jcm9103213. [PMID: 33036179 PMCID: PMC7601647 DOI: 10.3390/jcm9103213] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/25/2020] [Accepted: 10/02/2020] [Indexed: 12/20/2022] Open
Abstract
Prior gestational diabetes mellitus (pGDM) is associated with increased risk of nonalcoholic fatty liver disease (NAFLD). Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue liraglutide on NAFLD features in women with pGDM. Eighty-two overweight/obese, nondiabetic women with pGDM were included. We performed abdominal ultrasound, transient elastography with controlled attenuation parameter (CAP), and blood sampling at baseline and after 1 year. Thirty-seven women were randomized to liraglutide (1.8 mg once-daily) and 45 to placebo. Based on the ultrasound scan, 18 women (22%) had ultrasound-verified NAFLD at baseline and of these, 10 (56%) received liraglutide treatment. After 1 year, eight participants no longer had steatosis, four in each treatment group. The number of participants who developed NAFLD was similar in the two treatment groups; five in the liraglutide group and six in the placebo group (p = 0.74). Compared to placebo, liraglutide reduced the CAP-assessed intrahepatic fat content (−28 (−44;−11) vs. 2 (−13;18) dB/m, p < 0.01) and body weight (−4.7 (−6.4;−2.9) vs. −1.4 (−3;0.3) kg, p < 0.01). One-year’s liraglutide treatment had no effect on the presence of ultrasound-diagnosed NAFLD in overweight/obese nondiabetic women with pGDM, but reduced body weight and steatosis assessed by transient elastography with CAP.
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Affiliation(s)
- Louise Vedtofte
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820 Gentofte, Denmark; (L.V.); (E.B.); (S.F.); (J.I.B.); (C.A.); (F.K.K.)
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, 2900 Hellerup, Denmark
| | - Emilie Bahne
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820 Gentofte, Denmark; (L.V.); (E.B.); (S.F.); (J.I.B.); (C.A.); (F.K.K.)
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, 2900 Hellerup, Denmark
| | - Signe Foghsgaard
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820 Gentofte, Denmark; (L.V.); (E.B.); (S.F.); (J.I.B.); (C.A.); (F.K.K.)
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, 2900 Hellerup, Denmark
- Danish Diabetes Academy, Odense University Hospital, Kløvervænget 6, Entrance 93, 8th floor, 5000 Odense C, Denmark
| | - Jonatan I. Bagger
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820 Gentofte, Denmark; (L.V.); (E.B.); (S.F.); (J.I.B.); (C.A.); (F.K.K.)
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, 2900 Hellerup, Denmark
| | - Camilla Andreasen
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820 Gentofte, Denmark; (L.V.); (E.B.); (S.F.); (J.I.B.); (C.A.); (F.K.K.)
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, 2900 Hellerup, Denmark
| | - Charlotte Strandberg
- Department of Radiology, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 4A, 2900 Hellerup, Denmark;
| | - Peter M. Gørtz
- Department of Nuclear Medicine, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 2, 1st floor, 2900 Hellerup, Denmark;
| | - Jens J. Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark;
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
| | - Henning Grønbæk
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, University of Aarhus, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark;
| | - Jens A. Svare
- Department of Obstetrics and Gynaecology, Herlev Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 21, 2730 Herlev, Denmark;
| | - Tine D. Clausen
- Department of Gynaecology and Obstetrics, Nordsjaellands Hospital, University of Copenhagen, Dyrehavevej 29, 3400 Hillerød, Denmark;
| | - Elisabeth R. Mathiesen
- Center for Pregnant Women with Diabetes, Department of Endocrinology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark;
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark; (P.D.); (L.L.G.)
| | - Peter Damm
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark; (P.D.); (L.L.G.)
- Center for Pregnant Women with Diabetes, Department of Obstetrics, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark
| | - Lise L. Gluud
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark; (P.D.); (L.L.G.)
- Gastrounit, Hvidovre Hospital, University of Copenhagen, Kettegård Allé 30, 2650 Hvidovre, Denmark
| | - Filip K. Knop
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820 Gentofte, Denmark; (L.V.); (E.B.); (S.F.); (J.I.B.); (C.A.); (F.K.K.)
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, 2900 Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark; (P.D.); (L.L.G.)
| | - Tina Vilsbøll
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820 Gentofte, Denmark; (L.V.); (E.B.); (S.F.); (J.I.B.); (C.A.); (F.K.K.)
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, 2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark; (P.D.); (L.L.G.)
- Correspondence: ; Tel.: +45-4094-0825
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Budd J, Cusi K. Role of Agents for the Treatment of Diabetes in the Management of Nonalcoholic Fatty Liver Disease. Curr Diab Rep 2020; 20:59. [PMID: 33015726 DOI: 10.1007/s11892-020-01349-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/10/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver disease (NAFLD) is an often unrecognized complication of type 2 diabetes (T2DM) associated with significant economic burden and poor long-term hepatic and extrahepatic outcomes. Our goal is to review evidence about the complex association between NAFLD and T2DM and highlight the potential for disease co-management with the available medications used for the treatment of diabetes. RECENT FINDINGS A milieu of metabolic factors such as insulin resistance, glucotoxicity, and lipotoxicity, as well as genetics and other factors, contribute to the pathogenesis and co-existence of NAFLD with T2DM. The presence of T2DM in patients with NAFLD increases the risk of disease progression to steatohepatitis (NASH) and advanced fibrosis, cirrhosis, and even hepatocellular carcinoma. In addition to lifestyle modification, pioglitazone and glucagon-like peptide 1 receptor agonists (GLP-1RAs) both reduce the high cardiovascular risk and improve liver histology in patients with NAFLD. Sodium-glucose cotransporter (SGLT-2) inhibitors also appear to reverse metabolic abnormalities as well as liver disease in NAFLD, but their impact on liver histology has not been fully established. Lastly, metformin, dipeptidyl dipetidase-4 (DPP-4) inhibitors, and insulin appear to have modest to no effect on modifying the natural history of NAFLD. Early recognition of NAFLD and monitoring for NASH with advanced liver fibrosis in patients with T2DM are crucial. The presence of NASH in a patient with T2DM should call for taking advantage of antidiabetic medications with proven efficacy to improve cardiometabolic health and prevent liver disease progression.
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Affiliation(s)
- Jeffrey Budd
- Divisions of General Internal Medicine, University of Florida, Gainesville, FL, USA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, 1600 SW Archer Road, room H-2, Gainesville, FL, 32610, USA.
- Malcom Randall VAMC, Gainesville, FL, USA.
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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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Fang T, Huang S, Chen Y, Chen Z, Chen J, Hu W. Glucagon Like Peptide-1 Receptor Agonists Alters Pancreatic and Hepatic Histology and Regulation of Endoplasmic Reticulum Stress in High-fat Diet Mouse Model. Exp Clin Endocrinol Diabetes 2020; 129:625-633. [PMID: 32961563 DOI: 10.1055/a-1240-4936] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Obesity is a major health problem worldwide, and non-alcoholic fatty pancreas disease (NAFPD) and non-alcoholic fatty liver disease (NAFLD) are obesity-associated complications. Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, has been approved for treatment of obesity. We aimed to evaluate the therapeutic effects of liraglutide on the complications through its regulation of endoplasmic reticulum (ER) stress. METHODS A high-fat diet mouse model was established in C57BL/6J mice. Two groups of mice were fed a high-fat diet with 60% fat for 16 weeks and control mice were fed standard chow. A four-week 0.6 mg/kg/day liraglutide treatment was started in one high-fat diet group after 12 weeks of the high-fat diet. After sacrificing the mice, pancreatic and hepatic tissues were prepared for western blot and immunohistochemistry for ER stress proteins, including activating transcription factor 4 (ATF4), caspase 12, C/EBP homologous protein (CHOP) eukaryotic initiation factor 2 α (eIF2α), glucose regulated protein (GRP) 78 and protein kinase RNA-like endoplasmic reticulum kinase (PERK). RESULTS Liraglutide significantly decreased body weight gained by mice consuming a high-fat diet (27.6 g vs. 34.5 g, P<0.001), and levels of all ER proteins increased significantly in both the pancreas and liver (all P<0.05). Expression of most ER stress proteins in pancreatic tissue correlated with disease scores of NAFLD (all P<0.05). However, no significant differences were found in pancreatic ATF 4 expression between mice without NAFLD, and those with early non-alcoholic steatohepatitis (NASH) and fibrotic NASH (P=0.122). CONCLUSION Liraglutide reduces the severity of NAFPD and NAFLD may through regulating the ER stress pathway and downstream apoptosis signaling.
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Affiliation(s)
- Taiyong Fang
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Siying Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Yongpeng Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Zongchi Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Jiangmu Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Weitao Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
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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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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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Rigato M, Avogaro A, Vigili de Kreutzenberg S, Fadini GP. Effects of Basal Insulin on Lipid Profile Compared to Other Classes of Antihyperglycemic Agents in Type 2 Diabetic Patients. J Clin Endocrinol Metab 2020; 105:5818381. [PMID: 32271381 DOI: 10.1210/clinem/dgaa178] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 04/08/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The lipid profile represents a driver of cardiovascular risk in type 2 diabetes. The effect of chronic insulin therapy on cholesterol levels is unclear. We aim to evaluate the effect of basal insulin on lipid profile compared to other classes of antihyperglycemic agents in type 2 diabetic patients. DESIGN We performed a meta-analysis of randomized controlled trials reporting changes of lipid parameters in type 2 diabetic patients randomly assigned to basal insulin or other classes of anti-hyperglycemic agents. RESULTS The levels of total (TC) and low-density lipoprotein cholesterol (LDL-C) appeared to be significantly reduced by therapies with glucagon-like peptide-1 receptor agonists (GLP-1RA) in comparison to basal insulin (mean difference [MD] -3.80; 95% CI [-6.30 to -1.30] mg/dL, P < .001 and -4.17; 95% CI [-6.04 to -2.30] mg/dL, P < .0001), whereas no difference was detected between basal insulin and dipeptidyl peptidase-4 inhibitors (DPP4-I) or standard therapy (sulfonylurea ± metformin). Thiazolidinediones (TZD) produced a significant improvement in high-density lipoprotein cholesterol (HDL-C) (MD 3.55; 95% CI: 0.55 to 6.56 mg/dL, P = .02) but were associated with an increase in TC and LDL-C (MD 16.20; 95% CI: 9.09 to 23.31 mg/dL, P < .001 and 5.19: 95% CI: -3.00 to 13.39 mg/dL, P = .21). Basal insulin was superior to standard therapy in triglyceride reduction (MD 3.8; 95% CI: 0.99 to 6.63 mg/dL, P = .008). CONCLUSIONS GLP-1RA were superior to basal insulin in the control of TC and LDL-C. Basal insulin effectively reduced serum triglycerides. TZD led to improvement in HDL-C. DPP4-I and standard therapy did not have any significant effect on lipid levels.
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Affiliation(s)
| | - Angelo Avogaro
- Department of Medicine, University of Padova, Padova, Italy
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Dougherty JA, Guirguis E, Thornby KA. A Systematic Review of Newer Antidiabetic Agents in the Treatment of Nonalcoholic Fatty Liver Disease. Ann Pharmacother 2020; 55:65-79. [PMID: 32571083 DOI: 10.1177/1060028020935105] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To evaluate glucagon-like peptide 1 receptor agonists (GLP-1 RAs), dipeptidyl-peptidase IV (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SGLT) inhibitors to treat nondiabetic and type 2 diabetes mellitus (T2DM) nonalcoholic fatty liver disease (NAFLD) as it relates to improvement in hepatosteatosis (HS) or steatohepatitis (SH). DATA SOURCES MEDLINE and CINAHL were searched from inception through May 1, 2020. Search terms included nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, fatty liver, dipeptidyl-peptidase IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose transporter 2 inhibitors. STUDY SELECTION AND DATA EXTRACTION Full-text observational and randomized controlled studies in English were included. Patients diagnosed with NAFLD, treated with GLP-1 RAs, DPP-4 inhibitors, and SGLT2 inhibitors, with measures to evaluate HS or SH were evaluated. DATA SYNTHESIS Eight GLP-1 RA trials were reviewed; 7 GLP-1 RA trials showed improvement in HS. Two studies demonstrated improvement in liver histology in patients with SH. Seven SGLT2 inhibitor studies were reviewed; 6 studies demonstrated improvements in NAFLD. Five studies showed improvements in HS, whereas 1 displayed improvement in liver histology in NASH. Six studies that included DPP-4 inhibitors were evaluated, and only 2 demonstrated improvement in NASH. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Based on evidence reviewed, GLP-1 RAs and SGLT2 inhibitors decreased HS and SH in NAFLD patients, whereas DPP-4 inhibitor therapy was not effective for patients with HS. CONCLUSIONS Based on study data utilizing imaging studies and biopsy results, GLP-1 RAs or SGLT2 inhibitors can benefit NAFLD T2DM patients. Clinical trials with larger patient populations may augment these results.
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Affiliation(s)
- John A Dougherty
- Palm Beach Atlantic University: Lloyd L. Gregory School of Pharmacy, West Palm Beach, FL, USA
| | - Erenie Guirguis
- Palm Beach Atlantic University: Lloyd L. Gregory School of Pharmacy, West Palm Beach, FL, USA
| | - Krisy-Ann Thornby
- Palm Beach Atlantic University: Lloyd L. Gregory School of Pharmacy, West Palm Beach, FL, USA
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