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Wan X, Ma J, Bai H, Hu X, Ma Y, Zhao M, Liu J, Duan Z. Drug Advances in NAFLD: Individual and Combination Treatment Strategies of Natural Products and Small-Synthetic-Molecule Drugs. Biomolecules 2025; 15:140. [PMID: 39858534 PMCID: PMC11764138 DOI: 10.3390/biom15010140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 01/07/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease and is closely associated with metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. However, effective treatment strategies for NAFLD are still lacking. In recent years, progress has been made in understanding the pathogenesis of NAFLD, identifying multiple therapeutic targets and providing new directions for drug development. This review summarizes the recent advances in the treatment of NAFLD, focusing on the mechanisms of action of natural products, small-synthetic-molecule drugs, and combination therapy strategies. This review aims to provide new insights and strategies in treating NAFLD.
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Affiliation(s)
- Xing Wan
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
- Institute of Integrated Traditional Chinese and Western Medicine, Dalian Medical University, Dalian 116051, China
| | - Jingyuan Ma
- The First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang 110033, China; (J.M.); (Y.M.)
| | - He Bai
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
| | - Xuyang Hu
- The Second Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang 110033, China;
| | - Yanna Ma
- The First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang 110033, China; (J.M.); (Y.M.)
| | - Mingjian Zhao
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
| | - Jifeng Liu
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
| | - Zhijun Duan
- The First Affiliated Hospital of Dalian Medical University, Dalian 116012, China; (X.W.); (H.B.); (M.Z.)
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Sato G, Uchino H, Hirose T. Efficacy and Safety of Escalating the Dose of Oral Semaglutide from 7 to 14 mg: A Single-Center, Retrospective Observational Study. Diabetes Ther 2024; 15:2119-2130. [PMID: 39110375 PMCID: PMC11330422 DOI: 10.1007/s13300-024-01631-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 07/22/2024] [Indexed: 08/18/2024] Open
Abstract
INTRODUCTION The efficacy and safety of oral semaglutide, the first glucagon-like peptide 1 receptor agonist available in tablet form for the treatment of type 2 diabetes, were established in the phase 3a PIONEER program. However, evidence regarding the titration of oral semaglutide in real-world clinical settings remains insufficient. This study aimed to elucidate the therapeutic advantages of escalating the dose of oral semaglutide from 7 to 14 mg through clinical data analysis. METHODS This retrospective observational study was conducted at a single center in Japan, focusing on adults with type 2 diabetes who were initiated on 14 mg oral semaglutide. The primary endpoint was the alteration in HbA1c levels 24 weeks after the initial prescription of 14 mg oral semaglutide. Secondary endpoints included changes in metabolic parameters and the incidence of adverse events. RESULTS Data from 66 patients who met the inclusion criteria were analyzed. The mean change in HbA1c levels from baseline to 24 weeks following dose escalation was - 0.5 ± 0.8% [from 7.4 ± 1.0% at baseline to 7.0 ± 0.9% at 24 weeks (p < 0.01)]. Moreover, a significant reduction in body weight of - 2.0 ± 4.4 kg was observed at 24 weeks [from 90.0 ± 20.5 kg at baseline to 88.2 ± 21.4 kg at 24 weeks (p < 0.01)], with 41% of patients achieving at least a 3% reduction compared to baseline. Gastrointestinal disorders emerged as the most prevalent adverse event (10.6%), particularly nausea (7.6%), although predominantly of mild or moderate severity, with no instances of serious adverse events necessitating drug discontinuation. CONCLUSION Escalating the dose of oral semaglutide to 14 mg could be an effective approach for enhancing glycemic control and managing body weight in individuals with type 2 diabetes.
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Affiliation(s)
- Genki Sato
- Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan.
| | - Hiroshi Uchino
- Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan
| | - Takahisa Hirose
- Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan
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Gad AI, Ibrahim NF, Almadani N, Mahfouz R, Nofal HA, El-Rafey DS, Ali HT, El-Hawary AT, Sadek AMEM. Therapeutic Effects of Semaglutide on Nonalcoholic Fatty Liver Disease with Type 2 Diabetes Mellitus and Obesity: An Open-Label Controlled Trial. Diseases 2024; 12:186. [PMID: 39195185 DOI: 10.3390/diseases12080186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/11/2024] [Accepted: 08/15/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND GLP-1 receptor agonists (GLP-1 RAs) have been shown to improve glycemic control and insulin sensitivity and reduce body weight in obese patients with type 2 diabetes mellitus (T2D). This trial sought to evaluate the therapeutic effect of oral and subcutaneous semaglutide in NAFLD and its sequelae in obesity and/or T2D. METHODS In an open-labelled intervention study, the sample was 180 patients classified into three parallel groups (1:1:1): group I received oral semaglutide, group II patients received injectable semaglutide, and group III received pioglitazone and/or vitamin E. Patients were evaluated at 6 and 12 months. RESULTS There was a substantial improvement in lipid profile, liver enzymes, and body mass index, especially in group II. As for HDL, only group II showed a consistent increase at both 6 months (51 ± 4.62 mg/dL) and 12 months (50.08 ± 2.45 mg/dL) compared with baseline (45.6 ± 6.37 mg/dL) (p-value < 0.001). Despite the non-significant difference in NAFLD fibrosis score (NFS) (p-value = 0.45 and 0.63), group II had significantly lower scores of the fibrosis-4 score (FIB-4), liver stiffness measurement (LSM), and controlled attenuation parameter (CAP) at 6 and 12 months (p-value < 0.001). Conclusions: Semaglutide improves lipid profile, liver steatosis, and fibrosis parameters and reduces the BMI in T2D and obese patients with NAFLD.
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Affiliation(s)
- Ahmed I Gad
- Internal Medicine Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Nevin F Ibrahim
- Internal Medicine Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Noura Almadani
- Community and Psychiatric Mental Health Nursing Department, College of Nursing, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Rasha Mahfouz
- Community and Psychiatric Mental Health Nursing Department, College of Nursing, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Hanaa A Nofal
- Community, Environmental Occupational Medicine Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Dina S El-Rafey
- Community, Environmental Occupational Medicine Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | | | - Amr T El-Hawary
- Internal Medicine Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Ayman M E M Sadek
- Internal Medicine Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
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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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Bu T, Sun Z, Pan Y, Deng X, Yuan G. Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism. Diabetes Metab J 2024; 48:354-372. [PMID: 38650100 PMCID: PMC11140404 DOI: 10.4093/dmj.2023.0277] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 01/01/2024] [Indexed: 04/25/2024] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a 30-amino acid peptide hormone that is mainly expressed in the intestine and hypothalamus. In recent years, basic and clinical studies have shown that GLP-1 is closely related to lipid metabolism, and it can participate in lipid metabolism by inhibiting fat synthesis, promoting fat differentiation, enhancing cholesterol metabolism, and promoting adipose browning. GLP-1 plays a key role in the occurrence and development of metabolic diseases such as obesity, nonalcoholic fatty liver disease, and atherosclerosis by regulating lipid metabolism. It is expected to become a new target for the treatment of metabolic disorders. The effects of GLP-1 and dual agonists on lipid metabolism also provide a more complete treatment plan for metabolic diseases. This article reviews the recent research progress of GLP-1 in lipid metabolism.
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Affiliation(s)
- Tong Bu
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ziyan Sun
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yi Pan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xia Deng
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Guoyue Yuan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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Shah P, White M, Sievert A, Conway A, Kneepkens A, Sayuk G, Lisker-Melman M, Elwing J. Semaglutide improves metabolic dysfunction-associated steatohepatitis: A 10-year retrospective study. JGH Open 2024; 8:e13037. [PMID: 38389719 PMCID: PMC10883239 DOI: 10.1002/jgh3.13037] [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: 10/17/2023] [Revised: 12/18/2023] [Accepted: 01/28/2024] [Indexed: 02/24/2024]
Abstract
Background and Aims Semaglutide has been studied in patients with metabolic dysfunction-associated steatohepatitis (MASH) due to potential benefit from weight loss on liver inflammation. However, preclinical studies suggest that MASH improvement may be independent of weight loss. We aim to assess the impact of semaglutide on MASH in relation to weight loss. Methods This retrospective study included 420 patients with diabetes on semaglutide for at least 12 months between 2011 and 2022. Exclusion criteria were liver disease other than MASH, decompensated cirrhosis, malignancy, and bariatric surgery. Primary endpoints were clinically significant improvements in AST or ALT (mean difference > 6.3 U/L and > 10.6 U/L respectively). Statistical analysis included Student's t-test/ANOVA, Wilcoxon signed-rank test/Friedman test as appropriate, and binary logistic regression. Results Median duration of semaglutide was 22.5 months and 80% of patients received 1 mg/week. BMI improved by a mean (SD) of 1.9 points (2.8), weight by 13.3 lbs. (19.1), AST by 4.1 U/L (11.5), and ALT by 5.3 U/L (14.2). In 28% and 22% of patients respectively, AST and ALT had a clinically significant improvement. MASH scores (NFS, FIB4, APRI) improved after semaglutide (p < 0.001). No statistically significant differences in AST or ALT improvement were found when patients were stratified by BMI prior to semaglutide or when stratified by percentage of weight loss. On logistic regression, the duration of semaglutide and pretreatment APRI score increased the odds of clinically significant improvements of AST and ALT. Conclusion Semaglutide treatment was associated with improvement in transaminases and MASH scores. Higher odds of positive semaglutide effects were observed with longer treatment duration and were independent of weight loss.
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Affiliation(s)
- Parth Shah
- Division of Gastroenterology Washington University in Saint Louis Saint Louis Missouri USA
| | - Megan White
- Division of Gastroenterology Washington University in Saint Louis Saint Louis Missouri USA
| | - Alex Sievert
- Department of Medicine Washington University in Saint Louis Saint Louis Missouri USA
| | - Alexander Conway
- Washington University School of Medicine in Saint Louis Saint Louis Missouri USA
| | - Adam Kneepkens
- Department of Medicine Washington University in Saint Louis Saint Louis Missouri USA
| | - Gregory Sayuk
- Division of Gastroenterology John Cochran Veterans Affairs Medical Center in Saint Louis Saint Louis Missouri USA
| | - Mauricio Lisker-Melman
- Division of Gastroenterology John Cochran Veterans Affairs Medical Center in Saint Louis Saint Louis Missouri USA
| | - Jill Elwing
- Division of Gastroenterology John Cochran Veterans Affairs Medical Center in Saint Louis Saint Louis Missouri USA
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Zhu K, Kakkar R, Chahal D, Yoshida EM, Hussaini T. Efficacy and safety of semaglutide in non-alcoholic fatty liver disease. World J Gastroenterol 2023; 29:5327-5338. [PMID: 37899788 PMCID: PMC10600803 DOI: 10.3748/wjg.v29.i37.5327] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/23/2023] [Accepted: 09/12/2023] [Indexed: 09/25/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. The prevalence and disease burden of NAFLD are projected to exponentially increase resulting in significant healthcare expenditures and lower health-related quality of life. To date, there are no approved pharmacotherapies for NAFLD or non-alcoholic steatohepatitis (NASH). Semaglutide has glycemic and weight loss benefits that may be advantageous for patients with NAFLD. AIM To investigate the efficacy and safety of semaglutide in patients with NAFLD. METHODS MEDLINE, CENTRAL, and EMBASE were searched from inception to May 1, 2023, to identify eligible randomized controlled trials (RCTs). Meta-analysis was performed using random effects model expressing continuous outcomes as mean differences (MD) or standardized MDs (SMD), and dichotomous outcomes as odds ratios (OR) with 95% confidence intervals (CI). Statistical heterogeneity was assessed using the Cochran's Q test and I2 statistic. RESULTS Three RCTs involving 458 patients were included. Semaglutide increased the likelihood of NASH resolution (OR: 3.18, 95%CI: 1.70, 5.95; P < 0.001), improvement in steatosis (OR: 2.83, 95%CI: 1.19, 6.71; P = 0.03), lobular inflammation (OR: 1.81, 95%CI: 1.11, 2.96; P = 0.02), and hepatocellular ballooning (OR: 2.92, 95%CI: 1.83, 4.65; P < 0.001), but not fibrosis stage (OR: 0.71, 95%CI: 0.15, 3.41; P = 0.67). Radiologically, semaglutide reduced liver stiffness (SMD: -0.48, 95%CI: -0.86, -0.11; P = 0.01) and steatosis (MD: -4.96%, 95%CI: -9.92, 0.01; P = 0.05). It also reduced alanine aminotransferase (MD: -14.06 U/L, 95%CI: -22.06, -6.07; P < 0.001) and aspartate aminotransferase (MD: -11.44 U/L, 95%CI: -17.23, -5.65; P < 0.001). Semaglutide led to improved cardiometabolic outcomes, including decreased HgA1c (MD: -0.77%, 95%CI: -1.18, -0.37; P < 0.001) and weight loss (MD: -6.53 kg, 95%CI: -11.21, -1.85; P = 0.006), but increased the occurrence of GI-related side effects (OR: 3.72, 95%CI: 1.68, 8.23; P = 0.001). Overall risk of serious adverse events was similar compared to placebo (OR: 1.40, 95%CI: 0.75, 2.62; P < 0.29). CONCLUSION Semaglutide is effective in the treatment of NAFLD while maintaining a well-tolerated safety profile. Future studies are required to evaluate its effects on fibrosis regression and different phases of NAFLD.
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Affiliation(s)
- Kai Zhu
- Internal Medicine, University of British Columbia, Vancouver V5Z 1M9, BC, Canada
| | - Rohan Kakkar
- Internal Medicine, University of British Columbia, Vancouver V5Z 1M9, BC, Canada
| | - Daljeet Chahal
- Department of Gastroenterology, University of British Columbia, Vancouver V5Z 1M9, BC, Canada
- BC Liver Transplant Program, Vancouver General Hospital, Vancouver V5Z 1M9, BC, Canada
| | - Eric M Yoshida
- Department of Gastroenterology, University of British Columbia, Vancouver V5Z 1M9, BC, Canada
- BC Liver Transplant Program, Vancouver General Hospital, Vancouver V5Z 1M9, BC, Canada
| | - Trana Hussaini
- BC Liver Transplant Program, Vancouver General Hospital, Vancouver V5Z 1M9, BC, Canada
- Pharmaceutical Sciences, University of British Columbia, Vancouver V5Z 1M9, BC, Canada
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O'Hara V, Cuda S, Kharofa R, Censani M, Conroy R, Browne NT. Clinical review: Guide to pharmacological management in pediatric obesity medicine. OBESITY PILLARS 2023; 6:100066. [PMID: 37990657 PMCID: PMC10661861 DOI: 10.1016/j.obpill.2023.100066] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 11/23/2023]
Abstract
Introduction Newer pharmacotherapy agents (anti-obesity medication [AOM]) are revolutionizing the management of children and adolescents with obesity. Previously, treatment based on intensive behavioral therapy involved many patient and family contact hours and yielded improvements in obesity status of 1-3 percent of the 95th percentile of the body mass index (BMI). Newer AOMs are yielding more clinically significant improvement of 5-18 percent. This review provides guidance for practitioners in the care of children and adolescents with obesity who frequently have complex medical and behavioral health care needs. Specifically, we discuss the use of newer AOMs in these complex patients. Methods This review details an approach to the care of the child and adolescent with obesity using AOMs. A shared decision-making process is presented in which the provider and the patient and family collaborate on care. Management of medical and behavioral components of the disease of obesity in the child are discussed. Results Early aggressive treatment is recommended, starting with an assessment of associated medical and behavioral complications, weight promoting medications, use of AOMs and ongoing care. Intensive behavioral therapy is foundational to treatment, but not a specific treatment. Patients and families deserve education on expected outcomes with each therapeutic option. Conclusions The use of new AOMs in children and adolescents has changed expected clinical outcomes in the field of pediatric obesity management. Clinically significant improvement in obesity status occurs when AOMs are used early and aggressively. Ongoing, chronic care is the model for optimizing outcomes using a shared decision-making between provider and patient/family. Depending on the experience and comfort level of the primary care practitioner, referral to an obesity medicine specialist may be appropriate, particularly when obesity related co-morbidities are present and pharmacotherapy and metabolic and bariatric surgery are considerations.
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Affiliation(s)
- Valerie O'Hara
- Weight & Wellness Clinic, Maine Medical Center, S. Portland, ME, 04106, USA
| | - Suzanne Cuda
- Alamo City Healthy Kids and Families, 1919 Oakwell Farms Parkway, Ste 145, San Antonio, TX, 78218, USA
| | - Roohi Kharofa
- Department of Pediatrics, University of Cincinnati College of Medicine, Center for Better Health & Nutrition, The Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA
| | - Marisa Censani
- Clinical Pediatrics, Division of Pediatric Endocrinology, Department of Pediatrics, New York Presbyterian Hospital, Weill Cornell Medicine, 525 East 68th Street, Box 103, New York, NY, 10021, USA
| | - Rushika Conroy
- Division of Pediatric Endocrinology, Baystate Children's Hospital Subspecialty Center, 50 Wason Avenue, Springfield, MA, 01107, USA
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Wang J, Wang L, Zhang XJ, Zhang P, Cai J, She ZG, Li H. Recent updates on targeting the molecular mediators of NAFLD. J Mol Med (Berl) 2023; 101:101-124. [PMID: 36792729 DOI: 10.1007/s00109-022-02282-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 11/29/2022] [Accepted: 12/21/2022] [Indexed: 02/17/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common disease worldwide in an era of rapid economic growth. NAFLD is a multifactorial disease, involving multiple genetic, metabolic, and environmental factors, and is closely associated with metabolic syndrome, obesity, and cardiovascular disease. NAFLD can be classified into nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH), which can both progress to cirrhosis and even hepatocellular carcinoma (HCC). Due to the enormous burden of NAFLD and its complications, no FDA-approved drugs for the treatment of NAFLD are on the market, and therapeutic targets and drug therapies are being actively investigated. In view of the various pathological mechanisms of NAFLD, numbers of preclinical studies and clinical trials have made rapid progress. This review mainly summarizes the most recently characterized mechanisms and therapeutic targets in each mechanism of NAFLD, focusing on the mechanism and application potential.
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Affiliation(s)
- Jia Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Luojia Mount Wuchang, Wuhan, China
- Institute of Model Animal, Wuhan University, Wuhan, China
| | - Lei Wang
- Department of Neurosurgery, Huanggang Central Hospital of Yangtze University, Huanggang, China
- Translation Medicine Research Center, Yangtze University, Huanggang, China
| | - Xiao-Jing Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Peng Zhang
- Institute of Model Animal, Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jingjing Cai
- Institute of Model Animal, Wuhan University, Wuhan, China
- Department of Cardiology, The Third Xiangya Hospital, Central South University, The Third Xiangya Hospital, Changsha, China
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Luojia Mount Wuchang, Wuhan, China.
- Institute of Model Animal, Wuhan University, Wuhan, China.
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Luojia Mount Wuchang, Wuhan, China.
- Institute of Model Animal, Wuhan University, Wuhan, China.
- Translation Medicine Research Center, Yangtze University, Huanggang, China.
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Toth PP, Schwartz GG, Nicholls SJ, Khan A, Szarek M, Ginsberg HN, Johansson JO, Kalantar-Zadeh K, Kulikowski E, Lebioda K, Wong NC, Sweeney M, Ray KK. Reduction in the risk of major adverse cardiovascular events with the BET protein inhibitor apabetalone in patients with recent acute coronary syndrome, type 2 diabetes, and moderate to high likelihood of non-alcoholic fatty liver disease. Am J Prev Cardiol 2022; 11:100372. [PMID: 36039183 PMCID: PMC9419281 DOI: 10.1016/j.ajpc.2022.100372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 12/02/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is common among patients with type 2 diabetes mellitus (T2DM) and is associated with increased risk for coronary atherosclerosis and acute cardiovascular (CV) events. We employed the validated, non-invasive Angulo NAFLD fibrosis score (FS) in an intervention study in patients with T2DM and recent acute coronary syndrome (ACS) to determine the association of FS with CV risk and treatment response to apabetalone. Apabetalone is a novel selective inhibitor of the second bromodomain of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. Methods The Phase 3 BETonMACE trial compared apabetalone with placebo in 2,425 patients with T2DM and recent ACS. In this post hoc analysis, we evaluated the impact of apabetalone therapy on CV risk, defined as a composite of major adverse cardiovascular events (MACE: CV death, non-fatal myocardial infarction [MI], or stroke) and hospitalization for heart failure (HHF) in two patient categories of FS that reflect the likelihood of underlying NAFLD. Patients were initially classified into three mutually exclusive categories according to a baseline Angulo FS <-1.455 (F0-F2), -1.455 to 0.675 (indeterminant), and >0.675 (F3-F4), where F0 through F4 connote fibrosis severity none, mild, moderate, severe, and cirrhosis, respectively. The composite of ischemic MACE and HHF in the placebo group was higher in indeterminant and F3-F4 categories compared to the F0-F2 category (17.2% vs 15.0% vs 9.7%). Therefore, for the present analysis, the former two categories were combined into an elevated NAFLD CVD risk group (FS+) that was compared with the F0-F2 group (lower NAFLD risk, FS0-2). Results In 73.7% of patients, FS was elevated and consistent with a moderate-to-high likelihood of advanced liver fibrosis (FS+); 26.3% of patients had a lower FS (FS0-2). In the placebo group, FS+ patients had a higher incidence of ischemic MACE and HHF (15.4%) than FS0-2 patients (9.7%). In FS+ patients, addition of apabetalone to standard of care treatment lowered the rate of ischemic MACE compared with placebo (HR = 0.79; 95% CI 0.60-1.05; p=0.10), HHF (HR = 0.53; 95% CI 0.33-0.86; p=0.01), and the composite of ischemic MACE and HHF (HR = 0.76; 95% CI 0.59-0.98; p=0.03). In contrast, there was no apparent benefit of apabetalone in FS0-2 patients (HR 1.24; 95% CI 0.75-2.07; p=0.40; HR 1.12; 95% CI 0.30-4.14; p=0.87; and HR 1.13; 95% CI 0.69-1.86; p=0.62, respectively). Over a median duration of 26.5 months, FS increased from baseline in both treatment groups, but the increase was smaller in patients assigned to apabetalone than to placebo (p=0.04). Conclusions Amongst patients with T2DM, recent ACS, and a moderate-to-high likelihood of advanced liver fibrosis, apabetalone was associated with a significantly lower rate of ischemic MACE and HHF and attenuated the increase in hepatic FS over time.
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Updates on novel pharmacotherapeutics for the treatment of nonalcoholic steatohepatitis. Acta Pharmacol Sin 2022; 43:1180-1190. [PMID: 35190696 PMCID: PMC9061746 DOI: 10.1038/s41401-022-00860-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 01/03/2022] [Indexed: 12/14/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD), characterized with hepatocellular steatosis, ballooning, lobular inflammation, fibrotic progression, and insulin resistance. NASH may progress to cirrhosis and hepatocellular carcinoma (HCC), which are the major indications for liver transplantation and the causes for mortality. Thus far, there are no approved pharmacotherapeutics for the treatment of NASH. Given the complexity of NASH pathogenesis at multifaceted aspects, such as lipotoxicity, inflammation, insulin resistance, mitochondrial dysfunction and fibrotic progression, pharmacotherapeutics under investigation target different key pathogenic pathways to gain either the resolution of steatohepatitis or regression of fibrosis, ideally both. Varieties of pharmacologic candidates have been tested in clinical trials and have generated some positive results. On the other hand, recent failure or termination of a few phase II and III trials is disappointing in this field. In face to growing challenges in pharmaceutical development, this review intends to summarize the latest data of new medications which have completed phase II or III trials, and discuss the rationale and preliminary results of several combinatory options. It is anticipated that with improved understanding of NASH pathogenesis and critical endpoints, efficient pharmacotherapeutics will be available for the treatment of NASH with an acceptable safety profile.
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Rong L, Zou J, Ran W, Qi X, Chen Y, Cui H, Guo J. Advancements in the treatment of non-alcoholic fatty liver disease (NAFLD). Front Endocrinol (Lausanne) 2022; 13:1087260. [PMID: 36726464 PMCID: PMC9884828 DOI: 10.3389/fendo.2022.1087260] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/28/2022] [Indexed: 01/17/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a series of diseases, involving excessive lipid deposition in the liver and is often accompanied by obesity, diabetes, dyslipidemia, abnormal blood pressure, and other metabolic disorders. In order to more accurately reflect its pathogenesis, an international consensus renamed NAFLD in 2020 as metabolic (dysfunction) associated with fatty liver disease (MAFLD). The changes in diet and lifestyle are recognized the non-drug treatment strategies; however, due to the complex pathogenesis of NAFLD, the current drug therapies are mainly focused on its pathogenic factors, key links of pathogenesis, and related metabolic disorders as targets. There is still a lack of specific drugs. In clinical studies, the common NAFLD treatments include the regulation of glucose and lipid metabolism to protect the liver and anti-inflammation. The NAFLD treatments based on the enterohepatic axis, targeting gut microbiota, are gradually emerging, and various new metabolism-regulating drugs are also under clinical development. Therefore, this review article has comprehensively discussed the research advancements in NAFLD treatment in recent years.
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Affiliation(s)
- Li Rong
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Chongqing, China
| | - Junyan Zou
- Medical Research Institute, Southwest University, Chongqing, China
- Medical Research Institute, Southwest University, Public Health Hospital Affiliated to Southwest University, Chongqing, China
| | - Wei Ran
- Medical Research Institute, Southwest University, Public Health Hospital Affiliated to Southwest University, Chongqing, China
| | - Xiaohong Qi
- Department of General surgery, Baoshan People’s Hospital of Yunnan Province, Baoshan, Yunnan, China
| | - Yaokai Chen
- Medical Research Institute, Southwest University, Public Health Hospital Affiliated to Southwest University, Chongqing, China
| | - Hongjuan Cui
- Medical Research Institute, Southwest University, Chongqing, China
| | - Jinjun Guo
- Department of Gastroenterology, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Chongqing, China
- *Correspondence: Jinjun Guo,
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Negi CK, Babica P, Bajard L, Bienertova-Vasku J, Tarantino G. Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease. Metabolism 2022; 126:154925. [PMID: 34740573 DOI: 10.1016/j.metabol.2021.154925] [Citation(s) in RCA: 148] [Impact Index Per Article: 49.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. With no Food and Drug Administration approved drugs, current treatment options include dietary restrictions and lifestyle modification. NAFLD is closely associated with metabolic disorders such as obesity, type 2 diabetes, and dyslipidemia. Hence, clinically various pharmacological approaches using existing drugs such as antidiabetic, anti-obesity, antioxidants, and cytoprotective agents have been considered in the management of NAFLD and nonalcoholic steatohepatitis (NASH). However, several pharmacological therapies aiming to alleviate NAFLD-NASH are currently being examined at various phases of clinical trials. Emerging data from these studies with drugs targeting diverse molecular mechanisms show promising outcomes. This review summarizes the current understanding of the pathogenic mechanisms of NAFLD and provides an insight into the pharmacological targets and emerging therapeutics with specific interventional mechanisms. In addition, we also discuss the importance and utility of new approach methodologies and regulatory perspectives for NAFLD-NASH drug development.
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Affiliation(s)
- Chander K Negi
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic
| | - Pavel Babica
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic.
| | - Lola Bajard
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic
| | - Julie Bienertova-Vasku
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Giovanni Tarantino
- Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Naples, Italy
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