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Osumili B, Sapin H, Yang Z, Ranta K, Paik JS, Blüher M. Efficacy and Safety of Tirzepatide Compared with GLP-1 RAs in Patients with Type 2 Diabetes Treated with Basal Insulin: A Network Meta-analysis. Diabetes Ther 2025; 16:1279-1311. [PMID: 40214900 PMCID: PMC12085526 DOI: 10.1007/s13300-025-01728-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 03/12/2025] [Indexed: 05/18/2025] Open
Abstract
INTRODUCTION The relative efficacy and safety of tirzepatide was compared with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes mellitus (T2DM) treated with basal insulin using a network meta-analysis (NMA). METHODS A systematic literature review was performed to identify randomized controlled trials of GLP-1 RAs in patients with T2DM treated with insulin and an antihyperglycaemic drug. For the NMA, studies included trials with 100% of patients treated with basal insulin background therapy with a titration scheme comparable to the SURPASS-5 trial. The following data were extracted for efficacy and safety assessment at the primary endpoint of each study: changes from baseline in glycated haemoglobin (HbA1c) and body weight and the incidence of nausea, vomiting or diarrhoea, hypoglycaemia, and patients discontinuing treatment because of adverse events. In this study, a comparative analysis of tirzepatide was performed with the GLP-1 RAs dulaglutide, exenatide, and lixisenatide in addition to placebo. RESULTS A total of six studies were included across the analyses. Tirzepatide 5, 10, and 15 mg showed statistically significant, greater reductions in HbA1c and body weight at the primary endpoint versus all GLP-1 RA comparators and placebo. Tirzepatide 5, 10, and 15 mg showed a statistically significant, higher likelihood of experiencing nausea compared with those who received placebo or exenatide 2 mg; no statistically significant differences were observed when compared with all other GLP-1 RA comparators. No statistically significant differences were observed in the proportions of patients who discontinued treatment because of adverse events when tirzepatide 5, 10, and 15 mg were compared with GLP-1 RA comparators, apart from tirzepatide 10 and 15 mg versus placebo. CONCLUSION Tirzepatide demonstrated statistically significantly greater reductions in HbA1c and body weight when compared with selected GLP-1 RAs and placebo in patients with T2DM treated with basal insulin. Overall, the safety profile of tirzepatide was similar to that of GLP-1RAs.
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Affiliation(s)
- Beatrice Osumili
- Health Economics and Outcomes Research, Eli Lilly and Company Limited, Bracknell, UK
| | - Hélène Sapin
- Research and Development Statistics, Lilly France SAS, Neuilly-Sur-Seine, France
| | | | - Kari Ranta
- Medical Affairs, Eli Lilly Finland, Helsinki, Finland.
| | - Jim S Paik
- Medical Affairs, Eli Lilly and Company, Indianapolis, IN, USA
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, Leipzig, Germany
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2
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Ren Q, Tan Y, Zhang G, Dai Y, Yang L, Wu Y, He H, Chen J. Efficacy of Hypoglycemic Agents in Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD): A Systematic Review and Network Meta-Analysis. J Evid Based Med 2025; 18:e70021. [PMID: 40229658 DOI: 10.1111/jebm.70021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/12/2025] [Accepted: 03/12/2025] [Indexed: 04/16/2025]
Abstract
AIMS Metabolic dysfunction associated steatotic liver disease (MASLD) is a universal hepatic disease, and many recent randomized clinical trials (RCTs) have explored whether hypoglycemic agents may be beneficial for its treatment. This study aimed to assess the relative effectiveness of each hypoglycemic agent for MASLD. METHODS China National Knowledge Infrastructure(CNKI), WanFang, Weipu, PubMed, Embase, The Cochrane Library, and Web of Science Core Collection were searched for RCTs on the efficacy of hypoglycemic agents in MASLD published up to December 31, 2024. All statistical analyses were performed using R version 4.3.3. The network meta-analysis was conducted using Bayesian statistical methods. RESULTS A total of 26 hypoglycemic agents for treating MASLD in 37 studies with 2406 participants were included. Empagliflozin was most effective in improving liver stiffness measurement (LSM), whereas liraglutide showed significant benefits in body weight, body mass index (BMI), and waist circumference. Both sodium-glucose co-transporter 2 (SGLT-2) inhibitors (e.g., empagliflozin) and glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., liraglutide) improved liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyltransferase [GGT]), glucose metabolism (fasting plasma glucose [FPG], and homeostasis model assessment of insulin resistance [HOMA-IR]), and lipid profiles. Pioglitazone had limited benefits in these outcomes. Secondary outcomes such as inflammatory markers and fibrosis showed minimal changes. CONCLUSIONS Several hypoglycemic agents can improve laboratory and imaging indicators in adult patients with MASLD. Liraglutide is more effective than other agents, whereas empagliflozin emerged as the most effective for reducing LSM. However, different agents have different effects on the indicators; therefore, the relevant agents must be selected according to the specific patient condition.
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Affiliation(s)
- Qiao Ren
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Yao Tan
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, China
- Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, China
| | - Guixiang Zhang
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yuzhao Dai
- Department of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Lidan Yang
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, China
| | - Yunmo Wu
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - He He
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, China
- Department of Laboratory Medicine, The Second People's Hospital of Yibin, Yibin, China
| | - Jie Chen
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, China
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Konings LAM, Miguelañez‐Matute L, Boeren AMP, van de Luitgaarden IAT, Dirksmeier F, de Knegt RJ, Tushuizen ME, Grobbee DE, Holleboom AG, Cabezas MC. Pharmacological treatment options for metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus: A systematic review. Eur J Clin Invest 2025; 55:e70003. [PMID: 39937036 PMCID: PMC11891831 DOI: 10.1111/eci.70003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 01/24/2025] [Indexed: 02/13/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to type 2 diabetes mellitus (T2DM) through a common root in insulin resistance. The more severe stage, metabolic dysfunction-associated steatohepatitis (MASH), increases the risk for cardiovascular complications, liver cirrhosis and hepatocellular carcinoma. Several trials investigating established antidiabetic-drugs in patients with T2DM and MASLD have yielded promising results. Therefore, we aimed to systematically review the effect of T2DM-drug treatment on MALSD parameters. METHODS Medical databases were searched until January 2025 for controlled trials in patients with T2DM and MASLD/MASH. Studies that evaluated the effect of T2DM-medication on the severity of MASLD/MASH in T2DM patients were included. The quality of the studies was assessed by three independent reviewers using a set of Cochrane risk-of-bias tools. RESULTS Of 1748 references, 117 studies fulfilled the inclusion-criteria and were assessed for eligibility in full-text. Fifty-two articles were included. Data included a total of 64.708 patients and study populations ranged from 9 to 50.742. Heterogeneity in study-design and analysis hampered the comparability of the results. Most evidence was present for GLP-1 receptor agonists, SGLT2-inhibitors and PPAR-γ-agonists for regression of liver fibrosis and MASH. CONCLUSION Studies on the value of T2DM-drug treatment in the improvement of MASLD vary significantly in study design, size and quality. GLP-1 receptor agonists, PPAR-γ-agonists, SGLT2-inhibitors may all be preferred pharmacological interventions for patients with MASLD/MASH and T2DM. Newer agents like dual GLP-1/GIP or triple GLP-1/GIP/Glucagon agonists will likely play an important role in the treatment of MASLD/MASH in the near future.
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Affiliation(s)
- Laura A. M. Konings
- Department of Internal MedicineFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
- Department of Internal Medicine and EndocrinologyErasmus MCRotterdamthe Netherlands
| | | | - Anna M. P. Boeren
- Department of Internal MedicineFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
| | | | - Femme Dirksmeier
- Department of Gastroenterology and HepatologyFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
| | - Rob J. de Knegt
- Department of Gastroenterology and HepatologyErasmus MCRotterdamthe Netherlands
| | | | | | | | - Manuel Castro Cabezas
- Department of Internal MedicineFranciscus Gasthuis & VlietlandRotterdamthe Netherlands
- Department of Internal Medicine and EndocrinologyErasmus MCRotterdamthe Netherlands
- Julius ClinicalZeistthe Netherlands
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4
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Xu R, Liu B, Zhou X. Comparison of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter Protein-2 Inhibitors on Treating Metabolic Dysfunction-Associated Steatotic Liver Disease or Metabolic Dysfunction-Associated Steatohepatitis: Systematic Review and Network Meta-Analysis of Randomised Controlled Trials. Endocr Pract 2025; 31:521-535. [PMID: 39701283 DOI: 10.1016/j.eprac.2024.11.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/11/2024] [Accepted: 11/24/2024] [Indexed: 12/21/2024]
Abstract
OBJECTIVE To assess glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) and sodium-glucose cotransporter protein-2 inhibitors (SGLT-2 inhibitors) in patients with metabolic dysfunction-associated steatotic liver disease or metabolic dysfunction-associated steatohepatitis (previously known as nonalcoholic fatty liver disease [NAFLD] and nonalcoholic steatohepatitis [NASH]), we performed a systematic review and network meta-analysis of randomized controlled trials. METHODS The study searched Pubmed, Embase, the Cochrane Library, and Web of Science databases up to November 26, 2023. Two reviewers independently selected the studies, extracted the data, and assessed the risk of bias. RESULTS Thirty-seven studies were included in the analysis. GLP-1 receptor agonists were found to be more effective than placebo in resolving NASH (relative risk: 2.48, 95% CI:1.86 to 3.30). Both drugs were superior to placebo in reducing liver fat content, as well as decreasing levels of liver enzyme. Network meta-analysis indicated that SGLT-2 inhibitors were more effective than GLP-1 receptor agonists in reducing alanine aminotransferase and aspartate aminotransferase levels. According to the surface under the cumulative probability ranking curve values, GLP-1 receptor agonists and SGLT-2 inhibitors consistently ranked among the top 2 in terms of reducing anthropometric data compared to other included drugs. CONCLUSIONS GLP-1 receptor agonists and SGLT-2 inhibitors have significant effects on reducing liver fat content and liver enzymes in NAFLD or NASH patients compared to placebo. GLP-1 receptor agonists were found to be superior to placebo in resolving NASH. SGLT-2 inhibitors were more effective than GLP-1 receptor agonists in reducing alanine aminotransferase and aspartate aminotransferase levels.
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Affiliation(s)
- Ruhan Xu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Bo Liu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xianghai Zhou
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
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5
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Icer MA, Koçak T, Icer Y, Kocyigit E, Ağagündüz D, Gezmen-Karadag M, Yesil S, Budán F. Low Serum and Urine Fetuin-A Levels and High Composite Dietary Antioxidant Index as Risk Factors for Kidney Stone Formation. J Clin Med 2025; 14:1487. [PMID: 40094944 PMCID: PMC11899964 DOI: 10.3390/jcm14051487] [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: 01/30/2025] [Revised: 02/18/2025] [Accepted: 02/21/2025] [Indexed: 03/19/2025] Open
Abstract
Background: Fetuin-A prevents the precipitation of hydroxyapatite in supersaturated solutions of calcium and phosphate; however, its relationship with nephrolithiasis has yet to be clarified. The aim of this study was to investigate the protective and predictive roles of serum and urine fetuin-A levels in nephrolithiasis and their relationships with the composite dietary antioxidant index (CDAI). Methods: This study involved 75 adult patients with kidney stone disease and 71 healthy adults without kidney stone disease in the control group. Participants had specific anthropometric measurements taken, and three-day food records were kept. The CDAI was calculated by summing six standard antioxidants, including vitamins A, C, and E, manganese, selenium, and zinc, representing participants' antioxidant profile. In addition to some analyzed serum and urine parameters of the participants, fetuin-A levels were measured using the enzyme-linked immunosorbent assay (ELISA) method. Results: In patients with kidney stones, both serum and urine fetuin-A levels (676.3 ± 160.14 ng/mL; 166.6 ± 128.13 ng/mL, respectively) were lower than in the control group (1455.6 ± 420.52 ng/mL; 2267.5 ± 1536.78 ng/mL, respectively) (p < 0.00001). In contrast, the CDAI was higher in patients with kidney stones compared to those without kidney stones (p < 0.001). Besides, several dietary parameters had significant positive correlations with serum and/or urinary fetuin-A. Conclusions: The present study suggests that serum and urinary fetuin-A levels may serve as protective factors against kidney stones and could potentially be used as predictive markers for the development of nephrolithiasis. Furthermore, our results suggest that the CDAI above a certain level may increase the risk of stone formation and that some dietary parameters may affect the levels of this biomarker in serum and urine.
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Affiliation(s)
- Mehmet Arif Icer
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Amasya University, 05100 Amasya, Turkey
| | - Tevfik Koçak
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gümüşhane University, 29100 Gümüşhane, Turkey;
| | - Yusuf Icer
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh EH16 4SB, UK;
| | - Emine Kocyigit
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Ordu University, 52200 Ordu, Turkey;
| | - Duygu Ağagündüz
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, 06490 Ankara, Turkey; (D.A.); (M.G.-K.)
| | - Makbule Gezmen-Karadag
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, 06490 Ankara, Turkey; (D.A.); (M.G.-K.)
| | - Suleyman Yesil
- Department of Urology, School of Medicine, Gazi University, 06490 Ankara, Turkey;
| | - Ferenc Budán
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary
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6
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Huang X, Wu M, Huang B, Zhang Y. Gastrointestinal adverse events associated with GLP-1 receptor agonists in metabolic dysfunction-associated steatotic liver disease (MASLD): a systematic review and meta-analysis. Front Med (Lausanne) 2025; 12:1509947. [PMID: 40051726 PMCID: PMC11882565 DOI: 10.3389/fmed.2025.1509947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/10/2025] [Indexed: 03/09/2025] Open
Abstract
Background Metabolic dysfunction-associated steatotic liver disease, a prevalent chronic liver condition, can cause severe complications like hepatitis, cirrhosis, and hepatocellular carcinoma. In recent years, glucagon-like peptide-1 receptor agonists (GLP - 1RA) have shown unique therapeutic advantages and may become a preferred treatment for it. This meta-analysis aims to systematically examine GLP-1RA associated adverse events, providing a basis for guiding patient clinical management. Methods We conducted a search for randomized controlled trials (RCTs) investigating the therapeutic effects of GLP-1RA in the treatment of metabolic dysfunction-associated steatotic liver disease across four databases: PubMed, Embase, Web of Science, and Cochrane Library. The search period extended from the inception of each database until December 2023. Information pertaining to various adverse events was collected as outcome measures. Statistical analysis of the results and assessment of bias risk were conducted utilizing Review Manager (version 5.4.1) software. Results An analysis of 10 studies encompassing 960 participants revealed a significantly higher overall incidence of adverse events in the GLP-1RA group compared to the control group (OR: 2.40 [1.10, 5.26], P = 0.03). Subgroup analysis based on treatment duration demonstrated a higher rate of adverse events in the GLP-1RA group during follow-ups of less than 30 weeks (P = 0.0005, OR: 3.58 [1.75, 7.32]), but no statistical difference was observed between the two groups in follow-ups exceeding 30 weeks. There was no statistically significant difference between the two groups in adverse events leading to discontinuation (P = 0.29, OR: 1.47 [0.72, 2.98]). However, a notable difference was observed in gastrointestinal adverse events (P < 0.00001, OR: 4.83 [3.36, 6.95]). Conclusion GLP-1RA exhibits an overall higher incidence of adverse events in the treatment of metabolic dysfunction-associated steatotic liver disease, particularly in the gastrointestinal domain. Short-term use of GLP-1RA may be associated with a greater occurrence of adverse events, underscoring the importance of educating patients on preventive measures and establishing tolerance. However, there was no statistically significant difference between the two groups in severe adverse events and adverse events leading to discontinuation, confirming the safety profile of GLP-1RA application.
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Affiliation(s)
- Xiaoyan Huang
- Department of Endocrinology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, China
| | - Miaohui Wu
- School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Baoliang Huang
- Department of Endocrinology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, China
| | - Yi Zhang
- Department of Endocrinology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, China
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Nomoto H, Furusawa S, Yokoyama H, Suzuki Y, Izumihara R, Oe Y, Takahashi K, Miya A, Kameda H, Cho KY, Takeuchi J, Kurihara Y, Nakamura A, Atsumi T. Improvement of β-Cell Function After Switching From DPP-4 Inhibitors to Oral Semaglutide: SWITCH-SEMA2 Post Hoc Analysis. J Clin Endocrinol Metab 2025; 110:e583-e591. [PMID: 38695547 DOI: 10.1210/clinem/dgae213] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Indexed: 02/19/2025]
Abstract
CONTEXT Whether continuation of dipeptidyl peptidase-4 inhibitors (DPP-4is) or switching to oral semaglutide is more beneficial for β-cell function is unclear. OBJECTIVE To assess the efficacy of switching from DPP-4is to oral semaglutide for β-cell function compared with DPP-4i continuation. METHODS Post hoc analysis of SWITCH-SEMA 2, a multicenter prospective randomized controlled trial on the switch to oral semaglutide vs DPP-4i continuation without dose adjustment for 24 weeks in subjects with type 2 diabetes treated with DPP-4is, was conducted. Changes in markers for glucose metabolism, including homeostatic model assessment (HOMA2) scores and disposition index (DI), were compared between the groups. RESULTS A total of 146 subjects (semaglutide group, 69; DPP-4i group, 77) were analyzed. In the semaglutide group, glycemic control, liver enzyme deviations, and lipid profiles improved after 24 weeks. Regarding indices for β-cell function, changes in HOMA2-β as well as DI, reflecting the ability of β-cells to compensate for insulin resistance, were significantly higher in the semaglutide group compared with the DPP-4i group (mean change, +10.4 vs +0.6 in HOMA2-β [P = .001] and +0.09 vs 0.0 in DI [P < .001]). Improvement in DI in the semaglutide group was correlated significantly to changes in body mass index (BMI), HbA1c, and fatty liver index reflecting liver steatosis. Multiple linear regression analysis revealed that dose of semaglutide (≥ 7 mg/day), reduction in fatty liver index, and metformin nonuse were independently associated with improvement of DI. CONCLUSION Switching to oral semaglutide ameliorated β-cell function compared with DPP-4is, presumably via tissue-to-tissue crosstalk between liver and β-cells.
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Affiliation(s)
- Hiroshi Nomoto
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Sho Furusawa
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | | | - Yuka Suzuki
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Rimi Izumihara
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Yuki Oe
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Kiyohiko Takahashi
- Division of Diabetes and Endocrinology, Department of Medicine, Hakodate Central General Hospital, Hakodate 040-8585, Japan
| | - Aika Miya
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Hiraku Kameda
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Kyu Yong Cho
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Jun Takeuchi
- Sapporo Diabetes and Thyroid Clinic, Sapporo 060-0807, Japan
| | | | - Akinobu Nakamura
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
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Abou Jaoudeh RAR, Hartmann P, Olson O, Gupta O, Kumar S, Ibrahim SH, Fawaz R, Aqul A, Hassan S. Pharmacological management of pediatric metabolic dysfunction-associated steatotic liver disease. J Pediatr Gastroenterol Nutr 2025; 80:14-24. [PMID: 39526564 DOI: 10.1002/jpn3.12402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/28/2024] [Accepted: 07/16/2024] [Indexed: 11/16/2024]
Abstract
Pediatric obesity, characterized by a body mass index (BMI) at or above the 95th percentile for age, affects a substantial number of children and adolescents worldwide. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, represents a prominent hepatic manifestation of obesity and metabolic syndrome, emerging as the most prevalent hepatic disorder among pediatric patients and a significant contributor to liver transplantation in adults. The escalating prevalence of pediatric MASLD mirrors the alarming rise in childhood obesity rates over recent decades. While lifestyle modifications focusing on dietary changes and increased physical activity constitute the cornerstone of MASLD management, achieving and maintaining significant weight reduction remains challenging. Moreover, disease progression often persists despite standard-of-care interventions, warranting exploration into alternative therapeutic strategies. Pharmacological interventions, particularly, glucagon-like peptide-1 receptor agonists (GLP-1RA), have shown promise in addressing pediatric obesity and its associated comorbidities, including MASLD. Recent studies have demonstrated the efficacy of GLP-1RA in inducing weight loss and improving liver enzyme levels, suggesting a potential role in halting disease progression, and reducing the risk of major adverse liver outcomes. This review provides a comprehensive overview of the current pharmacotherapy landscape for pediatric MASLD, with a focus on novel agents such as GLP-1RA. Furthermore, the manuscript proposes a practical algorithm to assist in integrating GLP-1RA into the clinical management of pediatric patients with obesity and MASLD. Despite promising results, further research is warranted to elucidate the long-term efficacy and safety of GLP-1RA in pediatric populations.
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Affiliation(s)
| | - Phillipp Hartmann
- Department of Pediatrics, University of California San Diego, La Jolla, California, USA
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Rady Children's Hospital San Diego, San Diego, California, USA
| | - Ole Olson
- Division of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
| | - Olga Gupta
- Division of Diabetes and Endocrinology, Duke University, Durham, North Carolina, USA
| | - Seema Kumar
- Division of Pediatric Endocrinology, Mayo Clinic, Rochester, Minnesota, USA
| | - Samar H Ibrahim
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Rima Fawaz
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Yale New Haven Children's Hospital, New Haven, Connecticut, USA
| | - Amal Aqul
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Texas Southwester, Dallas, Texas, USA
| | - Sara Hassan
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
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9
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Milani I, Codini M, Guarisco G, Chinucci M, Gaita C, Leonetti F, Capoccia D. Hepatokines and MASLD: The GLP1-Ras-FGF21-Fetuin-A Crosstalk as a Therapeutic Target. Int J Mol Sci 2024; 25:10795. [PMID: 39409124 PMCID: PMC11477334 DOI: 10.3390/ijms251910795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/04/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024] Open
Abstract
The introduction of the term "Metabolic Steatotic Liver Disease" (MASLD) underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and emphasizes the need for strategies that address both liver disease and its metabolic comorbidities. In recent years, a liver-focused perspective has revealed that altered endocrine function of the fatty liver is a key contributor to the metabolic dysregulation observed in MASLD. Due to its secretory capacity, the liver's increased production of proteins known as "hepatokines" has been linked to the development of insulin resistance, explaining why MASLD often precedes dysfunction in other organs and ultimately contributes to systemic metabolic disease. Among these hepatokines, fibroblast growth factor 21 (FGF21) and fetuin-A play central roles in regulating the metabolic abnormalities associated with MASLD, explaining why their dysregulated secretion in response to metabolic stress has been implicated in the metabolic abnormalities of MASLD. This review postulates why their modulation by GLP1-Ras may mediate the beneficial metabolic effects of these drugs, which have increased attention to their emerging role as pharmacotherapy for MASLD. By discussing the crosstalk between GLP1-Ras-FGF21-fetuin-A, this review hypothesizes that the possible modulation of fetuin-A by the novel GLP1-FGF21 dual agonist pharmacotherapy may contribute to the management of metabolic and liver diseases. Although research is needed to go into the details of this crosstalk, this topic may help researchers explore the mechanisms by which this type of pharmacotherapy may manage the metabolic dysfunction of MASLD.
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Affiliation(s)
- Ilaria Milani
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
| | - Michela Codini
- Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, Italy;
| | - Gloria Guarisco
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
| | - Marianna Chinucci
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
| | - Chiara Gaita
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
| | - Frida Leonetti
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
| | - Danila Capoccia
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (I.M.); (G.G.); (M.C.); (C.G.); (F.L.)
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10
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Njei B, Al-Ajlouni Y, Lemos SY, Ugwendum D, Ameyaw P, Njei LP, Boateng S. Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cureus 2024; 16:e71366. [PMID: 39534801 PMCID: PMC11556413 DOI: 10.7759/cureus.71366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2024] [Indexed: 11/16/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a major global health challenge. glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential therapeutic benefits for MASLD patients, including improvements in liver function, inflammation, and fibrosis. This study aims to systematically review and meta-analyze randomized controlled trials (RCTs) to evaluate the efficacy and safety of GLP-1RAs in MASLD patients, focusing on hepatic outcomes, cardiovascular outcomes, anthropometric measurements, and mortality. Following PRISMA guidelines, a comprehensive database search was conducted to include RCTs assessing GLP-1RAs' effects on MASLD. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool. Our meta-analysis used a random-effects model, calculating standardized mean differences for continuous outcomes to determine the agents' efficacy and safety. Additionally, funnel plots were generated to assess publication bias, ensuring the integrity of our meta-analytical findings. The review included 27 trials, revealing GLP-1RAs significantly improved hepatic function markers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and liver fat content) and cardiovascular risk factors (fasting blood sugar, HbA1c levels, lipid profiles). Additionally, GLP-1RAs were associated with significant reductions in body weight, BMI, subcutaneous fat, and waist circumference. GLP-1RAs demonstrate a promising therapeutic role in managing MASLD, offering benefits that extend to improving liver function, mitigating cardiovascular risk, and promoting weight loss. Further research is needed to confirm these findings and optimize GLP-1RAs' usage in MASLD treatment.
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Affiliation(s)
- Basile Njei
- Department of Medicine, Yale School of Medicine, New Haven, USA
| | | | - Samira Y Lemos
- Department of Diabetes and Endocrinology, Yaoundé General Hospital, Yaoundé, CMR
| | - Derek Ugwendum
- Department of Internal Medicine, Richmond University Medical Center Affiliated with Mount Sinai Health System and Icahn School of Medicine at Mount Sinai, Staten Island, USA
| | - Prince Ameyaw
- Department of Internal Medicine, Bridgeport Hospital, Yale New Haven Health, Bridgeport, USA
| | - Lea-Pearl Njei
- Department of Biological Science, University of Maryland Baltimore County, Baltimore, USA
| | - Sarpong Boateng
- Department of Medicine, Bridgeport Hospital, Bridgeport, USA
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Akhverdyan N, Wieland A, Sullivan S, Lindsay M, Swartwood S, Arndt G, Kaizer LK, Jensen T. Changes in Transient Elastography with Glucagon-Like Peptide-1 Receptor Agonist Use in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Real-World Retrospective Analysis. Metab Syndr Relat Disord 2024; 22:608-618. [PMID: 38868900 DOI: 10.1089/met.2024.0115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2024] Open
Abstract
Introduction: Current guidelines recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD), especially in patients with comorbid diabetes and obesity. This study investigated the effects of GLP-1RAs on hepatic steatosis and fibrosis in patients with MASLD, as measured by changes in vibration-controlled transient elastography (VCTE) and other clinical parameters in a real-world clinical setting. Methods: We conducted a single-center, retrospective analysis of 96 patients with MASLD from a multidisciplinary care clinic who completed VCTE at baseline and follow-up within 6-24 months to compare changes in controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), as well as other metabolic markers, between GLP-1RA users and nonusers using two-sample t-tests and Wilcoxon rank-sum tests. We also assessed whether improvements in hepatic steatosis, defined as a change in CAP >38 dB/m as previously described in the literature, were associated with improvement in fibrosis. Results: GLP-1RA use resulted in significant improvements in weight (-8.1 kg vs. -3.5 kg, P = 0.009), body mass index (BMI) (-2.9 kg/m2 vs. -1.3 kg/m2, P = 0.012), alanine aminotransferase (-15.0 IU/L vs. -4.0 IU/L, P = 0.017), aspartate aminotransferase (-5.0 IU/L vs. -1.0 IU/L, P = 0.021), glycated hemoglobin (HbA1c) (-0.7% vs. 0.1%, P = 0.019), and CAP (-59.9 dB/m vs. -29.1 dB/m, P = 0.016). Responders also had significant improvements in weight (-9.2 kg vs. -1.9 kg, P < 0.001), BMI (-3.3 kg/m2 vs. -0.7 kg/m2, P < 0.001), diastolic blood pressure (-6.1 mmHg vs. -0.7 mmHg, P = 0.028), HbA1c (-0.8% vs. 0.3%, P < 0.001), and LSM (-1.5 kPa vs. 0.1 kPa, P < 0.001). Conclusions: Patients with MASLD treated with GLP-1RAs showed significant improvements in hepatic steatosis and multiple other metabolic parameters, with weight loss as the proposed mechanism for this liver improvement. In addition, change in CAP >38 dB/m was associated with improvements in LSM and other metabolic parameters, suggesting the clinical utility of VCTE in the surveillance of MASLD.
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Affiliation(s)
- Nazar Akhverdyan
- University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Amanda Wieland
- Division of Hepatology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Shelby Sullivan
- Division of Gastroenterology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Mark Lindsay
- Division of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Sheila Swartwood
- Division of Hepatology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Gretchen Arndt
- Division of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Laura Katherine Kaizer
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Thomas Jensen
- Division of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
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12
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Pramanik S, Pal P, Ray S. Non-alcoholic fatty liver disease in type 2 diabetes: Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies. World J Methodol 2024; 14:91319. [PMID: 38983664 PMCID: PMC11229880 DOI: 10.5662/wjm.v14.i2.91319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/20/2024] [Accepted: 02/27/2024] [Indexed: 06/13/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, affecting more than half of the people living with type 2 diabetes (T2D). The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other, which significantly increases the hepatic as well as extrahepatic complications. Until recently, there was no approved pharmacological treatment for NAFLD/ nonalcoholic steatohepatitits (NASH). However, there is evidence that drugs used for diabetes may have beneficial effects on NAFLD. Insulin sensitizers acting through peroxisome proliferator-activated receptor (PPAR) modulation act on multiple levels of NAFLD pathogenesis. Pioglitazone (PPARγ agonist) and saroglitazar (PPARα/γ agonist) are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D, although data on biopsy-proven NASH are lacking with the latter. Initial data on elafibanor (PPAR α/δ agonist) and Lanifibranor (pan PPAR agonist) are promising. On the other hand, incretin therapies based on glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and dual- and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties. GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual- and triple-agonists are required. Furthermore, the long-term safety of these therapies in NAFLD needs to be established. Collaborative efforts among healthcare providers such as primary care doctors, hepatologists, and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.
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Affiliation(s)
- Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Multispecialty Hospital, Siliguri 734010, West Bengal, India
| | - Partha Pal
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 500082, India
| | - Sayantan Ray
- Department of Endocrinology, All India Institute of Medical Sciences, Bhubaneswar, Bhubaneswar 751019, Odisha, India
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13
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Wang H, Ma Q, Chen Y, Luo L, Ye J, Zhong B. Optimized strategy among diet, exercise, and pharmacological interventions for nonalcoholic fatty liver disease: A network meta-analysis of randomized controlled trials. Obes Rev 2024; 25:e13727. [PMID: 38509775 DOI: 10.1111/obr.13727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 01/23/2024] [Accepted: 01/30/2024] [Indexed: 03/22/2024]
Abstract
BACKGROUND Emerging treatment methods, including exercise, diet, and drugs, for nonalcoholic fatty liver disease have been proposed. However, the differences in their efficacy have not been determined. We aimed to compare the effects of these treatments excluding surgery via a systematic review and network meta-analysis of randomized controlled trials. DATA SOURCE The data sources included PubMed, Embase, Web of Science and Cochrane up to February 1st, 2023. The endpoints consisted of body mass index (BMI), serum markers of metabolism and liver injury markers, liver fat content, and stiffness. RESULTS A total of 174 studies with 10,183 patients were included in this meta-analysis. In terms of improving BMI, Pan-agonist of peroxisome proliferator-activated receptors (PPAR) is the best treatment with the highest SUCRA (surface under the cumulative ranking) of 84.8% (mean = -3.40, 95% CI -5.55, -1.24) by the comparative effectiveness ranking. GLP-1 (glucagon-like peptide-1) has the best effect in improving the liver fat content based on the MRI-PDFF, steatosis score (SUCRA 99.7%, mean = -2.19, 95% CI -2.90, -1.48) and ballooning score (SUCRA 61.2%, mean = -0.82, 95% CI -4.46, 2.83). CONCLUSIONS Pan-agonist of PPAR was the most efficacious regimen in lowering BMIs, whereas GLP-1R agonists achieved the highest efficacy of steatosis improvement in this network meta-analysis.
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Affiliation(s)
- Hao Wang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Qianqian Ma
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Infectious Diseases, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Youpeng Chen
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Ling Luo
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Junzhao Ye
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bihui Zhong
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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14
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Xie C, Alkhouri N, Elfeki MA. Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease: Opportunities and challenges. World J Hepatol 2024; 16:731-750. [PMID: 38818288 PMCID: PMC11135259 DOI: 10.4254/wjh.v16.i5.731] [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: 12/30/2023] [Revised: 02/18/2024] [Accepted: 04/03/2024] [Indexed: 05/22/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, paralleling the rising pandemic of obesity and type 2 diabetes. Due to the growing global health burden and complex pathogenesis of MASLD, a multifaceted and innovative therapeutic approach is needed. Incretin receptor agonists, which were initially developed for diabetes management, have emerged as promising candidates for MASLD treatment. This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists: glucagon-like peptide-1 receptor agonists, glucose-dependent insulinotropic polypeptide receptor agonists, and glucagon receptor agonists. Incretins and glucagon directly or indirectly impact various organs, including the liver, brain, pancreas, gastrointestinal tract, and adipose tissue. Thus, these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis. Importantly, this study provides a summary of clinical trials analyzing the effectiveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function, hepatic steatosis, and intrahepatic inflammation. There are emerging challenges associated with the use of these medications in the real world, particularly adverse events, drug-drug interactions, and barriers to access, which are discussed in detail. Additionally, this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.
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Affiliation(s)
- Chencheng Xie
- Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, United States
- Department of Hepatology, Avera Mckennan University Hospital and Transplant Institute, Sioux Falls, SD 57105, United States
| | - Naim Alkhouri
- Department of Hepatology, Arizona Liver Health, Chandler, AZ 85712, United States
| | - Mohamed A Elfeki
- Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, United States
- Department of Hepatology, Avera McKennan University Hospital and Transplant Institute, Sioux Falls, SD 57105, United States.
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15
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Tsai MT, Tseng WC, Lee KH, Lin CC, Ou SM, Li SY. Associations of urinary fetuin-A with histopathology and kidney events in biopsy-proven kidney disease. Clin Kidney J 2024; 17:sfae065. [PMID: 38577269 PMCID: PMC10993056 DOI: 10.1093/ckj/sfae065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Indexed: 04/06/2024] Open
Abstract
Background Fetuin-A is implicated in the pathogenesis of vascular calcification in chronic kidney disease (CKD); however, the relationship between fetuin-A, histopathologic lesions and long-term kidney outcomes in patients with various types of kidney disease remains unclear. Methods We measured urinary fetuin-A levels in 335 individuals undergoing clinically indicated native kidney biopsy. The expressions of fetuin-A mRNA and protein in the kidney were assessed using RNA sequencing and immunohistochemistry. The association of urinary fetuin-A with histopathologic lesions and major adverse kidney events (MAKE), defined as a decline in estimated glomerular filtration rate (eGFR) of at least 40%, kidney failure or death, was analyzed. Results Urinary fetuin-A levels showed a positive correlation with albuminuria (rs = 0.67, P < .001) and a negative correlation with eGFR (rs = -0.46, P < .001). After multivariate adjustment, higher urinary fetuin-A levels were associated with glomerular inflammation, mesangial expansion, interstitial fibrosis and tubular atrophy, and arteriolar sclerosis. Using a 1 transcript per million gene expression cutoff, we found kidney fetuin-A mRNA levels below the threshold in both individuals with normal kidney function and those with CKD. Additionally, immunohistochemistry revealed reduced fetuin-A staining in tubular cells of CKD patients compared with normal controls. During a median 21-month follow-up, 115 patients experienced MAKE, and Cox regression analysis confirmed a significant association between elevated urinary fetuin-A and MAKE. This association remained significant after adjusting for potential confounding factors. Conclusion Urinary fetuin-A is associated with chronic histological damage and adverse clinical outcomes across a spectrum of biopsy-proven kidney diseases.
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Affiliation(s)
- Ming-Tsun Tsai
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Cheng Tseng
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Kuo-Hua Lee
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Ching Lin
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shuo-Ming Ou
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Szu-yuan Li
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
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Chrysavgis LG, Kazanas S, Bafa K, Rozani S, Koloutsou ME, Cholongitas E. Glucagon-like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide, and Glucagon Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Medication in New Liver Disease Nomenclature. Int J Mol Sci 2024; 25:3832. [PMID: 38612640 PMCID: PMC11012092 DOI: 10.3390/ijms25073832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 03/15/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open
Abstract
Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that regulate postprandial glucose regulation, stimulating insulin secretion from pancreatic β-cells in response to food ingestion. Modified GLP-1 receptor agonists (GLP-1RAs) are being administered for the treatment of obesity and type 2 diabetes mellitus (T2DM). Strongly related to those disorders, metabolic dysfunction-associated steatotic liver disease (MASLD), especially its aggressive form, defined as metabolic dysfunction-associated steatohepatitis (MASH), is a major healthcare burden associated with high morbidity and extrahepatic complications. GLP-1RAs have been explored in MASH patients with evident improvement in liver dysfunction enzymes, glycemic control, and weight loss. Importantly, the combination of GLP-1RAs with GIP and/or glucagon RAs may be even more effective via synergistic mechanisms in amelioration of metabolic, biochemical, and histological parameters of MASLD but also has a beneficial impact on MASLD-related complications. In this current review, we aim to provide an overview of incretins' physiology, action, and signaling. Furthermore, we provide insight into the key pathophysiological mechanisms through which they impact MASLD aspects, as well as we analyze clinical data from human interventional studies. Finally, we discuss the current challenges and future perspectives pertinent to this growing area of research and clinical medicine.
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Affiliation(s)
- Lampros G. Chrysavgis
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Spyridon Kazanas
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Konstantina Bafa
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Sophia Rozani
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
| | - Maria-Evangelia Koloutsou
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece;
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, 115 27 Athens, Greece; (L.G.C.); (S.K.); (K.B.); (S.R.)
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17
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Lupianez-Merly C, Dilmaghani S, Vosoughi K, Camilleri M. Review article: Pharmacologic management of obesity - updates on approved medications, indications and risks. Aliment Pharmacol Ther 2024; 59:475-491. [PMID: 38169126 DOI: 10.1111/apt.17856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 12/13/2023] [Accepted: 12/18/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Obesity has reached epidemic proportions, with >40% of the US population affected. Although traditionally managed by lifestyle modification, and less frequently by bariatric therapies, there are significant pharmacological advancements. AIMS To conduct a narrative review of the neurohormonal and physiological understanding of weight gain and obesity, and the development, clinical testing, indications, expected clinical outcomes, and associated risks of current FDA-approved and upcoming anti-obesity medications (AOMs). METHODS We conducted a comprehensive review in PubMed for articles on pathophysiology and complications of obesity, including terms 'neurohormonal', 'obesity', 'incretin', and 'weight loss'. Next, we searched for clinical trial data of all FDA-approved AOMs, including both the generic and trade names of orlistat, phentermine/topiramate, bupropion/naltrexone, liraglutide, and semaglutide. Additional searches were conducted for tirzepatide and retatrutide - medications expecting regulatory approval. Searches included combinations of terms related to mechanism of action, indications, side effects, risks, and future directions. RESULTS We reviewed the pathophysiology of obesity, including specific role of incretins and glucagon. Clinical data supporting the use of various FDA-approved medications for weight loss are presented, including placebo-controlled or, when available, head-to-head trials. Beneficial metabolic effects, including impact on liver disease, adverse effects and risks of medications are discussed, including altered gastrointestinal motility and risk for periprocedural aspiration. CONCLUSION AOMs have established efficacy and effectiveness for weight loss even beyond 52 weeks. Further pharmacological options, such as dual and triple incretins, are probable forthcoming additions to clinical practice for combating obesity and its metabolic consequences such as metabolic dysfunction-associated steatotic liver disease.
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Affiliation(s)
- Camille Lupianez-Merly
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Saam Dilmaghani
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Kia Vosoughi
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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18
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Zachou M, Flevari P, Nasiri-Ansari N, Varytimiadis C, Kalaitzakis E, Kassi E, Androutsakos T. The role of anti-diabetic drugs in NAFLD. Have we found the Holy Grail? A narrative review. Eur J Clin Pharmacol 2024; 80:127-150. [PMID: 37938366 PMCID: PMC10781828 DOI: 10.1007/s00228-023-03586-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 10/19/2023] [Indexed: 11/09/2023]
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease, affecting 30% of the global population. NAFLD prevalence is particularly high in obese individuals and patients with type 2 diabetes mellitus (T2DM). NAFLD ranges from simple fat deposition in the liver to necroinflammation and fibrosis (non-alcoholic steatohepatitis (NASH)), NASH-cirrhosis, and/or hepatocellular carcinoma. Insulin resistance plays a key role in NAFLD pathogenesis, alongside dysregulation of adipocytes, mitochondrial dysfunction, genetic factors, and changes in gut microbiota. Since insulin resistance is also a major predisposing factor of T2DM, the administration of anti-diabetic drugs for the management of NAFLD seems reasonable. METHODS In this review we provide the NAFLD-associated mechanisms of action of some of the most widely used anti-diabetic drugs, namely metformin, pioglitazone, sodium-glucose transport protein-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor analogs (GLP1 RAs), and dipeptyl-peptidase-4 inhibitors (DPP4i) and present available data regarding their use in patients with NAFLD, with and without T2DM. RESULTS Both metformin and DPP4i have shown rather contradictory results, while pioglitazone seems to benefit patients with NASH and is thus the only drug approved for NASH with concomitant significant liver fibrosis by all major liver societies. On the other hand, SGLT2i and GLP1 RAs seem to be beneficiary in patients with NAFLD, showing both remarkable results, with SGLT2i proving to be more efficient in the only head-to-head study so far. CONCLUSION In patients with NAFLD and diabetes, pioglitazone, GLP1 RAs, and SGLT2i seem to be logical treatment options. Larger studies are needed before these drugs can be recommended for non-diabetic individuals.
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Affiliation(s)
- Maria Zachou
- Gastroenterology Department, "Sismanoglio" General Hospital, 151 26, Athens, Greece
| | - Pagona Flevari
- Expertise Center in Rare Haematological Diseases-Haemoglobinopathies, "Laiko" General Hospital, 115 27, Athens, Greece
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | | | - Evangelos Kalaitzakis
- Department of Gastroenterology, University Hospital of Heraklion, University of Crete, 715 00, Heraklion, Greece
| | - Eva Kassi
- Unit of Molecular Endocrinology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, "Laiko" Hospital, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27, Athens, Greece.
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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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20
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Deng M, Wen Y, Yan J, Fan Y, Wang Z, Zhang R, Ren L, Ba Y, Wang H, Lu Q, Fan H. Comparative effectiveness of multiple different treatment regimens for nonalcoholic fatty liver disease with type 2 diabetes mellitus: a systematic review and Bayesian network meta-analysis of randomised controlled trials. BMC Med 2023; 21:447. [PMID: 37974258 PMCID: PMC10655371 DOI: 10.1186/s12916-023-03129-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 10/25/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely related and mutually contribute to the disease's development. There are many treatment options available to patients. We provide a comprehensive overview of the evidence on the treatment effects of several potential interventions for NAFLD with T2DM. METHODS This systematic review and network meta-analysis included searches of PubMed, Embase, Cochrane Library, and Web of Science from inception to June 30, 2023, for randomised controlled trials of treatment of NAFLD with T2DM. We performed Bayesian network meta-analyses to summarise effect estimates of comparisons between interventions. We applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks to rate all comparative outcomes' certainty in effect estimates, categorise interventions, and present the findings. This study was registered with PROSPERO, CRD42022342373. RESULTS Four thousand three hundred and sixty-nine records were retrieved from the database and other methods, of which 24 records were eligible for studies enrolling 1589 participants. Eight clinical indicators and 14 interventions were finally in focus. Referring to the lower surface under the cumulative ranking curves (SUCRA) and the league matrix table, exenatide and liraglutide, which are also glucagon-like peptide-1 receptor agonists (GLP-1RAs), showed excellent potential to reduce liver fat content, control glycemia, reduce body weight, and improve liver function and insulin resistance. Exenatide was more effective in reducing glycated haemoglobin (HbA1c) (mean difference (MD) 0.32, 95%CI 0.12 to 0.52), lowering BMI (MD 0.81, 95%CI 0.18 to 1.45), and lowering alanine transaminase (ALT) (MD 10.96, 95%CI 5.27 to 16.66) compared to liraglutide. However, this evidence was assessed as low certainty. Omega-3 was the only intervention that did not have a tendency to lower HbA1c, with standard-treatment (STA-TRE) as reference (MD - 0.17, 95%CI - 0.42 to 0.07). Glimepiride is the only intervention that causes an increase in ALT levels, with standard-treatment (STA-TRE) as reference (MD - 11.72, 95%CI - 17.82 to - 5.57). Based on the available evidence, the treatment effects of pioglitazone, dapagliflozin, and liraglutide have a high degree of confidence. CONCLUSIONS The high confidence mandates the confident application of these findings as guides for clinical practice. Dapagliflozin and pioglitazone are used for glycaemic control in patients with NAFLD combined with T2DM, and liraglutide is used for weight loss therapy in patients with abdominal obesity. The available evidence does not demonstrate the credibility of the effectiveness of other interventions in reducing liver fat content, visceral fat area, ALT, and insulin resistance. Future studies should focus on the clinical application of GLP-1Ras and the long-term prognosis of patients.
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Affiliation(s)
- Manjun Deng
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Yonghao Wen
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - JingXin Yan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Department of Interventional Therapy, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Yichen Fan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Zhixin Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Ruixia Zhang
- Department of Endocrinology, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Li Ren
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Yinggui Ba
- Department of Nephrology, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Haijiu Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Qian Lu
- Department of Hepatopancreatobiliary Surgery, Tsinghua Changgung Hospital, Tsinghua University, Beijing, 102218, China.
| | - Haining Fan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China.
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China.
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21
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Andreasen CR, Andersen A, Vilsbøll T. The future of incretins in the treatment of obesity and non-alcoholic fatty liver disease. Diabetologia 2023; 66:1846-1858. [PMID: 37498367 DOI: 10.1007/s00125-023-05966-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 06/02/2023] [Indexed: 07/28/2023]
Abstract
In the last few decades, glucagon-like peptide-1 receptor (GLP-1R) agonists have changed current guidelines and improved outcomes for individuals with type 2 diabetes. However, the dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonist, tirzepatide, has demonstrated superior efficacy regarding improvements in HbA1c and body weight in people with type 2 diabetes. This has led to increasing scientific interest in incretin hormones and incretin interactions, and several compounds based on dual- and multi-agonists are now being investigated for the treatment of metabolic diseases. Herein, we highlight the key scientific advances in utilising incretins for the treatment of obesity and, potentially, non-alcoholic fatty liver disease (NAFLD). The development of multi-agonists with multi-organ targets may alter the natural history of these diseases.
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Affiliation(s)
- Christine R Andreasen
- Clinical Research, Copenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Andreas Andersen
- Clinical Research, Copenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Tina Vilsbøll
- Clinical Research, Copenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark.
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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22
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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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23
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Kongmalai T, Srinonprasert V, Anothaisintawee T, Kongmalai P, McKay G, Attia J, Thakkinstian A. New anti-diabetic agents for the treatment of non-alcoholic fatty liver disease: a systematic review and network meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne) 2023; 14:1182037. [PMID: 37441498 PMCID: PMC10335801 DOI: 10.3389/fendo.2023.1182037] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/14/2023] [Indexed: 07/15/2023] Open
Abstract
Objectives This network meta-analysis aims to compare the efficacy and safety of new anti-diabetic medications for the treatment of non-alcoholic fatty liver disease (NAFLD). Materials and methods PubMed and Scopus were searched from inception to 27th March 2022 to identify all randomized controlled trials (RCTs) in NAFLD patients. Outcomes included reductions in intrahepatic steatosis (IHS) and liver enzyme levels. The efficacy and safety of DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, and other therapies were indirectly compared using a NMA approach. Unstandardized mean difference (USMD) with 95% confidence intervals (CI) were calculated. Results 2,252 patients from 31 RCTs were included. "Add-on" GLP-1 agonists with standard of care (SoC) treatment showed significantly reduced IHS compared to SoC alone [USMD (95%CI) -3.93% (-6.54%, -1.33%)]. Surface under the cumulative ranking curve (SUCRA) identified GLP-1 receptor agonists with the highest probability to reduce IHS (SUCRA 88.5%), followed by DPP-4 inhibitors (SUCRA 69.6%) and pioglitazone (SUCRA 62.2%). "Add-on" GLP-1 receptor agonists were also the most effective treatment for reducing liver enzyme levels; AST [USMD of -5.04 (-8.46, -1.62)], ALT [USMD of -9.84 (-16.84, -2.85)] and GGT [USMD of -15.53 (-22.09, -8.97)] compared to SoC alone. However, GLP-1 agonists were most likely to be associated with an adverse event compared to other interventions. Conclusion GLP-1 agonists may represent the most promising anti-diabetic treatment to reduce hepatic steatosis and liver enzyme activity in T2DM and NAFLD patients. Nevertheless, longer-term studies are required to determine whether this delays progression of liver cirrhosis in patients with NAFLD and T2DM. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42021259336.1.
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Affiliation(s)
- Tanawan Kongmalai
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Varalak Srinonprasert
- Siriraj Health Policy Unit, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Division of Geriatric Medicine, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Mahidol University Health Technology Assessment Graduate Program, Mahidol University, Bangkok, Thailand
| | - Thunyarat Anothaisintawee
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Pinkawas Kongmalai
- Department of Orthopaedics, Faculty of Medicine, Srinakharinwirot University, Ongkharak, Nakhon Nayok, Thailand
| | - Gareth McKay
- Centre for Public Health, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University, Belfast, Ireland
| | - John Attia
- School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia
| | - Ammarin Thakkinstian
- Mahidol University Health Technology Assessment Graduate Program, Mahidol University, Bangkok, Thailand
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Lee HA, Kim HY. Therapeutic Mechanisms and Clinical Effects of Glucagon-like Peptide 1 Receptor Agonists in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2023; 24:ijms24119324. [PMID: 37298276 DOI: 10.3390/ijms24119324] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/19/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) can lead to liver fibrosis and cirrhosis. Recently, glucagon-like peptide 1 receptor agonists (GLP-1RAs), a class of drugs used to treat type 2 diabetes and obesity, have shown therapeutic effects against NAFLD. In addition to reducing blood glucose levels and body weight, GLP-1RAs are effective in improving the clinical, biochemical, and histological markers of hepatic steatosis, inflammation, and fibrosis in patients with NAFLD. Additionally, GLP-1RAs have a good safety profile with minor side effects, such as nausea and vomiting. Overall, GLP-1RAs show promise as a potential treatment for NAFLD, and further studies are required to determine their long-term safety and efficacy.
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Affiliation(s)
- Han Ah Lee
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul 07985, Republic of Korea
| | - Hwi Young Kim
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul 07985, Republic of Korea
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25
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Gu Y, Sun L, Zhang W, Kong T, Zhou R, He Y, Deng C, Yang L, Kong J, Chen Y, Shi J, Hu Y. Comparative efficacy of 5 sodium-glucose cotransporter protein-2 (SGLT-2) inhibitor and 4 glucagon-like peptide-1 (GLP-1) receptor agonist drugs in non-alcoholic fatty liver disease: A GRADE-assessed systematic review and network meta-analysis of randomized controlled trials. Front Pharmacol 2023; 14:1102792. [PMID: 36992825 PMCID: PMC10040540 DOI: 10.3389/fphar.2023.1102792] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 02/28/2023] [Indexed: 03/14/2023] Open
Abstract
Background: The relative efficacy of 5 sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and 4 glucagon-like peptide-1 (GLP-1) receptor agonists for non-alcoholic fatty liver disease (NAFLD) therapy has not been sufficiently investigated. Methods: Randomized controlled trials (RCTs) in which patients with NAFLD were treated with SGLT-2 inhibitors or GLP-1 receptor agonists were included. Primary outcomes were improvements in liver enzymes and liver fat parameters, while secondary outcomes included anthropometric measures, blood lipids and glycemic parameters. The frequentist method was used to perform a network meta-analysis. Evidence certainty was assessed using the grading of recommendations assessment, development, and evaluation (GRADE). Results: The criteria were satisfied by 37 RCTs with 9 interventions (5 SGLT-2 inhibitors and 4 GLP-1 receptor agonists). Based on high certainty evidence, in patients with NAFLD (or comorbid with type 2 diabetes), semaglutide could lower alanine aminotransferase as well as aspartate aminotransferase, γ-glutamyl transferase, controlled attenuation parameter, liver stiffness measurement, body weight, systolic blood pressure, triglycerides, high-density lipoprotein-cholesterol, glycosylated hemoglobin. Liraglutide could lower alanine aminotransferase as well as subcutaneous adipose tissue, body mass index, fasting blood glucose, glycosylated hemoglobin, glucose and homeostasis model assessment, while dapagliflozin could lower alanine aminotransferase as well as body weight, fasting blood glucose, postprandial blood glucose, glycosylated hemoglobin, glucose and homeostasis model assessment. Conclusion: Semaglutide, liraglutide, and dapagliflozin all have a certain effect on NAFLD (or comorbid with type 2 diabetes) based on high confidence evidence from indirect comparisons, and semaglutide appears to have a therapeutic advantage over the other included medicines. Head-to-head studies are needed to provide more confidence in clinical decision-making.
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Affiliation(s)
- Yunpeng Gu
- School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Lei Sun
- Medical School, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Wei Zhang
- School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Tingting Kong
- School of Nursing, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Run Zhou
- School of Nursing, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yining He
- Medical School, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Chaohua Deng
- Medical School, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Luping Yang
- Medical School, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jianing Kong
- Medical School, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yutong Chen
- School of Nursing, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Junping Shi
- The Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yanli Hu
- School of Nursing, Guangzhou Medical University, Guangzhou, Guangdong, China
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Kosmalski M, Frankowski R, Ziółkowska S, Różycka-Kosmalska M, Pietras T. What's New in the Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD). J Clin Med 2023; 12:jcm12051852. [PMID: 36902639 PMCID: PMC10003344 DOI: 10.3390/jcm12051852] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/09/2023] [Accepted: 02/20/2023] [Indexed: 03/02/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a serious health problem due to its high incidence and consequences. In view of the existing controversies, new therapeutic options for NAFLD are still being sought. Therefore, the aim of our review was to evaluate the recently published studies on the treatment of NAFLD patients. We searched for articles in the PubMed database using appropriate terms, including "non-alcoholic fatty liver disease", "nonalcoholic fatty liver disease", "NAFLD", "diet", "treatment", "physical activity", "supplementation", "surgery", "overture" and "guidelines". One hundred forty-eight randomized clinical trials published from January 2020 to November 2022 were used for the final analysis. The results show significant benefits of NAFLD therapy associated with the use of not only the Mediterranean but also other types of diet (including low-calorie ketogenic, high-protein, anti-inflammatory and whole-grain diets), as well as enrichment with selected food products or supplements. Significant benefits in this group of patients are also associated with moderate aerobic physical training. The available therapeutic options indicate, above all, the usefulness of drugs related to weight reduction, as well as the reduction in insulin resistance or lipids level and drugs with anti-inflammatory or antioxidant properties. The usefulness of therapy with dulaglutide and the combination of tofogliflozin with pioglitazone should be emphasized. Based on the results of the latest research, the authors of this article suggest a revision of the therapeutic recommendations for NAFLD patients.
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Affiliation(s)
- Marcin Kosmalski
- Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
- Correspondence: ; Tel.: +48-728-358-504
| | - Rafał Frankowski
- Students’ Research Club, Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
| | - Sylwia Ziółkowska
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland
| | | | - Tadeusz Pietras
- Department of Clinical Pharmacology, Medical University of Lodz, 90-153 Lodz, Poland
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Zhao Y, Zhao W, Bu H, Toshiyoshi M, Zhao Y. Liraglutide on type 2 diabetes mellitus with nonalcoholic fatty liver disease: A systematic review and meta-analysis of 16 RCTs. Medicine (Baltimore) 2023; 102:e32892. [PMID: 36820578 PMCID: PMC9907937 DOI: 10.1097/md.0000000000032892] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity of type 2 diabetes mellitus (T2DM). Our aim is to investigate the effects of liraglutide on T2DM with NAFLD. METHODS Relevant articles published from the earliest publication to March 2022 were selected from several databases. The Cochrane Collaboration's RevMan software was used for the analysis. RESULTS Sixteen studies are selected for this meta-analysis, which includes totally 634 patients in the treatment group and 630 patients in the control group. As a result, 14 studies show that fasting plasma glucose levels of the experimental group are lower than that of the control group; 15 studies show that glycosylated hemoglobin A1c levels of the experimental group are lower than that of the control group; 13 studies show that triglyceride levels of the experimental group are lower than that of the control group; twelve studies show that total cholesterol levels of the experimental group are lower than that of the control group; 10 studies show that alanine aminotransferase levels of the experimental group is lower than that of the control group; 10 studies show that no significant difference in changes in aspartate transaminase between 2 groups; 13 studies show that low density lipoprotein cholesterol levels of the experimental group is lower than that of the control group; 9 studies show that no significant difference in changes in high density lipoprotein cholesterol between 2 groups; 7 studies mentioned adverse effects and the difference is significant. CONCLUSION Liraglutide is potentially curative for T2DM with NAFLD.
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Affiliation(s)
- Yan Zhao
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenli Zhao
- Department of Public Health, International College, Krirk University, Bangkok, Thailand
- Liver Center, Saga University Hospital, Saga University, Saga, Japan
| | - Huaien Bu
- School of Health Science and Engineering, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Maeda Toshiyoshi
- International Education College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ye Zhao
- Department of Public Health, International College, Krirk University, Bangkok, Thailand
- * Correspondence: Ye Zhao, Department of Public Health, International College, Krirk University, Bangkok 10220, Thailand (e-mail: )
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Targher G, Mantovani A, Byrne CD. Mechanisms and possible hepatoprotective effects of glucagon-like peptide-1 receptor agonists and other incretin receptor agonists in non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol 2023; 8:179-191. [PMID: 36620987 DOI: 10.1016/s2468-1253(22)00338-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/22/2022] [Accepted: 09/29/2022] [Indexed: 01/07/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that stimulate insulin secretion from pancreatic β cells in response to food ingestion. Modified GLP-1 and GIP peptides are potent agonists for their incretin receptors, and some evidence shows that the dual GLP-1 and GIP receptor agonist tirzepatide is effective in promoting marked weight loss. GLP-1 receptor agonists signal in the CNS to suppress appetite, increase satiety, and thereby decrease calorie intake, but many other effects of incretin signalling have been recognised that are relevant to the treatment of non-alcoholic fatty liver disease (NAFLD). This Review provides an overview of the literature supporting the notion that endogenous incretins and incretin-receptor agonist treatments are important not only for decreasing risk of developing NAFLD, but also for treating NAFLD and NAFLD-related complications. We discuss incretin signalling and related incretin-receptor agonist treatments, mechanisms in key relevant tissues affecting liver disease, and clinical data from randomised controlled trials. Finally, we present future perspectives in this rapidly developing field of research and clinical medicine.
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Affiliation(s)
- Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, UK; Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
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Zou CY, Sun Y, Liang J. Comparative efficacy of diabetes medications on liver enzymes and fat fraction in patients with nonalcoholic fatty liver disease: A network meta-analysis ,. Clin Res Hepatol Gastroenterol 2023; 47:102053. [PMID: 36403941 DOI: 10.1016/j.clinre.2022.102053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/03/2022] [Accepted: 11/16/2022] [Indexed: 11/18/2022]
Abstract
OBJECTIVES This network meta-analysis (NMA) aimed to evaluate the relative rank-order of existing diabetes medications in patients with nonalcoholic fatty liver disease (NAFLD) with or without type 2 diabetes mellitus (T2DM). METHODS A systematic literature search was conducted using the Medline, Embase and Cochrane databases. Clinical trials comparing the efficacy of diabetes medications with other interventions, including lifestyle modification and placebo, in patients with NAFLD were included. The results from the NMA are presented as the weighted mean difference (WMD) of the continuous results and the corresponding 95% confidence intervals (95% CIs). RESULTS The articles presented the results of 49 trials involving 3,836 subjects published between 2013 and 2021. According to our results, thiazolidinedione (TZD) was ranked as the best diabetes medication in the reduction of alanine aminotransferase (ALT) (WMD = -10.10, 95% CI: -15.18, -5.01), followed by dipeptidyl peptidase-4 inhibitor (DPP4i) (WMD = -8.90, 95% CI: -14.41, -3.40). DPP4i also resulted in the greatest reduction in aspartate aminotransferase (AST) (WMD = -6.89, 95% CI: -11.72, -2.07). γ-Glutamyl transferase (γ-GT) reduction was highest in patients treated with glucagon-like peptide 1 receptor agonists (GLP1RAs) (WMD = -15.48, 95% CI: -30.93, -0.02). Ultimately, SGLT2is and GLP1RAs were superior to other diabetes medications or placebo in reducing liver fat fraction (LFF) (WMD = -6.09, 95% CI: -10.50, -1.68; WMD = -5.55, 95% CI: -10.40, -0.69, respectively). CONCLUSION Diabetes medications, including TZD, DPP4i and GLP1RAs, were found to be suitable alternatives for liver enzyme reduction in the treatment of NAFLD patients. SGLT2is are considered the most effective therapies for lipid modulation in these patients.
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Affiliation(s)
- Cai-Yan Zou
- Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, China
| | - Yan Sun
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, China
| | - Jun Liang
- Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, China.
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Byrne CD. Banting memorial lecture 2022: 'Type 2 diabetes and nonalcoholic fatty liver disease: Partners in crime'. Diabet Med 2022; 39:e14912. [PMID: 35790023 PMCID: PMC9546361 DOI: 10.1111/dme.14912] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/14/2022] [Accepted: 06/29/2022] [Indexed: 11/28/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) was first described in the 1980s, but in the 21st century, NAFLD has become a very common condition. The explanation for this relatively recent problem is in large part due to the recent epidemic of obesity and type 2 diabetes (T2DM) increasing the risk of NAFLD. NAFLD is a silent condition that may not become manifest until severe liver damage (fibrosis or cirrhosis) has occurred. Consequently, NAFLD and its complications often remain undiagnosed. Research evidence shows that NAFLD is extremely common and some estimates suggest that it occurs in up to 70% of people with T2DM. In the last 5 years, it has become evident that NAFLD not only increases the risk of cirrhosis, primary liver cancer and end-stage liver disease, but NAFLD is also an important multisystem disease that has major implications beyond the liver. NAFLD increases the risk of incident T2DM, cardiovascular disease, chronic kidney disease and certain extra-hepatic cancers, and NAFLD and T2DM form part of a vicious spiral of worsening diseases, where one condition affects the other and vice versa. Diabetes markedly increases the risk of liver fibrosis and liver fibrosis is the most important risk factor for hepatocellular carcinoma. It is now possible to diagnose liver fibrosis with non-invasive tools and therefore it is important to have clear care pathways for the management of NAFLD in patients with T2DM. This review summarises key recent research that was discussed as part of the Banting lecture at the annual scientific conference in 2022.
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Affiliation(s)
- Christopher D. Byrne
- Division of Endocrinology & MetabolismUniversity Hospital Southampton and University of SouthamptonSouthamptonUK
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Vachher M, Bansal S, Kumar B, Yadav S, Arora T, Wali NM, Burman A. Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma. J Cell Biochem 2022; 123:1553-1584. [PMID: 35818831 DOI: 10.1002/jcb.30252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/17/2022] [Accepted: 03/29/2022] [Indexed: 12/16/2022]
Abstract
Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%-90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.
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Affiliation(s)
- Meenakshi Vachher
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Savita Bansal
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Bhupender Kumar
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Sandeep Yadav
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Taruna Arora
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Nalini Moza Wali
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
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Dar S, Siddiqi AK, Alabduladhem TO, Rashid AM, Sarfraz S, Maniya T, Menezes RG, Almas T. Effects of novel glucose-lowering drugs on the lipid parameters: A systematic review and meta-analysis. Ann Med Surg (Lond) 2022; 77:103633. [PMID: 35637990 PMCID: PMC9142616 DOI: 10.1016/j.amsu.2022.103633] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/12/2022] [Accepted: 04/12/2022] [Indexed: 01/10/2023] Open
Affiliation(s)
- Sophia Dar
- Hackensack University Medical Center, Hackensack, NJ, United States
| | | | | | | | - Saba Sarfraz
- Department of Medicine, Islamabad Medical and Dental College, Islamabad, Pakistan
| | - Talha Maniya
- Department of Medicine, Ziauddin Medical University, Karachi, Pakistan
| | - Ritesh G. Menezes
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Talal Almas
- Department of Medicine, Royal College of Surgeons in Ireland, Ireland
- Corresponding author.
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Ding C, Tang Y, Zhu W, Huang P, Lian P, Ran J, Huang X. Sodium-glucose cotransporter protein-2 inhibitors and glucagon-like peptide-1 receptor agonists versus thiazolidinediones for non-alcoholic fatty liver disease: A network meta-analysis. Acta Diabetol 2022; 59:519-533. [PMID: 34988690 DOI: 10.1007/s00592-021-01830-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023]
Abstract
AIMS Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disorders worldwide. Some hypoglycemic drugs can improve NAFLD. However, it is unclear which of these types of hypoglycemic drugs are more effective for NAFLD. Therefore, we conducted a network meta-analysis to determine the effect of thiazolidinediones (TZDs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists on NAFLD patients. METHODS A literature search of PubMed, EMBASE, the Cochrane Library, and Medline was conducted, and the literature from database inception up to April 30, 2021 was obtained. Liver function tests, lipid profiles, body mass index (BMI) and glycemic parameters were obtained from randomized controlled trials. Weighted mean differences (WMDs), relative risks and 95% confidence intervals (CIs) were calculated for continuous outcomes, and the I2 statistic was used to evaluate the heterogeneity of the studies. RESULTS In total, 22 trials, including 1361 patients, were selected. In direct meta-analysis, GLP-1 receptor agonists were superior to TZDs in decreasing alanine aminotransferase (WMD, -0.40, 95% CI: -0.60 to -0.20), γ-glutamyl transferase (WMD, -5.00, 95% CI: -6.47 to -3.53), BMI (WMD, -4.10, 95%CI: -6.55 to -1.65) and triglycerides (WMD, - 0.50, 95% CI: -0.68 to -0.32). Based on Bayesian network meta-analysis, the effect of SGLT-2 inhibitors on weight loss was superior to that of TZDs (WMD, -1.80, 95%CI: -3.30 to -0.41). CONCLUSIONS GLP-1 receptor agonists and SGLT-2 inhibitors improved liver enzymes, BMI, blood lipid, blood glucose and insulin resistance in NAFLD patients.
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Affiliation(s)
- Chen Ding
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yaxin Tang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Wenqiang Zhu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Piaopiao Huang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Pingan Lian
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Juanli Ran
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Xiansheng Huang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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Yan H, Huang C, Shen X, Li J, Zhou S, Li W. GLP-1 RAs and SGLT-2 Inhibitors for Insulin Resistance in Nonalcoholic Fatty Liver Disease: Systematic Review and Network Meta-Analysis. Front Endocrinol (Lausanne) 2022; 13:923606. [PMID: 35909522 PMCID: PMC9325993 DOI: 10.3389/fendo.2022.923606] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/20/2022] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce glycaemia and weight and improve insulin resistance (IR) via different mechanisms. We aim to evaluate and compare the ability of GLP-1 RAs and SGLT-2 inhibitors to ameliorate the IR of nonalcoholic fatty liver disease (NAFLD) patients. DATA SYNTHESIS Three electronic databases (Medline, Embase, PubMed) were searched from inception until March 2021. We selected randomized controlled trials comparing GLP-1 RAs and SGLT-2 inhibitors with control in adult NAFLD patients with or without T2DM. Network meta-analyses were performed using fixed and random effect models, and the mean difference (MD) with corresponding 95% confidence intervals (CI) were determined. The within-study risk of bias was assessed with the Cochrane collaborative risk assessment tool RoB. RESULTS 25 studies with 1595 patients were included in this network meta-analysis. Among them, there were 448 patients, in 6 studies, who were not comorbid with T2DM. Following a mean treatment duration of 28.86 weeks, compared with the control group, GLP-1 RAs decreased the HOMA-IR (MD [95%CI]; -1.573[-2.523 to -0.495]), visceral fat (-0.637[-0.992 to -0.284]), weight (-2.394[-4.625 to -0.164]), fasting blood sugar (-0.662[-1.377 to -0.021]) and triglyceride (- 0.610[-1.056 to -0.188]). On the basis of existing studies, SGLT-2 inhibitors showed no statistically significant improvement in the above indicators. Compared with SGLT-2 inhibitors, GLP-1 RAs decreased visceral fat (-0.560[-0.961 to -0.131]) and triglyceride (-0.607[-1.095 to -0.117]) significantly. CONCLUSIONS GLP-1 RAs effectively improve IR in NAFLD, whereas SGLT-2 inhibitors show no apparent effect. SYSTEMATIC REVIEW REGISTRATION PROSPERO https://www.crd.york.ac.uk/PROSPERO/, CRD42021251704.
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Affiliation(s)
- Hongle Yan
- Department of Endocrinology, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, China
| | - Chunyi Huang
- Department of Endocrinology, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, China
| | - Xuejun Shen
- Department of Endocrinology, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, China
| | - Jufang Li
- Department of Endocrinology, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, China
| | - Shuyi Zhou
- Department of Endocrinology, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, China
| | - Weiping Li
- Department of Endocrinology, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
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Mantovani A, Byrne CD, Targher G. Efficacy of peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease: a systematic review. Lancet Gastroenterol Hepatol 2022; 7:367-378. [PMID: 35030323 DOI: 10.1016/s2468-1253(21)00261-2] [Citation(s) in RCA: 145] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 12/14/2022]
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Kim TH, Hong DG, Yang YM. Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism. Biomedicines 2021; 9:biomedicines9121903. [PMID: 34944728 PMCID: PMC8698516 DOI: 10.3390/biomedicines9121903] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/12/2021] [Accepted: 12/12/2021] [Indexed: 12/16/2022] Open
Abstract
The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily attributed to signaling crosstalk between multiple organs via hepatic hormones, cytokines, and hepatokines. Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation. Mounting evidence has revealed that the secretory profiles of hepatokines are significantly altered in non-alcoholic fatty liver disease (NAFLD), the most common hepatic manifestation, which frequently precedes other metabolic disorders, including insulin resistance and type 2 diabetes. Therefore, deciphering the mechanism of hepatokine-mediated inter-organ communication is essential for understanding the complex metabolic network between tissues, as well as for the identification of novel diagnostic and/or therapeutic targets in metabolic disease. In this review, we describe the hepatokine-driven inter-organ crosstalk in the context of liver pathophysiology, with a particular focus on NAFLD progression. Moreover, we summarize key hepatokines and their molecular mechanisms of metabolic control in non-hepatic tissues, discussing their potential as novel biomarkers and therapeutic targets in the treatment of metabolic diseases.
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Affiliation(s)
- Tae Hyun Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women’s University, Seoul 04310, Korea;
| | - Dong-Gyun Hong
- Department of Pharmacy, Kangwon National University, Chuncheon 24341, Korea;
- KNU Researcher Training Program for Developing Anti-Viral Innovative Drugs, Kangwon National University, Chuncheon 24341, Korea
| | - Yoon Mee Yang
- Department of Pharmacy, Kangwon National University, Chuncheon 24341, Korea;
- KNU Researcher Training Program for Developing Anti-Viral Innovative Drugs, Kangwon National University, Chuncheon 24341, Korea
- Correspondence: ; Tel.: +82-33-250-6909
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Ng CH, Lin SY, Chin YH, Lee MH, Syn N, Goh XL, Koh JH, Quek J, Hao Tan DJ, Mok SF, Tan E, Dan YY, Chew N, Khoo CM, Siddiqui MS, Muthiah M. Antidiabetic Medications for Type 2 Diabetics with Nonalcoholic Fatty Liver Disease: Evidence From a Network Meta-Analysis of Randomized Controlled Trials. Endocr Pract 2021; 28:223-230. [PMID: 34606980 DOI: 10.1016/j.eprac.2021.09.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/17/2021] [Accepted: 09/25/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD) are closely related, and antidiabetic medications have been shown to be potential therapeutics in NAFLD. Using a network meta-analysis, we sought to examine the effectiveness of antidiabetic agents for the treatment of NAFLD in patients with type 2 diabetes mellitus. METHODS Medline and Embase were searched for randomized controlled trials relating to the use of antidiabetic agents, including sodium-glucose transport protein 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists, and peroxisome proliferator-activated receptor gamma (PPARγ) agonists, biguanides, sulfonylureas and insulin, on NAFLD in patients with diabetes. The p-score was used as a surrogate marker of effectiveness. RESULTS A total of 14 articles were included in the analysis. PPARγ agonists were ranked as the best treatment in steatosis reduction, resulting in the greatest reduction of steatosis. There was statistical significance between PPARγ agonists [mean difference (MD): -6.02%, confidence interval (CI): -10.37% to -1.67%] and SGLT2 inhibitors (MD: -2.60%, CI: -4.87% to -0.33%) compared with standard of care for steatosis reduction. Compared with PPARγ agonists, SGLT2 inhibitors resulted in a statistical significant reduction in fibrosis (MD: -0.06, CI: -0.10 to -0.02). Body mass index reduction was highest in SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists. Additionally, SGLT2 inhibitors were ranked as the best treatment for increasing high-density lipoprotein and reducing low-density lipoprotein. CONCLUSION Glucagon-like peptide-1 receptor agonists and SGLT2 inhibitors were suitable alternatives for the treatment of NAFLD in those with type 2 diabetes mellitus with a reduction in body mass index, fibrosis, and steatosis. SGLT2 inhibitors also have the added benefit of lipid modulation.
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Affiliation(s)
- Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Snow Yunni Lin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yip Han Chin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ming Hui Lee
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Biostatistics & Modelling Domain, Saw Swee Hock School of Public Health, Singapore
| | - Xin Lei Goh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jin Hean Koh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jingxuan Quek
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Shao Feng Mok
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Endocrinology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Eunice Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Yock Young Dan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Nicholas Chew
- Division of Cardiology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Chin Meng Khoo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Endocrinology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Mohammad Shadab Siddiqui
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Virginia
| | - Mark Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore.
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Huang YZ, Yang GY, Wang C, Chen XY, Zhang LL. Effectiveness of drug interventions in nonalcoholic fatty liver disease: A network meta-analysis. World J Diabetes 2021; 12:1576-1586. [PMID: 34630909 PMCID: PMC8472495 DOI: 10.4239/wjd.v12.i9.1576] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/09/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a major chronic liver disorder worldwide, and there is no established treatment for this disease. We conducted a network meta-analysis (NMA) to compare existing treatments, which include four classes of antidiabetic drugs, and examined the optimum treatments for NAFLD. AIM To compare the effectiveness of different treatments for NAFLD. METHODS An NMA was conducted using Stata 14.0 (Corporation LLC, College Station, United States) and R (X64 3.6.3 version) in this study. Eligible randomized controlled trials (RCTs) were searched in the PubMed, Cochrane Library, Embase, Medline and Web of Science databases from database inception to April 2021. Two researchers independently screened the available studies in strict accordance with inclusion and exclusion criteria. The Cochrane Risk of Bias tool was used to evaluate the risk of bias of the included studies. The variables with and without dimensional differences were calculated as the standardized mean difference and weighted mean difference, respectively. An inconsistency model and "node-splitting" technique were used to test for inconsistency. Funnel plots were used to evaluate publication bias. RESULTS Twenty-two eligible RCTs involving 1377 participants were eventually included in our analysis. Data were pooled using a random-effects model. Our NMA results revealed that glucagon-like peptide-1 receptor agonists (GLP-1RAs) were the most effective treatment, yielding improvements in hepatic fat content (HFC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum γ-glutamyl transferase (GGT) and body weight [surface under the cumulative ranking curve (SUCRA) = 99.6%, 92.6%, 82.8%, 92.3% and 99.6%, respectively], while thiazolidinediones (TZDs) were the best intervention for reducing the NAFLD activity score (NAS; SUCRA = 98.9%). In addition, moderate performance was observed for the sodium glucose cotransporter-2 inhibitors groups (SUCRA = 25.1%, 66.2%, 63.5%, 58.2% and 71.9% for HFC, ALT, AST, GGT and body weight, respectively). However, metformin performed poorly according to most indicators (SUCRA = 54.5%, 0.3%, 19.5%, 33.7%, 57.7% and 44.3% for HFC, NAS, ALT, AST, GGT and body weight, respectively). CONCLUSION GLP-1RAs may be the optimum choice for most patients with NAFLD. However, TZDs are considered the most effective therapies in NAFLD patients with histological disease activity.
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Affiliation(s)
- Yi-Zhou Huang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 404100, China
| | - Gang-Yi Yang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 404100, China
| | - Cong Wang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 404100, China
| | - Xing-Yu Chen
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 404100, China
| | - Li-Li Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 404100, China
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Sardana O, Goyal R, Bedi O. Molecular and pathobiological involvement of fetuin-A in the pathogenesis of NAFLD. Inflammopharmacology 2021; 29:1061-1074. [PMID: 34185201 DOI: 10.1007/s10787-021-00837-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023]
Abstract
The liver acts as a manufacturing unit for the production of fetuin-A, which is essential for various physiological characteristics. Scientific research has shown that a moderate upward push in fetuin-A serum levels is associated with a confirmed non-alcoholic fatty liver disease (NAFLD) diagnosis. Fetuin-A modulation is associated with a number of pathophysiological variables that cause liver problems, including insulin receptor signaling deficiencies, adipocyte dysfunction, hepatic inflammation, fibrosis, triacylglycerol production, macrophage invasion, and TLR4 activation. The focus of the present review is on the various molecular pathways, and genetic relevance of mRNA expression of fetuin-A which is correlated with progression of NAFLD. The other major area of exploration in the present review is based on the new targets for the modulation of fetuin-A, like calorie restriction and novel pharmacological agents, such as rosuvastatin, metformin, and pioglitazone which are successfully implicated in the management of various liver-related complications.
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Affiliation(s)
- Ojus Sardana
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Ravi Goyal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Onkar Bedi
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
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Jianping W, Xuelian Z, Anjiang W, Haiying X. Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Metabolic Associated Fatty Liver Disease: A Systematic Review and Meta-analysis. J Clin Gastroenterol 2021; 55:586-593. [PMID: 34039937 DOI: 10.1097/mcg.0000000000001556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Clinical trials examining the therapeutic benefits of glucagon-like peptide-1 receptor agonists (GLP-1RA) on patients with metabolic associated fatty liver disease (MAFLD) have reported inconsistent results. The aim of this meta-analysis was to verify the role of GLP-1RA in the treatment of MAFLD patients. MATERIALS AND METHODS We searched PubMed, Embase, Medline, and the Cochrane Library for randomized controlled trials published that compared GLP-1RA with the control treatment in patients with MAFLD till to July 30, 2020. The effects of GLP-1RA on liver histology, body mass index, waist circumference (WC), aspartate aminotransferase, total cholesterol, triglycerides (TG), low-density lipoprotein and high-density lipoprotein were evaluated. RESULTS Thirteen trials involving 704 patients were included in the meta-analysis. Compared with the control treatment, GLP-1RA treatment induced a greater resolution of steatohepatitis [RR=2.87; 95% confidence interval (CI): 0.89 to 9.23], delayed the progression of liver fibrosis (RR=3.83, 95% CI: 0.91 to 16.07) and reduced liver fat deposition (MD: -1.40; 95% CI: -2.75 to -0.05). In addition, it reduced the body mass index (MD: -1.15; 95% CI: -2.26 to -0.04), WC (MD: -3.33; 95% CI: -6.31 to -0.35) and improved serum aspartate aminotransferase (MD: -3.04; 95% CI: -5.93 to -0.16) and total cholesterol (MD: -0.20; 95% CI: -0.28 to -0.13). CONCLUSION GLP-1RA improves liver steatosis and fibrosis. It is also beneficial to metabolic syndrome as it reduces BMI, WC, and hyperlipidemia.
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Affiliation(s)
- Wu Jianping
- Departments of Gastroenterology
- Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zheng Xuelian
- Pharmacy, The First Affiliated Hospital of Nanchang University
| | | | - Xiao Haiying
- Department of Gastroenterology, Nanchang Third Hospital, Nanchang, Jiangxi
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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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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: 9] [Impact Index Per Article: 2.3] [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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Lian J, Fu J. Efficacy of Various Hypoglycemic Agents in the Treatment of Patients With Nonalcoholic Liver Disease With or Without Diabetes: A Network Meta-Analysis. Front Endocrinol (Lausanne) 2021; 12:649018. [PMID: 33841337 PMCID: PMC8024567 DOI: 10.3389/fendo.2021.649018] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/05/2021] [Indexed: 12/11/2022] Open
Abstract
Objective To comprehensively evaluate and compare the therapeutic effects of various hypoglycemic agents in NAFLD patients with or without diabetes. Methods All literature from the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Clinical Trials was searched, and the language was limited to English. Two reviewers independently assessed study eligibility, continuous data extraction, and independent assessment of bias risk. Our primary outcomes were alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride levels, while our secondary outcomes were high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels, body weight, BMI, and fasting glucose and glycosylated hemoglobin (HbA1c) levels. Results The review identified 20 eligible trials that met the inclusion criteria. We found that, compared to other drugs, thiazolidinediones, especially pioglitazone, had a greater effect on the levels of ALT (-8.01 (95% CI -14.3 to 2.02)) and AST (-5.0 (95% CI -9.21 to -1,22)) and other biological indicators, but they were also associated with an increased risk of weight gain (3.62 (95% CI 2.25 to 4.99) and increased BMI (0.59 (95% Cl -0.13 to 1.29). GLP1 RAs and metformin also had better therapeutic effects than other drugs as measured by the levels of ALT (liraglutide: -9.36 (95% Cl -18 to -0.34), metformin: -2.84 (95% CI -11.09 to 5.28)) and AST (liraglutide: -5.14 (95% CI -10.69 to 0.37), metformin: -2.39 (95% CI -7.55, 2.49)) and other biological indicators. Conclusion Despite the significant risk of weight gain, thiazolidinediones, especially pioglitazone, are beneficial in normalizing liver and glucose metabolism in NAFLD patients. In clinical practice, we believe that GLP1 RAs such as liraglutide and exenatide or metformin can be used in combination to offset the risk of weight gain associated with thiazolidinediones. However, long-term studies are still needed to verify the efficacy and safety of individual hypoglycemic agents. Systematic Review Registration [PROSPERO], identifier [CRD42020212025].
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Affiliation(s)
| | - Jianfang Fu
- Department of Endocrinology, Xijing Hospital of Air Force Medical University, Xi’an, China
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Babic I, Sellers D, Else PL, Nealon J, Osborne AL, Pai N, Weston-Green K. Effect of liraglutide on neural and peripheral markers of metabolic function during antipsychotic treatment in rats. J Psychopharmacol 2021; 35:284-302. [PMID: 33570012 DOI: 10.1177/0269881120981377] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that prevents metabolic side effects of the antipsychotic drugs (APDs) olanzapine and clozapine through unknown mechanisms. AIM This study aimed to investigate the effect of chronic APD and liraglutide co-treatment on key neural and peripheral metabolic signals, and acute liraglutide co-treatment on clozapine-induced hyperglycaemia. METHODS In study 1, rats were administered olanzapine (2 mg/kg), clozapine (12 mg/kg), liraglutide (0.2 mg/kg), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle for six weeks. Feeding efficiency was examined weekly. Examination of brain tissue (dorsal vagal complex (DVC) and mediobasal hypothalamus (MBH)), plasma metabolic hormones and peripheral (liver and kidney) cellular metabolism and oxidative stress was conducted. In study 2, rats were administered a single dose of clozapine (12 mg/kg), liraglutide (0.4 mg/kg), clozapine + liraglutide co-treatment or vehicle. Glucose tolerance and plasma hormone levels were assessed. RESULTS Liraglutide co-treatment prevented the time-dependent increase in feeding efficiency caused by olanzapine, which plateaued by six weeks. There was no effect of chronic treatment on melanocortinergic, GABAergic, glutamatergic or endocannabionoid markers in the MBH or DVC. Peripheral hormones and cellular metabolic markers were unaltered by chronic APD treatment. Acute liraglutide co-treatment was unable to prevent clozapine-induced hyperglycaemia, but it did alter catecholamine levels. CONCLUSION The unexpected lack of change to central and peripheral markers following chronic treatment, despite the presence of weight gain, may reflect adaptive mechanisms. Further studies examining alterations across different time points are required to continue to elucidate the mechanisms underlying the benefits of liraglutide on APD-induced metabolic side effects.
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Affiliation(s)
- Ilijana Babic
- School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.,Neurohorizons Laboratory, Molecular Horizons, University of Wollongong, Wollongong, Australia.,Illawarra Health and Medical Research Institute, Wollongong, Australia.,Illawarra and Shoalhaven Local Health District, Wollongong, Australia
| | - Dominic Sellers
- School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.,Illawarra Health and Medical Research Institute, Wollongong, Australia
| | - Paul L Else
- School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.,Illawarra Health and Medical Research Institute, Wollongong, Australia
| | - Jessica Nealon
- School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.,Illawarra Health and Medical Research Institute, Wollongong, Australia
| | - Ashleigh L Osborne
- School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.,Neurohorizons Laboratory, Molecular Horizons, University of Wollongong, Wollongong, Australia.,Illawarra Health and Medical Research Institute, Wollongong, Australia
| | - Nagesh Pai
- School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.,Illawarra Health and Medical Research Institute, Wollongong, Australia.,Illawarra and Shoalhaven Local Health District, Wollongong, Australia
| | - Katrina Weston-Green
- School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.,Neurohorizons Laboratory, Molecular Horizons, University of Wollongong, Wollongong, Australia.,Illawarra Health and Medical Research Institute, Wollongong, Australia.,Illawarra and Shoalhaven Local Health District, Wollongong, Australia
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Dai Y, He H, Li S, Yang L, Wang X, Liu Z, An Z. Comparison of the Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Metabolic Associated Fatty Liver Disease: Updated Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2021; 11:622589. [PMID: 33664710 PMCID: PMC7924308 DOI: 10.3389/fendo.2020.622589] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/28/2020] [Indexed: 02/05/2023] Open
Abstract
AIMS Metabolic associated fatty liver disease (MAFLD) is the most common cause of chronic liver disease and is a major health and economic burden in society. New drugs are urgently needed to treat MAFLD. This systematic review and meta-analysis was conducted to evaluate the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with MAFLD. METHOD We searched PubMed, Embase, Cochrane Library database, and Web of Science since 1977. We selected all randomized controlled trials which met the inclusion and exclusion criteria and evaluated the quality of evidence. A random-effects meta-analysis was performed to assess all the primary and second outcomes. RESULTS Eight randomized controlled trials, including 396 patients, of which 265 patients had type 2 diabetes mellitus, met the inclusion criteria. Compared with the placebo or active agents group, the GLP-RA group showed a significant reduction in the liver fat content [weight mean difference (WMD) -3.17%, 95%CI -5.30 to -1.03, P < 0.0001], body weight (WMD -4.58 kg, 95%CI -8.07 to -1.10, P = 0.010), waist circumference (WMD -3.74 cm, 95%CI -6.73 to -0.74, P = 0.010), alanine aminotransferase (WMD -10.73 U/L, 95%CI -20.94 to -0.52, P = 0.04), γ- glutamyl transferase (WMD -12.25 U/L,95% -18.85 to -5.66, P = 0.0003, with I²=23%), fasting blood glucose (MD, -0.36 mmol/L; 95%CI, -0.69 to -0.03, P = 0.030), and hemoglobin A1c (WMD -0.36%, 95%CI -0.52 to -0.19, P < 0.0001). The reported adverse events were gastrointestinal complications with no serious adverse events, and most symptoms were relieved within 1-2 weeks after dose titration. CONCLUSION GLP-RAs may improve liver injury and metabolic disorder in patients with MAFLD, regardless of the presence of type 2 diabetes mellitus. The benefits of GLP-RAs treatment outweigh the adverse effects of drugs in patients with MAFLD.
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Affiliation(s)
- Yuzhao Dai
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - He He
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Lidan Yang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xia Wang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zhi Liu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenmei An
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
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Ghadimi M, Foroughi F, Hashemipour S, Nooshabadi MR, Ahmadi MH, Yari MG, Kavianpour M, Haghighian HK. Decreased insulin resistance in diabetic patients by influencing Sirtuin1 and Fetuin-A following supplementation with ellagic acid: a randomized controlled trial. Diabetol Metab Syndr 2021; 13:16. [PMID: 33546744 PMCID: PMC7866694 DOI: 10.1186/s13098-021-00633-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/22/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The beneficial effects of polyphenols have been reported. This study aimed to investigate the effect of oral Ellagic acid (EA) supplement on insulin resistance (IR) and Fetuin-A and serum sirtuin1 (SIRT1) in type 2 diabetics. METHODS In this double-blind, randomized clinical trial, 44 diabetic patients were selected. Patients were assigned to the intervention group (22 subjects) and placebo (22 subjects) and received a capsule containing 180 mg of EA per day or placebo for eight weeks, respectively. At the beginning and end of the study, anthropometric indices, fasting plasma glucose (FPG), plasma insulin level, IR, Fetuin-A, and SIRT1 were measured. Statistical analysis was performed using SPSS software. RESULTS At the beginning and end of the study, there was no significant difference between the two groups regarding anthropometric indices (P > 0.05). At the end of the survey, EA supplementation significantly reduced FPG, insulin, IR, and Fetuin-A and increased SIRT1 levels compared with the placebo group (P < 0.05). However, these changes were not significant in the placebo group (P > 0.05). CONCLUSION EA with antioxidant properties plays an essential role in reducing the macrovascular and microvascular complications of diabetes by reducing inflammation and insulin resistance. Trial registration The protocol of this clinical trial is registered with the Iranian Registry of Clinical Trials ( http://www.IRCT.IR , identifier: IRCT20141025019669N13).
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Affiliation(s)
- Mahnaz Ghadimi
- Department of Nutrition, School of Health, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Farshad Foroughi
- Department of Immunology, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Sima Hashemipour
- Metabolic Diseases Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | - Mohammad Hossein Ahmadi
- Department of Laboratory Sciences, School of Allied Medical Sciences, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | - Maria Kavianpour
- Department of Tissue Engineering and Applied Cell Sciences, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Hossein Khadem Haghighian
- Department of Nutrition, School of Health, Qazvin University of Medical Sciences, Qazvin, Iran.
- Metabolic Diseases Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran.
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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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Icer MA, Yıldıran H. Effects of fetuin-A with diverse functions and multiple mechanisms on human health. Clin Biochem 2020; 88:1-10. [PMID: 33245873 DOI: 10.1016/j.clinbiochem.2020.11.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 12/14/2022]
Abstract
Fetuin-A (Alfa 2-Heremans-Schmid) is a glycoprotein that is mainly synthesized by hepatocytes and then released into the bloodstream. While fetuin-A, a multifunctional protein, has inhibitory effects on health in the processes of calcification, mineralization, coronary artery calcification (CAC), and kidney stone formation by various mechanisms, it has such stimulatory effects as obesity, diabetes, and tumor progression processes. Fetuin-A produces these effects on the organism mainly by playing a role in the secretion levels of some inflammatory cytokines and exosomes, preventing unwanted calcification, inhibiting the autophosphorylation of tyrosine kinase, suppressing the release of adiponectin and peroxisome proliferator-activated receptor-γ (PPARγ), activating the toll-like receptor 4 (TLR-4), triggering the phosphatidylinositol 3 (PI3) kinase/Akt signaling pathway and cell proliferation, and mimicking the transforming growth factor-beta (TGF-β) receptor. In the present review, fetuin-A was examined in a wide perspective from the structure and release of fetuin-A to its effects on health.
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Affiliation(s)
- Mehmet Arif Icer
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, 06500 Ankara, Turkey.
| | - Hilal Yıldıran
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, 06500 Ankara, Turkey
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Magalhães P, Zürbig P, Mischak H, Schleicher E. Urinary fetuin-A peptides as a new marker for impaired kidney function in patients with type 2 diabetes. Clin Kidney J 2020; 14:269-276. [PMID: 33564428 PMCID: PMC7857838 DOI: 10.1093/ckj/sfaa176] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 07/09/2020] [Indexed: 02/06/2023] Open
Abstract
Background The hepatokine fetuin-A, released by the human liver, promotes pro-inflammatory effects of perivascular fat. The involvement of inflammation in type 2 diabetes mellitus (T2DM) can affect the kidney and contribute to the development of diabetic kidney disease. Therefore we examined the association of urinary fetuin-A protein fragments with renal damage in T2DM patients. Methods Urinary peptides of 1491 individuals using proteome data available from the human urine proteome database were analysed. Prediction of proteases involved in urinary peptide generation was performed using the Proteasix tool. Results We identified 14 different urinary protein fragments that belong to the region of the connecting peptide (amino acid 301–339) of the total fetuin-A protein. Calpains (CAPN1 and CAPN2), matrix metalloproteinase and pepsin A-3 were identified as potential proteases that were partially confirmed by previous in vitro studies. Combined fetuin-A peptides (mean of amplitudes) were significantly increased in T2DM patients with kidney disease and to a lesser extent with cardiovascular risk. Furthermore, fetuin-A peptide levels displayed a significant negative correlation with baseline estimated glomerular filtration rate (eGFR) values (r = −0.316, P < 0.0001) and with the slope (%) of eGFR per year (r = −0.096, P = 0.023). A multiple regression model including fetuin-A peptide and albuminuria resulted in a significantly improved correlation with eGFR (r = −0.354, P < 0.0001) compared with albuminuria, indicating an added value of this novel biomarker. Conclusions The urinary proteome analysis demonstrated the association of fetuin-A peptides with impaired kidney function in T2DM patients. Furthermore, fetuin-A peptides displayed early signs of kidney damage before albuminuria appeared and therefore can be used as markers for kidney disease detection.
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Affiliation(s)
| | | | - Harald Mischak
- Mosaiques Diagnostics GmbH, Hannover, Germany.,Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Erwin Schleicher
- Institute for Clinical Chemistry and Pathobiochemistry/Central Laboratory, University of Tübingen, Tübingen, Germany.,German Center for Diabetes Research, Tübingen; Germany.,Institute for Diabetes Research and Metabolic Diseases, Helmholtz Centre Munich, University of Tübingen, Tübingen, Germany
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