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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 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] [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 Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
- Department of Internal Medicine and Endocrinology, Erasmus MC, Rotterdam, the Netherlands
| | | | - Anna M P Boeren
- Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | | | - Femme Dirksmeier
- Department of Gastroenterology and Hepatology, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | - Rob J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands
| | - Maarten E Tushuizen
- Department of Gastroenterology and Hepatology, LUMC, Leiden, the Netherlands
| | | | | | - Manuel Castro Cabezas
- Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
- Department of Internal Medicine and Endocrinology, Erasmus MC, Rotterdam, the Netherlands
- Julius Clinical, Zeist, the Netherlands
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Gao X, Zhu C, Zhu W, Wang L. Dapagliflozin treatment alleviates fatty liver in patients with type 2 diabetes. Biomed Rep 2025; 22:26. [PMID: 39720302 PMCID: PMC11668134 DOI: 10.3892/br.2024.1904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/11/2024] [Indexed: 12/26/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is common in patients with type 2 diabetes mellitus (T2DM). The present study evaluated the effect of dapagliflozin on the liver fat content in patients with T2DM and NAFLD. The changes in biochemical data and metabolic parameters were analyzed. Clinical data of patients with T2DM and NAFLD treated by dapagliflozin were retrospectively collected between June 2022 and December 2022. A total of 35 patients, with a mean age of 45.8±2.2 years, consisting of 60.0% male patients, were included in the final analysis. After 20 weeks of dapagliflozin treatment, the parameters of diabetes improved. Plasma glucose and hemoglobin A1C levels significantly decreased (P<0.01), and insulin resistance improved. The change in liver fat content was evaluated by quantitative computed tomography, which revealed a decrease from 16.1±2.2 to 11.2±1.3% after treatment (P<0.01). Liver function (alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase levels) also improved. Visceral and subcutaneous fat areas showed a significant decrease after treatment, and there was a more significant reduction in visceral fat area. The factors associated with liver fat content were determined by Pearson's correlation and regression analyses. Pearson's correlation analysis indicated that the post-treatment decrease in liver fat content was positively correlated with the change in body weight (r=0.642, P=0.033), index of homeostasis model assessment-insulin resistance (r=0.670, P=0.048), triglycerides (r=0.627, P=0.039), high sensitivity C-reactive protein (r=0.608, P=0.047) and interleukin (IL)-6 (r=0.604, P=0.049). Linear regression analysis revealed that body weight (β=0.416, P=0.001), IL-6 (β=0.284, P=0.009), triglycerides (β=0.262, P=0.011) and total cholesterol (β=0.388, P=0.001) were independent factors related to liver fat content. In conclusion, dapagliflozin can reduce liver fat in patients with T2DM and NAFLD. The reduction in liver fat is associated with improvement of metabolic parameters and inflammatory cytokines.
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Affiliation(s)
- Xiuying Gao
- Department of Endocrinology, Beijing Aerospace General Hospital, Beijing 100076, P.R. China
| | - Chuanming Zhu
- Department of Radiology, Beijing Aerospace General Hospital, Beijing 100076, P.R. China
| | - Wei Zhu
- Department of Endocrinology, Beijing Aerospace General Hospital, Beijing 100076, P.R. China
| | - Lin Wang
- Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, P.R. China
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Michalopoulou E, Thymis J, Lampsas S, Pavlidis G, Katogiannis K, Vlachomitros D, Katsanaki E, Kostelli G, Pililis S, Pliouta L, Kountouri A, Papanikolaou IS, Lambadiari V, Ikonomidis I. The Triad of Risk: Linking MASLD, Cardiovascular Disease and Type 2 Diabetes; From Pathophysiology to Treatment. J Clin Med 2025; 14:428. [PMID: 39860434 PMCID: PMC11765821 DOI: 10.3390/jcm14020428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 12/30/2024] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.
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Affiliation(s)
- Eleni Michalopoulou
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - John Thymis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Stamatios Lampsas
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - George Pavlidis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Konstantinos Katogiannis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Dimitrios Vlachomitros
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Eleni Katsanaki
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Gavriella Kostelli
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Sotirios Pililis
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Loukia Pliouta
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Aikaterini Kountouri
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Ioannis S. Papanikolaou
- Hepatogastroenterology Unit, Second Department of Internal Medicine-Propaedeutic, Attikon University Hospital, Rimini 1, Chaidari, 12462 Athens, Greece;
| | - Vaia Lambadiari
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Ignatios Ikonomidis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
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Procyk G, Jaworski J, Gąsecka A, Filipiak KJ, Borovac JA. Metabolic dysfunction-associated steatotic liver disease - A new indication for sodium-glucose Co-transporter-2 inhibitors. Adv Med Sci 2024; 69:407-415. [PMID: 39260740 DOI: 10.1016/j.advms.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 07/09/2024] [Accepted: 09/09/2024] [Indexed: 09/13/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed as a new name for the previous non-alcoholic fatty liver disease (NAFLD). There are some differences between MASLD and NAFLD, e.g., diagnostic criteria. MASLD is a hepatic steatosis without harmful alcohol consumption and is caused by metabolic factors. The prevalence of MASLD varies amongst different populations. The change in lifestyle plays a fundamental role in MASLD management, while there is no registered pharmacotherapy in this indication. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to have a beneficial effect on hepatic steatosis, hence, they have been widely investigated as potential therapeutics in MASLD. In this review, we aimed to thoroughly summarize current evidence from original research about the effects of SGLT2i use on MASLD. Almost all discussed studies advocate using SGLT2i in MASLD because of their beneficial effects. It includes the loss of body weight, which is beneficial per se, and the improvement in hepatic parameters. Most importantly, steatosis reduction has been observed in patients using SGLT2i. We highly recommend further research in this field, which we believe will eventually lead to a new indication for SGLT2i, i.e., MASLD.
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Affiliation(s)
- Grzegorz Procyk
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland; Doctoral School, Medical University of Warsaw, Warsaw, Poland.
| | - Jakub Jaworski
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Aleksandra Gąsecka
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof J Filipiak
- Institute of Clinical Science, Maria Sklodowska-Curie Medical Academy, Warsaw, Poland; Department of Hypertension, Angiology and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Josip A Borovac
- Cardiovascular Diseases Department, University Hospital of Split, Split, Croatia
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Isogawa M, Makino H, Son C, Nishimura K, Hirata T, Kasama S, Miyamoto Y, Noguchi M, Kasahara M, Hosoda K. Comparison of canagliflozin and teneligliptin on energy intake and body weight in Japanese patients with Type 2 diabetes: a subanalysis of the CANTABILE study. BMC Endocr Disord 2024; 24:153. [PMID: 39160513 PMCID: PMC11331643 DOI: 10.1186/s12902-024-01690-6] [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: 05/10/2023] [Accepted: 08/13/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND While the Sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) are widely used for the glycemic control in type 2 diabetes mellitus, the differences in the effects of SGLT2 inhibitors and DPP4 inhibitors on energy intake and diabetes-related indicators are unclear. METHODS This was a subanalysis of the CANTABILE study which compared the effects of canagliflozin and teneligliptin on metabolic factors in Japanese patients with Type 2 diabetes. The changes at 24 weeks from the baseline of the diabetes-related indicators including Hemoglobin A1c (HbA1c), energy intake and body weight were compared between the canagliflozin and teneligliptin groups. RESULTS Seventy-five patients in the canagliflozin group and 70 patients in the teneligliptin group were analyzed. A significant decrease in HbA1c was observed in both groups. In the teneligliptin group, although energy intake was significantly reduced, there was no significant change in body weight. Conversely, in the canagliflozin group, although energy intake tended to increase, body weight significantly decreased. CONCLUSION Canagliflozin and teneligliptin have different effects on the dietary status of patients with Type 2 diabetes. Our result suggests that canagliflozin can manage blood glucose without weight gain, even with increased energy intake.
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Affiliation(s)
- Masahiro Isogawa
- Institute for Clinical and Translational Science, Nara Medical University Hospital, 840 Shijo-Cho, Kashihara, Nara, 634-8522, Japan
| | - Hisashi Makino
- Division of Diabetes and Lipid Metabolism, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan.
| | - Cheol Son
- Department of Diabetes and Endocrinology, Kobe City Nishi-Kobe Medical Center, 5-7-1 Koji-Dai Nishi-Ku, Kobe, Hyogo, 651-2273, Japan
| | - Kunihiro Nishimura
- Department of Preventive Medicine, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan
| | - Takumi Hirata
- Human Care Research Team, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi-Ku, Tokyo, 173-0015, Japan
| | - Shu Kasama
- Center for Clinical Research and Advanced Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Yoshihiro Miyamoto
- Open Innovation Center (OIC), National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan
| | - Michio Noguchi
- Division of Diabetes and Lipid Metabolism, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan
| | - Masato Kasahara
- Institute for Clinical and Translational Science, Nara Medical University Hospital, 840 Shijo-Cho, Kashihara, Nara, 634-8522, Japan
| | - Kiminori Hosoda
- Diabetes Center, Ijinkai Takeda General Hospital, 28-1 Ishidamoriminami-cho, Fushimi-ku, Kyoto, 601-1495, Japan
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Suzuki A, Hayashi A, Oda S, Fujishima R, Shimizu N, Matoba K, Taguchi T, Toki T, Miyatsuka T. Prolonged impacts of sodium glucose cotransporter-2 inhibitors on metabolic dysfunction-associated steatotic liver disease in type 2 diabetes: a retrospective analysis through magnetic resonance imaging. Endocr J 2024; 71:767-775. [PMID: 38811192 DOI: 10.1507/endocrj.ej24-0005] [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] [Indexed: 05/31/2024] Open
Abstract
The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in people with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) have been suggested in several reports based on serological markers, imaging data, and histopathology associated with steatotic liver disease. However, evidence regarding their long-term effects is currently insufficient. In this retrospective observational study, 34 people with T2D and MASLD, treated with SGLT2 inhibitors, were examined by proton density fat fraction derived by magnetic resonance imaging (MRI-PDFF) and other clinical data before, one year after the treatment. Furthermore, 22 of 34 participants underwent MRI-PDFF five years after SGLT2 inhibitors were initiated. HbA1c decreased from 8.9 ± 1.8% to 7.8 ± 1.0% at 1 year (p = 0.006) and 8.0 ± 1.1% at 5 years (p = 0.122). Body weight and fat mass significantly reduced from baseline to 1 and 5 year(s), respectively. MRI-PDFF significantly decreased from 15.3 ± 7.8% at baseline to 11.9 ± 7.6% (p = 0.001) at 1 year and further decreased to 11.3 ± 5.7% (p = 0.013) at 5 years. Thus, a 5-year observation demonstrated that SGLT2 inhibitors have beneficial effects on liver steatosis in people with T2D and MASLD.
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Affiliation(s)
- Agena Suzuki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Akinori Hayashi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Satoshi Oda
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Rei Fujishima
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Naoya Shimizu
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Kenta Matoba
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Tomomi Taguchi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Takuya Toki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Takeshi Miyatsuka
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
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Sato-Espinoza K, Chotiprasidhi P, Huaman MR, Díaz-Ferrer J. Update in lean metabolic dysfunction-associated steatotic liver disease. World J Hepatol 2024; 16:452-464. [PMID: 38577539 PMCID: PMC10989317 DOI: 10.4254/wjh.v16.i3.452] [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: 12/26/2023] [Revised: 01/19/2024] [Accepted: 02/28/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND A new nomenclature consensus has emerged for liver diseases that were previously known as non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD). They are now defined as metabolic dysfunction-associated steatotic liver disease (MASLD), which includes cardiometabolic criteria in adults. This condition, extensively studied in obese or overweight patients, constitutes around 30% of the population, with a steady increase worldwide. Lean patients account for approximately 10%-15% of the MASLD population. However, the pathogenesis is complex and is not well understood. AIM To systematically review the literature on the diagnosis, pathogenesis, characteristics, and prognosis in lean MASLD patients and provide an interpretation of these new criteria. METHODS We conducted a comprehensive database search on PubMed and Google Scholar between January 2012 and September 2023, specifically focusing on lean NAFLD, MAFLD, or MASLD patients. We include original articles with patients aged 18 years or older, with a lean body mass index categorized according to the World Health Organization criteria, using a cutoff of 25 kg/m2 for the general population and 23 kg/m2 for the Asian population. RESULTS We include 85 studies in our analysis. Our findings revealed that, for lean NAFLD patients, the prevalence rate varied widely, ranging from 3.8% to 34.1%. The precise pathogenesis mechanism remained elusive, with associations found in genetic variants, epigenetic modifications, and adaptative metabolic response. Common risk factors included metabolic syndrome, hypertension, and type 2 diabetes mellitus, but their prevalence varied based on the comparison group involving lean patients. Regarding non-invasive tools, Fibrosis-4 index outperformed the NAFLD fibrosis score in lean patients. Lifestyle modifications aided in reducing hepatic steatosis and improving cardiometabolic profiles, with some medications showing efficacy to a lesser extent. However, lean NAFLD patients exhibited a worse prognosis compared to the obese or overweight counterpart. CONCLUSION MASLD is a complex disease comprising epigenetic, genetic, and metabolic factors in its pathogenesis. Results vary across populations, gender, and age. Limited data exists on clinical practice guidelines for lean patients. Future studies employing this new nomenclature can contribute to standardizing and generalizing results among lean patients with steatotic liver disease.
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Affiliation(s)
- Karina Sato-Espinoza
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55902, United States.
| | - Perapa Chotiprasidhi
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55902, United States
| | - Mariella R Huaman
- Obesity and Metabolic, Center for Obesity and Metabolic Health, Lima 02002, Lima, Peru
| | - Javier Díaz-Ferrer
- Hepatology Service, Department of Digestive Diseases, Hospital Nacional Edgardo Rebagliati Martins, Lima 02002, Lima, Peru
- Medicine Faculty, Universidad San Martin de Porres, Lima 02002, Lima, Peru
- Gastroenterology Service, Clinica Internacional, Lima 02002, Lima, Peru
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Wei S, Wang L, Evans PC, Xu S. NAFLD and NASH: etiology, targets and emerging therapies. Drug Discov Today 2024; 29:103910. [PMID: 38301798 DOI: 10.1016/j.drudis.2024.103910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 01/22/2024] [Accepted: 01/26/2024] [Indexed: 02/03/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) pose a significant threat to human health and cause a tremendous socioeconomic burden. Currently, the molecular mechanisms of NAFLD and NASH remain incompletely understood, and no effective pharmacotherapies have been approved. In the past five years, significant advances have been achieved in our understanding of the pathomechanisms and potential pharmacotherapies of NAFLD and NASH. Research advances include the investigation of the effects of the fibroblast growth factor 21 (FGF21) analog pegozafermin and the thyroid hormone receptor-β (THRβ) agonist resmetriom on hepatic fat content, NASH resolution and/or fibrosis regression. Future directions of NAFLD and NASH research (including combination therapy, organoids and humanized mouse models) are also discussed in this state-of-the-art review.
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Affiliation(s)
- Shulin Wei
- School of Life Sciences, Jilin University, Changchun, China; Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China
| | - Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, China
| | - Paul C Evans
- Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ, UK
| | - Suowen Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China.
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Shakour N, Karami S, Iranshahi M, Butler AE, Sahebkar A. Antifibrotic effects of sodium-glucose cotransporter-2 inhibitors: A comprehensive review. Diabetes Metab Syndr 2024; 18:102934. [PMID: 38154403 DOI: 10.1016/j.dsx.2023.102934] [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: 09/14/2023] [Revised: 11/25/2023] [Accepted: 12/20/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND AND AIMS Scar tissue accumulation in organs is the underlying cause of many fibrotic diseases. Due to the extensive array of organs affected, the long-term nature of fibrotic processes and the large number of people who suffer from the negative impact of these diseases, they constitute a serious health problem for modern medicine and a huge economic burden on society. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a relatively new class of anti-diabetic pharmaceuticals that offer additional benefits over and above their glucose-lowering properties; these medications modulate a variety of diseases, including fibrosis. Herein, we have collated and analyzed all available research on SGLT2is and their effects on organ fibrosis, together with providing a proposed explanation as to the underlying mechanisms. METHODS PubMed, ScienceDirect, Google Scholar and Scopus were searched spanning the period from 2012 until April 2023 to find relevant articles describing the antifibrotic effects of SGLT2is. RESULTS The majority of reports have shown that SGLT2is are protective against lung, liver, heart and kidney fibrosis as well as arterial stiffness. According to the results of clinical trials and animal studies, many SGLT2 inhibitors are promising candidates for the treatment of fibrosis. Recent studies have demonstrated that SGLT2is affect an array of cellular processes, including hypoxia, inflammation, oxidative stress, the renin-angiotensin system and metabolic activities, all of which have been linked to fibrosis. CONCLUSION Extensive evidence indicates that SGLT2is are promising treatments for fibrosis, demonstrating protective effects in various organs and influencing key cellular processes linked to fibrosis.
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Affiliation(s)
- Neda Shakour
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shima Karami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Adliya, Bahrain
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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10
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Alfayez AI, Alfallaj JM, Mobark MA, Alalwan AA, Alfayez OM. An Update on the Effect Of Sodium Glucose Cotransporter 2 Inhibitors on Non-Alcoholic Fatty Liver Disease: A Systematic Review of Clinical Trials. Curr Diabetes Rev 2024; 20:e250523217349. [PMID: 37231725 DOI: 10.2174/1573399820666230525150437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/11/2023] [Accepted: 04/17/2023] [Indexed: 05/27/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of liver disease, specifically chronic liver disease. Type 2 diabetes (T2DM) is associated with the risk of NAFLD given that patients usually have insulin resistance as one of the observed complications with NAFLD. Hypoglycemic agents, including sodium glucose cotransporter 2 (SGLT-2), have shown to improve NAFLD. The objective of this study is to evaluate the effect of SGLT-2 inhibitors on NAFLD patients' outcomes, whether they have T2DM or not. We conducted a comprehensive search using the PubMed and Ovid databases to identify published studies that addressed the use of SGLT-2 inhibitors in NAFLD patients. The outcomes assessed include changes in liver enzymes, lipid profiles, weight changes, the fibrosis-4-index (FIB4), and magnetic resonance imaging proton density-based fat fraction (MRI-PDFF). Only clinical trials that met the quality measures were included in this review. Out of 382 potential studies, we included 16 clinical trials that discussed the use of SGLT-2 inhibitors in NAFLD patients. A total of 753 patients were enrolled in these trials. The majority of the trials reported positive effects of SGLT-2 inhibitors on liver enzymes; alanine transaminase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase. All 10 trials that reported changes in body mass index (BMI) from baseline showed a statistically significant reduction with SGLT-2 inhibitor use, while 11 studies reported a significant increase in high density lipoprotein (HDL) levels, 3 studies reported a reduction in triglycerides (TG) levels, and 2 studies showed a decrease in low density lipoprotein (LDL) levels. The available evidence shows that the use of SGLT-2 inhibitors in NAFLD is associated with positive outcomes on liver enzymes, lipid profiles, and BMI. Further studies with larger sample size and longer follow-up time are warranted.
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Affiliation(s)
- Abdulrahman I Alfayez
- Department of Pharmaceutical Services Administration, King Fahad Medical City, Riyadh, Saudi Arabia
| | | | - Mugahid A Mobark
- Department of Pharmacy Practice, College of Pharmacy, Qassim University, Qassim, Saudi Arabia
| | - Abdullah A Alalwan
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 16278, Saudi Arabia
| | - Osamah M Alfayez
- Department of Pharmacy Practice, College of Pharmacy, Qassim University, Qassim, Saudi Arabia
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11
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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: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [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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12
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Shi M, Zhang H, Wang W, Zhang X, Liu J, Wang Q, Wang Y, Zhang C, Guo X, Qiao Q, Cui C, Xu J, Wang J. Effect of dapagliflozin on liver and pancreatic fat in patients with type 2 diabetes and non-alcoholic fatty liver disease. J Diabetes Complications 2023; 37:108610. [PMID: 37722211 DOI: 10.1016/j.jdiacomp.2023.108610] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/23/2023] [Accepted: 08/31/2023] [Indexed: 09/20/2023]
Abstract
AIMS To evaluate the effect of dapagliflozin on liver fat content (LFC) and pancreatic fat content (PFC). MATERIALS AND METHODS 84 patients with type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) were randomly assigned to receive either dapagliflozin (n = 42) or serve as controls (n = 42). The primary endpoint is changes in LFC and PFC using magnetic resonance imaging estimated proton density fat fraction. Secondary outcomes include liver fibrosis index, inflammatory cytokine levels, and liver enzyme levels. RESULTS At week 24, the dapagliflozin group significantly reduced LFC (P < 0.001) and PFC (P = 0.033) compared to the control group. Differences were also observed in serum levels of tumor necrosis factor-α (TNF-α) (P = 0.004), interleukin-6 (IL-6) (P = 0.001), and alanine aminotransferase (ALT) (P < 0.001) between the two groups. CONCLUSIONS Dapagliflozin can significantly decrease LFC and PFC in patients with T2D and NAFLD. It also improves serum ALT, TNF-α, and IL-6 levels, making it a promising treatment option for NAFLD. The trial is registered on Chinese Clinical Trial Registry (Registration No. ChiCTR2100054612).
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Affiliation(s)
- Mengran Shi
- Department of Nutrition of Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hao Zhang
- Department of Nutrition of Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Wei Wang
- Department of Nutrition of Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Xiao Zhang
- Department of Endocrinology of Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jiawei Liu
- Department of Endocrinology of Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Qixian Wang
- Department of Endocrinology of Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yuan Wang
- Department of Endocrinology of Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Chunlin Zhang
- Department of Endocrinology of Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Xiaoqin Guo
- Department of Endocrinology of Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Qiao Qiao
- Department of Endocrinology of Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Chun Cui
- Department of Imaging of Xinqiao Hospital, Army Medical University, China
| | - Jing Xu
- Department of Endocrinology of Xinqiao Hospital, Army Medical University, Chongqing, China.
| | - Jian Wang
- Department of Nutrition of Xinqiao Hospital, Army Medical University, Chongqing, China.
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13
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Salom Vendrell C, García Tercero E, Moro Hernández JB, Cedeno-Veloz BA. Sarcopenia as a Little-Recognized Comorbidity of Type II Diabetes Mellitus: A Review of the Diagnosis and Treatment. Nutrients 2023; 15:4149. [PMID: 37836433 PMCID: PMC10574035 DOI: 10.3390/nu15194149] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND Type II diabetes mellitus (T2DM) is one of the most widespread metabolic diseases worldwide, with a significant impact on morbi-mortality. Sarcopenia has a high risk in this population (two times more risk) and a high impact at the functional level, especially in older adults. In addition, it poses enormous challenges in the diagnosis, prevention, and treatment of this disease concomitantly. The objective is to review the current knowledge on the state of muscle mass and the pathogenesis, diagnosis, and treatment of sarcopenia in people with T2DM. METHODS A bibliographic search was conducted in the PubMed-Medline databases for articles from 2015 with previously defined terms. RESULTS A loss of muscle mass in older diabetic patients who are malnourished or at risk of malnutrition has a proven negative impact on their autonomy and is closely related to the risk of sarcopenia as a high-impact disease, and also with frailty, as an associated multidimensional syndrome. Notably, we found that malnutrition and protein deficiency are often underdiagnosed in obese and overweight T2DM patients. Biochemical markers could help in the future with approaches to managing T2DM and sarcopenia concomitantly. The four essential elements which form the basis of care for patients with diabetes and sarcopenia are pharmacological treatment, nutrition management, regular physical exercise, and correct daily regime. CONCLUSIONS The increasing prevalence of sarcopenia among older patients with T2DM has significant negative impacts on quality of life and is a public health concern. Effective diagnosis and management require a multidisciplinary approach involving pharmacological treatment, nutrition, exercise, and correct daily regime, with future research needed to understand the underlying mechanisms and improve diagnostic and treatment strategies.
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14
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Gorgojo-Martinez JJ, Ferreira-Ocampo PJ, Galdón Sanz-Pastor A, Cárdenas-Salas J, Antón-Bravo T, Brito-Sanfiel M, Almodóvar-Ruiz F. Effectiveness and Tolerability of the Intensification of Canagliflozin Dose from 100 mg to 300 mg Daily in Patients with Type 2 Diabetes in Real Life: The INTENSIFY Study. J Clin Med 2023; 12:4248. [PMID: 37445283 DOI: 10.3390/jcm12134248] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 05/30/2023] [Accepted: 06/06/2023] [Indexed: 07/15/2023] Open
Abstract
Aim: This study aimed to evaluate the effectiveness and tolerability of intensifying the dose of canagliflozin from 100 mg/day (CANA100) to 300 mg/day (CANA300) in patients with type 2 diabetes (T2DM) and suboptimal metabolic control in a real-world setting. Methods: A multicenter observational study was conducted on adult patients with T2DM who initiated treatment with CANA100 and subsequently required intensification to CANA300. The primary outcome measures were changes in HbA1c and weight at 6 months after the switch and at the end of the follow-up period. Results: A total of 317 patients met the inclusion criteria (59.6% male, mean age 62.2 years, baseline HbA1c 7.55%, weight 88.6 kg, median duration of treatment with CANA100 9.9 months). Switching to CANA300 resulted in a significant reduction in HbA1c (6 months: -0.33%; last visit: -0.47%, both p < 0.0001) and weight (6 months: -1.8 kg; last visit: -2.9 kg, both p < 0.0001) over a median follow-up period of 20.8 months. The proportion of patients that achieved HbA1c < 7% increased from 26.7% with CANA100 to 51.6% with CANA300 (p < 0.0001). Among individuals with poor baseline glycemic control (HbA1c > 8%, mean 9.0%), HbA1c was significantly reduced by -1.24% (p < 0.0001). Furthermore, significant improvements were observed in fasting plasma glucose (FPG), blood pressure (BP), liver enzymes, and albuminuria. No unexpected adverse events were reported. Conclusions: Intensifying the treatment to CANA300 in a real-world setting resulted in further significant and clinically relevant reductions in FPG, HbA1c, weight, and BP in patients with T2DM. The switch was particularly effective in patients with higher baseline HbA1c levels.
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Affiliation(s)
- Juan J Gorgojo-Martinez
- Department of Endocrinology and Nutrition, Hospital Universitario Fundación Alcorcón, 28922 Madrid, Spain
| | - Pablo José Ferreira-Ocampo
- Department of Endocrinology and Nutrition, Hospital Universitario Fundación Alcorcón, 28922 Madrid, Spain
| | - Alba Galdón Sanz-Pastor
- Department of Endocrinology and Nutrition, Hospital Universitario Gregorio Marañón, 28007 Madrid, Spain
| | - Jersy Cárdenas-Salas
- Department of Endocrinology and Nutrition, Fundación Jiménez Díaz, 28040 Madrid, Spain
| | - Teresa Antón-Bravo
- Department of Endocrinology and Nutrition, Hospital Universitario de Móstoles, 28935 Madrid, Spain
| | - Miguel Brito-Sanfiel
- Department of Endocrinology and Nutrition, Hospital Universitario Puerta de Hierro, 28222 Madrid, Spain
| | - Francisca Almodóvar-Ruiz
- Department of Endocrinology and Nutrition, Hospital Universitario Fundación Alcorcón, 28922 Madrid, Spain
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15
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Huang X, Chen H, Wen S, Dong M, Zhou L, Yuan X. Therapeutic Approaches for Nonalcoholic Fatty Liver Disease: Established Targets and Drugs. Diabetes Metab Syndr Obes 2023; 16:1809-1819. [PMID: 37366486 PMCID: PMC10290856 DOI: 10.2147/dmso.s411400] [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: 03/06/2023] [Accepted: 06/16/2023] [Indexed: 06/28/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), as a multisystemic disease, is the most prevalent chronic liver disease characterized by extremely complex pathogenic mechanisms and multifactorial etiology, which often develops as a consequence of obesity, metabolic syndrome. Pathophysiological mechanisms involved in the development of NAFLD include diet, obesity, insulin resistance (IR), genetic and epigenetic determinants, intestinal dysbiosis, oxidative/nitrosative stress, autophagy dysregulation, hepatic inflammation, gut-liver axis, gut microbes, impaired mitochondrial metabolism and regulation of hepatic lipid metabolism. Some of the new drugs for the treatment of NAFLD are introduced here. All of them achieve therapeutic objectives by interfering with certain pathophysiological pathways of NAFLD, including fibroblast growth factors (FGF) analogues, peroxisome proliferator-activated receptors (PPARs) agonists, glucagon-like peptide-1 (GLP-1) agonists, G protein-coupled receptors (GPCRs), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), farnesoid X receptor (FXR), fatty acid synthase inhibitor (FASNi), antioxidants, etc. This review describes some pathophysiological mechanisms of NAFLD and established targets and drugs.
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Affiliation(s)
- Xiaojing Huang
- Graduate School of Fudan University, Shanghai, People’s Republic of China
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Huiling Chen
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Song Wen
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Meiyuan Dong
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Ligang Zhou
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Xinlu Yuan
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
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16
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Bhat N, Mani A. Dysregulation of Lipid and Glucose Metabolism in Nonalcoholic Fatty Liver Disease. Nutrients 2023; 15:2323. [PMID: 37242206 PMCID: PMC10222271 DOI: 10.3390/nu15102323] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/08/2023] [Accepted: 05/12/2023] [Indexed: 05/28/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is a highly prevalent condition affecting approximately a quarter of the global population. It is associated with increased morbidity, mortality, economic burden, and healthcare costs. The disease is characterized by the accumulation of lipids in the liver, known as steatosis, which can progress to more severe stages such as steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). This review focuses on the mechanisms that contribute to the development of diet-induced steatosis in an insulin-resistant liver. Specifically, it discusses the existing literature on carbon flux through glycolysis, ketogenesis, TCA (Tricarboxylic Acid Cycle), and fatty acid synthesis pathways in NAFLD, as well as the altered canonical insulin signaling and genetic predispositions that lead to the accumulation of diet-induced hepatic fat. Finally, the review discusses the current therapeutic efforts that aim to ameliorate various pathologies associated with NAFLD.
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Affiliation(s)
| | - Arya Mani
- Cardiovascular Research Center, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA
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17
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Bril F, Sanyal A, Cusi K. Metabolic Syndrome and Its Association with Nonalcoholic Steatohepatitis. Clin Liver Dis 2023; 27:187-210. [PMID: 37024202 DOI: 10.1016/j.cld.2023.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
The relationship between insulin resistance, metabolic syndrome (MetS), and nonalcoholic fatty liver disease (NAFLD) is complicated. Although insulin resistance is almost universal in people with NAFLD and MetS, NAFLD may be present without features of MetS and vice versa. While NAFLD has a strong correlation with cardiometabolic risk factors, these are not intrinsic components of this condition. Taken together, our knowledge gaps call for caution regarding the common assertion that NAFLD is the hepatic manifestation of the MetS, and for defining NAFLD in broad terms as a "metabolic dysfunction" based on a diverse and poorly understood constellation of cardiometabolic features.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Arun Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, School of Medicine Internal Medicine, Virginia Commonwealth University
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
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Méndez-Sánchez N, Pal SC, Córdova-Gallardo J. How far are we from an approved drug for non-alcoholic steatohepatitis? Expert Opin Pharmacother 2023; 24:1021-1038. [PMID: 37092896 DOI: 10.1080/14656566.2023.2206953] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
INTRODUCTION Metabolic associated fatty liver disease (MAFLD) previously known but still debatable, as non-alcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease and subsequent cirrhosis worldwide, accounting for around 30% of liver diseases. The change in its nomenclature has been brought about by the novel discoveries regarding its pathogenesis, in which metabolic dysfunction plays the most important role. It is widely known that for every disease, the treatment should always be targeted toward the underlying etiology and pathogenesis. AREAS COVERED MAFLD/NAFLD pathogenesis is heterogeneous, and includes multiple gene polymorphisms, presence of insulin resistance, as well as concomitant diseases that contribute to the disease onset and progression. As a result of this, even though lifestyle modification (owing to metabolic abnormalities) is the first line of treatment, multiple drugs have been tested to target each of the known pathways leading to MAFLD/NAFLD and progression of steatohepatitis. We aim to review the most relevant information regarding previous and ongoing research and recommendations regarding treatment of MAFLD/NAFLD. EXPERT OPINION Combination therapies associated to weight loss and exercise will be the optimal approach for these patients. It is important to evaluate each patient to select the specific combination according to patient characteristics.
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Affiliation(s)
- Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation, 14050 Mexico, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | - Shreya C Pal
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | - Jacqueline Córdova-Gallardo
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Department of Hepatology, Service of Surgery, General Hospital "Dr. Manuel Gea González", 14080 Mexico City, Mexico
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Polyzos SA, Goulis DG, Giouleme O, Germanidis GS, Goulas A. Anti-obesity Medications for the Management of Nonalcoholic Fatty Liver Disease. Curr Obes Rep 2022; 11:166-179. [PMID: 35501557 DOI: 10.1007/s13679-022-00474-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/11/2022] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW Obesity is closely associated with nonalcoholic fatty liver disease (NAFLD), a highly prevalent disease without any approved medication. The aim of this review was to summarize the evidence on the effect of anti-obesity medications on NAFLD, especially focusing on hepatic histology. RECENT FINDINGS Orlistat and some glucagon-like peptide-1 receptor analogs, including liraglutide and semaglutide, have beneficial effects on hepatic steatosis and inflammation, but not fibrosis. Other anti-obesity medications, including lorcaserin, setmelanotide, phentermine hydrochloric, phentermine/topiramate, and naltrexone/bupropion, have been minimally investigated in NAFLD. Furthermore, medications like sodium-glucose cotransporter-2 inhibitors and farnesoid X receptor have shown beneficial effects in both NAFLD and obesity, but they have not been licensed for either disease. Liraglutide, semaglutide, and orlistat may be currently used in selected patients with obesity and NAFLD. Further research is warranted, since targeting obesity may provide additional benefits on its comorbidities, including NAFLD.
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Affiliation(s)
- Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
| | - Dimitrios G Goulis
- Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Olga Giouleme
- 2nd Propedeutic Department of Internal Medicine, Hippocration Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgios S Germanidis
- 1st Department of Internal Medicine, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Campus of Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
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20
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Takeshita Y, Honda M, Harada K, Kita Y, Takata N, Tsujiguchi H, Tanaka T, Goto H, Nakano Y, Iida N, Arai K, Yamashita T, Mizukoshi E, Nakamura H, Kaneko S, Takamura T. Comparison of Tofogliflozin and Glimepiride Effects on Nonalcoholic Fatty Liver Disease in Participants With Type 2 Diabetes: A Randomized, 48-Week, Open-Label, Active-Controlled Trial. Diabetes Care 2022; 45:2064-2075. [PMID: 35894933 PMCID: PMC9472500 DOI: 10.2337/dc21-2049] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 05/21/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown. RESEARCH DESIGN AND METHODS We conducted a 48 week, randomized, open-label, parallel-group trial involving participants with biopsy-confirmed NAFLD. A total of 40 participants were randomly assigned to receive once daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary outcome was the percentage of participants with at least an improvement in all individual scores for histological categories of steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis by at least 1 point. The secondary end points were the changes in liver enzymes, metabolic markers, and hepatic gene expression profiles. RESULTS Fibrosis scores improved in the tofogliflozin group (60%, P = 0.001), whereas the change from baseline did not differ significantly between the groups (P = 0.172). The histological variables of steatosis (65%, P = 0.001), hepatocellular ballooning (55%, P = 0.002), and lobular inflammation (50%, P = 0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P = 0.025). Hepatic gene expression profiling revealed histology-associated signatures in energy metabolism, inflammation, and fibrosis that were reversed with tofogliflozin. CONCLUSIONS Tofogliflozin and, to a lesser degree, glimepiride led to liver histological and metabolic improvement in participants with type 2 diabetes and NAFLD, with no significant difference between the agents. The hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis was well correlated with liver histological changes and rescued by tofogliflozin. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors.
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Affiliation(s)
- Yumie Takeshita
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yuki Kita
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noboru Takata
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Hiromasa Tsujiguchi
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takeo Tanaka
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hisanori Goto
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yujiro Nakano
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noriho Iida
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Hiroyuki Nakamura
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University Kanazawa, Ishikawa, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
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21
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García-Compeán D, Kumar R, Cueto-Aguilera ÁND, Maldonado-Garza HJ, Villarreal-Pérez JZ. Body weight loss and glycemic control on the outcomes of patients with NAFLD. The role of new antidiabetic agents. Ann Hepatol 2022:100751. [PMID: 36002119 DOI: 10.1016/j.aohep.2022.100751] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/09/2022] [Accepted: 08/12/2022] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide affecting a third of adults and 12% of children in Western countries. In around 50-60%% of cases, NAFLD and type 2 diabetes mellitus (T2DM) coexist and act synergistically to increase the risk of adverse hepatic and extra-hepatic outcomes. T2DM is a strong risk factor for rapid progression of NAFLD to nonalcoholic steatohepatitis (NASH), cirrhosis or hepatocellular carcinoma (HCC), which have become frequent indications of liver transplantation. The pathophysiology of NAFLD is complex and its relationship with T2DM is bidirectional, where lipotoxicity and insulin resistance (IR), act as the strongest pillars. To date, no pharmacological treatment has been approved for NAFLD. However, there is an intense research with numerous drugs focused on reversing inflammation and liver fibrosis through modulation of molecular targets without good results. It has been known for some time that weight reduction >10% is associated to histological improvement of NAFLD. Recently, glycemic control has been shown to induce similar results. Diet and physical exercise for weight reduction have limitations, so alternative methods (pharmacologic, endoscopic or surgical) may be required. Currently, new antidiabetic drugs inducing weight loss, have been recently approved for the treatment of obesity. Nevertheless, their therapeutic effects on NAFLD have not been extensively studied. We will review here, recently published data on the effects of weight loss and glycemic control on the histological and metabolic parameters of NAFLD and recent published data on therapeutic studies of NAFLD with new antidiabetic drugs.
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Affiliation(s)
- Diego García-Compeán
- Gastroenterology Service and Internal Medicine Department, Faculty of Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey 64700, Nuevo León, Mexico.
| | - Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Ángel Noe Del Cueto-Aguilera
- Gastroenterology Service and Internal Medicine Department, Faculty of Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey 64700, Nuevo León, Mexico
| | - Héctor Jesús Maldonado-Garza
- Gastroenterology Service and Internal Medicine Department, Faculty of Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey 64700, Nuevo León, Mexico
| | - Jesús Zacarías Villarreal-Pérez
- Endocrinology Service and Internal Medicine Department, University Hospital. Autonomous University of Nuevo León, México. Madero y Gonzalitos Colonia Mitras CP 64700 Monterrey Nuevo León, México., Monterrey 64700, Mexico
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22
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Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, Wei Q, Zhao C, Lin C, Yang J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther 2022; 7:287. [PMID: 35963848 PMCID: PMC9376100 DOI: 10.1038/s41392-022-01119-3] [Citation(s) in RCA: 162] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/15/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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Affiliation(s)
- Xiaohan Xu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Kyle L Poulsen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Lijuan Wu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shan Liu
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Qiaoling Song
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qingda Wei
- School of Medicine, Zhengzhou University, Zhengzhou, China
| | - Chenyang Zhao
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinbo Yang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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23
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Xu Z, Hu W, Wang B, Xu T, Wang J, Wei D. Canagliflozin Ameliorates Nonalcoholic Fatty Liver Disease by Regulating Lipid Metabolism and Inhibiting Inflammation through Induction of Autophagy. Yonsei Med J 2022; 63:619-631. [PMID: 35748073 PMCID: PMC9226837 DOI: 10.3349/ymj.2022.63.7.619] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 01/17/2022] [Accepted: 02/09/2022] [Indexed: 12/28/2022] Open
Abstract
PURPOSE Nonalcoholic fatty liver disease (NAFLD) is closely associated with metabolic diseases, including obesity and diabetes, and has gradually become the most common cause of chronic liver disease. We investigated the effects of sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin on NAFLD in high-fat diet (HFD)-induced obese mice and possible underlying mechanisms. MATERIALS AND METHODS Male C57BL/6 mice were fed a normal-diet, HFD, or HFD with canagliflozin for 14 weeks. AML-12 hepatocytes were treated with canagliflozin. Expression of related pathways was assessed. RESULTS Canagliflozin administration reduced body weight and fat mass, compared with HFD alone. Canagliflozin improved glucose and lipid metabolic disorders. Compared with HFD-fed mice, liver weight, serum alanine transaminase (ALT) levels, and hepatic lipid accumulation were decreased after canagliflozin administration. Additionally, canagliflozin upregulated lipolysis markers (CPT1a, ACOX1, and ACADM), downregulated lipogenesis markers (SREBP-1c and FASN), and suppressed the production of inflammatory cytokines (TNFα, MCP1, IL-1β, and IL-6), consistent with significantly increased LC3 II/I and Atg7 levels in the liver following canagliflozin treatment. In vitro, canagliflozin increased CPT1a, ACOX1, and ACADM expression, decreased SREBP-1c and FASN protein expression, and reduced TNFα, MCP1, IL-1β, and IL-6 mRNA levels in lipid mixture (LM)-induced hepatocytes in a dose-dependent manner. These changes were reversed by 3-MA, an autophagy inhibitor. CONCLUSION Our findings suggest that canagliflozin ameliorates the pathogenesis of NAFLD by regulating lipid metabolism and inhibiting inflammation, which may be associated with its promotion of autophagy.
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Affiliation(s)
- Zhipeng Xu
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Organ Transplantation and Nephrosis, Shandong Institute of Nephrology, Jinan, Shandong, China
| | - Wenxin Hu
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Organ Transplantation and Nephrosis, Shandong Institute of Nephrology, Jinan, Shandong, China
| | - Bin Wang
- Department of Breast and Thyroid Surgery, Tengzhou Central People's Hospital, Zaozhuang, Shandong, China
| | - Ting Xu
- Department of Urology, Weifang Medical University, Weifang, Shandong, China
| | - Jianning Wang
- Department of Urology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Organ Transplantation and Nephrosis, Shandong Institute of Nephrology, Jinan, Shandong, China
| | - Dan Wei
- Department of Comprehensive Internal Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Jinan, Shandong, China.
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24
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Hypoglycaemic therapy in frail older people with type 2 diabetes mellitus-a choice determined by metabolic phenotype. Aging Clin Exp Res 2022; 34:1949-1967. [PMID: 35723859 PMCID: PMC9208348 DOI: 10.1007/s40520-022-02142-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 04/21/2022] [Indexed: 11/01/2022]
Abstract
Frailty is a newly emerging complication of diabetes in older people and increasingly recognised in national and international clinical guidelines. However, frailty remains less clearly defined and frail older people with diabetes are rarely characterised. The general recommendation of clinical guidelines is to aim for a relaxed glycaemic control, mainly to avoid hypoglycaemia, in this often-vulnerable group of patients. With increasing age and development of frailty, body composition changes are characterised by an increase in visceral adipose tissue and a decrease in body muscle mass. Depending on the overall body weight, differential loss of muscle fibre types and body adipose/muscle tissue ratio, the presence of any associated frailty can be seen as a spectrum of metabolic phenotypes that vary in insulin resistance of which we have defined two specific phenotypes. The sarcopenic obese (SO) frail phenotype with increased visceral fat and increased insulin resistance on one side of spectrum and the anorexic malnourished (AM) frail phenotype with significant muscle loss and reduced insulin resistance on the other. In view of these varying metabolic phenotypes, the choice of hypoglycaemic therapy, glycaemic targets and overall goals of therapy are likely to be different. In the SO phenotype, weight-limiting hypoglycaemic agents, especially the new agents of GLP-1RA and SGLT-2 inhibitors, should be considered early on in therapy due to their benefits on weight reduction and ability to achieve tight glycaemic control where the focus will be on the reduction of cardiovascular risk. In the AM phenotype, weight-neutral agents or insulin therapy should be considered early on due to their benefits of limiting further weight loss and the possible anabolic effects of insulin. Here, the goals of therapy will be a combination of relaxed glycaemic control and avoidance of hypoglycaemia; and the focus will be on maintenance of a good quality of life. Future research is still required to develop novel hypoglycaemic agents with a positive effect on body composition in frailty and improvements in clinical outcomes.
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25
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Moon JS, Hong JH, Jung YJ, Ferrannini E, Nauck MA, Lim S. SGLT-2 inhibitors and GLP-1 receptor agonists in metabolic dysfunction-associated fatty liver disease. Trends Endocrinol Metab 2022; 33:424-442. [PMID: 35491295 DOI: 10.1016/j.tem.2022.03.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/22/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic condition that affects nearly one billion people globally, characterized by triacylglycerol accumulation in the liver as a consequence of metabolic abnormalities (obesity and impaired glucose regulation). Low-grade inflammation, oxidative stress, mitochondrial dysfunction, and dysbiosis in gut microbiota are involved in the etiology of MAFLD, and both cardiovascular events and hepatic complications are the long-term consequences. In the absence of approved therapies for this condition, sodium-glucose cotransporter 2 inhibitors (SGLT-2 Is) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have the specific advantage of lowering body weight and providing cardiovascular benefits. Here, we discuss potential roles for SGLT-2 Is and GLP-1 RAs in the prevention and treatment of intrahepatic triacylglycerol accumulation and associated inflammation and/or fibrosis.
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Affiliation(s)
- Jun Sung Moon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Jun Hwa Hong
- Department of Internal Medicine, Eulji University Hospital, School of Medicine, Daejeon, Republic of Korea
| | - Yong Jin Jung
- Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | - Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital (Ruhr-University, Bochum), Bochum, Germany.
| | - Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
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26
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Lingli X, Wenfang X. Characteristics and molecular mechanisms through which SGLT2 inhibitors improve metabolic diseases: A mechanism review. Life Sci 2022; 300:120543. [PMID: 35421452 DOI: 10.1016/j.lfs.2022.120543] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 11/26/2022]
Abstract
Metabolic diseases, such as diabetes, gout and hyperlipidemia are global health challenges. Among them, diabetes has been extensively investigated. Type 2 diabetes mellitus (T2DM), which is characterized by hyperglycemia, is a complex metabolic disease that is associated with various metabolic disorders. The newly developed oral hypoglycemic agent, sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been associated with glucose-lowering effects and it affects metabolism in various ways. However, the potential mechanisms of SGLT2 inhibitors in metabolic diseases have not fully reviewed. Many of the effects beyond glycemic control must be considered off-target effects. Therefore, we reviewed the effects of SGLT2 inhibition on metabolic diseases such as obesity, hypertension, hyperlipidemia, hyperuricemia, fatty liver disease, insulin resistance, osteoporosis and fractures. Moreover, we elucidated their molecular mechanisms to provide a theoretical basis for metabolic disease treatment.
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Affiliation(s)
- Xie Lingli
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China
| | - Xia Wenfang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China.
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27
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Zhou H, Luo P, Li P, Wang G, Yi X, Fu Z, Sun X, Cui B, Zhu L, Zhu S. Bariatric Surgery Improves Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis. Obes Surg 2022; 32:1872-1883. [PMID: 35386040 DOI: 10.1007/s11695-022-06011-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 12/15/2022]
Abstract
PURPOSE Bariatric surgery has been uncovered to relieve nonalcoholic fatty liver disease (NAFLD) in patients with obesity, while current studies have neutral or opposite results. This systematic review and meta-analysis aimed to evaluate the effects of bariatric surgery on NAFLD in patients with obesity. MATERIALS AND METHODS PubMed, Embase, Cochrane Central, and Web of Science databases were performed to obtain publications containing comparison results of liver biopsy before and after bariatric surgery in obesity. Primary outcomes were biopsy-confirmed remission of NAFLD and NAFLD activity scores. Secondary outcomes were liver function. This study was registered with PROSPERO, CRD42021240346. RESULTS Thirty-seven studies were included. After bariatric surgery, a biopsy-confirmed resolution of steatosis was improved in 56% of patients, ballooning degeneration in 49%, inflammation in 45%, and fibrosis in 25%. Bariatric surgery significantly decreased mean NAFLD activity scores. RYGB achieved the most obviously improvements in steatosis, and SG attained the most notably ameliorations in fibrosis. The percentage of patients with improved steatosis and hepatic fibrosis in Asian countries was higher than non-Asian countries. The reduction of ALT and AST was 11.95U/L and 6.44 U/L after surgery. CONCLUSION Our study has revealed that bariatric surgery brought out significantly resolution of NAFLD in individuals with obesity. RYGB and SG have been proved to be of benefit to many hepatic parameters, and the improvement of liver steatosis and fibrosis, particularly in Asian countries. It is strongly suggested that bariatric surgery should be considered as a novel treatment for NAFLD.
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Affiliation(s)
- Hui Zhou
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Ping Luo
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Pengzhou Li
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Guohui Wang
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Xianhao Yi
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Zhibing Fu
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Xulong Sun
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Beibei Cui
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Liyong Zhu
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, China.
| | - Shaihong Zhu
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, China.
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28
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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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SGLT2 Inhibitors as the Most Promising Influencers on the Outcome of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23073668. [PMID: 35409028 PMCID: PMC8998221 DOI: 10.3390/ijms23073668] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/20/2022] [Accepted: 03/22/2022] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease in the Western world, is a common hepatic manifestation of metabolic syndrome (MetS). A specific cure has not yet been identified, and its treatment is currently based on risk factor therapy. Given that the initial accumulation of triglycerides in the liver parenchyma, in the presence of inflammatory processes, mitochondrial dysfunction, lipotoxicity, glucotoxicity, and oxidative stress, can evolve into non-alcoholic steatohepatitis (NASH). The main goal is to identify the factors contributing to this evolution because, once established, untreated NASH can progress through fibrosis to cirrhosis and, ultimately, be complicated by hepatocellular carcinoma (HCC). Several drugs have been tested in clinical trials for use as specific therapy for NAFLD; most of them are molecules used to cure type 2 diabetes mellitus (T2DM), which is one of the main risk factors for NAFLD. Among the most studied is pioglitazone, either alone or in combination with vitamin E, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors. Actually, the most promising category seems to be sodium-glucose cotransporter (SGLT2) inhibitors. Their action is carried out by inhibiting glucose reabsorption in the proximal renal tubule, leading to its increased excretion in urine and decreased levels in plasma. Experimental studies in animal models have suggested that SGLT2 inhibitors may have beneficial modulatory effects on NAFLD/NASH, and several trials in patients have proven their beneficial effects on liver enzymes, BMI, blood lipids, blood glucose, and insulin resistance in NAFLD patients, thus creating strong expectations for their possible use in preventing the evolution of liver damage in these patients. We will review the main pathogenetic mechanisms, diagnostic modalities, and recent therapies of NAFLD, with particular attention to the use of SGLT2 inhibitors.
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Koo BK, Lim S. Metabolic Syndrome and Metabolic Dysfunction‐Associated Fatty Liver Disease. CLINICAL OBESITY IN ADULTS AND CHILDREN 2022:159-177. [DOI: 10.1002/9781119695257.ch13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Cai M, Shao X, Xing F, Zhang Y, Gao X, Zeng Q, Dilimulati D, Qu S, Zhang M. Efficacy of canagliflozin versus metformin in women with polycystic ovary syndrome: A randomized, open-label, noninferiority trial. Diabetes Obes Metab 2022; 24:312-320. [PMID: 34726324 DOI: 10.1111/dom.14583] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/07/2021] [Accepted: 10/20/2021] [Indexed: 01/10/2023]
Abstract
OBJECTIVES To determine the safety and efficacy of canagliflozin in comparison to metformin in polycystic ovary syndrome (PCOS) patients with insulin resistance (IR). METHODS A single-centre, prospective, randomized open-label (ratio 1:1) noninferiority trial was conducted at the Department of Endocrinology, Shanghai Tenth People's Hospital, between July 2019 and April 2021. Women aged 18 to 45 years with PCOS and IR were enrolled and randomly assigned to either 100 mg (n = 33) canagliflozin daily or 1500 to 2000 mg metformin daily (n = 35) for 12 weeks. The primary outcome was changes in homeostatic model assessment (HOMA)-IR after 12 weeks of treatment. The secondary outcomes included changes in anthropometric measurements, menstrual frequency, sex hormone levels, metabolic variables and body fat distribution. RESULTS For lowering of HOMA-IR after 12 weeks of treatment, canagliflozin was found to be noninferior to metformin (least-squares mean difference -0.81% [95% confidence interval -2.13 to 0.51]). Both canagliflozin and metformin significantly improved menstrual pattern, reduced body weight and total fat mass, and decreased triglyceride levels. Compared with metformin, canagliflozin had significant advantages in reducing uric acid and dehydroepiandrosterone sulphate levels. Pruritus vulvae (9.09%) and gastrointestinal reaction (55.55%) were the main adverse events in the metformin group and canagliflozin group, respectively. CONCLUSION This study demonstrates that canagliflozin was not inferior to metformin in PCOS patients with IR, which suggests that sodium-glucose cotransporter-2 inhibitors should be considered as effective drugs in the treatment of PCOS patients with IR.
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Affiliation(s)
- Meili Cai
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaowen Shao
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Feng Xing
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuqin Zhang
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xinyu Gao
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiongjing Zeng
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Diliqingna Dilimulati
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- National Metabolic Management Center, Shanghai Tenth People's Hospital, Shanghai, China
| | - Manna Zhang
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- National Metabolic Management Center, Shanghai Tenth People's Hospital, Shanghai, China
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Choosongsang P, Soonthornpun S. Overestimation of glomerular filtration rate calculated from creatinine as compared with cystatin C in patients with type 2 diabetes receiving sodium-glucose cotransportor 2 inhibitors. Diabet Med 2022; 39:e14659. [PMID: 34309941 DOI: 10.1111/dme.14659] [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: 06/21/2021] [Revised: 07/16/2021] [Accepted: 07/24/2021] [Indexed: 11/28/2022]
Abstract
AIM The aim of this cross-sectional study is to compare creatinine-based estimated glomerular filtration rate (eGFRcr) and cystatin C-based estimated glomerular filtration rate (eGFRcys) between patients with type 2 diabetes receiving and not receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors. METHODS The plasma specimens from 90 patients with type 2 diabetes who had been receiving SGLT2 inhibitors for at least 24 weeks (SGLT2 inhibitors group) were selected. Meanwhile, the plasma specimens from age-, sex- and BMI-matched patients with type 2 diabetes not receiving SGLT2 inhibitors (non-SGLT2 inhibitors group) in 1:1 matching were also selected for comparison. eGFRcr and eGFRcys were calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS When compared with the non-SGLT2 inhibitors group, eGFRcr was significantly higher in the SGLT2 inhibitors group (70.54 ± 24.87 vs. 79.95 ± 19.57 mL/min/1.73 m2 , p = 0.014) while eGFRcys was not different (66.32 ± 24.98 vs 69.17 ± 20.10 ml/min/1.73 m2 , p = 0.401). Based on eGFRcr, the chronic kidney disease (CKD) stage in the SGLT2 inhibitors group was lower than that in the non-SGLT2 inhibitors group, but it was not different when CKD stage was classified by eGFRcys. The difference between eGFRcr and eGFRcys (eGFRcr-cys) was significantly higher in the SGLT2 inhibitors group (4.22 ± 11.20 vs. 10.78 ± 10.42 ml/min/1.73 m2 , p < 0.001). In male patients, there was significant correlation between the eGFRcr-cys and duration of receiving SGLT-2 inhibitors (r = 0.398, p = 0.004). This correlation was not found in female patients. CONCLUSIONS There was a discrepancy between eGFRcr and eGFRcys in patients with type 2 diabetes receiving SGLT2 inhibitors when compared with those not receiving SGLT2 inhibitors.
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Affiliation(s)
- Pensiri Choosongsang
- Department of Pathology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Supamai Soonthornpun
- Department of Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
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Negi CK, Babica P, Bajard L, Bienertova-Vasku J, Tarantino G. Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease. Metabolism 2022; 126:154925. [PMID: 34740573 DOI: 10.1016/j.metabol.2021.154925] [Citation(s) in RCA: 145] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. With no Food and Drug Administration approved drugs, current treatment options include dietary restrictions and lifestyle modification. NAFLD is closely associated with metabolic disorders such as obesity, type 2 diabetes, and dyslipidemia. Hence, clinically various pharmacological approaches using existing drugs such as antidiabetic, anti-obesity, antioxidants, and cytoprotective agents have been considered in the management of NAFLD and nonalcoholic steatohepatitis (NASH). However, several pharmacological therapies aiming to alleviate NAFLD-NASH are currently being examined at various phases of clinical trials. Emerging data from these studies with drugs targeting diverse molecular mechanisms show promising outcomes. This review summarizes the current understanding of the pathogenic mechanisms of NAFLD and provides an insight into the pharmacological targets and emerging therapeutics with specific interventional mechanisms. In addition, we also discuss the importance and utility of new approach methodologies and regulatory perspectives for NAFLD-NASH drug development.
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Affiliation(s)
- Chander K Negi
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic
| | - Pavel Babica
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic.
| | - Lola Bajard
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic
| | - Julie Bienertova-Vasku
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Giovanni Tarantino
- Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Naples, Italy
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Main Risk Factors of Type 2 Diabetes Mellitus with Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2021; 2021:7764817. [PMID: 34691178 PMCID: PMC8528616 DOI: 10.1155/2021/7764817] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/15/2021] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD) is a pathological metabolic disease characterized by high ketone lipid based on abnormal lipid metabolism. Compared with patients with single T2DM or NAFLD, T2DM complicated with NAFLD has more complicated pathogenic factors and pathological processes. Hepatocellular carcinoma (HCC), the leading malignancy arising from cirrhosis, is the second most lethal cancer globally. The purpose of this study was to clarify the main risk factors of T2DM with NAFLD and HCC. There are many challenges in the diagnosis and treatment of T2DM patients with NAFLD and HCC. The current gold standard is to adjust treatment strategy, optimize metabolic control, and improve liver phenotype. It is necessary to identify further the risk factors driving the progression of T2DM with NAFLD and HCC and evaluate new therapeutic targets, in addition to exploring the syndromic forms of T2DM combined with NAFLD and providing a theoretical basis for early prevention, diagnosis, and treatment of the disease using traditional Chinese medicine (TCM).
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Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes. Biomedicines 2021; 9:biomedicines9091154. [PMID: 34572340 PMCID: PMC8472728 DOI: 10.3390/biomedicines9091154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 12/28/2022] Open
Abstract
Background: Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin–C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated the effects of the SGLT2i tofogliflozin on metabolic clearance rate of insulin (MCRI) with a hyperinsulinemic euglycemic clamp study, the gold standard for measuring systemic insulin clearance. Methods: Study participants were 12 Japanese men with type 2 diabetes. We evaluated MCRI and tissue-specific insulin sensitivity with a hyperinsulinemic euglycemic clamp (insulin infusion rate, 40 mU/m2·min) before and immediately after a single dose (n = 12) and 8 weeks (n = 9) of tofogliflozin. We also measured ectopic fat in muscle and liver and the abdominal fat area using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively, before and after 8 weeks of tofogliflozin. Results: MCRI did not change after a single dose of tofogliflozin (594.7 ± 67.7 mL/min·m2 and 608.3 ± 90.9 mL/min·m2, p = 0.61) or after 8 weeks (582.5 ± 67.3 mL/min·m2 and 602.3 ± 67.0 mL/min·m2, p = 0.41). The 8-week treatment significantly improved glycated hemoglobin and decreased body weight (1.7%) and the subcutaneous fat area (6.4%), whereas insulin sensitivity and ectopic fat in muscle and liver did not change significantly. Conclusions: MCRI did not change after a single dose or 8 weeks of tofogliflozin. Increased MCRI does not precede a decrease in body fat or improved glycemic control.
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Coelho FDS, Borges-Canha M, von Hafe M, Neves JS, Vale C, Leite AR, Carvalho D, Leite-Moreira A. Effects of sodium-glucose co-transporter 2 inhibitors on liver parameters and steatosis: A meta-analysis of randomized clinical trials. Diabetes Metab Res Rev 2021; 37:e3413. [PMID: 33010191 DOI: 10.1002/dmrr.3413] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/12/2020] [Accepted: 08/23/2020] [Indexed: 12/17/2022]
Abstract
AIMS Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in Western countries and a common comorbidity with type 2 diabetes (T2D). It lacks effective pharmacotherapy. We aimed to summarize the evidence on the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on liver structure and function. MATERIALS AND METHODS Meta-analysis of randomized clinical trials in PubMed, Web of Science and ClinicalTrials.gov from their inception to April 2019. Trials evaluating liver function and/or structure and comparing SGLT2 inhibitors with placebo or other oral antidiabetic drugs in patients with T2D were included. Twenty studies (from 3033) were included. A total of 1950 patients with T2D, with or without NAFLD, were treated with SGLT2 inhibitors for at least 8 weeks, and 1900 patients were used as controls. Independent extraction was carried out by two observers. This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis. RESULTS SGLT2 inhibitors induced a significant decrease in serum alanine (-7.43U/L, [95%CI -12.14, -2.71], p < 0.01), in aspartate aminotransferases (-2.83U/L, [-4.71, -0.95], p < 0.01), as well as in gamma glutamyl transferase (-8.21U/L, [-9.52, -6.91], p < 0.01), and an increase in total plasma bilirubin (8.19% [0.79, 15.59], p < 0.01), comparing with placebo or other oral antidiabetic drugs. SGLT2 inhibitors treatment was associated with a decrease in liver steatosis (-3.39% [-6.01, -0.77], p < 0.0.1). CONCLUSIONS Treatment with SGLT2 inhibitors improves liver structure and function in patients with T2D. This meta-analysis suggests that SGLT2 inhibitors are a promising pharmacological approach for treatment of NAFLD.
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Affiliation(s)
- Francisca Dos Santos Coelho
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Marta Borges-Canha
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Madalena von Hafe
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - João Sérgio Neves
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Catarina Vale
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Ana Rita Leite
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Davide Carvalho
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de São João, Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3s), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Adelino Leite-Moreira
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Serviço de Cirurgia Cardiotorácica, Centro Hospitalar Universitário de São João, Porto, Portugal
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Massimino E, Izzo A, Riccardi G, Della Pepa G. The Impact of Glucose-Lowering Drugs on Sarcopenia in Type 2 Diabetes: Current Evidence and Underlying Mechanisms. Cells 2021; 10:1958. [PMID: 34440727 PMCID: PMC8393336 DOI: 10.3390/cells10081958] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/25/2021] [Accepted: 07/29/2021] [Indexed: 12/19/2022] Open
Abstract
The age-related decrease in skeletal muscle mass together with the loss of muscle power and function is defined sarcopenia. Mounting evidence suggests that the prevalence of sarcopenia is higher in patients with type 2 diabetes mellitus (T2DM), and different mechanisms may be responsible for this association such as impaired insulin sensitivity, chronic hyperglycemia, advanced glycosylation end products, subclinical inflammation, microvascular and macrovascular complications. Glucose-lowering drugs prescribed for patients with T2DM might impact on these mechanisms leading to harmful or beneficial effect on skeletal muscle. Importantly, beyond their glucose-lowering effects, glucose-lowering drugs may affect per se the equilibrium between protein anabolism and catabolism through several mechanisms involved in skeletal muscle physiology, contributing to sarcopenia. The aim of this narrative review is to provide an update on the effects of glucose-lowering drugs on sarcopenia in individuals with T2DM, focusing on the parameters used to define sarcopenia: muscle strength (evaluated by handgrip strength), muscle quantity/quality (evaluated by appendicular lean mass or skeletal muscle mass and their indexes), and physical performance (evaluated by gait speed or short physical performance battery). Furthermore, we also describe the plausible mechanisms by which glucose-lowering drugs may impact on sarcopenia.
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Affiliation(s)
| | | | | | - Giuseppe Della Pepa
- Department of Clinical Medicine and Surgery, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy; (E.M.); (A.I.); (G.R.)
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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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Euh W, Lim S, Kim JW. Sodium-Glucose Cotransporter-2 Inhibitors Ameliorate Liver Enzyme Abnormalities in Korean Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease. Front Endocrinol (Lausanne) 2021; 12:613389. [PMID: 34177796 PMCID: PMC8222919 DOI: 10.3389/fendo.2021.613389] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 05/24/2021] [Indexed: 12/25/2022] Open
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are reported to reduce body fat in patients with type 2 diabetes mellitus (T2DM), and SGLT2i-induced weight reduction may help improve comorbid nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the potential benefit of SGLT2is over other oral antidiabetic drugs (OADs) in patients with T2DM-associated NAFLD. We enrolled real-world Korean patients with T2DM-associated NAFLD in whom initial metformin therapy had been modified by stepwise addition of OAD(s) due to insufficient glucose control. Propensity score (PS) matching was used for the comparison of changes in clinical and biochemical parameters to balance potential covariates. Among the 765 enrolled patients, 663 patients received additional OADs other than SGLT2i and 102 patients received SGLT2i therapy. PS matching selected 150 and 100 patients from the control and the SGLT2i group, respectively. The SGLT2i group lost more weight than the control group at 6 months (mean -1.3 kg vs. 0.0 kg; P < 0.001). Alanine aminotransferase (ALT) levels also decreased more in the SGLT2i group at 3 (-11 U/L vs. -1 U/L), 6 (-12 U/L vs. -1 U/L), and 12 months (-14 U/L vs. -2 U/L) (all P < 0.05). Addition of SGLT2is was an independent predictor of ALT improvement in a multivariate logistic regression model (odds ratio 1.91; P = 0.016). Compared with other OADs, addition of SGLT2is was more effective in weight reduction and ALT improvement in patients with T2DM and comorbid NAFLD.
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Affiliation(s)
- Won Euh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Jin-Wook Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
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Finotti M, Romano M, Auricchio P, Scopelliti M, Brizzolari M, Grossi U, Piccino M, Benvenuti S, Morana G, Cillo U, Zanus G. Target Therapies for NASH/NAFLD: From the Molecular Aspect to the Pharmacological and Surgical Alternatives. J Pers Med 2021; 11:499. [PMID: 34199535 PMCID: PMC8229090 DOI: 10.3390/jpm11060499] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 05/25/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease represents an increasing cause of chronic hepatic disease in recent years. This condition usually arises in patients with multiple comorbidities, the so-called metabolic syndrome. The therapeutic options are multiple, ranging from lifestyle modifications, pharmacological options, to liver transplantation in selected cases. The choice of the most beneficial one and their interactions can be challenging. It is mandatory to stratify the patients according to the severity of their disease to tailor the available treatments. In our contribution, we review the most recent pharmacological target therapies, the role of bariatric surgery, and the impact of liver transplantation on the NAFLD outcome.
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Affiliation(s)
- Michele Finotti
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Maurizio Romano
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Pasquale Auricchio
- Hepatobiliary Surgery and Liver Transplantation Unit, DISCOG, University of Padua, 35121 Padua, Italy; (P.A.); (U.C.)
| | - Michele Scopelliti
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Marco Brizzolari
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Ugo Grossi
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Marco Piccino
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
| | - Stefano Benvenuti
- Gastroenterology Unit (IV), Cà Foncello Regional Hospital, 31100 Treviso, Italy;
| | - Giovanni Morana
- Division of Radiology, Treviso Regional Hospital, 31100 Treviso, Italy;
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, DISCOG, University of Padua, 35121 Padua, Italy; (P.A.); (U.C.)
| | - Giacomo Zanus
- 4th Surgery Unit, Regional Hospital Treviso, DISCOG, University of Padua, 31100 Padua, Italy; (M.R.); (M.S.); (M.B.); (U.G.); (M.P.); (G.Z.)
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Song T, Chen S, Zhao H, Wang F, Song H, Tian D, Yang Q, Qi L. Meta-analysis of the effect of sodium-glucose cotransporter 2 inhibitors on hepatic fibrosis in patients with type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease. Hepatol Res 2021; 51:641-651. [PMID: 33847462 DOI: 10.1111/hepr.13645] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 03/28/2021] [Accepted: 04/01/2021] [Indexed: 12/12/2022]
Abstract
AIM This study aimed to analyze the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the indexes of liver fibrosis in patients with type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease, and also to observe the effects on liver enzymes and liver fat. METHODS This meta-analysis was performed using RevMan 5.3 statistical software. RESULTS SGLT2 inhibitors could significantly reduce the level of hepatic fibrosis index: fibrosis-4 (mean difference [MD] 0.25, 95% CI -0.39 to -0.11, p = 0.0007); serum type Ⅳ collagen 7s (MD 0.32, 95% CI -0.59 to -0.04, p = 0.02); and ferritin (MD 26.7, 95% CI 50.64, 2.76, p = 0.03). SGLT2 inhibitors could significantly reduce the level of liver enzymes: alanine aminotransferase (MD 3.49, 95% CI -5.1 to 1.58, p < 0.0001); aspartate aminotransferase (MD 3.64, 95% CI -5.10 to -2.18, p < 0.00001); and glutamate aminotransferase (MD 7.13, 95% CI -12.95 to -1.32, p = 0.02). SGLT2 inhibitors could significantly reduce the level of liver fat: liver-to-spleen attenuation ratio (MD 0.16, 95% CI 0.10-0.22, p < 0.00001); magnetic resonance imaging proton density fat fraction (MD 1.97, 95% CI -3.49 to -0.45, p = 0.01); liver controlled attenuation parameter (MD 0.29, 95% CI -26.95 to -13.64, p < 0.00001); liver fat score (MD 0.55, 95% CI 1.04 to -0.05, p = 0.03); and liver fat index (MD 11.21, 95% CI -16.53 to -5.89, p < 0.0001). CONCLUSION SGLT2 inhibitors could improve liver fibrosis, liver enzymes, liver fat, and metabolic indexes in patients with type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease.
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Affiliation(s)
- Tiantian Song
- Graduate School of Hebei Medical University, Shijiazhuang, China.,Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China
| | - Shuchun Chen
- Graduate School of Hebei Medical University, Shijiazhuang, China.,Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China.,Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, China
| | - Hang Zhao
- 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
| | - Huan Song
- Graduate School of Hebei Medical University, Shijiazhuang, China.,The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Dongliang Tian
- Graduate School of Hebei Medical University, Shijiazhuang, China.,The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qiwen Yang
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China.,Hebei Northern University, Zhangjiakou, China
| | - Licui Qi
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, China.,Hebei Northern University, Zhangjiakou, China
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Sun P, Wang Y, Ding Y, Luo J, Zhong J, Xu N, Zhang Y, Xie W. Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α pathway. iScience 2021; 24:102521. [PMID: 34142035 PMCID: PMC8188479 DOI: 10.1016/j.isci.2021.102521] [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: 02/04/2021] [Revised: 04/12/2021] [Accepted: 05/05/2021] [Indexed: 11/19/2022] Open
Abstract
Lipotoxicity plays an important role in the development of diabetic heart failure (HF). Canagliflozin (CAN), a marketed sodium-glucose co-transporter 2 inhibitor, has significantly beneficial effects on HF. In this study, we evaluated the protective effects and mechanism of CAN in the hearts of C57BL/6J mice induced by high-fat diet/streptozotocin (HFD/STZ) for 12 weeks in vivo and in HL-1 cells (a type of mouse cardiomyocyte line) induced by palmitic acid (PA) in vitro. The results showed that CAN significantly ameliorated heart functions and inflammatory responses in the hearts of the HFD/STZ-induced diabetic mice. CAN significantly attenuated the inflammatory injury induced by PA in the HL-1 cells. Furthermore, CAN seemed to bind to the mammalian target of rapamycin (mTOR) and then inhibit mTOR phosphorylation and hypoxia-inducible factor-1α (HIF-1α) expression. These results indicated that CAN might attenuate lipotoxicity in cardiomyocytes by inhibiting the mTOR/HIF-1α pathway and then show protective effects on diabetic hearts.
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Affiliation(s)
- Pengbo Sun
- Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- State Key Laboratory of Chemical Oncogenomic, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Key Lab in Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Yangyang Wang
- Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- State Key Laboratory of Chemical Oncogenomic, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Key Lab in Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Yipei Ding
- State Key Laboratory of Chemical Oncogenomic, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Key Lab in Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Jingyi Luo
- State Key Laboratory of Chemical Oncogenomic, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Key Lab in Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Jin Zhong
- Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- State Key Laboratory of Chemical Oncogenomic, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Key Lab in Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Naihan Xu
- Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- State Key Laboratory of Chemical Oncogenomic, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Key Lab in Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Yaou Zhang
- Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- State Key Laboratory of Chemical Oncogenomic, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Key Lab in Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Weidong Xie
- Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- State Key Laboratory of Chemical Oncogenomic, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Key Lab in Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Corresponding author
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Zhang E, Zhao Y, Hu H. Impact of Sodium Glucose Cotransporter 2 Inhibitors on Nonalcoholic Fatty Liver Disease Complicated by Diabetes Mellitus. Hepatol Commun 2021; 5:736-748. [PMID: 34027265 PMCID: PMC8122372 DOI: 10.1002/hep4.1611] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 08/25/2020] [Accepted: 08/30/2020] [Indexed: 02/06/2023] Open
Abstract
Sodium glucose cotransporter 2 (SGLT2), a type of membrane protein highly expressed in the kidney, can regulate plasma glucose through the glomerular filtration process by reabsorption from the kidney. SGLT2 inhibitors, which are newly developed oral antidiabetic drugs, can play a role in liver diseases by inhibiting SGLT2-mediated renal glucose reabsorption and inducing glycosuria. Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease, resulting in severe liver dysfunction. During the progression of NAFLD, there are some hallmark complications, including lipid metabolism disorders, inflammation induction, and hepatocyte death. Herein, we review several SGLT2 inhibitors that are capable of protecting individuals with NAFLD from severe complications by inhibiting de novo lipogenesis, oxidative responses, inflammation induction, and hepatocyte death.
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Affiliation(s)
- Enxiang Zhang
- Key Laboratory of Growth Regulation and Transformation Research of Zhejiang ProvinceSchool of Life SciencesWestlake Institute for Advanced StudyWestlake UniversityShilongshanHangzhouChina.,Beijing Advanced Innovation Center for Food Nutrition and Human HealthCollege of Food Science and Nutritional EngineeringChina Agricultural UniversityBeijingChina.,Department of Biochemistry, Molecular Biology, and BiophysicsUniversity of MinnesotaMinneapolisMN
| | - Yang Zhao
- Department of CardiologyZhejiang Provincial People's HospitalHangzhouChina.,Cardiovascular DivisionDepartment of MedicineUniversity of MinnesotaMinneapolisMN
| | - Hongbo Hu
- Beijing Advanced Innovation Center for Food Nutrition and Human HealthCollege of Food Science and Nutritional EngineeringChina Agricultural UniversityBeijingChina
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Momozono A, Hayashi A, Takano K, Shichiri M. The effectiveness of growth hormone replacement on energy expenditure and body composition in patients with adult growth hormone deficiency. Endocr J 2021; 68:469-475. [PMID: 33361693 DOI: 10.1507/endocrj.ej20-0644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Numerous studies have shown that growth hormone (GH) replacement in adult GH deficiency (AGHD) improves the body composition and metabolic rate; however, data about the relationship between body composition and energy expenditure in these patients is scarce. Our study aimed to investigate the changes in resting energy expenditure (REE) and body composition after GH replacement in patients with AGHD. We enrolled 15 patients diagnosed with AGHD and evaluated the effect of GH replacement administered once daily for 12 months on REE, body composition measured by bioelectrical impedance analysis, and serological markers. GH replacement therapy significantly increased the serum insulin growth factor-1 levels after 4, 8, and 12 months. The REE and REE/basal energy expenditure (REE/BEE) ratio significantly increased from 1278.0 ± 490.0 kcal/day and 0.87 ± 0.23 at baseline to 1505.5 ± 449.2 kcal/day and 1.11 ± 0.21 at 4 months, 1,918.7 ± 631.2 kcal/day and 1.29 ± 0.27 at 8 months, and 1,511.1 ± 271.2 kcal/day, 1.14 ± 0.29 at 12 months (p < 0.005, p < 0.005; p < 0.01, p < 0.01; p < 0.01, p < 0.005, respectively). There was no change in the body weight, while the lean body mass increased significantly from 45.8 ± 9.5 kg at baseline to 46.9 ± 9.4 kg at 4 months and 47.5 ± 10.1 kg at 8 months (p < 0.005, p < 0.01, respectively). The fat mass also decreased at 12 months. Lipid metabolism improved after 4 and 8 months. GH replacement therapy in patients with AGHD significantly improved the REE and body composition.
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Affiliation(s)
- Akari Momozono
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Akinori Hayashi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Koji Takano
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Masayoshi Shichiri
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
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Lamos EM, Kristan M, Siamashvili M, Davis SN. Effects of anti-diabetic treatments in type 2 diabetes and fatty liver disease. Expert Rev Clin Pharmacol 2021; 14:837-852. [PMID: 33882758 DOI: 10.1080/17512433.2021.1917374] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are significant non-communicable diseases that often affect individuals concurrently. In individuals with both T2DM and NAFLD, there is evidence that anti-diabetic therapies may demonstrate potential combined beneficial metabolic and reduced hepatic inflammatory effects.Areas covered: A PubMed and Google Scholar search was performed to find relevant literature. Included studies focused on individuals with T2DM and NAFLD receiving anti-diabetic treatments including bariatric surgery, insulin sensitizers, incretin mimetics, and SGLT2 inhibitors. Additional articles highlight investigational treatments.Expert opinion: In individuals with T2DM and NAFLD, 5-10% weight loss or bariatric surgery if unable to lose weight or maintain weight loss are appropriate. GLP-1 receptor agonists and SGLT2 inhibitors result in weight loss, appear safe and may provide beneficial hepatic outcomes. Whether their effects are related to favorable weight changes or intrinsic hepatic effects is unclear. Thiazolidinediones have advantageous anti-hyperglycemic and hepatic effects but individuals must be monitored for weight gain and edema. Metformin and DPP-4 inhibitor beneficial hepatic effects remain debated. There are opportunities to standardize markers and imaging of NAFLD. Studies powered to evaluate the possible cardiovascular benefits of anti-diabetic therapies in individuals with T2DM and NAFLD are needed.
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Affiliation(s)
- Elizabeth M Lamos
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Megan Kristan
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Maka Siamashvili
- Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA
| | - Stephen N Davis
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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Canagliflozin ameliorates hepatic fat deposition in obese diabetic mice: Role of prostaglandin E 2. Biochem Biophys Res Commun 2021; 557:62-68. [PMID: 33862461 DOI: 10.1016/j.bbrc.2021.04.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 04/02/2021] [Indexed: 12/11/2022]
Abstract
Clinical and animal studies have suggested a possible beneficial effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH). Although SGLT2 inhibitors have been shown to reduce hepatic fat deposition in association with loss of body weight, the mechanism of this action has remained unknown. We here show that the SGLT2 inhibitor canagliflozin ameliorated fatty liver and hyperglycemia without affecting body weight or epididymal fat weight in obese diabetic KKAy mice. Lipidomics analysis based on liquid chromatography and tandem mass spectrometry revealed that canagliflozin treatment increased the amounts of prostaglandin E2 (PGE2) and resolvin E3 in the liver of these mice. We also found that PGE2 attenuated fat deposition in mouse primary hepatocytes exposed to palmitic acid. Our results thus suggest that PGE2 may play an important role in the amelioration of hepatic fat deposition by canagliflozin, with elucidation of its mechanism of action potentially providing a basis for the development of new therapeutics for NAFLD-NASH.
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Chrysavgis L, Papatheodoridi AM, Chatzigeorgiou A, Cholongitas E. The impact of sodium glucose co-transporter 2 inhibitors on non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2021; 36:893-909. [PMID: 33439540 DOI: 10.1111/jgh.15202] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/29/2020] [Accepted: 07/23/2020] [Indexed: 12/13/2022]
Abstract
Affecting one fourth of the global population, non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver disorder. It encompasses the simple liver fat accumulation to more progressive steatosis, inflammation, and fibrosis characterized as non-alcoholic steatohepatitis (NASH) and in some cases cirrhosis and hepatocellular carcinoma. NAFLD regularly coexists with metabolic disorders, such as obesity and mostly type 2 diabetes mellitus (T2DM). A relatively new class of antidiabetic drugs, the sodium glucose co-transporter 2 (SGLT2) inhibitors exert their action by increasing the urinary glucose and calorie excretion leading to ameliorated plasma glucose levels and lower bodyweight. Recently, several animal studies and human clinical trial have emphasized the possible beneficial impact of SGLT2 inhibitors on NAFLD and its progression to NASH. In this present review, we summarize the current literature regarding the efficacy of the aforementioned category of drugs on anthropometric, laboratory, and histological features of patients with NAFLD. Conclusively, as SGLT2 inhibitors seem to be an appealing therapeutic opportunity for NAFLD management, we identify the open issues and questions to be addressed in order to clarify the impact in choosing antidiabetic medication to treat NAFLD patients associated with T2DM.
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Affiliation(s)
- Lampros Chrysavgis
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | | | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School of National and Kapodistrian University, General Hospital of Athens "Laiko", Athens, Greece
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Bouchi R, Sonoda N, Itoh J, Ono Y, Fukuda T, Takeuchi T, Kishimoto J, Yamada T, Ogawa Y. Effects of intensive exercise combined with dapagliflozin on body composition in patients with type 2 diabetes: a randomized controlled trial. Endocr J 2021; 68:329-343. [PMID: 33390421 DOI: 10.1507/endocrj.ej20-0599] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
This study was aimed to evaluate the effects of intensive exercise in addition to the administration of sodium-glucose cotransporter 2 inhibitor dapagliflozin (DAPA) on body composition, including fat-free mass, in type 2 diabetes. We randomly assigned 146 patients to 24 weeks of treatment with intensive exercise, including resistance training, plus 5 mg (up to 10 mg) of DAPA daily (IT group) or DAPA alone (CT group). The primary endpoint was the difference in the change in fat-free mass from baseline to 24 weeks between the groups. The skeletal muscle mass index (SMI); metabolic profile, including HbA1c; and regional fat mass were also determined. ANCOVA was used for the group comparison, with least squares mean (LSM) differences and 95% confidence interval (CI). There was no significant difference in the change in fat-free mass (LSM difference -0.1 kg (95% CI: -0.5 to 0.4) and SMI (LSM difference -0.1 kg (95% CI: -0.2 to 0.1) between the groups. In contrast, the reduction of trunk fat mass was significantly higher in the IT group than in the CT group ((LSM difference -0.5 kg [95% CI -0.9 to -0.1]). Higher adherence to the resistance training tended to be associated with changes in HbA1c and high-sensitivity CRP levels. Our study suggests that intensive exercise do not prevent the reduction of fat-free mass after administration of SGLT2 inhibitors but can increase the reduction in abdominal fat, presumably leading to further improvements of hyperglycemia and chronic inflammation than DAPA alone in type 2 diabetes patients.
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Affiliation(s)
- Ryotaro Bouchi
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine, Tokyo, Japan
- Diabetes and Metabolism Information Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Noriyuki Sonoda
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Itoh
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuhiro Ono
- Department of Internal Medicine, Takagi Hospital, Fukuoka, Japan
| | - Tatsuya Fukuda
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takato Takeuchi
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Junji Kishimoto
- ARO Advanced Medical Center, Kyushu University Hospital, Fukuoka, Japan
| | - Tetsuya Yamada
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshihiro Ogawa
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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Arai T, Atsukawa M, Tsubota A, Mikami S, Ono H, Kawano T, Yoshida Y, Tanabe T, Okubo T, Hayama K, Nakagawa-Iwashita A, Itokawa N, Kondo C, Kaneko K, Emoto N, Nagao M, Inagaki K, Fukuda I, Sugihara H, Iwakiri K. Effect of sodium-glucose cotransporter 2 inhibitor in patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus: a propensity score-matched analysis of real-world data. Ther Adv Endocrinol Metab 2021; 12:20420188211000243. [PMID: 33815743 PMCID: PMC7989116 DOI: 10.1177/20420188211000243] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/12/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Although sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) improve not only glycemic control but also liver inflammation and fatty changes in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), its sustainability and effect on liver fibrosis have remained unclear. The current study aimed to clarify the effects of 48-week SGLT2-I therapy on liver inflammation, fatty changes, and fibrosis in NAFLD patients with T2DM. METHODS This study evaluated the effects of SGLT2-I on NAFLD, including liver fibrosis assessed via transient elastography, in 56 patients with NAFLD who received SGLT2-I for 48 weeks. Moreover, changes in each clinical parameter between patients receiving SGLT2-I (the SGLT2-I group) and those receiving other oral hypoglycemic agents (OHAs) (the non-SGLT2-I group) were compared, using 1:1 propensity score matching to adjust for baseline factors. RESULTS The SGLT2-I group exhibited a significant decrease in controlled attenuation parameter (312 dB/m at baseline to 280 dB/m at week 48) and liver stiffness measurement (9.1-6.7 kPa) (p < 0.001 for both). After propensity score matching (44 patients each in the SGLT2-I and non-SGLT2-I groups), no significant difference in HbA1c decrease was observed between the two groups. However, compared with the non-SGLT2-I group, the SGLT2-I group showed a significant decrease in body weight (p < 0.001), alanine aminotransferase (p = 0.02), uric acid (p < 0.001), and Fibrosis-4 (FIB-4) index (p = 0.01) at week 48. The improvement in FIB-4 index, defined as a ⩾10% decline from baseline at week 48, was 56.8% (25/44) in the SGLT2-I group and 20.5% (9/44) in the non-SGLT2-I group (p < 0.001). CONCLUSION SGLT2-Is improved not only glycemic control but also liver fatty infiltration and fibrosis in patients with NAFLD and T2DM, suggesting their possible superiority to other OHAs concerning these effects.
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Affiliation(s)
- Taeang Arai
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Research Center for Medical Sciences, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Shigeru Mikami
- Division of Gastroenterology, Department of Internal Medicine, Kikkoman General Hospital, Miyazaki Noda, Japan
| | - Hiroki Ono
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Tadamichi Kawano
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Yuji Yoshida
- Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai-shi, Chiba, Japan
| | - Tomohide Tanabe
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Tomomi Okubo
- Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai-shi, Chiba, Japan
| | - Korenobu Hayama
- Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai-shi, Chiba, Japan
| | - Ai Nakagawa-Iwashita
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Norio Itokawa
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Chisa Kondo
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Keiko Kaneko
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Naoya Emoto
- Division of Endocrinology, Nippon Medical School Chiba Hokusoh Hospital, Inzai-shi, Chiba, Japan
| | - Mototsugu Nagao
- Division of Endocrinology, Diabetes and Metabolism, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Kyoko Inagaki
- Division of Endocrinology, Diabetes and Metabolism, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Izumi Fukuda
- Division of Endocrinology, Diabetes and Metabolism, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Hitoshi Sugihara
- Division of Endocrinology, Diabetes and Metabolism, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Katsuhiko Iwakiri
- Division of Gastroenterology and Hepatology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
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Cernea S, Raz I. NAFLD in type 2 diabetes mellitus: Still many challenging questions. Diabetes Metab Res Rev 2021; 37:e3386. [PMID: 32677717 DOI: 10.1002/dmrr.3386] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 06/16/2020] [Accepted: 07/07/2020] [Indexed: 02/06/2023]
Abstract
Epidemiologic data consistently show that in patients with type 2 diabetes (T2DM) the prevalence of non-alcoholic fatty liver disease (NAFLD), including advanced fibrosis, is double compared to the general population, and it associates with high risk of liver-related morbidity (advanced fibrosis, hepatocellular carcinoma) and mortality, but also with other systemic consequences, such as cardiovascular (CV) disease, chronic kidney disease, and overall mortality. There are still many answers that need to be clarified regarding NAFLD in T2DM, including deciphering the complex pathogenetic mechanisms, the intertwined relationships with the extrahepatic organs and tissues (mainly heart, kidneys, adipose tissue, gut), the prognostic value of NAFLD for CV risk stratification, and more importantly, what would be the most appropriate screening algorithm, diagnostic method and therapeutic approach. We advocate here for proactive action, in order to identify NAFLD in a timely manner, and suggest a simple algorithm to be used in clinical practice, based on risk stratification and on experts' opinions. We discuss the current therapeutic options for NAFLD in T2DM, for which a multifactorial approach is needed, that concomitantly addresses the liver and the cardio-reno-metabolic disturbances.
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Affiliation(s)
- Simona Cernea
- Department M4/Internal Medicine IV, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, Târgu Mureş, Romania
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş, Romania
| | - Itamar Raz
- Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel
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