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Hirao Y, Morihara C, Sempokuya T. Kill two birds with one stone: Hapatologist's approach to metabolic dysfunction-associated steatotic liver disease and heart failure. World J Cardiol 2024; 16:660-664. [PMID: 39600994 PMCID: PMC11586731 DOI: 10.4330/wjc.v16.i11.660] [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: 05/11/2024] [Revised: 09/25/2024] [Accepted: 10/21/2024] [Indexed: 10/30/2024] Open
Abstract
Heart failure (HF) is a major global public health concern, and one of the less commonly known risk factors for HF development is metabolic dysfunction-associated steatotic liver disease (MASLD), as they share a similar pathophysiological background. In this article, we evaluated a recently published review article by Arriola-Montenegro et al. This article briefly summarizes the common pathophysiology of HF and MASLD development and evaluates the available therapeutic options to treat both conditions. Clinical practice guidelines highlight the importance of initiating and titrating guideline-directed medication therapy (GDMT) for patients with HF with reduced ejection fraction. GDMT is comprised of the four pillars currently proposed in most clinical practice guidelines, namely angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors (SGLT-2i). Given the similarity of pathophysiology and risk factors, recent studies for GDMT regarding ACEIs, ARBs, mineralocorticoid receptor antagonists, and SGLT-2i have shown beneficial effects on MASLD. Nonetheless, other medications for both conditions and novel therapies require more robust data and well-designed clinical studies to demonstrate their efficacies in both conditions.
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Affiliation(s)
- Yusuke Hirao
- Department of Medicine, John A Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, United States
| | - Clarke Morihara
- Department of Medicine, John A Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, United States
| | - Tomoki Sempokuya
- Division of Gastroenterology and Hepatology, Department of Medicine, John A Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, United States.
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2
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Lukic N, Macvanin MT, Gluvic Z, Rizzo M, Radak D, Suri JS, Isenovic ER. SGLT-2 Inhibitors: The Next-generation Treatment for Type 2 Diabetes Mellitus. Curr Med Chem 2024; 31:4781-4806. [PMID: 37855338 DOI: 10.2174/0109298673251493231011192520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 06/19/2023] [Accepted: 08/17/2023] [Indexed: 10/20/2023]
Abstract
Type 2 diabetes mellitus (T2DM) has become a worldwide concern in recent years, primarily in highly developed Western societies. T2DM causes systemic complications, such as atherosclerotic heart disease, ischemic stroke, peripheral artery disease, kidney failure, and diabetes-related maculopathy and retinopathy. The growing number of T2DM patients and the treatment of long-term T2DM-related complications pressurize and exhaust public healthcare systems. As a result, strategies for combating T2DM and developing novel drugs are critical global public health requirements. Aside from preventive measures, which are still the most effective way to prevent T2DM, novel and highly effective therapies are emerging. In the spotlight of next-generation T2DM treatment, sodium-glucose co-transporter 2 (SGLT-2) inhibitors are promoted as the most efficient perspective therapy. SGLT-2 inhibitors (SGLT2i) include phlorizin derivatives, such as canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. SGLT-2, along with SGLT-1, is a member of the SGLT family of proteins that play a role in glucose absorption via active transport mediated by Na+/K+ ATPase. SGLT-2 is only found in the kidney, specifically the proximal tubule, and is responsible for more than 90% glucose absorption. Inhibition of SGLT-2 reduces glucose absorption, and consequently increases urinary glucose excretion, decreasing blood glucose levels. Thus, the inhibition of SGLT-2 activity ultimately alleviates T2DM-related symptoms and prevents or delays systemic T2DM-associated chronic complications. This review aimed to provide a more detailed understanding of the effects of SGLT2i responsible for the acute improvement in blood glucose regulation, a prerequisite for T2DM-associated cardiovascular complications control.
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Affiliation(s)
- Nikola Lukic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- Department of Endocrinology and Diabetes, Clinic for Internal Medicine, Faculty of Medicine, Zemun Clinical Hospital, University of Belgrade, Belgrade, Serbia
| | - Manfredi Rizzo
- Department of Internal Medicine and Medical Specialties (DIMIS), Università degli Studi di Palermo (UNIPA), 90128 Palermo, Italy
| | - Djordje Radak
- Department of Vascular Surgery, Serbian Academy of Art and Sciences, Euromedic Clinic, 11000, Belgrade, Serbia
| | | | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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Arriola-Montenegro J, Beas R, Cerna-Viacava R, Chaponan-Lavalle A, Hernandez Randich K, Chambergo-Michilot D, Flores Sanga H, Mutirangura P. Therapies for patients with coexisting heart failure with reduced ejection fraction and non-alcoholic fatty liver disease. World J Cardiol 2023; 15:328-341. [PMID: 37576545 PMCID: PMC10415861 DOI: 10.4330/wjc.v15.i7.328] [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: 05/04/2023] [Revised: 06/09/2023] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
Heart failure with reduced ejection fraction (HFrEF) and nonalcoholic fatty liver disease (NAFLD) are two common comorbidities that share similar pathophysiological mechanisms. There is a growing interest in the potential of targeted therapies to improve outcomes in patients with coexisting HFrEF and NAFLD. This manuscript reviews current and potential therapies for patients with coexisting HFrEF and NAFLD. Pharmacological therapies, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoids receptor antagonist, and sodium-glucose cotransporter-2 inhibitors, have been shown to reduce fibrosis and fat deposits in the liver. However, there are currently no data showing the beneficial effects of sacubitril/valsartan, ivabradine, hydralazine, isosorbide nitrates, digoxin, or beta blockers on NAFLD in patients with HFrEF. This study highlights the importance of considering HFrEF and NAFLD when developing treatment plans for patients with these comorbidities. Further research is needed in patients with coexisting HFrEF and NAFLD, with an emphasis on novel therapies and the importance of a multidisciplinary approach for managing these complex comorbidities.
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Affiliation(s)
- Jose Arriola-Montenegro
- Department of Internal Medicine, University of Minnesota, Minneapolis, MN 55455, United States.
| | - Renato Beas
- Department of Medicine, Indiana University School of Medicine, Indiana, IN 46202, United States
| | | | | | | | | | - Herson Flores Sanga
- Department of Telemedicine, Cardiology, Hospital Nacional Carlos Alberto Seguin Escobedo, Arequipa 8610, Peru
| | - Pornthira Mutirangura
- Department of Medicine, University of Minnesota, Minneapolis, MN 55415, United States
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4
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Tang X, Zhang H, Wang X, Yang D. Empagliflozin for the treatment of non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Afr Health Sci 2022; 22:391-398. [PMID: 36910362 PMCID: PMC9993318 DOI: 10.4314/ahs.v22i3.42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The efficacy of empagliflozin for non-alcoholic fatty liver disease remains controversial. This meta-analysis aims to explore the influence of empagliflozin versus placebo on the treatment of non-alcoholic fatty liver disease and we have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through July 2021 for related randomized controlled trials (RCTs). Three RCTs involving 212 patients are included in the meta-analysis. Compared with control group for non-alcoholic fatty liver disease, empagliflozin treatment has no improvement in controlled attenuation parameter (CAP) score, hepatic steatosis and liver stiffness measurement (LSM) score, alanine aminotransferase (ALT), aspartate-aminotransferase (AST), low density lipoprotein (LDL) or triglyceride (TG). These indicate that empagliflozin treatment may be not effective for non-alcoholic fatty liver disease.
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Affiliation(s)
- Xue Tang
- Department of Gastroenterology, Qianjiang Central Hospital of ChongQing,400900, China.,Department of Obstetrics, Qianjiang Central Hospital of ChongQing.,Department of General Medicine, Qianjiang Central Hospital of ChongQing,400900, China
| | - Huaping Zhang
- Department of Gastroenterology, Qianjiang Central Hospital of ChongQing,400900, China.,Department of Obstetrics, Qianjiang Central Hospital of ChongQing.,Department of General Medicine, Qianjiang Central Hospital of ChongQing,400900, China
| | - Xin Wang
- Department of Gastroenterology, Qianjiang Central Hospital of ChongQing,400900, China.,Department of Obstetrics, Qianjiang Central Hospital of ChongQing.,Department of General Medicine, Qianjiang Central Hospital of ChongQing,400900, China
| | - Dan Yang
- Department of Gastroenterology, Qianjiang Central Hospital of ChongQing,400900, China.,Department of Obstetrics, Qianjiang Central Hospital of ChongQing.,Department of General Medicine, Qianjiang Central Hospital of ChongQing,400900, China
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5
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Kim KS, Hong S, Ahn HY, Park CY. Triglyceride and glucose index is a simple and easy-to-calculate marker associated with nonalcoholic fatty liver disease. Obesity (Silver Spring) 2022; 30:1279-1288. [PMID: 35674697 DOI: 10.1002/oby.23438] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/10/2022] [Accepted: 03/06/2022] [Indexed: 11/11/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the relationship between the triglyceride and glucose (TyG) index and nonalcoholic fatty liver disease (NAFLD) using a large, population-based cohort study database. METHODS A total of 52,575 participants were enrolled from 2007 to 2013 in the Kangbuk Samsung Health Study cohort. The presence of NAFLD was ascertained by ultrasonography in the absence of other known liver diseases. RESULTS Over a median 5.1 years of follow-up, 7,292 participants (13.87%) were diagnosed with NAFLD. In a multivariate-adjusted model, the hazard ratio for NAFLD of the TyG index was 1.413 (95% CI: 1.349-1.480) in the first 6 months, 1.480 (95% CI: 1.408-1.556) in months 6 to 12, 1.427 (95% CI: 1.370-1.485) in months 12 to 18, and 1.246 (95% CI: 1.159-1.339) in months >18. The hazard ratios of triglycerides, glucose, fatty liver index, and homeostatic model assessment of insulin resistance for NAFLD in months >18 were 1.124 (95% CI: 1.061-1.190), 1.037 (95% CI: 0.970-1.109), 1.508 (95% CI: 1.417-1.605), and 1.177 (95% CI: 1.116-1.242), respectively. The NAFLD-free rate decreased with increasing TyG index quartile (p < 0.001). The TyG index level from which the risk of NAFLD increased appeared to be 8.24. CONCLUSIONS This study found that the TyG index is a simple and easy-to-calculate marker associated with NAFLD.
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Affiliation(s)
- Kyung-Soo Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Sangmo Hong
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea
| | - Hong-Yup Ahn
- Department of Statistics, Dongguk University-Seoul, Seoul, Republic of Korea
| | - Cheol-Young Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Galatou E, Mourelatou E, Hatziantoniou S, Vizirianakis IS. Nonalcoholic Steatohepatitis (NASH) and Atherosclerosis: Explaining Their Pathophysiology, Association and the Role of Incretin-Based Drugs. Antioxidants (Basel) 2022; 11:1060. [PMID: 35739957 PMCID: PMC9220192 DOI: 10.3390/antiox11061060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 11/17/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the most severe manifestation of nonalcoholic fatty liver disease (NAFLD), a common complication of type 2 diabetes, and may lead to cirrhosis and hepatocellular carcinoma. Oxidative stress and liver cell damage are the major triggers of the severe hepatic inflammation that characterizes NASH, which is highly correlated with atherosclerosis and coronary artery disease. Regarding drug therapy, research on the role of GLP-1 analogues and DPP4 inhibitors, novel classes of antidiabetic drugs, is growing. In this review, we outline the association between NASH and atherosclerosis, the underlying molecular mechanisms, and the effects of incretin-based drugs, especially GLP-1 RAs, for the therapeutic management of these conditions.
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Affiliation(s)
- Eleftheria Galatou
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
| | - Elena Mourelatou
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
| | - Sophia Hatziantoniou
- Laboratory of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, University of Patras, 26504 Patras, Greece;
| | - Ioannis S. Vizirianakis
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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Xu B, Li S, Kang B, Zhou J. The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management. Cardiovasc Diabetol 2022; 21:83. [PMID: 35614469 PMCID: PMC9134641 DOI: 10.1186/s12933-022-01512-w] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic, complex metabolic disease characterized by chronic hyperglycemia causing from insufficient insulin signaling because of insulin resistance or defective insulin secretion, and may induce severe complications and premature death. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are oral drugs used to reduce hyperglycemia in patients with T2DM, including empagliflozin, ertugliflozin, dapagliflozin and canagliflozin. The primary objective of this article is to examine the clinical benefit, safety, and tolerability of the four SGLT2 inhibitors approved by the US FDA. SGLT2 inhibitors increase urinary glucose excretion via inhibiting SGLT2 to decrease renal reabsorption of filtered glucose and reduce the renal threshold for glucose. Rather than stimulating insulin release, SGLT2 inhibitors improve β-cell function by improving glucotoxicity, as well as reduce insulin resistance and increase insulin sensitivity. Early clinical trials have confirmed the beneficial effects of SGLT2 in T2DM with acceptable safety and excellent tolerability. In recent years, SGLT2 inhibitors has been successively approved by the FDA to decrease cardiovascular death and decrease the risk of stroke and cardiac attack in T2DM adults who have been diagnosed with cardiovascular disease, treating heart failure (HF) with reduced ejection fraction and HF with preserved ejection fraction, and treat diabetic kidney disease (DKD), decrease the risk of hospitalization for HF in T2DM and DKD patients. SGLT2 inhibitors are expected to be an effective treatment for T2DM patients with non alcoholic fatty liver disease. SGLT2 inhibitors have a similar safety profile to placebo or other active control groups, with major adverse events such as Ketoacidosis or hypotension and genital or urinary tract infections.
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Affiliation(s)
- Bo Xu
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Shaoqian Li
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Bo Kang
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Jiecan Zhou
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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8
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Abdel-Rahman R. Non-alcoholic fatty liver disease: Epidemiology, pathophysiology and an update on the therapeutic approaches. Asian Pac J Trop Biomed 2022. [DOI: 10.4103/2221-1691.338919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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9
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Flint A, Andersen G, Hockings P, Johansson L, Morsing A, Sundby Palle M, Vogl T, Loomba R, Plum‐Mörschel L. Randomised clinical trial: semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non-alcoholic fatty liver disease assessed by magnetic resonance imaging. Aliment Pharmacol Ther 2021; 54:1150-1161. [PMID: 34570916 PMCID: PMC9292692 DOI: 10.1111/apt.16608] [Citation(s) in RCA: 126] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/04/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists may be a treatment option in patients with non-alcoholic fatty liver disease (NAFLD). AIMS To investigate the effects of semaglutide on liver stiffness and liver fat in subjects with NAFLD using non-invasive magnetic resonance imaging (MRI) methods. METHODS This randomised, double-blind, placebo-controlled trial enrolled subjects with liver stiffness 2.50-4.63 kPa by magnetic resonance elastography (MRE) and liver steatosis ≥10% by MRI proton density fat fraction (MRI-PDFF). The primary endpoint was change from baseline to week 48 in liver stiffness assessed by MRE. RESULTS Sixty-seven subjects were randomised to once-daily subcutaneous semaglutide 0.4 mg (n = 34) or placebo (n = 33). Change from baseline in liver stiffness was not significantly different between semaglutide and placebo at week 48 (estimated treatment ratio 0.96 (95% CI 0.89, 1.03; P = 0.2798); significant differences in liver stiffness were not observed at weeks 24 or 72. Reductions in liver steatosis were significantly greater with semaglutide (estimated treatment ratios: 0.70 [0.59, 0.84], P = 0.0002; 0.47 [0.36, 0.60], P < 0.0001; and 0.50 [0.39, 0.66], P < 0.0001) and more subjects achieved a ≥ 30% reduction in liver fat content with semaglutide at weeks 24, 48 and 72, (all P < 0.001). Decreases in liver enzymes, body weight and HbA1c were also observed with semaglutide. CONCLUSIONS The change in liver stiffness in subjects with NAFLD was not significantly different between semaglutide and placebo. However, semaglutide significantly reduced liver steatosis compared with placebo which, together with improvements in liver enzymes and metabolic parameters, suggests a positive impact on disease activity and metabolic profile. ClinicalTrials.gov identifier: NCT03357380.
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Affiliation(s)
| | | | - Paul Hockings
- Antaros MedicalBioVenture HubMölndalSweden
- MedTech WestChalmers University of TechnologyGothenburgSweden
| | | | | | | | | | - Rohit Loomba
- University of California San Diego School of MedicineSan DiegoCaliforniaUSA
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Shin Y, Choi H, Lim S. Comparison betweeen dapagliflozin add-on therapy and insulin dose escalation in patients with uncontrolled type 2 diabetes treated with insulin: DVI study. Diabetes Res Clin Pract 2021; 175:108843. [PMID: 33933498 DOI: 10.1016/j.diabres.2021.108843] [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] [Received: 01/06/2021] [Revised: 03/22/2021] [Accepted: 04/27/2021] [Indexed: 10/21/2022]
Abstract
AIM To assess the efficacy and tolerability of adjunct therapy with a sodium-glucose cotransporter-2 inhibitor, dapagliflozin, compared with insulin escalation for patients with uncontrolled type 2 diabetes on current insulin therapy. METHODS A 12-month retrospective case-control study of patients with glycated hemoglobin (HbA1c) > 7% on insulin therapy. The study group received add-on therapy with dapagliflozin (10 mg once daily); the control group received titrated increases of their existing insulin dose by a mean of 21.6% from baseline. The primary endpoint was the change in HbA1c after 12 months. Secondary outcomes included changes in fasting plasma glucose, postprandial 2-h glucose levels, insulin requirements, and body weight. RESULTS After 12 months, the reduction in HbA1c was significantly greater in the dapagliflozin group than in the control group (from 8.9 ± 1.2% to 8.0 ± 1.0% vs 9.1 ± 1.2% to 8.7 ± 1.5%, respectively). Results for fasting plasma glucose and postprandial 2-h glucose were similar. Dapagliflozin therapy decreased systolic blood pressure (-4.7 mmHg) and body weight (-1.4 kg) significantly, whereas body weight increased by 0.6 kg in the control group. The dapagliflozin group showed significantly fewer hypoglycemic events than the control group (18.5% vs 32.6%, respectively). Daily insulin dose increased by 5.4 ± 6.1 U (21.6%) in the control group but decreased by 1.9 ± 5.3 U (-4.5%) in the dapagliflozin group (p < 0.001). CONCLUSION As an adjunct to insulin therapy, dapagliflozin therapy significantly improved glycemic control, with the clinical advantages of weight loss, insulin sparing, and less hypoglycemia.
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Affiliation(s)
- Yujin Shin
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Haeri Choi
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, South Korea.
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11
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Gillard P, Schnell O, Groop PH. The nephrological perspective on SGLT-2 inhibitors in type 1 diabetes. Diabetes Res Clin Pract 2020; 170:108462. [PMID: 32971152 DOI: 10.1016/j.diabres.2020.108462] [Citation(s) in RCA: 9] [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] [Received: 07/20/2020] [Revised: 09/10/2020] [Accepted: 09/16/2020] [Indexed: 12/19/2022]
Abstract
Prevalence of type 1 diabetes mellitus (T1DM) is globally continuously increasing. T1DM is accompanied by a high risk of developing cardiovascular and renal comorbidities and is one of the leading causes of end-stage renal disease (ESRD). However, current therapeutic approaches for chronic and/or diabetic kidney disease (CKD/DKD) existed for a long time, and offer room for improvement, particularly in T1DM. In 2019, the European Medicines Agency (EMA) approved a first sodium/glucose co-transporter 2 inhibitor (SGLT-2i) and a first dual SGLT-1/-2i to improve glycaemic control, as an adjunctive treatment to insulin in persons with T1DM and a body mass index ≥27 kg/m2. Of note, SGLT-1/2is and SGLT-2is are not approved by the Food and Drug Administration (FDA) as an adjunct treatment in T1DM, nor approved for the treatment of CKD or DKD by EMA and FDA. SGLT is have shown to mediate different renoprotective effects in type 2 diabetes mellitus in corresponding cardiovascular and renal outcome trials. First efficacy trials offer insights into potential positive effects on renal function and kidney disease of SGLTis in T1DM. This review summarizes and discusses latest available data on SGLT inhibition and provides an update on the nephrological perspective on SGLTis, specifically in T1DM.
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Affiliation(s)
- Pieter Gillard
- Department of Endocrinology, University Hospitals Leuven, KU Leuven, Belgium
| | - Oliver Schnell
- Sciarc GmbH, Baierbrunn, Germany; Forschergruppe Diabetes e.V., München - Neuherberg, Germany.
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland; Abdominal Centre, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland; Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
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12
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Taheri H, Malek M, Ismail-Beigi F, Zamani F, Sohrabi M, Reza babaei M, Khamseh ME. Effect of Empagliflozin on Liver Steatosis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial. Adv Ther 2020; 37:4697-4708. [PMID: 32975679 PMCID: PMC7547956 DOI: 10.1007/s12325-020-01498-5] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 09/03/2020] [Indexed: 02/08/2023]
Abstract
Introduction Despite the high prevalence of non-alcoholic fatty liver disease (NAFLD) and its associated co-morbidities, no efficient treatment in a high percentage of individuals is available. Beneficial effects of sodium–glucose co-transporter 2 inhibitors on fatty liver have been investigated in people with type 2 diabetes (T2DM). The aim of this study was to explore the effect of empagliflozin on liver steatosis and fibrosis in patients with NAFLD without T2DM. Methods In this prospective randomized, double-blind, placebo-controlled clinical trial, participants with NAFLD were randomized to empagliflozin (10 mg/day) (n = 43) or placebo (n = 47) for 24 weeks. Hepatic steatosis and fibrosis were assessed using transient elastography to measure the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). The primary outcome was the change in CAP score at 24 weeks. Results There was significant decrease in CAP score in both groups but no significant difference was observed between the two groups (P = 0.396). LSM was significantly decreased in the empagliflozin-treated group (6.03 ± 1.40 to 5.33 ± 1.08 kPa; P = 0.001), while no change was found in the placebo group. In subgroups analysis of patients with significant steatosis at baseline (CAP ≥ 302 dB/m), steatosis significantly improved in the empagliflozin group (37.2% vs. 17%; P = 0.035). There was a significant decrease in the grade of liver fat on visual analysis of ultrasound images, AST, ALT, and fasting insulin levels in the empagliflozin group, while no changes were observed in the placebo group. Conclusions Empagliflozin improves liver steatosis and, more importantly, measures of liver fibrosis in patients with NAFLD without T2DM. Trial registration ClinicalTrials.gov identifier, IRCT20190122042450N1.
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Practical Considerations and Rationale for Glucagon-Like Peptide-1 Receptor Agonist Plus Sodium-Dependent Glucose Cotransporter-2 Inhibitor Combination Therapy in Type 2 Diabetes. Can J Diabetes 2020; 45:291-302. [PMID: 33189580 DOI: 10.1016/j.jcjd.2020.09.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/31/2020] [Accepted: 09/07/2020] [Indexed: 02/07/2023]
Abstract
Glucagon-like peptide-1 receptor agonists and sodium-dependent glucose cotransporter-2 inhibitors have demonstrated clinically significant benefits on glycated hemoglobin, weight, blood pressure and cardiorenal outcomes. The emerging evidence from clinical trials and meta-analyses that assessed the combination of these 2 classes of drugs has been promising. An expert forum that included individuals with expertise in endocrine, cardiology and nephrology issues was held in May 2020 to review the literature on the metabolic and cardiorenal benefits of these 2 classes, independently and in combination, in adults with type 2 diabetes mellitus. Although hard outcome data are not available, the group concluded that the combination of glucagon-like peptide-1 receptor agonists with sodium-dependent glucose cotransporter-2 inhibitors is an emerging option for managing adults with type 2 diabetes as long as cost is not a barrier. Ongoing research may offer further insights on hard cardiorenal outcomes for this therapeutic combination as well as provide direction on the potential of this approach in obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and populations without diabetes.
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Selby LV, Ejaz A, Brethauer SA, Pawlik TM. Fatty liver disease and primary liver cancer: disease mechanisms, emerging therapies and the role of bariatric surgery. Expert Opin Investig Drugs 2020; 29:107-110. [PMID: 31986920 DOI: 10.1080/13543784.2020.1721457] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Luke V Selby
- Department of Surgery, Divisions of Surgical Oncology and GI/General Surgery, The Ohio State University Medical Center, Columbus, OH, USA
| | - Aslam Ejaz
- Department of Surgery, Divisions of Surgical Oncology and GI/General Surgery, The Ohio State University Medical Center, Columbus, OH, USA
| | - Stacy A Brethauer
- Department of Surgery, Divisions of Surgical Oncology and GI/General Surgery, The Ohio State University Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, Divisions of Surgical Oncology and GI/General Surgery, The Ohio State University Medical Center, Columbus, OH, USA
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Lajara R. Combination therapy with SGLT-2 inhibitors and GLP-1 receptor agonists as complementary agents that address multi-organ defects in type 2 diabetes. Postgrad Med 2019; 131:555-565. [PMID: 31580737 DOI: 10.1080/00325481.2019.1670017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Type 2 diabetes (T2D) has a complex pathophysiology composed of multiple underlying defects that lead to impaired glucose homeostasis and the development of macrovascular and microvascular complications. Of the currently available glucose-lowering therapies, sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) both provide effective glycemic control and have been shown to reduce cardiovascular (CV) events in patients with T2D and a high CV risk or established CV disease. Because these agents have complementary mechanisms of action, they are able to act on multiple defects of T2D when used in combination. This review discusses the rationale for and potential benefits of SGLT-2i plus GLP-1RA combination therapy in patients with T2D. A search of the PubMed database was conducted for studies and reviews describing the combined use of SGLT-2is and GLP-1RAs, with a specific focus on identifying clinical studies of combination therapy in patients with T2D. In clinical studies, glycated hemoglobin (A1c) was significantly reduced over 28-52 weeks with SGLT-2i plus GLP-1RA therapy versus the individual agents or baseline. Several CV risk factors, including body weight, blood pressure, and lipid parameters, were also improved. SGLT-2i plus GLP-1RA therapy was generally well tolerated, with a low risk of hypoglycemia and no unexpected findings. Taken together with results from large CV outcomes trials of SGLT-2is and GLP-1RAs, combination therapy with these agents potentially provides effective durable glycemic control and CV benefits due to their complementary actions on the defects of T2D.
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