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Ali MA, Michel HE, Menze ET, Tadros MG, Wahdan SA. The potential neuroprotective effect of empagliflozin against depressive-like behavior induced by chronic unpredictable mild stress in rats: Involvement of NLRP3 inflammasome. Eur J Pharmacol 2025; 998:177525. [PMID: 40107336 DOI: 10.1016/j.ejphar.2025.177525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 03/15/2025] [Accepted: 03/17/2025] [Indexed: 03/22/2025]
Abstract
Depression is a prevalent and debilitating condition that has a severe negative impact on a person's life. Chronic stress exposure plays a substantial role in the development of depression. In the present study, rats were exposed to chronic unpredictable mild stress (CUMS) for four weeks. Empagliflozin (EMPA), a Sodium-Glucose Cotransporter-2 (SGLT-2) inhibitor, is an oral antidiabetic agent exhibiting antioxidant, anti-inflammatory, and antiapoptotic effects. This study aimed to examine the antidepressant effect of EMPA in an experimental animal model of depression induced by CUMS in rats and explore the probable underlying mechanisms. Rats were treated with EMPA, per-orally, at a dose of 10 mg/kg/day for four weeks. EMPA treatment counteracted CUMS-induced histopathological, biochemical and behavioral alterations. EMPA suppressed the CUMS-induced increase in the oxidative stress, inflammatory, and apoptotic markers, where levels of MDA, IL-1β, TNF-α, NF-κB, NLRP3 and active caspase 3 were reduced by 29.6 %, 24.8 %, 17.9 %, 36.6 %, 24.5 % and 41.5 %, respectively, compared to the disease group. Furthermore, EMPA decreased the level of the microglial activation marker, iba-1 by 24 % in comparison to the disease group. In addition, EMPA treatment decreased blood glucose levels by 39 %, decreased serum insulin levels by 60.6 %, decreased HOMA-IR by 76.5 % and increased GLUT 4 expression, compared to the CUMS group, all which proves that EMPA has an effect insulin signaling and alleviates insulin resistance. Our results conclude that modulating key factors involved in depression, such as inflammation, oxidative stress, and NLRP3 inflammasome pathway, accounts for the anti-depressant effect of EMPA.
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Affiliation(s)
- Marwa A Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Haidy E Michel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Esther T Menze
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Marianne G Tadros
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Sara A Wahdan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.
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Parli£eanu OA, Nemes RM, Balteanu MA, Radu D, Gherlan G. Pathophysiological mechanisms and benefits of SGLT?2 inhibitors in a patient with cerebral artery aneurysm: A case report. Exp Ther Med 2025; 29:112. [PMID: 40242598 PMCID: PMC12000862 DOI: 10.3892/etm.2025.12862] [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: 12/12/2024] [Accepted: 03/03/2025] [Indexed: 04/18/2025] Open
Abstract
The present study described the case of a 50-year-old male patient. The patient had type 2 diabetes since the age of 38 years (in 2013) with an initial elevated glycated hemoglobin A1c of 7.2%, with a significant cardiovascular (CV) history consisting of an aneurysm of the anterior communicating artery that had been operated on in 1998 and a ruptured basilar artery tip aneurysm embolized with a stent in 2013; the case was also associated with bronchiectasis (since 2020), non-alcoholic fatty liver disease (since 2018), diabetic neuropathy (since 2023) and obesity with a body mass index of 31.72 kg/m2 (since 2010). Over the years the patient exhibited good metabolic control, initially treated with Metformin and managed through a change of diet. However, due to intolerance to Metformin, the patient stopped receiving treatments and only managed his diet. Since diabetes is by definition a condition that implies a high CV risk by itself, the primary focus with this patient was to provide additional CV protection, particularly secondary protection against any other potential future, and possibly fatal, CV events. After a brief introduction regarding the available therapeutic options, the case is presented along with the medical history, concomitant medications and evolution after 1 year. In the discussion section, similar documented cases in the literature were compared with the present case, and the potential effects of the therapeutic intervention in the present study were compared.
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Affiliation(s)
- Oana-Andreea Parli£eanu
- Department of Diabetes, ‘Marius Nasta’ National Institute of Pneumology, 050159 Bucharest, Romania
| | - Roxana-Maria Nemes
- Department of Pneumology, ‘Marius Nasta’ National Institute of Pneumology, 050159 Bucharest, Romania
- Faculty of Medicine, Titu Maiorescu University, 031592 Bucharest, Romania
| | - Mara Amalia Balteanu
- Department of Pneumology, ‘Marius Nasta’ National Institute of Pneumology, 050159 Bucharest, Romania
- Faculty of Medicine, Titu Maiorescu University, 031592 Bucharest, Romania
| | - Daniel Radu
- Department of Emergency, Ilfov County Emergency Clinical Hospital, 022104 Bucharest, Romania
| | - George Gherlan
- Department of Gastroenterology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Gastroenterology, ‘Dr. Victor Babes’ Clinical Hospital of Infectious and Tropical Diseases, Affiliated to Carol Davila' University of Medicine and Pharmacy, 030303 Bucharest, Romania
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Kallash M, Frishman W. Investigating the Relationship Between Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors and Blood Pressure. Cardiol Rev 2025:00045415-990000000-00413. [PMID: 39898627 DOI: 10.1097/crd.0000000000000861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors were originally approved for use in type 2 diabetes, but in recent years, these medications were found to also have significant cardiovascular benefits in patients with heart failure with reduced and preserved ejection fraction and chronic kidney disease. Part of the cardiovascular benefits of SGLT2 inhibitors likely comes from their antihypertensive effect in addition to other unknown effects, but the mechanism by which these medications reduce blood pressure has not been identified yet. Multiple mechanisms have been proposed to describe SGLT2 inhibitors' antihypertensive effect, including their associated weight loss and diuretic effect. However, studies have shown that these indirect mechanisms alone do not account for the antihypertensive effect seen with this medication, with more recent studies identifying a new potential mechanism by which SGLT2 inhibitors may derive their direct antihypertensive and cardiovascular benefits. In animal models, SGLT2 receptors were identified in parts of the brain responsible for regulating the sympathetic nervous system and adjusting blood pressure. In these studies, SGLT2 inhibitors suppressed the neuronal activity in these brain regions, reducing the sympathetic nervous system activity and blood pressure of the animals. Further investigation is needed to identify whether there are SGLT2 receptors in the central nervous system of humans and whether SGLT2 inhibitors can suppress neuronal activity in these brain regions. This information could be significant in learning more about the susceptibility and severity of primary hypertension in certain patient populations, as well as identifying whether SGLT2 inhibitors can be considered as a primary antihypertensive agent.
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Affiliation(s)
- Mohammed Kallash
- From the School of Medicine, New York Medical College, Valhalla, NY
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Xiong B, He L, Zhang A, Ling Z. Effect of sodium glucose cotransporter 2 inhibitors on all cause death and rehospitalization for heart failure in patients with acute myocardial infarction. Sci Rep 2024; 14:30148. [PMID: 39627297 PMCID: PMC11615227 DOI: 10.1038/s41598-024-81954-2] [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: 08/08/2024] [Accepted: 12/02/2024] [Indexed: 12/06/2024] Open
Abstract
The impact of sodium-glucose co-transporter 2 inhibitors (SGLT2-i) on reducing the risk of all-cause mortality and rehospitalization for heart failure (HF) in patients with acute myocardial infarction (AMI) remains unclear. This study aims to evaluate the effect of SGLT2-i on all-cause mortality and rehospitalization for HF in patients diagnosed with AMI. A comprehensive search was conducted in PubMed, Web of Science, the Cochrane Library, and Embase for relevant studies published up to May 2024, following the PICOS principle. Eligible studies included randomized clinical trials and cohort studies comparing SGLT2-i with placebo regarding all-cause mortality, rehospitalization for HF, cardiovascular mortality, and the incidence of nonfatal MI in AMI patients. Patient-level data from each trial were synthesized into a pooled dataset and analyzed using a mixed-effects or random-effects model based on the I2 statistic. Ten clinical trials enrolling 15,748 participants (6913 in the SGLT2-i group and 8835 in the placebo group) were included. The follow-up duration ranged from 12 weeks to 2.1 years. SGLT2-i significantly reduced rehospitalization for HF (RR: 0.69, 95% CI 0.60-0.81, P < 0.00001, I2 = 39%) compared to placebo. However, SGLT2-i did not significantly reduce the risk of all-cause death (RR: 0.85, 95% CI 0.72-1.00, P = 0.05, I2 = 46%), cardiovascular death (RR: 0.96, 95% CI 0.78-1.18, P = 0.67, I2 = 24%) or nonfatal MI (RR: 0.71, 95% CI 0.44-1.14, P = 0.16, I2 = 64%) during follow-up. Compared to placebo, SGLT2-i significantly reduced rehospitalization for HF in patients with AMI, but did not reduce the risk of all-cause death, cardiovascular death and nonfatal MI.
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Affiliation(s)
- Bin Xiong
- Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Limin He
- Department of Nursing, The First Branch Hospital, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - An Zhang
- Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Zhiyu Ling
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Mu Y, Luo LB, Huang R, Shen ZY, Huang D, Zhao SH, Yang J, Ma ZG. Cardiac-derived CTRP9 mediates the protection of empagliflozin against diabetes-induced male subfertility in mice. Clin Sci (Lond) 2024; 138:1421-1440. [PMID: 39392219 DOI: 10.1042/cs20241477] [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: 07/25/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 10/12/2024]
Abstract
Previous studies have shown beneficial effects of empagliflozin (Empa), a selective inhibitor of the sodium-glucose cotransporter 2 (SGLT2), on diabetes and cardiovascular outcomes in patients with diabetes. However, whether Empa could ameliorate diabetes mellitus (DM)-induced male spermatogenesis dysfunction remains unclear. Our study aimed to investigate the effect of Empa in the development of DM-induced male spermatogenesis dysfunction and to reveal the molecular mechanisms. DM mice were orally treated with Empa to investigate the effects of Empa on DM-induced male mice spermatogenesis dysfunction. We employed a cardiac-specific C1q/tumor necrosis factor-related protein 9 (CTRP9)-deficient mouse model and a cardiac-specific CTRP9 overexpression mouse model to investigate its role in the protection of Empa against diabetes-induced male subfertility. We found that Empa treatment could improve DM-induced male mice subfertility. Interestingly, we discovered that cardiac-derived CTRP9 was decreased in DM mice and this decrease was prevented by Empa treatment. A CTRP9 blocking antibody or cardiac-specific depletion of CTRP9 abolished the protection of Empa on DM-induced male subfertility. Cardiac-specific CTRP9 overexpression ameliorated DM-induced male subfertility. Mechanistically, we identified that cardiac-derived CTRP9 increased steroidogenesis in mice with diabetes in a PKA-dependent manner. We also provided direct evidence that activation of AMP activated protein kinase α (AMPKα)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signalling pathway by CTRP9 was responsible for the attenuation of ferroptosis in Leydig cells. In conclusions, we supposed that Empa was a potential therapeutic agent against DM-induced male mice spermatogenesis dysfunction.
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Affiliation(s)
- Yang Mu
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Ling-Bo Luo
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Rong Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Zhuo-Yu Shen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Dan Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Shu-Hong Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Jing Yang
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Zhen-Guo Ma
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
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Jing Y, Ding Y, Fu H, Li T, Long T, Ye Q. Empagliflozin ameliorates ventricular arrhythmias by inhibiting sympathetic remodeling via nerve growth factor/tyrosine kinase receptor A pathway inhibition. J Cardiovasc Med (Hagerstown) 2024; 25:664-673. [PMID: 38949125 PMCID: PMC11296263 DOI: 10.2459/jcm.0000000000001630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 03/02/2024] [Accepted: 04/25/2024] [Indexed: 07/02/2024]
Abstract
BACKGROUND AND AIMS Sodium-glucose cotransporter 2 inhibitors (SGLT2is) can ameliorate arrhythmias; however, the mechanisms underlying their antiarrhythmic effect remain unclear. Therefore, we aimed to test the hypothesis that the SGLT2i empagliflozin (EMPA) ameliorates ventricular arrhythmias caused by myocardial infarction (MI) by inhibiting sympathetic remodeling. METHODS Male nondiabetic Sprague-Dawley rats were divided into Sham ( n = 10), MI ( n = 13), low-EMPA (10 mg/kg/day; n = 13), and high-EMPA (30 mg/kg/day; n = 13) groups. Except for the Sham group, MI models were established by ligation of the left anterior descending coronary artery. After 4 weeks, the hearts were removed. Echocardiography, electrical stimulation, hematoxylin-eosin staining and Masson's staining, Western blotting, immunohistochemistry (IHC), and ELISA were performed. RESULTS Except for left ventricular posterior wall thickness (LVPWT), EMPA treatment significantly ameliorated the left ventricular anterior wall thickness (LVAWT), interventricular septum thickness (IVST), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and left ventricular ejection fraction (LVEF) in MI rats; there was no statistical difference between the low-EMPA and high-EMPA groups. The threshold for ventricular fibrillation induction and myocardial fibrosis was significantly ameliorated in EMPA-treated rats, and there was no statistical difference between the high-EMPA and low-EMPA groups. EMPA decreased the expression of nerve growth factor (NGF), tyrosine kinase receptor A (TrkA), tyrosine hydroxylase, and growth-associated protein 43 (GAP43) in the left ventricular infarction margin myocardium of MI rats, especially in the high-EMPA group, with a statistically significant difference between the high-EMPA and low-EMPA groups. High-EMPA significantly decreased noradrenaline (NE) levels in the blood of MI rats; however, there was no statistical difference between the low-EMPA and MI groups. CONCLUSION EMPA ameliorated the occurrence of ventricular arrhythmias in MI rats, which may be related to a reduction in sympathetic activity, inhibition of the NGF/TrkA pathway, inhibition of sympathetic remodeling, and improvement in cardiac function and cardiac structural remodeling.
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Affiliation(s)
- Yuling Jing
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University
| | - Yanling Ding
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University
| | - Hengsong Fu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University
| | - Tao Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University
| | - Ting Long
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University
- Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Qiang Ye
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University
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Li X, Zhou X, Gao L. Diabetes and Heart Failure: A Literature Review, Reflection and Outlook. Biomedicines 2024; 12:1572. [PMID: 39062145 PMCID: PMC11274420 DOI: 10.3390/biomedicines12071572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/08/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Heart failure (HF) is a complex clinical syndrome caused by structural or functional dysfunction of the ventricular filling or blood supply. Diabetes mellitus (DM) is an independent predictor of mortality for HF. The increase in prevalence, co-morbidity and hospitalization rates of both DM and HF has further fueled the possibility of overlapping disease pathology between the two. For decades, antidiabetic drugs that are known to definitively increase the risk of HF are the thiazolidinediones (TZDs) and saxagliptin in the dipeptidyl peptidase-4 (DPP-4) inhibitor, and insulin, which causes sodium and water retention, and whether metformin is effective or safe for HF is not clear. Notably, sodium-glucose transporter 2 (SGLT2) inhibitors and partial glucagon-like peptide-1 receptor agonists (GLP-1 RA) all achieved positive results for HF endpoints, with SGLT2 inhibitors in particular significantly reducing the composite endpoint of cardiovascular mortality and hospitalization for heart failure (HHF). Further understanding of the mutual pathophysiological mechanisms between HF and DM may facilitate the detection of novel therapeutic targets to improve the clinical outcome. This review focuses on the association between HF and DM, emphasizing the efficacy and safety of antidiabetic drugs and HF treatment. In addition, recent therapeutic advances in HF and the important mechanisms by which SGLT2 inhibitors/mineralocorticoid receptor antagonist (MRA)/vericiguat contribute to the benefits of HF are summarized.
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Affiliation(s)
| | | | - Ling Gao
- Department of Endocrinology, Renmin Hospital, Wuhan University, Wuhan 430060, China; (X.L.); (X.Z.)
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Lee YE, Im DS. SGLT2 Inhibitors Empagliflozin and Canagliflozin Ameliorate Allergic Asthma Responses in Mice. Int J Mol Sci 2024; 25:7567. [PMID: 39062810 PMCID: PMC11277224 DOI: 10.3390/ijms25147567] [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: 06/10/2024] [Revised: 07/03/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Inhibitors of sodium/glucose cotransporter 2 (SGLT2), such as empagliflozin and canagliflozin, have been widely used to block glucose reabsorption in the proximal tubules of kidneys in patients with diabetes. A meta-analysis suggested that SGLT2 inhibitors are associated with a decreased risk of asthma development. Therefore, we investigated whether SGLT2 inhibitors could suppress allergic asthma. Empagliflozin and canagliflozin suppressed the in vitro degranulation reaction induced by antigens in a concentration-dependent manner in RBL-2H3 mast cells. Empagliflozin and canagliflozin were administered to BALB/c mice sensitized to ovalbumin (OVA). The administration of empagliflozin or canagliflozin significantly suppressed OVA-induced airway hyper-responsiveness and increased the number of immune cells and pro-inflammatory cytokine mRNA expression levels in bronchoalveolar lavage fluid. The administration of empagliflozin and canagliflozin also suppressed OVA-induced histopathological changes in the lungs. Empagliflozin and canagliflozin also suppressed serum IgE levels. These results suggested that empagliflozin and canagliflozin may be applicable for the treatment of allergic asthma by suppressing immune responses.
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Affiliation(s)
| | - Dong-Soon Im
- Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea;
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Mondal S, Pramanik S, Khare VR, Fernandez CJ, Pappachan JM. Sodium glucose cotransporter-2 inhibitors and heart disease: Current perspectives. World J Cardiol 2024; 16:240-259. [PMID: 38817648 PMCID: PMC11135334 DOI: 10.4330/wjc.v16.i5.240] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 04/08/2024] [Accepted: 04/28/2024] [Indexed: 05/23/2024] Open
Abstract
Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.
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Affiliation(s)
- Sunetra Mondal
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Multispecialty Hospitals, Siliguri 734010, West Bengal, India
| | - Vibhu Ranjan Khare
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Cornelius James Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, United Kingdom.
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Upadhyay A. SGLT2 Inhibitors and Kidney Protection: Mechanisms Beyond Tubuloglomerular Feedback. KIDNEY360 2024; 5:771-782. [PMID: 38523127 PMCID: PMC11146657 DOI: 10.34067/kid.0000000000000425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 03/19/2024] [Indexed: 03/26/2024]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for kidney failure and are a key component of guideline-directed therapy for CKD. While SGLT2 inhibitors' ability to activate tubuloglomerular feedback and reduce hyperfiltration-mediated kidney injury is considered to be the central mechanism for kidney protection, recent data from experimental studies raise questions on the primacy of this mechanism. This review examines SGLT2 inhibitors' role in tubuloglomerular feedback and summarizes emerging evidence on following of SGLT2 inhibitors' other putative mechanisms for kidney protection: optimization of kidney's energy substrate utilization and delivery, regulation of autophagy and maintenance of cellular homeostasis, attenuation of sympathetic hyperactivity, and improvement in vascular health and microvascular function. It is imperative to examine the effect of SGLT2 inhibition on these different physiologic processes to help our understanding of mechanisms underpinning kidney protection with this important class of drugs.
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Affiliation(s)
- Ashish Upadhyay
- Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts
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11
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Xu H, Fu J, Tu Q, Shuai Q, Chen Y, Wu F, Cao Z. The SGLT2 inhibitor empagliflozin attenuates atherosclerosis progression by inducing autophagy. J Physiol Biochem 2024; 80:27-39. [PMID: 37792168 DOI: 10.1007/s13105-023-00974-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 07/10/2023] [Indexed: 10/05/2023]
Abstract
Cardiovascular disease due to atherosclerosis is one of the leading causes of death worldwide; however, the underlying mechanism has yet to be defined. The sodium-dependent glucose transporter 2 inhibitor (SGLT2i) empagliflozin is a new type of hypoglycemic drug. Recent studies have shown that empagliflozin not only reduces high glucose levels but also exerts cardiovascular-protective effects and slows the process of atherosclerosis. The purpose of this study was to elucidate the mechanism by which empagliflozin ameliorates atherosclerosis. Male apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat Western diet to establish an atherosclerosis model. The area and size of atherosclerotic lesions in ApoE-/- mice were then assessed by performing hematoxylin-eosin (HE) staining after empagliflozin treatment. Concurrently, oxidized low-density lipoprotein (oxLDL) was used to mimic atherosclerosis in three different types of cells. Then, following empagliflozin treatment of macrophage cells (RAW264.7), human aortic smooth muscle cells (HASMCs), and human umbilical vein endothelial cells (HUVECs), western blotting was applied to measure the levels of autophagy-related proteins and proinflammatory cytokines, and green fluorescent protein (GFP)-light chain 3 (LC3) puncta were detected using confocal microscopy to confirm autophagosome formation. Oil Red O staining was performed to detect the foaming of macrophages and HASMCs, and flow cytometry was used for the cell cycle analysis. 5-ethynyl-2'-deoxyuridine (EdU), cell counting kit-8 (CCK-8), and scratch assays were also performed to examine the proliferation and migration of HASMCs. Empagliflozin suppressed the progression of atherosclerotic lesions in ApoE-/- mice. Empagliflozin also induced autophagy in RAW246.7 cells, HASMCs, and HUVECs via the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, and it significantly increased the levels of the Beclin1 protein, the LC3B-II/I ratio, and p-AMPK protein. In addition, empagliflozin decreased the expression of P62 and the protein levels of inflammatory cytokines, and it inhibited the foaming of RAW246.7 cells and HASMCs, as well as the expression of inflammatory factors by inducing autophagy. Empagliflozin activated autophagy through the AMPK signaling pathway to delay the progression of atherosclerosis. Furthermore, the results of flow cytometry, EdU assays, CCK-8 cell viability assays, and scratch assays indicated that empagliflozin blocked HASMCs proliferation and migration. Empagliflozin activates autophagy through the AMPK signaling pathway to delay the evolution of atherosclerosis, indicating that it may represent a new and effective drug for the clinical treatment of atherosclerosis.
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Affiliation(s)
- Hualin Xu
- Postgraduate Training Basement of Jinzhou Medical University, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
- Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Jie Fu
- Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Qiang Tu
- Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Qingyun Shuai
- Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Yizhi Chen
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Fuyun Wu
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
| | - Zheng Cao
- Postgraduate Training Basement of Jinzhou Medical University, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China.
- Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
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12
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Makaro A, Świerczyński M, Pokora K, Sarniak B, Kordek R, Fichna J, Salaga M. Empagliflozin attenuates intestinal inflammation through suppression of nitric oxide synthesis and myeloperoxidase activity in in vitro and in vivo models of colitis. Inflammopharmacology 2024; 32:377-392. [PMID: 37086302 PMCID: PMC10907478 DOI: 10.1007/s10787-023-01227-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 04/07/2023] [Indexed: 04/23/2023]
Abstract
Inflammatory bowel diseases (IBD) are characterized by chronic and relapsing inflammation affecting the gastrointestinal (GI) tract. The incidence and prevalence of IBD are relatively high and still increasing. Additionally, current therapeutic strategies for IBD are not optimal. These facts urge todays' medicine to find a novel way to treat IBD. Here, we focused on the group of anti-diabetic drugs called gliflozins, which inhibit sodium glucose co-transporter type 2 (SGLT-2). Numerous studies demonstrated that gliflozins exhibit pleiotropic effect, including anti-inflammatory properties. In this study, we tested the effect of three gliflozins; empagliflozin (EMPA), dapagliflozin (DAPA), and canagliflozin (CANA) in in vitro and in vivo models of intestinal inflammation. Our in vitro experiments revealed that EMPA and DAPA suppress the production of nitric oxide in LPS-treated murine RAW264.7 macrophages. In in vivo part of our study, we showed that EMPA alleviates acute DSS-induced colitis in mice. Treatment with EMPA reduced macro- and microscopic colonic damage, as well as partially prevented from decrease in tight junction gene expression. Moreover, EMPA attenuated biochemical inflammatory parameters including reduced activity of myeloperoxidase. We showed that SGLT-2 inhibitors act as anti-inflammatory agents independently from their hypoglycemic effects. Our observations suggest that gliflozins alleviate inflammation through their potent effects on innate immune cells.
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Affiliation(s)
- Adam Makaro
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Mikołaj Świerczyński
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Kacper Pokora
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Barbara Sarniak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Radzisław Kordek
- Department of Pathology, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Maciej Salaga
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
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13
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Hu Y, Bao J, Gao Z, Ye L, Wang L. Sodium-Glucose Cotransporter Protein 2 Inhibitors: Novel Application for the Treatment of Obesity-Associated Hypertension. Diabetes Metab Syndr Obes 2024; 17:407-415. [PMID: 38292009 PMCID: PMC10826576 DOI: 10.2147/dmso.s446904] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/13/2024] [Indexed: 02/01/2024] Open
Abstract
Obesity is becoming increasingly prevalent in China and worldwide and is closely related to the development of hypertension. The pathophysiology of obesity-associated hypertension is complex, including an overactive sympathetic nervous system (SNS), activation of the renin-angiotensin-aldosterone system (RAAS), insulin resistance, hyperleptinemia, renal dysfunction, inflammatory responses, and endothelial function, which complicates treatment. Sodium-glucose cotransporter protein 2 (SGLT-2) inhibitors, novel hypoglycemic agents, have been shown to reduce body weight and blood pressure and may serve as potential novel agents for the treatment of obesity-associated hypertension. This review discusses the beneficial mechanisms of SGLT-2 inhibitors for the treatment of obesity-associated hypertension. SGLT-2 inhibitors can inhibit SNS activity, reduce RAAS activation, ameliorate insulin resistance, reduce leptin secretion, improve renal function, and inhibit inflammatory responses. SGLT-2 inhibitors can, therefore, simultaneously target multiple mechanisms of obesity-associated hypertension and may serve as an effective treatment for obesity-associated hypertension.
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Affiliation(s)
- Yilan Hu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China
| | - Jiaqi Bao
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China
| | - Zhicheng Gao
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China
| | - Lifang Ye
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China
| | - Lihong Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China
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14
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Zhang Q, Deng Z, Li T, Chen K, Zeng Z. SGLT2 inhibitor improves the prognosis of patients with coronary heart disease and prevents in-stent restenosis. Front Cardiovasc Med 2024; 10:1280547. [PMID: 38274313 PMCID: PMC10808651 DOI: 10.3389/fcvm.2023.1280547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 12/27/2023] [Indexed: 01/27/2024] Open
Abstract
Coronary heart disease is a narrowing or obstruction of the vascular cavity caused by atherosclerosis of the coronary arteries, which leads to myocardial ischemia and hypoxia. At present, percutaneous coronary intervention (PCI) is an effective treatment for coronary atherosclerotic heart disease. Restenosis is the main limiting factor of the long-term success of PCI, and it is also a difficult problem in the field of intervention. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new oral glucose-lowering agent used in the treatment of diabetes in recent years. Recent studies have shown that SGLT2 inhibitors can effectively improve the prognosis of patients after PCI and reduce the occurrence of restenosis. This review provides an overview of the clinical studies and mechanisms of SGLT2 inhibitors in the prevention of restenosis, providing a new option for improving the clinical prognosis of patients after PCI.
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Affiliation(s)
| | | | | | | | - Zhihuan Zeng
- Department of Cardiovascular Diseases, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
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15
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Li J, Li C, Huang Z, Huang C, Liu J, Wu T, Xu S, Mai P, Geng D, Zhou S, Zhang K, Liu Z. Empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of vascular smooth muscle cells. Front Pharmacol 2023; 14:1295463. [PMID: 38094889 PMCID: PMC10716287 DOI: 10.3389/fphar.2023.1295463] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 11/13/2023] [Indexed: 01/21/2025] Open
Abstract
SGLT-2 inhibitors, such as empagliflozin, have been shown to reduce the occurrence of cardiovascular events and delay the progression of atherosclerosis. However, its role in atherosclerotic calcification remains unclear. In this research, ApoE-/- mice were fed with western diet and empagliflozin was added to the drinking water for 24 weeks. Empagliflozin treatment significantly alleviated arterial calcification assessed by alizarin red and von kossa staining in aortic roots and reduced the lipid levels, while had little effect on body weight and blood glucose levels in ApoE-/- mice. In vitro studies, empagliflozin significantly inhibits calcification of primary vascular smooth muscle cells (VSMCs) and aortic rings induced by osteogenic media (OM) or inorganic phosphorus (Pi). RNA sequencing of VSMCs cultured in OM with or without empagliflozin showed that empagliflozin negatively regulated the osteogenic differentiation of VSMCs. And further studies confirmed that empagliflozin significantly inhibited osteogenic differentiation of VSMCs via qRT-PCR. Our study demonstrates that empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of VSMCs, which addressed a critical need for the discovery of a drug-based therapeutic approach in the treatment of atherosclerotic calcification.
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Affiliation(s)
- Junping Li
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Cardiology, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Changping Li
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Cardiology, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhaoqi Huang
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Cardiology, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chunling Huang
- Medical Research Center, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Juanzhang Liu
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Cardiology, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Tao Wu
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Cardiology, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shuwan Xu
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Peibiao Mai
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Dengfeng Geng
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Cardiology, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shuxian Zhou
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Cardiology, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Kun Zhang
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Cardiology, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhaoyu Liu
- Medical Research Center, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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16
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Mazzieri A, Basta G, Calafiore R, Luca G. GLP-1 RAs and SGLT2i: two antidiabetic agents associated with immune and inflammation modulatory properties through the common AMPK pathway. Front Immunol 2023; 14:1163288. [PMID: 38053992 PMCID: PMC10694219 DOI: 10.3389/fimmu.2023.1163288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 10/30/2023] [Indexed: 12/07/2023] Open
Abstract
Immune cells and other cells respond to nutrient deprivation by the classic catabolic pathway of AMPK (Adenosine monophosphate kinase). This kinase is a pivotal regulator of glucose and fatty acids metabolism, although current evidence highlights its role in immune regulation. Indeed AMPK, through activation of Foxo1 (Forkhead box O1) and Foxo3 (Forkhead box O3), can regulate FOXP3, the key gene for differentiation and homeostasis of Tregs (T regulators lymphocytes). The relevance of Tregs in the onset of T1D (Type 1 diabetes) is well-known, while their role in the pathogenesis of T2D (Type 2 diabetes) is not fully understood yet. However, several studies seem to indicate that Tregs may oppose the progression of diabetic complications by mitigating insulin resistance, atherosclerosis, and damage to target organs (as in kidney disease). Hence, AMPK and AMPK-activating agents may play a role in the regulation of the immune system. The connection between metformin and AMPK is historically known; however, this link and the possible related immune effects are less studied about SGLT2i (Sodium-glucose co-transport 2 inhibitors) and GLP1-RAs (Glucagon-like peptide-1 receptor agonists). Actual evidence shows that the negative caloric balance, induced by SGLT2i, can activate AMPK. Conversely and surprisingly, an anabolizing agent like GLP-1RAs can also upregulate this kinase through cAMP (Cyclic adenosine monophosphate) accumulation. Therefore, both these drugs can likely lead to the activation of the AMPK pathway and consequential proliferation of Tregs. These observations seem to confirm not only the metabolic but also the immunoregulatory effects of these new antidiabetic agents.
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Affiliation(s)
- Alessio Mazzieri
- Translational Medicine and Surgery, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giuseppe Basta
- Division of Internal Medicine and Endocrine and Metabolic Sciences (MISEM), Laboratory for Endocrine Cell Transplants and Biohybrid Organs, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Riccardo Calafiore
- Diabetes Research Foundation, Confindustria Umbria, Perugia, Italy
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giovanni Luca
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- Division of Medical Andrology and Endocrinology of Reproduction, Saint Mary Hospital, Terni, Italy
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17
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Matthews J, Herat L, Schlaich MP, Matthews V. The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status. Int J Mol Sci 2023; 24:14243. [PMID: 37762542 PMCID: PMC10532235 DOI: 10.3390/ijms241814243] [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: 08/17/2023] [Revised: 09/12/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
Chronic Kidney Disease (CKD) and Cardiovascular Disease (CVD) are two devastating diseases that may occur in nondiabetics or individuals with diabetes and, when combined, it is referred to as cardiorenal disease. The impact of cardiorenal disease on society, the economy and the healthcare system is enormous. Although there are numerous therapies for cardiorenal disease, one therapy showing a great deal of promise is sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors. The SGLT family member, SGLT2, is often implicated in the pathogenesis of a range of diseases, and the dysregulation of the activity of SGLT2 markedly effects the transport of glucose and sodium across the luminal membrane of renal cells. Inhibitors of SGLT2 were developed based on the antidiabetic action initiated by inhibiting renal glucose reabsorption, thereby increasing glucosuria. Of great medical significance, large-scale clinical trials utilizing a range of SGLT2 inhibitors have demonstrated both metabolic and biochemical benefits via numerous novel mechanisms, such as sympathoinhibition, which will be discussed in this review. In summary, SGLT2 inhibitors clearly exert cardio-renal protection in people with and without diabetes in both preclinical and clinical settings. This exciting class of inhibitors improve hyperglycemia, high blood pressure, hyperlipidemia and diabetic retinopathy via multiple mechanisms, of which many are yet to be elucidated.
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Affiliation(s)
- Jennifer Matthews
- Royal Perth Hospital Unit, Dobney Hypertension Centre, School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; (J.M.); (L.H.)
| | - Lakshini Herat
- Royal Perth Hospital Unit, Dobney Hypertension Centre, School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; (J.M.); (L.H.)
| | - Markus P. Schlaich
- Royal Perth Hospital Unit, Dobney Hypertension Centre, School of Medicine, University of Western Australia, Crawley, WA 6009, Australia;
- Department of Cardiology and Department of Nephrology, Royal Perth Hospital, Perth, WA 6000, Australia
| | - Vance Matthews
- Royal Perth Hospital Unit, Dobney Hypertension Centre, School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; (J.M.); (L.H.)
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18
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Tanaka A, Sata M, Okada Y, Teragawa H, Eguchi K, Shimabukuro M, Taguchi I, Matsunaga K, Kanzaki Y, Yoshida H, Ishizu T, Ueda S, Kitakaze M, Murohara T, Node K, the PROTECT study investigators
NodeKoichiMuroharaToyoakiKitakazeMasafumiNishioYoshihikoInoueTeruoOhishiMitsuruKarioKazuomiSataMasatakaShimabukuroMichioShimizuWataruJinnouchiHideakiTaguchiIsaoTomiyamaHirofumiMaemuraKojiSuzukiMakotoAndoShinichiEguchiKazuoKamiyaHaruoSakamotoTomohiroTeragawaHirokiNanasatoMamoruMatsuhisaMunehideAkoJunyaAsoYoshimasaIshiharaMasaharuKitagawaKazuoYamashinaAkiraIshizuTomokoIkeharaYumiUedaShinichiroTakamoriAyakoTanakaAtsushiMoriMikiYamaguchiKaoriAsakaMachikoKanekoTetsuyaSakumaMasashiToyodaShigeruNasunoTakahisaKageyamaMichiyaTeruoJojimaToshieIijimaKishiHarukaYamadaHirotsuguKusunoseKenyaFukudaDaijuYagiShusukeYamaguchiKojiIseTakayukiKawabataYutakaKurodaAkioAkasakiYuichiKuranoMihokoHoshideSatoshiKomoriTakahiroKabutoyaTomoyukiOgataYukiyoKoideYujiKawanoHiroakiIkedaSatoshiFukaeSatokiKogaSeijiHigashiYukihitoKishimotoShinjiKajikawaMasatoMaruhashiTatsuyaKubotaYoshiakiShibataYoshisatoKuriyamaNehiroNakamuraIkukoHironoriKanemitsuTakaseBonpeiOritaYuichiOshitaChikageUchimuraYukoYoshidaRukaYoshidaYukihikoSuzukiHirohikoOguraYasuhiroMaedaMayuhoTakenakaMasakiHayashiTakumiHiroseMiraiHisauchiItaruKadokamiToshiakiNakamuraRyoKandaJunjiMatsunagaKazuoHoshigaMasaakiSohmiyaKoichiKanzakiYumikoKoyosueArihiroUeharaHirokiMiyagiNaotoChinenToshiyaNakamuraKentaroNagoChikashiChibaSuguruHatanoShoGimaYoshikatsuAbeMasamiAjiokaMasayoshiAsanoHiroshiNakashimaYoshihiroOsanaiHiroyukiKanbaraTakahiroSakamotoYusukeOguriMitsutoshiOhguchiShiouTakaharaKunihikoIzumiKazuhiroYasudaKenichiroKudoAkihiroMachiiNoritakaMorimotoRyotaBandoYasukoOkumuraTakahiroKondoToruMiuraShin-ichiroShigaYuheiMiriiJojiSugiharaMakotoArimuraTadaakiNakanoJunkoSakamotoTomohiroKodamaKazuhisaOhteNobuyukiSugiuraTomonoriWakamiKazuakiTakemotoYasuhikoYoshiyamaMinoruShutoTaichiFukumotoKazuoOkadaYosukeTanakaKenichiSonodaSatomiTokutsuAkemiOtsukaTakashiUemuraFumiKoikawaKenjiMiyazakiMegumiUmikawaMaikoNarisawaManabuFurutaMachiMinamiHiroshiDoiMasaruSugimotoKazuhiroSuzukiSusumuKurozumiAkiraNishioKosuke, Murohara T, Kitakaze M, Nishio Y, Inoue T, Ohishi M, Kario K, Sata M, Shimabukuro M, Shimizu W, Jinnouchi H, Taguchi I, Tomiyama H, Maemura K, Suzuki M, Ando S, Eguchi K, Kamiya H, Sakamoto T, Teragawa H, Nanasato M, Matsuhisa M, Ako J, Aso Y, Ishihara M, Kitagawa K, Yamashina A, Ishizu T, Ikehara Y, Ueda S, Takamori A, Tanaka A, Mori M, Yamaguchi K, Asaka M, Kaneko T, Sakuma M, Toyoda S, Nasuno T, Kageyama M, Teruo J, Toshie I, Kishi H, Yamada H, Kusunose K, Fukuda D, Yagi S, Yamaguchi K, Ise T, Kawabata Y, Kuroda A, Akasaki Y, Kurano M, Hoshide S, Komori T, Kabutoya T, Ogata Y, Koide Y, Kawano H, Ikeda S, Fukae S, Koga S, Higashi Y, Kishimoto S, Kajikawa M, Maruhashi T, Kubota Y, Shibata Y, Kuriyama N, Nakamura I, Hironori K, Takase B, Orita Y, Oshita C, Uchimura Y, Yoshida R, Yoshida Y, Suzuki H, Ogura Y, Maeda M, Takenaka M, Hayashi T, Hirose M, Hisauchi I, Kadokami T, et alTanaka A, Sata M, Okada Y, Teragawa H, Eguchi K, Shimabukuro M, Taguchi I, Matsunaga K, Kanzaki Y, Yoshida H, Ishizu T, Ueda S, Kitakaze M, Murohara T, Node K, the PROTECT study investigators
NodeKoichiMuroharaToyoakiKitakazeMasafumiNishioYoshihikoInoueTeruoOhishiMitsuruKarioKazuomiSataMasatakaShimabukuroMichioShimizuWataruJinnouchiHideakiTaguchiIsaoTomiyamaHirofumiMaemuraKojiSuzukiMakotoAndoShinichiEguchiKazuoKamiyaHaruoSakamotoTomohiroTeragawaHirokiNanasatoMamoruMatsuhisaMunehideAkoJunyaAsoYoshimasaIshiharaMasaharuKitagawaKazuoYamashinaAkiraIshizuTomokoIkeharaYumiUedaShinichiroTakamoriAyakoTanakaAtsushiMoriMikiYamaguchiKaoriAsakaMachikoKanekoTetsuyaSakumaMasashiToyodaShigeruNasunoTakahisaKageyamaMichiyaTeruoJojimaToshieIijimaKishiHarukaYamadaHirotsuguKusunoseKenyaFukudaDaijuYagiShusukeYamaguchiKojiIseTakayukiKawabataYutakaKurodaAkioAkasakiYuichiKuranoMihokoHoshideSatoshiKomoriTakahiroKabutoyaTomoyukiOgataYukiyoKoideYujiKawanoHiroakiIkedaSatoshiFukaeSatokiKogaSeijiHigashiYukihitoKishimotoShinjiKajikawaMasatoMaruhashiTatsuyaKubotaYoshiakiShibataYoshisatoKuriyamaNehiroNakamuraIkukoHironoriKanemitsuTakaseBonpeiOritaYuichiOshitaChikageUchimuraYukoYoshidaRukaYoshidaYukihikoSuzukiHirohikoOguraYasuhiroMaedaMayuhoTakenakaMasakiHayashiTakumiHiroseMiraiHisauchiItaruKadokamiToshiakiNakamuraRyoKandaJunjiMatsunagaKazuoHoshigaMasaakiSohmiyaKoichiKanzakiYumikoKoyosueArihiroUeharaHirokiMiyagiNaotoChinenToshiyaNakamuraKentaroNagoChikashiChibaSuguruHatanoShoGimaYoshikatsuAbeMasamiAjiokaMasayoshiAsanoHiroshiNakashimaYoshihiroOsanaiHiroyukiKanbaraTakahiroSakamotoYusukeOguriMitsutoshiOhguchiShiouTakaharaKunihikoIzumiKazuhiroYasudaKenichiroKudoAkihiroMachiiNoritakaMorimotoRyotaBandoYasukoOkumuraTakahiroKondoToruMiuraShin-ichiroShigaYuheiMiriiJojiSugiharaMakotoArimuraTadaakiNakanoJunkoSakamotoTomohiroKodamaKazuhisaOhteNobuyukiSugiuraTomonoriWakamiKazuakiTakemotoYasuhikoYoshiyamaMinoruShutoTaichiFukumotoKazuoOkadaYosukeTanakaKenichiSonodaSatomiTokutsuAkemiOtsukaTakashiUemuraFumiKoikawaKenjiMiyazakiMegumiUmikawaMaikoNarisawaManabuFurutaMachiMinamiHiroshiDoiMasaruSugimotoKazuhiroSuzukiSusumuKurozumiAkiraNishioKosuke, Murohara T, Kitakaze M, Nishio Y, Inoue T, Ohishi M, Kario K, Sata M, Shimabukuro M, Shimizu W, Jinnouchi H, Taguchi I, Tomiyama H, Maemura K, Suzuki M, Ando S, Eguchi K, Kamiya H, Sakamoto T, Teragawa H, Nanasato M, Matsuhisa M, Ako J, Aso Y, Ishihara M, Kitagawa K, Yamashina A, Ishizu T, Ikehara Y, Ueda S, Takamori A, Tanaka A, Mori M, Yamaguchi K, Asaka M, Kaneko T, Sakuma M, Toyoda S, Nasuno T, Kageyama M, Teruo J, Toshie I, Kishi H, Yamada H, Kusunose K, Fukuda D, Yagi S, Yamaguchi K, Ise T, Kawabata Y, Kuroda A, Akasaki Y, Kurano M, Hoshide S, Komori T, Kabutoya T, Ogata Y, Koide Y, Kawano H, Ikeda S, Fukae S, Koga S, Higashi Y, Kishimoto S, Kajikawa M, Maruhashi T, Kubota Y, Shibata Y, Kuriyama N, Nakamura I, Hironori K, Takase B, Orita Y, Oshita C, Uchimura Y, Yoshida R, Yoshida Y, Suzuki H, Ogura Y, Maeda M, Takenaka M, Hayashi T, Hirose M, Hisauchi I, Kadokami T, Nakamura R, Kanda J, Matsunaga K, Hoshiga M, Sohmiya K, Kanzaki Y, Koyosue A, Uehara H, Miyagi N, Chinen T, Nakamura K, Nago C, Chiba S, Hatano S, Gima Y, Abe M, Ajioka M, Asano H, Nakashima Y, Osanai H, Kanbara T, Sakamoto Y, Oguri M, Ohguchi S, Takahara K, Izumi K, Yasuda K, Kudo A, Machii N, Morimoto R, Bando Y, Okumura T, Kondo T, Miura SI, Shiga Y, Mirii J, Sugihara M, Arimura T, Nakano J, Sakamoto T, Kodama K, Ohte N, Sugiura T, Wakami K, Takemoto Y, Yoshiyama M, Shuto T, Fukumoto K, Okada Y, Tanaka K, Sonoda S, Tokutsu A, Otsuka T, Uemura F, Koikawa K, Miyazaki M, Umikawa M, Narisawa M, Furuta M, Minami H, Doi M, Sugimoto K, Suzuki S, Kurozumi A, Nishio K, the PROTECT study investigators. Effect of ipragliflozin on carotid intima-media thickness in patients with type 2 diabetes: a multicenter, randomized, controlled trial. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2023; 9:165-172. [PMID: 36308299 PMCID: PMC9892869 DOI: 10.1093/ehjcvp/pvac059] [Show More Authors] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/13/2022] [Accepted: 10/24/2022] [Indexed: 11/11/2022]
Abstract
AIMS To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. METHODS AND RESULTS In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0-10.0% (42-86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), -0.0155-0.0182] mm and 0.0015 (95% CI, -0.0155-0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of -0.0001 mm (95% CI, -0.0191-0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [-0.1% (95% CI, -0.2-0.1); P = 0.359]. CONCLUSION Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.
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Affiliation(s)
- Atsushi Tanaka
- Corresponding authors: Tel: +81-952-34-2364, Fax +81-952-34-2089,
| | - Masataka Sata
- Department of Cardiovascular Medicine, Tokushima University Hospital, 2-50-1 Kuramoto-machi, Tokushima, Tokushima, 770-8503, Japan
| | - Yosuke Okada
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku Kitakyushu, 807-8556, Japan
| | - Hiroki Teragawa
- Department of Cardiovascular Medicine, JR Hiroshima Hospital, 3-1-36 Futabanosato, Higashi-ku, Hiroshima, 732-0057, Japan
| | - Kazuo Eguchi
- Department of General Internal Medicine, Saitama Red Cross Hospital, 1-5 Shintoshin, Chuo-ku, Saitama, 330-0081, Japan
| | - Michio Shimabukuro
- Department of Diabetes, Endocrinology, and Metabolism, Fukushima Medical University, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Isao Taguchi
- Department of Cardiology, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minamikoshigaya, Koshigaya, 343-8555, Japan
| | - Kazuo Matsunaga
- Department of Internal Medicine, Imari-Arita Kyoritsu Hospital, 860 Ninoseko, Matsuura, Saga, 849-4141, Japan
| | - Yumiko Kanzaki
- Department of Cardiology, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Hisako Yoshida
- Department of Medical Statistics, Osaka Metropolitan University, 1-4-3 Asahimachi, Abeno-ku, Osaka, Osaka, 545-8585, Japan
| | - Tomoko Ishizu
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, 2-1-1 Amakubo, Tsukuba, 305-8576, Japan
| | - Shinichiro Ueda
- Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus, 207 Uehara, Nishihara, 903-0215, Okinawa, Japan
| | - Masafumi Kitakaze
- Hanwa Daini Senboku Hospital, 3176 Fukaikitamachi, Naka-ku, Sakai, 599-8271, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumaicho, Showa-ku Nagoya, 466-0065, Japan
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Zuo Q, Zhang G, He L, Ma S, Ma H, Zhai J, Wang Z, Zhang T, Wang Y, Guo Y. Canagliflozin Attenuates Hepatic Steatosis and Atherosclerosis Progression in Western Diet-Fed ApoE-Knockout Mice. Drug Des Devel Ther 2022; 16:4161-4177. [PMID: 36510490 PMCID: PMC9741490 DOI: 10.2147/dddt.s388823] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Purpose To investigate the effect of canagliflozin (20 mg/kg) on hepatic steatosis and atherosclerosis, and further to explore its possible mechanism. Methods Blood glucose, blood lipid, oxidative stress response and inflammatory cytokines were examined by intraperitoneal glucose tolerance test and ELISA assay. HE and Oil Red O staining were used to estimate the extent of hepatic steatosis and atherosclerosis. RNA-seq and qRT-PCR were used to further investigate the potential mechanism. The effects of canagliflozin on autophagy were detected using transmission electron microscopy and Western blotting. The endothelial function-related markers were determined by qRT-PCR. Results Canagliflozin notably alleviated the elevation in blood glucose and insulin resistance in western diet-fed ApoE-/- mice. In ApoE-/-+Cana group, ApoE-/- mice had lower levels of TG, TC, LDL-C, TNF-α, IL-6, IL-1β, and MCP-1. HE and Oil Red O staining presented that canagliflozin restrained the atherosclerotic plaque development and lipid accumulation. RNA-seq showed that 87 DEGs were relevant to improvement of hepatic steatosis and atherosclerosis by canagliflozin. Among them, CPS1, ASS1, ASL, ARG1, MATLA, GLS2, GOT1, SREBP1, Plin5, Retreg1, and C/EBPβ were verified. KEGG enrichment analysis indicated that DEGs were mainly involved in amino acid metabolism. Besides, we observed that canagliflozin reduced the contents of aspartic acid and citrulline in liver. Western blotting showed that ASS1 and p-AMPK/AMPK was remarkably elevated after administration of canagliflozin. Correspondingly, canagliflozin down-regulated SREBP1, FAS, ACC1, HMGCR, p-mTOR/m-TOR, p-ULK1/ULK1 and p62, but up-regulated CPT1, Beclin 1 and LC3 II/LC3I. TEM showed that canagliflozin reduced the number of lipid droplets and increased the autophagosomes. Moreover, we found that canagliflozin elevated the aortic endothelial function-associated markers including ASS1, ASL and eNOS. Conclusion Canagliflozin may attenuate hepatic steatosis by improving lipid metabolism, enhancing autophagy, and reducing inflammatory response through ASS1/AMPK pathway. Besides, canagliflozin further effectively improves the aortic endothelial function, thereby suppressing atherosclerosis development.
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Affiliation(s)
- Qingjuan Zuo
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China,Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Guorui Zhang
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China,Department of Cardiology, the Third Hospital of Shijiazhuang City Affiliated to Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Lili He
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Sai Ma
- Department of Internal Medicine, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Huijuan Ma
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Jianlong Zhai
- Department of Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Zhongli Wang
- Department of Physical Examination Center, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Tingting Zhang
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Yan Wang
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Yifang Guo
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China,Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China,Correspondence: Yifang Guo, Department of Geriatric Cardiology, Hebei General Hospital, No. 348, Heping West Road, Xinhua District, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel +86-15100189182, Email
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Theofilis P, Sagris M, Oikonomou E, Antonopoulos AS, Siasos G, Tsioufis K, Tousoulis D. The impact of SGLT2 inhibitors on inflammation: A systematic review and meta-analysis of studies in rodents. Int Immunopharmacol 2022; 111:109080. [PMID: 35908505 DOI: 10.1016/j.intimp.2022.109080] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/28/2022] [Accepted: 07/18/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND Inhibition of sodium-glucose cotransporter-2 (SGLT2) has received remarkable attention due to the beneficial effects observed in diabetes mellitus, heart failure, and kidney disease. Several mechanisms have been proposed for these pleiotropic effects, including anti-inflammatory ones. Our systematic review and meta-analysis aimed to assess the effect of SGLT2 inhibition on inflammatory markers in experimental models. METHODS A literature search was conducted to detect studies examining the effect of SGLT2 inhibitors on inflammatory markers [interleukin-6 (IL-6), C reactive protein (CRP), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1)]. Consequently, a meta-analysis of the included studies was performed, assessing the differences in the levels of the inflammatory markers between the treatment groups as its primary outcome. Moreover, risk of bias, sensitivity analysis and publication bias were evaluated. RESULTS The systematic literature review yielded 30 studies whose meta-analysis suggested that treatment with an SGLT2 inhibitor resulted in decreases of IL-6 [standardized mean difference (SMD): -1.56, 95% CI -2.06 to -1.05), CRP (SMD: -2.17, 95% CI -2.80 to -1.53), TNF-α (SMD: -1.75, 95% CI -2.14 to -1.37), and MCP-1 (SMD: -2.04, 95% CI -2.91 to -1.17). The effect on CRP and TNF-α was of lesser magnitude in cases of empagliflozin use. Moderate-to-substantial heterogeneity and possible publication bias were noted. The findings remained largely unaffected after the sensitivity analyses, the exclusion of outlying studies, and trim-and-fill analyses. CONCLUSION The present meta-analysis suggests that SGLT2 inhibition results in reduction of inflammatory markers in animal models, further validating the suggested anti-inflammatory mechanism of action.
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Affiliation(s)
- Panagiotis Theofilis
- 1st Cardiology Department, "Hippokration" General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Marios Sagris
- 1st Cardiology Department, "Hippokration" General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Evangelos Oikonomou
- 1st Cardiology Department, "Hippokration" General Hospital, University of Athens Medical School, 11527 Athens, Greece; 3rd Cardiology Department, "Sotiria" Regional Hospital for Chest Diseases, University of Athens Medical School, 11527 Athens, Greece
| | - Alexios S Antonopoulos
- 1st Cardiology Department, "Hippokration" General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Gerasimos Siasos
- 1st Cardiology Department, "Hippokration" General Hospital, University of Athens Medical School, 11527 Athens, Greece; 3rd Cardiology Department, "Sotiria" Regional Hospital for Chest Diseases, University of Athens Medical School, 11527 Athens, Greece
| | - Konstantinos Tsioufis
- 1st Cardiology Department, "Hippokration" General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Dimitris Tousoulis
- 1st Cardiology Department, "Hippokration" General Hospital, University of Athens Medical School, 11527 Athens, Greece.
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21
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Lu YP, Zhang ZY, Wu HW, Fang LJ, Hu B, Tang C, Zhang YQ, Yin L, Tang DE, Zheng ZH, Zhu T, Dai Y. SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease. J Transl Med 2022; 20:420. [PMID: 36104729 PMCID: PMC9476562 DOI: 10.1186/s12967-022-03629-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 09/07/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. SGLT2 inhibitors are clinically effective in halting DKD progression. However, the underlying mechanisms remain unclear. The serum and kidneys of mice with DKD were analyzed using liquid chromatography with tandem mass spectrometry (LC–MS/MS)-based metabolomic and proteomic analyses. Three groups were established: placebo-treated littermate db/m mice, placebo-treated db/db mice and EMPA-treated db/db mice. Empagliflozin (EMPA) and placebo (10 mg/kg/d) were administered for 12 weeks. EMPA treatment decreased Cys-C and urinary albumin excretion compared with placebo by 78.60% and 57.12%, respectively (p < 0.001 in all cases). Renal glomerular area, interstitial fibrosis and glomerulosclerosis were decreased by 16.47%, 68.50% and 62.82%, respectively (p < 0.05 in all cases). Multi-omic analysis revealed that EMPA treatment altered the protein and metabolic profiles in the db/db group, including 32 renal proteins, 51 serum proteins, 94 renal metabolites and 37 serum metabolites. Five EMPA-related metabolic pathways were identified by integrating proteomic and metabolomic analyses, which are involved in renal purine metabolism; pyrimidine metabolism; tryptophan metabolism; nicotinate and nicotinamide metabolism, and glycine, serine and threonine metabolism in serum. In conclusion, this study demonstrated metabolic reprogramming in mice with DKD. EMPA treatment improved kidney function and morphology by regulating metabolic reprogramming, including regulation of renal reductive stress, alleviation of mitochondrial dysfunction and reduction in renal oxidative stress reaction.
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22
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Tang X, Zhu Y, Guan W, Zhou W, Wei P. Advances in nanosensors for cardiovascular disease detection. Life Sci 2022; 305:120733. [DOI: 10.1016/j.lfs.2022.120733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 06/10/2022] [Accepted: 06/21/2022] [Indexed: 12/25/2022]
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Xie L, Xiao Y, Tai S, Yang H, Zhou S, Zhou Z. Emerging Roles of Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitors in Diabetic Cardiovascular Diseases: Focusing on Immunity, Inflammation and Metabolism. Front Pharmacol 2022; 13:836849. [PMID: 35295328 PMCID: PMC8920092 DOI: 10.3389/fphar.2022.836849] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/07/2022] [Indexed: 11/29/2022] Open
Abstract
Diabetes mellitus (DM) is one of the most fast evolving global issues characterized by hyperglycemia. Patients with diabetes are considered to face with higher risks of adverse cardiovascular events. Those are the main cause of mortality and disability in diabetes patients. There are novel antidiabetic agents that selectively suppress sodium-glucose cotransporter-2 (SGLT-2). They work by reducing proximal tubule glucose reabsorption. Although increasing evidence has shown that SGLT-2 inhibitors can contribute to a series of cardiovascular benefits in diabetic patients, including a reduced incidence of major adverse cardiovascular events and protection of extracardiac organs, the potential mechanisms of SGLT2 inhibitors’ cardiovascular protective effects are still not fully elucidated. Given the important role of inflammation and metabolism in diabetic cardiovascular diseases, this review is intended to rationally compile the multifactorial mechanisms of SGLT-2 inhibitors from the point of immunity, inflammation and metabolism, depicting the fundamental cellular and molecular processing of SGLT-2 inhibitors exerting regulating immunity, inflammation and metabolism. Finally, future directions and perspectives to prevent or delay cardiovascular complications in DM by SGLT-2 inhibitors are presented.
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Affiliation(s)
- Lingxiang Xie
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yang Xiao
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shi Tai
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Huijie Yang
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shenghua Zhou
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
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24
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Targeting Features of the Metabolic Syndrome Through Sympatholytic Effects of SGLT2 Inhibition. Curr Hypertens Rep 2022; 24:67-74. [PMID: 35235172 PMCID: PMC8942945 DOI: 10.1007/s11906-022-01170-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW The moderate glucose-lowering effect of sodium glucose co-transporter 2 (SGLT2) inhibitors is unlikely to explain SGLT2 inhibitor-mediated beneficial outcomes, and unravelling the underlying mechanisms is a high priority in the research community. Given the dominant pathophysiologic role of the sympathetic nervous system activation in conditions such as hypertension and perturbed glucose homeostasis, it is pertinent to postulate that SGLT2 inhibitors may exert their beneficial effects at least in part via sympathetic inhibition. RECENT FINDINGS SGLT2 inhibitors have shown enormous potential to improve cardiovascular outcomes in patients with type 2 diabetes, and their therapeutic potential is currently being investigated in a range of associated comorbidities such as heart failure and chronic kidney disease. Indeed, recent experimental data in relevant animal models highlight a bidirectional interaction between sympathetic nervous system activation and SGLT2 expression, and this facilitates several of the features associated with SGLT2 inhibition observed in clinical trials including improved glucose metabolism, weight loss, increased diuresis, and lowering of blood pressure. Currently available data highlight the various levels of interaction between the sympathetic nervous system and SGLT2 expression and explores the potential for SGLT2 inhibition as a therapeutic strategy in conditions commonly characterised by sympathetic activation.
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Huang D, Ju F, Du L, Liu T, Zuo Y, Abbott GW, Hu Z. Empagliflozin Protects against Pulmonary Ischemia/Reperfusion Injury via an Extracellular Signal-Regulated Kinases 1 and 2-Dependent Mechanism. J Pharmacol Exp Ther 2022; 380:230-241. [PMID: 34893552 DOI: 10.1124/jpet.121.000956] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/06/2021] [Indexed: 02/05/2023] Open
Abstract
Ischemia/reperfusion (I/R) injury of the lung can lead to extensive pulmonary damage. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are insulin-independent, oral antihyperglycemic agents used for treating type 2 diabetes mellitus (T2DM). Although their cardioprotective properties have been reported, their potential roles in pulmonary protection in vivo are poorly characterized. Here, we tested a hypothesis that empagliflozin, an SGLT2 inhibitor, can protect lungs in a mouse model of lung I/R injury induced by pulmonary hilum ligation in vivo. We assigned C57/BL6 mice to sham-operated, nonempagliflozin-treated control, or empagliflozin-treated groups. Pulmonary I/R injury was induced by 1-hour left hilum ligation followed by 2-hour reperfusion. Using quantitative polymerase chain reaction (q-PCR) and Western blot analysis, we demonstrate that SGLT2 is highly expressed in mouse kidney but is weakly expressed in mouse lung (n = 5-6 per group, P < 0.01 or P < 0.001). Empagliflozin improved respiratory function, attenuated I/R-induced lung edema, lessened structural damage, inhibited apoptosis, and reduced inflammatory cytokine production and protein concentration in bronchoalveolar lavage (BAL) fluid [P < 0.05 or P < 0.001 versus control group (CON)]. In addition, empagliflozin enhanced phosphorylation of pulmonary extracellular signal-regulated kinases 1 and 2 (ERK1/2) post-I/R injury in vivo (P < 0.001, versus CON, n = 5 per group). We further showed that pharmacological inhibition of ERK1/2 activity reversed these beneficial effects of empagliflozin. In conclusion, we showed that empagliflozin exerts strong lung protective effects against pulmonary I/R injury in vivo, at least in part via the ERK1/2-mediated signaling pathway. SIGNIFICANCE STATEMENT: Pulmonary ischemia-reperfusion (I/R) can exacerbate lung injury. Empagliflozin is a new antidiabetic agent for type 2 diabetes mellitus. This study shows that empagliflozin attenuates lung damage after pulmonary I/R injury in vivo. This protective phenomenon was mediated at least in part via the extracellular signal-regulated kinases 1 and 2-mediated signaling pathway. This opens a new avenue of research for sodium-glucose cotransporter-2 inhibitors in the treatment of reperfusion-induced acute pulmonary injury.
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Affiliation(s)
- Dou Huang
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Feng Ju
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Lei Du
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Ting Liu
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Yunxia Zuo
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Geoffrey W Abbott
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
| | - Zhaoyang Hu
- Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
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Yang L, Zhang X, Wang Q. Effects and mechanisms of SGLT2 inhibitors on the NLRP3 inflammasome, with a focus on atherosclerosis. Front Endocrinol (Lausanne) 2022; 13:992937. [PMID: 36589841 PMCID: PMC9797675 DOI: 10.3389/fendo.2022.992937] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
Atherosclerosis is a lipid-driven chronic inflammatory disease that is widespread in the walls of large and medium-sized arteries. Its pathogenesis is not fully understood. The currently known pathogenesis includes activation of pro-inflammatory signaling pathways in the body, increased oxidative stress, and increased expression of cytokines/chemokines. In the innate immune response, inflammatory vesicles are an important component with the ability to promote the expression and maturation of inflammatory factors, release large amounts of inflammatory cytokines, trigger a cascade of inflammatory responses, and clear pathogens and damaged cells. Studies in the last few years have demonstrated that NLRP3 inflammatory vesicles play a crucial role in the development of atherosclerosis as well as its complications. Several studies have shown that NLRP3 binding to ligands promotes inflammasome formation, activates caspase-1, and ultimately promotes its maturation and the maturation and production of IL-1β and IL-18. IL-1β and IL-18 are considered to be the two most prominent inflammatory cytokines in the inflammasome that promote the development of atherosclerosis. SGLT2 inhibitors are novel hypoglycemic agents that also have significant antiatherosclerotic effects. However, their exact mechanism is not yet clear. This article is a review of the literature on the effects and mechanisms of SGLT2 inhibitors on the NLRP3 inflammasome, focusing on their role in antiatherosclerosis.
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Heart failure and its treatment from the perspective of sympathetic nerve activity. J Cardiol 2021; 79:691-697. [PMID: 34924233 DOI: 10.1016/j.jjcc.2021.11.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 11/01/2021] [Accepted: 11/10/2021] [Indexed: 12/11/2022]
Abstract
Heart failure is the end-stage phenotype of several cardiac diseases. The number of heart failure patients is increasing in accordance with an increase in the number of elderly people. The prognosis of heart failure is poor and its 5-year death rate is comparable to that of stage III cancer. It is important to understand the essential mechanism of the worsening prognosis of heart failure and to practice effective treatment from the perspective of improving the prognosis of heart failure based on its essential mechanism. Plasma noradrenaline level is a good predictor of the survival rate of heart failure patients, and sympathetic nerve activity is augmented in patients with heart failure as evidenced by a higher noradrenaline release rate (spillover) from the sympathetic nerve endings especially in the heart and kidney. Noradrenaline release is regulated by presynaptic receptors at the sympathetic nerve endings, and the kidney affects the sympathetic nerve activity. Although the short-term reflex augmentation of sympathetic nerve activity caused by reduced cardiac function may help to improve cardiac function, long-term augmentation of sympathetic nerve activity damages the heart and deteriorates the prognosis of heart failure. Currently, drugs such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, mineralocorticoid antagonists, ivabradine, angiotensin receptor-neprilysin inhibitor, and sodium-glucose transport protein 2 inhibitors, are used for the treatment of heart failure, and had a good prognosis in large randomized, controlled clinical trials. Interestingly, the same characteristics in common of these drugs is the ability to optimize excessively augmented sympathetic nerve activity. This review discusses insights into essential mechanism of heart failure that determines the prognosis of heart failure, focusing on the interaction between sympathetic nerve activity and anti-heart failure drugs currently recommended by the 2021 guidelines of the Japanese Circulation Society and the Japanese Heart Failure Society for heart failure treatment.
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