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Felício Macarini A, Bolda Mariano LN, de Cássia Vilhena da Silva R, Corrêa R, de Souza P. Involvement of Cholinergic and Cyclooxygenase Pathways in the Diuretic Effects of Rosmarinic Acid. Chem Biodivers 2025; 22:e202401634. [PMID: 39417798 DOI: 10.1002/cbdv.202401634] [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: 07/06/2024] [Revised: 10/04/2024] [Accepted: 10/17/2024] [Indexed: 10/19/2024]
Abstract
Rosmarinic acid (RA) is a natural antioxidant known for its diverse biological activities. Although its diuretic activity has been previously established, the mode of action remained unclear. To investigate this, we examined the diuretic activity of RA alone and in combination with hydrochlorothiazide (HCTZ), amiloride (AML), atropine (ATR), and indomethacin (INDO) to see if any of these drugs could interfere with RA's activity in an 8 hour acute diuresis animal model. We observed that RA increases urine excretion and may have a synergistic effect in the HCTZ+RA group, with a potassium-sparing capacity. In the AML+RA group, we also noted increased urine excretion while sodium and potassium excretion decreased. ATR and INDO prevented RA from increasing urine excretion, suggesting a potential interaction with muscarinic receptors or a role in promoting prostaglandin production. Additionally, molecular docking analysis indicated possible interactions with key receptors involved in increased diuresis or free-electrolyte water excretion.
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Affiliation(s)
- Anelise Felício Macarini
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, 88302-901 -, Itajaí, Santa Catarina, Brasil
| | - Luísa Nathalia Bolda Mariano
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, 88302-901 -, Itajaí, Santa Catarina, Brasil
| | - Rita de Cássia Vilhena da Silva
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, 88302-901 -, Itajaí, Santa Catarina, Brasil
| | - Rogério Corrêa
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, 88302-901 -, Itajaí, Santa Catarina, Brasil
| | - Priscila de Souza
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, 88302-901 -, Itajaí, Santa Catarina, Brasil
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Ni Y, Du H, Ke L, Zheng L, Nan S, Ni L, Pan Y, Fu Z, He Q, Jin J. Gut-kidney interaction reinforces dapagliflozin-mediated alleviation in diabetic nephropathy. Am J Physiol Cell Physiol 2025; 328:C452-C466. [PMID: 39740794 DOI: 10.1152/ajpcell.00651.2024] [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: 09/06/2024] [Revised: 12/02/2024] [Accepted: 12/18/2024] [Indexed: 01/02/2025]
Abstract
Intestinal microbiota are pathophysiologically involved in diabetic nephropathy (DN). Dapagliflozin, recognized for its blood glucose-lowering effect, has demonstrated efficacy in improving DN. However, the mechanisms beyond glycemic control that mediate the impact of dapagliflozin on DN remain unclear. Here, we investigated the effects of dapagliflozin on DN and gut microbiota, elucidating how it mitigates DN via the gut-kidney axis. Low-dose dapagliflozin markedly ameliorated renal inflammation and fibrosis and improved gut barrier function in high-fat diet (HFD)/streptozotocin (STZ)-induced DN mice and db/db mice without affecting blood glucose levels. These effects were associated with altered gut microbial composition and function. Eradication of the resident microbiota abolished the protective effects of dapagliflozin against kidney injury in DN mice. Moreover, dapagliflozin significantly altered microbial metabolites in DN mice, decreasing argininosuccinic acid (ASA) and palmitic acid (PA), while increasing S-allylcysteine (SAC) levels. ASA and PA increased the expression of renal inflammation- and fibrosis-related markers in HK-2 cells, whereas SAC ameliorated renal damage and altered the microbial composition in a manner similar to dapagliflozin in DN mice. Notably, Muribaculaceae and Desulfovibrionaceae were correlated with the alleviation of DN-associated renal dysfunction by low- and high-dose dapagliflozin treatments in DN mice. These findings demonstrate a potential application of dapagliflozin in managing DN by targeting the gut microbiota.NEW & NOTEWORTHY We demonstrated that dapagliflozin administration alleviated renal inflammation and fibrosis in vivo and in vitro, along with reshaping the gut microbiota composition and altering levels of key microbial metabolites, including argininosuccinic acid (ASA) and palmitic acid (PA), while increasing S-allylcysteine (SAC). Importantly, the genera Muribaculaceae and Desulfovibrionaceae emerged as pivotal microbial genera mediating the protective effects of dapagliflozin against diabetic nephropathy.
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Affiliation(s)
- Yinhua Ni
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Haimei Du
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Lehui Ke
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Liujie Zheng
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Sujie Nan
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Liyang Ni
- Laboratory of Food Biochemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Yuxiang Pan
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Zhengwei Fu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Qiang He
- Department of Nephrology, First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Research and Translation for Kidney Deficiency-Stasis-Turbidity Disease, Hangzhou, Zhejiang, China
| | - Juan Jin
- Department of Nephrology, First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Research and Translation for Kidney Deficiency-Stasis-Turbidity Disease, Hangzhou, Zhejiang, China
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Mariscal de Gante L, Salanova L, Valdivia Mazeyra M, Serrano Pardo R, Quiroga B. Secondary hyperoxaluria: Cause and consequence of chronic kidney disease. Nefrologia 2025; 45:5-14. [PMID: 39800598 DOI: 10.1016/j.nefroe.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 06/08/2024] [Indexed: 02/01/2025] Open
Abstract
Secondary hyperoxaluria is a metabolic disorder characterized by an increase in urinary oxalate excretion. The etiology may arise from an increase in the intake of oxalate or its precursors, decreased elimination at the digestive level, or heightened renal excretion. Recently, the role of the SLC26A6 transporter in the etiopathogenesis of this disease has been identified. This transporter is active at both the intestinal and renal levels, and its mechanism of action is disrupted during systemic inflammation and metabolic syndrome, which could explain the rising incidence of secondary hyperoxaluria in recent decades. Treatment includes hygienic dietary measures, and medications aimed at reducing intestinal absorption by increasing fecal excretion. Different immunomodulatory drugs, microbiome modifiers and SGLT2 inhibitors could constitute new therapeutic targets. Currently, specific treatments for secondary hyperoxaluria are lacking, making early diagnosis and preventive measures against kidney failure the main therapeutic strategies.
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Affiliation(s)
| | - Laura Salanova
- Servicio de Nefrología, Hospital Universitario de la Princesa, Madrid, Spain
| | | | - Rosario Serrano Pardo
- Servicio de Anatomía Patológica, Hospital Universitario de la Princesa, Madrid, Spain
| | - Borja Quiroga
- Servicio de Nefrología, Hospital Universitario de la Princesa, Madrid, Spain.
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Aydemir S, Aydın SŞ, Aksakal E, Altınkaya O, Özmen M, Birdal O. Effect of sodium glucose cotransporter-2 inhibitors (SGLT-2is) on the clinical outcomes of patients with diabetic atrial fibrillation. BMC Cardiovasc Disord 2024; 24:760. [PMID: 39736518 DOI: 10.1186/s12872-024-04454-1] [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: 09/13/2024] [Accepted: 12/26/2024] [Indexed: 01/01/2025] Open
Abstract
BACKGROUND Diabetes mellitus (DM) and atrial Fibrillation (AF) are among the most common health issues. They are responsible for the highest rates of morbidity and mortality. The importance of sodium glucose cotransporter-2 inhibitors (SGLT-2is) in treating DM has increased significantly in recent years. In our article, we aimed to evaluate the effect of SGLT-2i on the clinical outcomes of AF patients with DM. METHODS Our study is a retrospective, observational study. The patients with AF and DM were divided into two groups: those using SGLT-2i or not using SGLT-2i, and 3-year follow-up results were examined. The endpoints of the study were defined as all-cause death, the development of myocardial infarction (MI), major bleeding requiring hospitalization, and an ischemic cerebrovascular event (CVE). Differences between groups according to SGLT-2i use were analyzed. RESULTS The study included 485 patients, 205 (42.3%) of whom were male and had an average age of 70.7 ± 9.7 years. A total of 138 of 485 patients (28.5%) received SGLT-2i. All-cause mortality was lower in the group receiving SGLT-2i (p < 0.001). Similarly, a significant reduction in major bleeding events was observed among those who received SGLT-2i treatment (p = 0.009). The incidence of CVEs was lower among SGLT-2i recipients, but the difference was not statistically significant (p = 0.066). SGLT2i usage did not mitigate the risk of MI development (p = 0.317). CONCLUSIONS In our study, SGLT-2i treatment was associated with a significant reduction in all-cause mortality and major bleeding in diabetic AF patients. Our study provides evidence of the clinical benefit of SGLT-2i in AF patients.
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Affiliation(s)
- Selim Aydemir
- Department of Cardiology, University of Health Sciences, Erzurum City Hospital, Erzurum, Turkey.
| | - Sidar Şiyar Aydın
- Department of Cardiology, Atatürk University Faculty of Medicine, Erzurum, Turkey
| | - Emrah Aksakal
- Department of Cardiology, University of Health Sciences, Erzurum City Hospital, Erzurum, Turkey
| | - Onur Altınkaya
- Department of Cardiology, University of Health Sciences, Erzurum City Hospital, Erzurum, Turkey
| | - Murat Özmen
- Department of Cardiology, University of Health Sciences, Erzurum City Hospital, Erzurum, Turkey
| | - Oğuzhan Birdal
- Department of Cardiology, Atatürk University Faculty of Medicine, Erzurum, Turkey
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Meybodi SMM, Karimi MA, Mousazadeh K, Khorsand K, Masoumi S, Pakmehr SA, Asadi Anar M, Samadi N, Poudineh M, Rahmanian M, Yaghoobpoor S, Rahimi A, Arbab Mojeni F, Banihashemian SZ, Masoodi M, Aghazadeh-Habashi K, Ghorbani A, Faridzadeh A, Deravi N. The influence of SGLT-2 inhibitors on lipid profiles in heart failure patients: a systematic review and meta-analysis. AMERICAN JOURNAL OF CARDIOVASCULAR DISEASE 2024; 14:295-305. [PMID: 39839562 PMCID: PMC11744213 DOI: 10.62347/aapz2726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 08/29/2024] [Indexed: 01/23/2025]
Abstract
BACKGROUND AND AIM Sodium-glucose cotransporter two inhibitors can reduce cardiovascular events by modulating lipid profiles in patients with heart failure, irrespective of diabetes status. In this study, we aimed to assess the effects of SGLT-2 inhibitors on the lipid profiles of patients with heart failure via a meta-analysis. METHODS The PubMed, Scopus, Web of Science, and Google Scholar databases were searched up to 2023 to retrieve relevant article titles, abstracts, and full texts. STATA software was used to conduct the meta-analysis. RESULT The Forest plot of fasting blood sugar levels in patients receiving SGLT-2 inhibitors differed significantly from those the in control group (mean difference = -0.08, 95% CI [-0.13, -0.02], P < 0.05). Analysis of lipid profile parameters, including total cholesterol, triglyceride, HDL, and LDL in patients with HF receiving SGLT-2 inhibitors, did not show a notable difference from the control group (P > 0.005). However, the mean difference was towards the reduction of LDL, cholesterol, and triglycerides and showed an increase in HDL levels. Egger's test for publication bias revealed some publication bias (P < 0.05). CONCLUSION Our topic analysis did not reveal any notable alterations in the lipid profile. To arrive at a more definite agreement, further research on subjects with heart failure is necessary because there is currently insufficient evidence.
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Affiliation(s)
- Seyed Mohammad Mahdi Meybodi
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN)Tehran, Iran
- Young Researchers and Elite Club, Islamic Azad UniversityTabriz Branch, Tabriz, Iran
| | | | | | | | - Samira Masoumi
- Islamic Azad University, Pharmaceutical Sciences Branch (IAUPS)Tehran, Iran
| | | | - Mahsa Asadi Anar
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical SciencesTehran, Iran
| | - Nahid Samadi
- Student Research Committee, Health Research Institute, Babol University of Medical SciencesBabol, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical SciencesZanjan, Iran
| | - Mohammad Rahmanian
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical SciencesTehran, Iran
| | - Shirin Yaghoobpoor
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical SciencesTehran, Iran
| | - Arash Rahimi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical SciencesTehran, Iran
| | - Fariba Arbab Mojeni
- Student Research Committee, School of Medicine, Mazandaran University of Medical SciencesSari, Iran
| | | | - Mina Masoodi
- Faculty of Medicine, Islamic Azad UniversityShahrood Branch, Shahrood, Iran
| | | | - Atousa Ghorbani
- Department of Biology, Faculty of Basic Sciences, Islamic Azad University, East Tehran Branch (Ghiamdasht)Tehran, Iran
| | - Arezoo Faridzadeh
- Department of Immunology and Allergy, School of Medicine, Mashhad University of Medical SciencesMashhad, Iran
- Immunology Research Center, Mashhad University of Medical SciencesMashhad, Iran
| | - Niloofar Deravi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical SciencesTehran, Iran
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Wo E, Trulli C, Wilczynski J, Gonzalez J. Evaluation of Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitor Prescribing Patterns in Heart Failure Patients at Hospital Discharge. J Pharm Pract 2024; 37:1318-1324. [PMID: 38803216 DOI: 10.1177/08971900241256772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) dapagliflozin and empagliflozin are indicated for heart failure with reduced ejection fraction (HFrEF) for cardiovascular death and heart failure hospitalization risk reduction. Due to the recent nature of these data, prescribing of SGLT2is may be suboptimal. Objective: This study sought to assess the prevalence of SGLT2i prescriptions at hospital discharge for HFrEF. Methods: A retrospective chart review was conducted on HFrEF patients discharged from April 1st to December 31st, 2021 from one academic medical center in the United States. The primary objective was to determine the percentage of eligible patients prescribed SGLT2i at discharge and the secondary objective was to characterize covariates impacting prescription. Results: Overall, 115 patients were included. The mean age was 72 ± 14.25 years. The majority were male (73.9%) and Caucasian (74.8%). At discharge, 15.7% of patients were prescribed an SGLT2i, although 94.8% were eligible. Baseline characteristics and concomitant medications did not differ significantly, although the mean number of discharge medications differed significantly between those prescribed an SGLT2i (15.78 ± 6.77) and those not (12.05 ± 5.28) (P = 0.023). Conclusions: SGLT2is are under-prescribed at discharge for HFrEF patients, despite many being eligible. Further studies should be done to elucidate factors that influence the under-prescription of SGLT2is.
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Affiliation(s)
- Emily Wo
- Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA
| | | | - Jessica Wilczynski
- Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA
- Department of Pharmacy, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Jimmy Gonzalez
- Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA
- Department of Pharmacy, Jersey Shore University Medical Center, Neptune, NJ, USA
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7
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Alsereidi FR, Khashim Z, Marzook H, Al-Rawi AM, Salomon T, Almansoori MK, Madkour MM, Hamam AM, Ramadan MM, Peterson QP, Saleh MA. Dapagliflozin mitigates cellular stress and inflammation through PI3K/AKT pathway modulation in cardiomyocytes, aortic endothelial cells, and stem cell-derived β cells. Cardiovasc Diabetol 2024; 23:388. [PMID: 39472869 PMCID: PMC11520772 DOI: 10.1186/s12933-024-02481-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 10/21/2024] [Indexed: 11/02/2024] Open
Abstract
Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is well-recognized for its therapeutic benefits in type 2 diabetes (T2D) and cardiovascular diseases. In this comprehensive in vitro study, we investigated DAPA's effects on cardiomyocytes, aortic endothelial cells (AECs), and stem cell-derived beta cells (SC-β), focusing on its impact on hypertrophy, inflammation, and cellular stress. Our results demonstrate that DAPA effectively attenuates isoproterenol (ISO)-induced hypertrophy in cardiomyocytes, reducing cell size and improving cellular structure. Mechanistically, DAPA mitigates reactive oxygen species (ROS) production and inflammation by activating the AKT pathway, which influences downstream markers of fibrosis, hypertrophy, and inflammation. Additionally, DAPA's modulation of SGLT2, the Na+/H + exchanger 1 (NHE1), and glucose transporter (GLUT 1) type 1 highlights its critical role in maintaining cellular ion balance and glucose metabolism, providing insights into its cardioprotective mechanisms. In aortic endothelial cells (AECs), DAPA exhibited notable anti-inflammatory properties by restoring AKT and phosphoinositide 3-kinase (PI3K) expression, enhancing mitogen-activated protein kinase (MAPK) activation, and downregulating inflammatory cytokines at both the gene and protein levels. Furthermore, DAPA alleviated tumor necrosis factor (TNFα)-induced inflammation and stress responses while enhancing endothelial nitric oxide synthase (eNOS) expression, suggesting its potential to preserve vascular function and improve endothelial health. Investigating SC-β cells, we found that DAPA enhances insulin functionality without altering cell identity, indicating potential benefits for diabetes management. DAPA also upregulated MAFA, PI3K, and NRF2 expression, positively influencing β-cell function and stress response. Additionally, it attenuated NLRP3 activation in inflammation and reduced NHE1 and glucose-regulated protein GRP78 expression, offering novel insights into its anti-inflammatory and stress-modulating effects. Overall, our findings elucidate the multifaceted therapeutic potential of DAPA across various cellular models, emphasizing its role in mitigating hypertrophy, inflammation, and cellular stress through the activation of the AKT pathway and other signaling cascades. These mechanisms may not only contribute to enhanced cardiac and endothelial function but also underscore DAPA's potential to address metabolic dysregulation in T2D.
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Affiliation(s)
- Fatmah R Alsereidi
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Emirates Health Services (EHS), Dubai, United Arab Emirates
| | - Zenith Khashim
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Hezlin Marzook
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Ahmed M Al-Rawi
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Tiana Salomon
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Mahra K Almansoori
- College of Medicine and Health Sciences, United Arab Emirates University, Abu Dhabi, United Arab Emirates
| | - Moustafa M Madkour
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Ahmed Mohamed Hamam
- Endocrinology and Metabolism Department, Armed Forces College of Medicine, Cairo, Egypt
| | - Mahmoud M Ramadan
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Department of Cardiology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Quinn P Peterson
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
| | - Mohamed A Saleh
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
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Hershenson R, Nardi-Agmon I, Leshem-Lev D, Kornowski R, Eisen A. The effect of empagliflozin on circulating endothelial progenitor cells in patients with diabetes and stable coronary artery disease. Cardiovasc Diabetol 2024; 23:386. [PMID: 39468546 PMCID: PMC11520434 DOI: 10.1186/s12933-024-02466-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/10/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is associated with premature atherosclerotic disease, coronary artery disease (CAD) and chronic heart failure (HF), leading to increased morbidity and mortality. Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2i) exhibit cardioprotective benefits beyond glucose lowering, reducing the risk of major cardiovascular events (MACE) and HF hospitalizations in patients with DM and CAD. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in vascular repair, mobilized in response to vascular injury. The number and function of circulating EPCs (cEPCs) are negatively affected by cardiovascular risk factors, including DM. This study aimed to examine the response of cEPCs to SGLT2i treatment in DM patients with stable CAD. METHODS A prospective single-center study included patients with DM and stable CAD who were started on an SGLT2i (empagliflozin). Peripheral blood samples were collected at baseline, 1 month, and 3 months to evaluate cEPC levels and function by flow cytometry, immunohistochemistry and MTT assays. RESULTS Eighteen patients were included in the study (median age 73, (IQR 69, 77) years, 67% male). After 1 month of treatment with empagliflozin, there was no significant change in cEPCs level or function. However, following 3 months of treatment, a significant increase was observed both in cell levels (CD34(+)/VEGFR-2(+): from 0.49% (IQR 0.32, 0.64) to 1.58% (IQR 0.93, 1.82), p = 0.0006; CD133(+)/VEGFR-2(+): from 0.38% (IQR 0.27, 0.6) to 0.82% (IQR 0.7, 1.95), p = 0.0001) and in cell function (from 0.25 CFUs (IQR 0, 0.5) at baseline, to 2 CFUs (IQR 1, 2) at 3 months, p = 0.0012). CONCLUSIONS Empagliflozin treatment in patients with DM and stable CAD increases cEPC levels and function, implying a cardioprotective mechanism. These findings highlight the potential of SGLT2i in treating cardiovascular diseases, warranting further research to explore these effects and their long-term implications.
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Affiliation(s)
- Roy Hershenson
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel.
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Inbar Nardi-Agmon
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel
| | - Dorit Leshem-Lev
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel
| | - Ran Kornowski
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Alon Eisen
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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9
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Yu Z, Lu Y, Zhang M, Lin Y, Wong TS, Guan B, Meng Y, Hu B, Liu FN, Yin L, Li Y, Zhang H, Tang D, Dai Y. Mechanism of the cardioprotective effect of empagliflozin on diabetic nephropathy mice based on the basis of proteomics. Proteome Sci 2024; 22:9. [PMID: 39427190 PMCID: PMC11490188 DOI: 10.1186/s12953-024-00232-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 09/23/2024] [Indexed: 10/21/2024] Open
Abstract
Diabetic nephropathy affects a significant proportion of individuals with diabetes, and its progression often leads to cardiovascular disease and infections before the need for renal replacement therapy arises. Empagliflozin has been shown to have various protective effects in cardiovascular disease studies, such as improving diabetic myocardial structure and function, and reducing myocardial oxidative stress. However, the impact of empagliflozin on cardiac protein expression and signaling pathways has not been comprehensively analyzed. To address this gap, we conducted proteome analysis to identify specific protein markers in cardiac tissue from the diabetes model group, including Myh7, Wdr37, Eif3k, Acot1, Acot2, Cat, and Scp2, in cardiac tissue from the diabetes model group. In our drug model, empagliflozin primarily modulates the fat-related metabolic signaling pathway within the heart. Empagliflozin downregulated the protein expression levels of ACOX1, ACADVL and CPT1A in the model group. Overall, our findings demonstrate that empagliflozin provides cardiac protection by targeting metabolic signaling pathways, particularly those related to fat metabolism. Moreover, the identification of cardiac biomarkers in a mouse model of diabetic nephropathy lays the foundation for further exploration of disease biomarkers in cardiac tissue.
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Affiliation(s)
- Zongchao Yu
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yongping Lu
- Department of Nephrology, Center of Kidney and Urology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Mengxian Zhang
- Department of Internal Medicine, Humen Hospital, Dongguan City, Guangdong Province, China
| | - Yanshan Lin
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Tak-Sui Wong
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Baozhang Guan
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yu Meng
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Bo Hu
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Fan-Na Liu
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Lianghong Yin
- Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yankun Li
- Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, China
| | - Han Zhang
- Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, China.
| | - Donge Tang
- Clinical Medical Research Center, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, 518020, China.
| | - Yong Dai
- The First Affiliated Hospital, School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, China.
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10
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Pasqualotto E, Rodrigues FR, E Silva Ribeiro GB, de Oliveira Almeida G, Kabariti JC, Ferreira ROM, Chavez MP, Clemente MRC, Sur NB, Di Luca DG. The effect of sodium-glucose transporter 2 inhibitors on stroke in patients with type 2 diabetes: A meta-analysis. J Stroke Cerebrovasc Dis 2024; 33:107730. [PMID: 38679214 DOI: 10.1016/j.jstrokecerebrovasdis.2024.107730] [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: 03/06/2024] [Revised: 04/17/2024] [Accepted: 04/21/2024] [Indexed: 05/01/2024] Open
Abstract
OBJECTIVES To provide an update on the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on stroke in patients with type 2 diabetes (T2D). METHODS PubMed, Embase, and Cochrane Library were systematically searched for randomized controlled trials (RCTs) comparing SGLT2 inhibitors versus placebo or other therapies in patients with T2D and reporting stroke endpoint. We computed the risk ratios (RRs) to binary endpoints, with 95 % confidence intervals (CIs). RESULTS A total of 71 RCTs and 105,914 patients were included, of whom 62,488 (59 %) were randomized to the SGLT2 inhibitors group. The follow-up ranged from 12 weeks to 4.2 years. There were no significant differences between groups in all types of stroke (RR 0.96; 95 % CI 0.89-1.04), ischemic stroke (RR 0.89; 95 % CI 0.76-1.04), and transient ischemic attack (RR 0.96; 95 % CI 0.79-1.16). Patients on SGLT2 inhibitors experienced lower rates of hemorrhagic stroke (RR 0.62; 95 % CI 0.39-0.98). In the subgroup analysis of the type of drug, sotagliflozin significantly reduced all types of stroke (RR 0.74; 95 % CI 0.56-0.97). CONCLUSION In this meta-analysis of 71 RCTs comprising 105,914 patients with T2D, SGLT2 inhibitors were not associated with a reduced risk of stroke and transient ischemic attack compared to placebo or other therapies; however, there was a trend toward reduced risk of hemorrhagic stroke. Among all SGLT2 inhibitors, sotagliflozin significantly reduced the risk of stroke.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Nicole B Sur
- Department of Neurology, University of Miami Miller School of Medicine, USA.
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11
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Tanashat M, Manasrah A, Abouzid M. Effects of dapagliflozin and empagliflozin on 6-min walk distance in heart failure with preserved and reduced ejection fraction: A systematic review and meta-analysis of randomized controlled trials involving 2624 patients. Eur J Clin Pharmacol 2024; 80:951-963. [PMID: 38498097 DOI: 10.1007/s00228-024-03660-2] [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: 01/05/2024] [Accepted: 02/25/2024] [Indexed: 03/20/2024]
Abstract
BACKGROUND Dapagliflozin and empagliflozin are antidiabetic medications. They are the first two sodium-glucose cotransporter-2 inhibitors (SGLT2i) to receive the US Food and Drug Administration approval to manage heart failure. Emerging new trials have examined changes in the 6-min walk distance as a clinically significant response to dapagliflozin and empagliflozin in patients with heart failure with reduced ejection fraction (HFpEF) and heart failure with preserved ejection fraction (HFrEF). This meta-analysis aims to evaluate the effects of dapagliflozin and empagliflozin on the 6-min walk distance in patients with HFpEF and HFrEF. To our knowledge, no such meta-analysis has been published. METHODS Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched four electronic databases (PubMed, EMBASE, Cochrane Library, and Web of Science) to identify eligible studies reported up to December 16, 2023. Using Review Manager software, we reported outcomes as risk ratios (RRs) or mean difference (MD) and confidence intervals (CIs). A p-value ≤ 0.05 is considered as statistically significant. RESULTS The meta-analysis included a total of 8 studies with 2624 patients. Overall, the results showed insignificant differences in the 6-min walk between the SGLT2i and placebo (MD 24, 95% CI -0.30 to 18.78, p = 0.06). Results became significant after resolving the heterogeneity (MD 6.72, 95% CI 0.13 to 13.31, p = 0.05). Notably, the results of each drug separately were insignificant. More robust observations occurred in the HFpEF group (MD 10.73, 95% CI 1.08 to 20.39, p = 0.03). Compared to placebo, patients on dapagliflozin reported significant improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary (KCCQ-CS) and Overall Summary (KCCQ-OS) with values of MD 5.18 (95% CI 2.80 to 7.57, p < 0.0001) and MD 4.06 (95% CI 1.66 to 6.46, p = 0.0009), respectively. The dapagliflozin group and patients with HFpEF had reported a significant reduction in their weight compared with the control group (MD -0.59 CI -1.09 to -0.08, p = 0.02) and (MD -0.80 CI -1.47 to -0.13, p = 0.02), respectively. No significant side effects were observed for dapagliflozin or empagliflozin. CONCLUSION Patients with HFpEF experienced benefits from SGLT2i administration, as evidenced by improved 6-min walk distances and weight reduction. Dapagliflozin demonstrated clinical and overall improvements in KCCQ scores and was more effective in reducing weight than the placebo. Both Dapagliflozin and Empagliflozin were well-tolerated and exhibited favorable safety profiles. Future studies could benefit from a larger patient population, a longer follow-up period, and a broader range of SGLT2i.
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Affiliation(s)
| | | | - Mohamed Abouzid
- Department of Physical Pharmacy and Pharmacokinetics, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3 St, 60-806, Poznan, Poland.
- Doctoral School, Poznan University of Medical Sciences, 60-812, Poznan, Poland.
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12
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Gami A, Blumenthal RS, McGuire DK, Sarkar S, Kohli P. New Perspectives in Management of Cardiovascular Risk Among People With Diabetes. J Am Heart Assoc 2024; 13:e034053. [PMID: 38879449 PMCID: PMC11255726 DOI: 10.1161/jaha.123.034053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/19/2024]
Abstract
Following the publication of results from multiple landmark cardiovascular outcome trials of antihyperglycemic medications over the past 8 years, there has been a major shift in the focus of care for people with type 2 diabetes, from control of hyperglycemia to managing cardiovascular risk. Multiple international cardiology and diabetes society guidelines and recommendations now endorse sodium-glucose cotransporter-2 inhibitors and glucagon-like protein-1 receptor agonists as first-line therapies to mitigate cardiovascular risk. The most recent publication is the 2023 European Society of Cardiology guideline on the management of cardiovascular disease in those with type 2 diabetes that, for the first time, recommends use of both classes of medications for the mitigation of cardiovascular risk for those with or at high risk for atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. Here, we review the evidence behind contemporary society guidelines and recommendations for the management of type 2 diabetes and cardiovascular risk.
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Affiliation(s)
- Abhishek Gami
- Department of Internal MedicineJohns Hopkins University School of MedicineBaltimoreMD
| | - Roger S. Blumenthal
- Division of CardiologyJohns Hopkins University School of MedicineBaltimoreMD
| | - Darren K. McGuire
- Division of Cardiology, Department of Internal MedicineUniversity of Texas Southwestern Medical Center and Parkland HealthDallasTX
| | - Sudipa Sarkar
- Division of Endocrinology, Diabetes, and MetabolismJohns Hopkins University School of MedicineBaltimoreMD
| | - Payal Kohli
- Department of CardiologyUniversity of Colorado AnschutzAuroraCO
- Department of CardiologyVeterans Affairs HospitalAuroraCO
- Cherry Creek HeartAuroraCO
- Tegna BroadcastingAuroraCO
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13
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Khakhar Z, Manji S, Patel RK, Ali SK. Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors and the Risk of Pancreatitis: A Case Report. Cureus 2024; 16:e62957. [PMID: 39044894 PMCID: PMC11265328 DOI: 10.7759/cureus.62957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2024] [Indexed: 07/25/2024] Open
Abstract
Acute pancreatitis is a condition seldom encountered with the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors. They are beneficial in the treatment of various conditions and offer great promise. Despite this, they are associated with several adverse effects, necessitating vigilance and further research. This case study reports a 69-year-old male with multiple comorbidities who presented with epigastric pain radiating to the back. Laboratory tests revealed elevated AST, ALT, GGT and lipase. The patient was diagnosed with acute pancreatitis secondary to the SGLT2 inhibitor therapy regimen. Cessation of dapagliflozin resulted in a complete resolution of symptoms. There is credible evidence to suggest the presence of an association between SGLT2 inhibitors and acute pancreatitis, although extensive research is warranted to consolidate this association.
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Affiliation(s)
| | - Soraiya Manji
- Department of Internal Medicine, Aga Khan University Hospital, Nairobi, KEN
| | - Ronak Kumar Patel
- Department of Internal Medicine, Aga Khan University Hospital, Nairobi, KEN
| | - Sayed K Ali
- Department of Internal Medicine, Aga Khan University Hospital, Nairobi, KEN
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14
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Antwi-Amoabeng D, Beutler BD, Ghuman J, Ulanja MB, Ghuman J, Gullapalli N. Sociodemographic Disparities in Sodium-Glucose Co-Transporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists Prescription Patterns Among Patients With Poorly Controlled Diabetes. Cureus 2024; 16:e56845. [PMID: 38659524 PMCID: PMC11039430 DOI: 10.7759/cureus.56845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2024] [Indexed: 04/26/2024] Open
Abstract
Introduction Sodium-glucose co-transporter-2 inhibitors (SGLT2Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are novel antihyperglycemic agents that reduce cardiovascular mortality through insulin-independent mechanisms. In this cross-sectional study, we investigated prescription patterns of these drugs and identified inequities in antihyperglycemic utilization. Methods Unique encounters for diabetes care between January 1, 2020, and December 31, 2020, were identified through a systematic query of our healthcare system's database. All patients ≥18 years old with a hemoglobin A1C level of ≥8% were included in the sample. Demographic data, SGLT2I or GLP-1RA prescription status, diabetes-related complications, and mortality were abstracted. Results A total of 2,746 patients were included in the sample. Among these individuals, 670 (24.4%) were prescribed either an SGLT2I or a GLP-1RA (users) and 2,076 (75.6%) were not prescribed either agent (non-users). There were significantly more males than females in the cohort, but there was no significant difference in the sex distribution between users and non-users. Compared to non-users, users were younger (mean age of 65.1 ± 9.4 years versus 66.4 ± 9.9 years, p-value = 0.005), more likely to be non-Hispanic (86.3% versus 13.7%), more likely to live in a middle-income zip code, and have private insurance. The mortality rate was lower among users when compared to non-users, but the difference did not reach statistical significance (2.7% versus 5.5%, p-value = 0.62). SGLT2I use was associated with a 60% lower risk of mortality. Conclusion Ethnicity, median household income, and insurance type influence the likelihood of being prescribed an SGLT2I or a GLP-1RA. Individuals prescribed either agent appear to have better mortality outcomes than those prescribed other medications. Further investigation may reveal underlying causes and potential solutions for disparities in prescription patterns.
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Affiliation(s)
| | - Bryce D Beutler
- Radiology, University of Southern California Keck School of Medicine, Los Angeles, USA
| | - Jasmine Ghuman
- Internal Medicine, University of Nevada Reno School of Medicine, Reno, USA
| | - Mark B Ulanja
- Internal Medicine, Christus Ochsner St. Patrick Hospital, Lake Charles, USA
| | - Joban Ghuman
- Internal Medicine, University of Nevada Reno School of Medicine, Reno, USA
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15
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Gao X, Zhang N, Lu L, Gao T, Chou OHI, Wong WT, Chang C, Wai AKC, Lip GYH, Zhang Q, Tse G, Liu T, Zhou J. New-onset syncope in diabetic patients treated with sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors: a Chinese population-based cohort study. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2024; 10:103-117. [PMID: 37962962 DOI: 10.1093/ehjcvp/pvad086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/17/2023] [Accepted: 11/11/2023] [Indexed: 11/16/2023]
Abstract
BACKGROUND AND AIMS Syncope is a symptom that poses an important diagnostic and therapeutic challenge, and generates significant cost for the healthcare system. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated beneficial cardiovascular effects, but their possible effects on incident syncope have not been fully investigated. This study compared the effects of SGLT2i and dipeptidyl peptidase-4 inhibitors (DPP4i) on new-onset syncope. METHODS AND RESULTS This was a retrospective, territory-wide cohort study enrolling type 2 diabetes mellitus (T2DM) patients treated with SGLT2i or DPP4i between 1 January 2015 and 31 December 2020, in Hong Kong, China. The outcomes were hospitalization of new-onset syncope, cardiovascular mortality, and all-cause mortality. Multivariable Cox regression and different approaches using the propensity score were applied to evaluate the association between SGLT2i and DPP4i with incident syncope and mortality. After matching, a total of 37 502 patients with T2DM were included (18 751 SGLT2i users vs. 18 751 DPP4i users). During a median follow-up of 5.56 years, 907 patients were hospitalized for new-onset syncope (2.41%), and 2346 patients died from any cause (6.26%), among which 471 deaths (1.26%) were associated with cardiovascular causes. Compared with DPP4i users, SGLT2i therapy was associated with a 51% lower risk of new-onset syncope [HR 0.49; 95% confidence interval (CI) 0.41-0.57; P < 0.001], 65% lower risk of cardiovascular mortality (HR 0.35; 95% CI 0.26-0.46; P < 0.001), and a 70% lower risk of all-cause mortality (HR 0.30; 95% CI 0.26-0.34; P < 0.001) in the fully adjusted model. Similar associations with syncope were observed for dapagliflozin (HR 0.70; 95% CI 0.58-0.85; P < 0.001), canagliflozin (HR 0.48; 95% CI 0.36-0.63; P < 0.001), and ertugliflozin (HR 0.45; 95% CI 0.30-0.68; P < 0.001), but were attenuated for empagliflozin (HR 0.79; 95% CI 0.59-1.05; P = 0.100) after adjusting for potential confounders. The subgroup analyses suggested that, compared with DPP4i, SGLT2i was associated with a significantly decreased risk of incident syncope among T2DM patients, regardless of gender, age, glucose control status, Charlson comorbidity index, and the association remained constant amongst those with common cardiovascular drugs and most antidiabetic drugs at baseline. CONCLUSION Compared with DPP4i, SGLT2i was associated with a significantly lower risk of new-onset syncope in patients with T2DM, regardless of gender, age, degree of glycaemic control, and comorbidity burden.
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Affiliation(s)
- Xinyi Gao
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Nan Zhang
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Lei Lu
- Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford, UK
| | - Tianyu Gao
- School of Physical Education, Jinan University, Guangzhou, China
| | - Oscar Hou In Chou
- Department of Medicine, Division of Clinical Pharmacology and Therapeutics, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
- Diabetes Research Unit, Cardiovascular Analytics Group, PowerHealth Limited, Hong Kong, China
| | - Wing Tak Wong
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Carlin Chang
- Department of Medicine, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Abraham Ka Chung Wai
- Emergency Medicine Unit, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Sciences, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Qingpeng Zhang
- Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, and the Musketeers Foundation Institute of Data Science, University of Hong Kong, Hong Kong, China
| | - Gary Tse
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
- School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong, China
| | - Tong Liu
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Jiandong Zhou
- Department of Family Medicine and Primary Care, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Division of Health Science, Warwick Medical School, University of Warwick, Coventry, UK
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16
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Shoaib A, Shahid S, Mansoor S, Javed M, Iqbal S, Mahmood S, Bahadur A, Jaber F, Alshalwi M. Tailoring of an anti-diabetic drug empagliflozin onto zinc oxide nanoparticles: characterization and in vitro evaluation of anti-hyperglycemic potential. Sci Rep 2024; 14:2499. [PMID: 38291095 PMCID: PMC10827742 DOI: 10.1038/s41598-024-52523-4] [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: 11/06/2023] [Accepted: 01/19/2024] [Indexed: 02/01/2024] Open
Abstract
Diabetes is a serious health issue that can be a great risk factor related to numerous physical problems. A class of drugs "Gliflozin" especially Sodium Glucose Co. Transporter 2 was inhibited by a novel drug, which is known as "empagliflozin". While ZnO nanoparticles (NPs) had considerable promise for combating diabetes, it was employed in the treatment and management of type-2 diabetes mellitus. The new drug empagliflozin was initially incorporated into Zinc Oxide NPs in this study using the surface physio-sorption technique, and the degree of drug adsorption was assessed using the HPLC method. The tailored product was characterized by using the FTIR, EDX, Ultraviolet-Visible, XRD and SEM techniques. With an average particle size of 17 nm, SEM revealed mono-dispersion of NPs and sphere-like form. The Freundlich isotherm model best fits and explains the data for the physio-sorption investigation, which examined adsorption capabilities using adsorption isotherms. The enzymes α-amylase and α-glucosidase, which are involved in the human metabolism of carbohydrates, were used in the in-vitro anti-diabetic assays. It was discovered that the composite showed the highest levels of 81.72 and 92.77% inhibition of -α-amylase and -glucosidase at an absolute concentration of 1000 μg per ml with IC50 values of 30.6 μg per ml and 72 μg per ml.
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Affiliation(s)
- Abdullah Shoaib
- Department of Chemistry, School of Science, University of Management and Technology, Lahore, 54770, Pakistan
| | - Sammia Shahid
- Department of Chemistry, School of Science, University of Management and Technology, Lahore, 54770, Pakistan
| | - Sana Mansoor
- Department of Chemistry, School of Science, University of Management and Technology, Lahore, 54770, Pakistan
| | - Mohsin Javed
- Department of Chemistry, School of Science, University of Management and Technology, Lahore, 54770, Pakistan
| | - Shahid Iqbal
- Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo, 315100, China.
| | - Sajid Mahmood
- Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo, 315100, China
- Functional Materials Group, Gulf University for Science and Technology, 32093, Mishref, Kuwait
| | - Ali Bahadur
- Department of Chemistry, College of Science, Mathematics, and Technology, Wenzhou-Kean University, Wenzhou, 325060, China.
- Dorothy and George Hennings College of Science, Mathematics and Technology, Kean University, 1000 Morris Ave, Union, New Jersey, 07083, USA.
| | - Fadi Jaber
- Department of Biomedical Engineering, Ajman University, Ajman, UAE.
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, UAE.
| | - Matar Alshalwi
- Department of Chemistry, College of Science, King Saud University, PO Box 2455, 11541, Riyadh, Saudi Arabia
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Endo A, Hirose T, Sato S, Ito H, Takahashi C, Ishikawa R, Kamada A, Oba-Yabana I, Kimura T, Takahashi K, Mori T. Sodium glucose cotransporter 2 inhibitor suppresses renal injury in rats with renal congestion. Hypertens Res 2024; 47:33-45. [PMID: 37749334 PMCID: PMC10766540 DOI: 10.1038/s41440-023-01437-1] [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: 07/31/2023] [Revised: 09/10/2023] [Accepted: 09/10/2023] [Indexed: 09/27/2023]
Abstract
Renal congestion is an issue of cardiorenal syndrome in patients with heart failure. Recent clinical and basic studies suggest a renoprotective potential of sodium-glucose cotransporter (SGLT) 2 inhibitors. However, the effect on renal congestion and its mechanism is not fully understood. Thus, we aimed to clarify the effect of SGLT inhibition in a renal congestion model. Renal congestion was induced in the left kidney of male Sprague-Dawley rats by ligation of the inferior vena cava between the renal veins. The SGLT2 inhibitor tofogliflozin or vehicle was orally administered daily from the day before IVC ligation until two days after surgery. On the third postoperative day, both the right control kidney and the left congested kidney were harvested and analyzed. Kidney weight and water content was increased, and renal injury and fibrosis were observed in the left congested kidney. Kidney weight gain and hydration were improved with tofogliflozin treatment. Additionally, this treatment effectively reduced renal injury and fibrosis, particularly in the renal cortex. SGLT2 expression was observed in the congested kidney, but suppressed in the damaged tubular cells. Molecules associated with inflammation were increased in the congested kidney and reversed by tofogliflozin treatment. Mitochondrial dysfunction provoked by renal congestion was also improved by tofogliflozin treatment. Tofogliflozin protects against renal damage induced by renal congestion. SGLT2 inhibitors could be a candidate strategy for renal impairment associated with heart failure.
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Affiliation(s)
- Akari Endo
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takuo Hirose
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan.
- Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
| | - Shigemitsu Sato
- Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Hiroki Ito
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Chika Takahashi
- Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Risa Ishikawa
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Ayaka Kamada
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Ikuko Oba-Yabana
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Tomoyoshi Kimura
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Kazuhiro Takahashi
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takefumi Mori
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
- Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
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Koutentakis M, Kuciński J, Świeczkowski D, Surma S, Filipiak KJ, Gąsecka A. The Ketogenic Effect of SGLT-2 Inhibitors-Beneficial or Harmful? J Cardiovasc Dev Dis 2023; 10:465. [PMID: 37998523 PMCID: PMC10672595 DOI: 10.3390/jcdd10110465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/09/2023] [Accepted: 11/14/2023] [Indexed: 11/25/2023] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, also called gliflozins or flozins, are a class of drugs that have been increasingly used in the management of type 2 diabetes mellitus (T2DM) due to their glucose-lowering, cardiovascular (CV), and renal positive effects. However, recent studies suggest that SGLT-2 inhibitors might also have a ketogenic effect, increasing ketone body production. While this can be beneficial for some patients, it may also result in several potential unfavorable effects, such as decreased bone mineral density, infections, and ketoacidosis, among others. Due to the intricate and multifaceted impact caused by SGLT-2 inhibitors, this initially anti-diabetic class of medications has been effectively used to treat both patients with chronic kidney disease (CKD) and those with heart failure (HF). Additionally, their therapeutic potential appears to extend beyond the currently investigated conditions. The objective of this review article is to present a thorough summary of the latest research on the mechanism of action of SGLT-2 inhibitors, their ketogenesis, and their potential synergy with the ketogenic diet for managing diabetes. The article particularly discusses the benefits and risks of combining SGLT-2 inhibitors with the ketogenic diet and their clinical applications and compares them with other anti-diabetic agents in terms of ketogenic effects. It also explores future directions regarding the ketogenic effects of SGLT-2 inhibitors.
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Affiliation(s)
- Michail Koutentakis
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland;
| | - Jakub Kuciński
- Central Clinical Hospital, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland;
| | - Damian Świeczkowski
- Department of Toxicology, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdańsk, Poland;
| | - Stanisław Surma
- Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland;
| | - Krzysztof J. Filipiak
- Department of Clinical Sciences, Maria Sklodowska-Curie Medical Academy, 00-001 Warsaw, Poland;
- Department of Hypertensiology, Angiology and Internal Medicine, Poznań University of Medical Sciences, 61-848 Poznań, Poland
| | - Aleksandra Gąsecka
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland;
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Mahmoud MM, Rashed LA, Soliman SA, Sayed SM, Kamel O, Kamar SS, Hussien RES. SGLT-2 inhibitors enhance the effect of metformin to ameliorate hormonal changes and inflammatory markers in a rat PCOS model. Physiol Rep 2023; 11:e15858. [PMID: 37985173 PMCID: PMC10659952 DOI: 10.14814/phy2.15858] [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: 05/06/2023] [Revised: 10/30/2023] [Accepted: 10/30/2023] [Indexed: 11/22/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine, reproductive, and metabolic disorder affecting females. The management of PCOS is challenging and current interventions are not enough to deal with all consequences of this syndrome. We explored the beneficial effect of combined sodium glucose co transporter-2 inhibitor (SGLT-2i); (empagliflozin) and metformin on hormonal and metabolic parameters in an animal model of PCOS and insulin resistance (IR). Forty adult female Wistar rats divided into five groups: control, PCOS-IR, PCOS-IR treated with metformin, PCOS-IR treated with empagliflozin, and PCOS-IR treated with combined metformin and empagliflozin. Single modality treatment with metformin or empagliflozin yielded significant improvement in body mass index, insulin resistance, lipid profile, sex hormones, inflammatory markers, and ovarian cystic follicles. Combined metformin with empagliflozin expressed further significant improvement in sex hormones, inflammatory markers with disappearance of ovarian cystic follicles. The superior significant improvement with combined treatment over the single modality was in line with significant improvement in the ovarian AMPKα-SIRT1 expression.
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Affiliation(s)
| | - Laila Ahmed Rashed
- Department of Biochemistry Faculty of MedicineCairo UniversityCairoEgypt
| | | | | | - Omneya Kamel
- Department of Physiology, School of MedicineNew Giza UniversityCairoEgypt
| | - Samaa Samir Kamar
- Department of Histology, Faculty of MedicineCairo UniversityCairoEgypt
- Department of HistologyArmed Forces College of MedicineCairoEgypt
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Andreea MM, Surabhi S, Razvan-Ionut P, Lucia C, Camelia N, Emil T, Tiberiu NI. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Harms or Unexpected Benefits? MEDICINA (KAUNAS, LITHUANIA) 2023; 59:742. [PMID: 37109700 PMCID: PMC10143699 DOI: 10.3390/medicina59040742] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/29/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023]
Abstract
There is a need for innovative pharmaceutical intervention in light of the increasing prevalence of metabolic disease and cardiovascular disease. The kidneys' sodium-glucose cotransporter 2 inhibitors (SGLT2) receptors are targeted to reduce glucose reabsorption by SGLT2. Patients with type 2 diabetes mellitus (T2DM) benefit the most from reduced blood glucose levels, although this is just one of the numerous physiological consequences. To establish existing understanding and possible advantages and risks for SGLT2 inhibitors in clinical practice, this article will explore the influence of SGLT2 inhibitors on six major organ systems. In addition, this literature review will discuss the benefits and potential drawbacks of SGLT2 inhibitors on various organ systems and their potential application in therapeutic settings.
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Affiliation(s)
- Munteanu Madalina Andreea
- Department of Cardiology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
- “Theodor Burghele” Clinical Hospital, 050653 Bucharest, Romania
| | - Swarnkar Surabhi
- Department of Cardiovascular Science, University Medical Center Gottingen, 37075 Gottingen, Germany
| | - Popescu Razvan-Ionut
- “Theodor Burghele” Clinical Hospital, 050653 Bucharest, Romania
- Department of Urology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
| | - Ciobotaru Lucia
- Department of Nephrology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
| | - Nicolae Camelia
- Department of Cardiology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
- “Theodor Burghele” Clinical Hospital, 050653 Bucharest, Romania
| | - Tufanoiu Emil
- Department of Neurology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
- Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Nanea Ioan Tiberiu
- Department of Cardiology, University of Medicine and Pharmacy “Carol Davila”, 050474 Bucharest, Romania
- “Theodor Burghele” Clinical Hospital, 050653 Bucharest, Romania
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Kuang Z, Hou N, Kan C, Han F, Qiu H, Sun X. The protective effects of SGLT-2 inhibitors, GLP-1 receptor agonists, and RAAS blockers against renal injury in patients with type 2 diabetes. Int Urol Nephrol 2023; 55:617-629. [PMID: 36036316 DOI: 10.1007/s11255-022-03355-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 08/21/2022] [Indexed: 10/15/2022]
Abstract
Diabetic kidney disease is one of the most severe complications of type 2 diabetes mellitus. Patients with diabetic kidney disease have a worse prognosis in terms of mortality and morbidity, compared with patients who have diabetes alone. Strict control of blood pressure and blood glucose is the primary method for prevention of initial kidney damage and delaying further progression of existing damage. Other management approaches include the use of exogenous drugs that can effectively protect the kidneys from diabetes, such as sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers. These drugs may protect against kidney injury through various molecular mechanisms. This review focuses on renal impairment in patients with type 2 diabetes; it discusses the direct and indirect effects of sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers on diabetic kidney disease. Finally, it discusses the effects of combination treatment with two or three types of drugs in patients with chronic kidney disease.
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Affiliation(s)
- Zengguang Kuang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Ningning Hou
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China
| | - Chengxia Kan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Hongyan Qiu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China.
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China.
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China.
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China.
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.
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Panchal R, Nguyen D, Ghule P, Li N, Giannouchos T, Pan RJ, Biskupiak J, Britton L, Nohavec R, Slager S, Ngorsuraches S, Brixner D. Understanding patient cost-sharing thresholds for diabetes treatment attributes via a discrete choice experiment. J Manag Care Spec Pharm 2023; 29:139-150. [PMID: 36705280 PMCID: PMC10387929 DOI: 10.18553/jmcp.2023.29.2.139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND: The process used to prefer certain products across drug classes for diabetes is generally focused on comparative effectiveness and cost. However, payers rarely tie patient preference for treatment attributes to formulary management resulting in a misalignment of value defined by providers, payers, and patients. OBJECTIVES: To explore patients' willingness to pay (WTP) for the predetermined high-value and low-value type 2 diabetes mellitus (T2DM) treatments within a health plan. METHODS: A cross-sectional discrete choice experiment (DCE) survey was used to determine patient preference for the benefit, risk, and cost attributes of T2DM treatments. A comprehensive literature review of patient preference studies in diabetes and a review of guidelines and medical literature identified study attributes. Patients and diabetes experts were interviewed and instructed to identify, prioritize, and comment on which attributes of diabetes treatments were most important to T2DM patients. The patients enrolled in a health plan were asked to respond to the survey. A multinomial logit model was developed to determine the relative importance and the patient's WTP of each attribute. The patients' relative values based on WTPs for T2DM treatments were calculated and compared with the treatments by a health plan. RESULTS: A total of 7 attributes were selected to develop a web-based DCE questionnaire survey. The responses from a total of 58 patients were analyzed. Almost half (48.3%) of the respondents took oral medications and injections for T2DM. The most prevalent side effects due to diabetes medications were gastrointestinal (43.1%), followed by weight gain (39.7%) and nausea (32.8%). Patients were willing to pay more for treatments with proven cardiovascular benefit and for the risk reduction of hospitalization from heart failure. On the other hand, they would pay less for treatments with higher gastrointestinal side effects. Patients were willing to pay the most for sodium-glucose cotransporter 2 inhibitor and glucagon-like peptide 1 receptor agonist agents and the least for dipeptidyl peptidase-4 inhibitors and thiazolidinediones. CONCLUSIONS: This study provides information to better align patient, provider, and payer preferences in both benefit design and value-based formulary strategy for diabetes treatments. A preferred placement of treatments with cardiovascular benefits and lower adverse gastrointestinal side effects may lead to increased adherence to medications and improved clinical outcomes at a lower overall cost to both patients and their health plan. DISCLOSURES: This study was supported by a grant from the PhRMA Foundation.
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Affiliation(s)
- Rupesh Panchal
- Pharmacotherapy Outcomes Research Center, University of Utah, Salt Lake City
- University of Utah Health Plans, Murray
| | - Danielle Nguyen
- Pharmacotherapy Outcomes Research Center, University of Utah, Salt Lake City
| | - Priyanka Ghule
- Pharmacotherapy Outcomes Research Center, University of Utah, Salt Lake City
| | - Niying Li
- Pharmacotherapy Outcomes Research Center, University of Utah, Salt Lake City
| | | | - Raymond J Pan
- Pharmacotherapy Outcomes Research Center, University of Utah, Salt Lake City
| | - Joseph Biskupiak
- Pharmacotherapy Outcomes Research Center, University of Utah, Salt Lake City
| | - Laura Britton
- Pharmacotherapy Outcomes Research Center, University of Utah, Salt Lake City
- University of Utah Health Plans, Murray
| | - Robert Nohavec
- Pharmacotherapy Outcomes Research Center, University of Utah, Salt Lake City
- University of Utah Health Plans, Murray
| | - Stacey Slager
- Pharmacotherapy Outcomes Research Center, University of Utah, Salt Lake City
| | | | - Diana Brixner
- Pharmacotherapy Outcomes Research Center, University of Utah, Salt Lake City
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Muacevic A, Adler JR, Sameera M, Fahad M, Brendan O, Deion S, Pemminati S. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Benefits Versus Risk. Cureus 2023; 15:e33939. [PMID: 36819350 PMCID: PMC9937770 DOI: 10.7759/cureus.33939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
With the growing burden of metabolic disease, cardiovascular disease, and diabetes mellitus, there is an implication for new pharmacological intervention. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a class of drugs that work on SGLT2 receptors in the kidneys to decrease glucose reabsorption. Lowering glucose levels mainly aids those with type 2 diabetes (T2DM), but they also have many other effects on the body. This article will investigate the impact of SGLT2i on six relevant organ systems; to establish current knowledge and potential benefits and risk for SGLTi in clinical practice. The medications that inhibit SGLT2 suffix with flozins are known to help decrease hypertension, acute cardiac failure, and bradycardia in the cardiovascular system. Flozins were found to aid with acute pulmonary edema, asthma, bronchitis, and chronic obstructive pulmonary disease (COPD) in the pulmonary system. SGLT2 is also found in the blood-brain barrier (BBB), and as such, SGLT2i can also affect the central nervous system (CNS). They reduced reactive oxygen species (ROS), BBB leakage, microglia burden, and acetylcholinesterase (AChE) levels. In the liver, this class of drugs can also assist with non-alcoholic fatty liver disease (NAFLD), hepatotoxicity, and weight loss. In the pancreas, SGLT2i has been shown to help with primarily diabetes and hyperglycemia. Finally, SGLT2i's are known to aid in decreasing nephrotoxicity and stopping the progression of the glomerular filtration rate (GFR) decrease. New studies have shown that the flozin drugs have been helpful for those who were receiving kidney transplants. Despite the positive effects, there are some concerns about SGLT2i and its notable adverse effects. Flozin drugs are known to cause urinary tract infections (UTIs), dehydration, orthostatic hypotension, postural dizziness, syncope, hypotension, hyperkalemia-induced cardiac arrest, and pancreatitis. This literature review will discuss, in detail, the benefits and risks that SGTL2i have on different organ systems and implicate the role they may play in clinical practice.
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Abstract
Objective Young people with type 1 diabetes are likely to gain body weight and not achieve optimal glycemic control with only high doses of insulin. This study examined the efficacy of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin as an adjunct-to-insulin therapy in young Japanese subjects with type 1 diabetes who had been diagnosed before 15 years old, were overweight, and had inadequate control despitereceiving intensive insulin therapy. Methods Twenty-two patients with type 1 diabetes (12 boys and 10 girls 16.0-33.9 years old) were involved in the study. All patients had a body mass index (BMI) >25 kg/m2, glycated hemoglobin (HbA1c) level >7.0%, and daily insulin dose >0.5 units/kg. They were treated with a low dose of dapagliflozin (5.0 mg/day) as an adjunctive therapy to insulin. Fourteen patients were treated with multiple daily injections of insulin, while eight used an insulin pump. Results The body weights and BMIs were significantly reduced during the 12-month study period (change of -4.4 kg and -1.7 kg/m2, p<0.001, respectively). Their insulin dose was significantly decreased (-0.17 units/kg, P <0.001), and glycemic control was significantly improved (fasting plasma glucose: -18.7 mg/dL, HbA1c: -0.62%, p<0.001) during the study period. There was one episode of diabetic ketoacidosis, with no other problematic adverse events, including severe hypoglycemia, observed. Conclusion The use of low-dose dapagliflozin as an adjunct therapy may be beneficial in overweight young people with poorly controlled type 1 diabetes.
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Affiliation(s)
- Tatsuhiko Urakami
- Department of Pediatrics, Nihon University School of Medicine, Japan
| | - Kei Yoshida
- Department of Pediatrics, Nihon University School of Medicine, Japan
| | - Junichi Suzuki
- Department of Pediatrics, Nihon University School of Medicine, Japan
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25
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Maiorana A, Tagliaferri F, Dionisi-Vici C. Current understanding on pathogenesis and effective treatment of glycogen storage disease type Ib with empagliflozin: new insights coming from diabetes for its potential implications in other metabolic disorders. Front Endocrinol (Lausanne) 2023; 14:1145111. [PMID: 37152929 PMCID: PMC10160627 DOI: 10.3389/fendo.2023.1145111] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 04/10/2023] [Indexed: 05/09/2023] Open
Abstract
Glycogen storage type Ib (GSDIb) is a rare inborn error of metabolism caused by glucose-6-phosphate transporter (G6PT, SLC37A4) deficiency. G6PT defect results in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa and into both glycogenolysis and gluconeogenesis impairment. Clinical features include hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia, and growth retardation. Long-term complications are liver adenoma, hepatocarcinoma, nephropathy and osteoporosis. The hallmark of GSDIb is neutropenia, with impaired neutrophil function, recurrent infections and inflammatory bowel disease. Alongside classical nutritional therapy with carbohydrates supplementation and immunological therapy with granulocyte colony-stimulating factor, the emerging role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction led to repurpose empagliflozin, an inhibitor of the renal glucose transporter SGLT2: the current literature of its off-label use in GSDIb patients reports beneficial effects on neutrophil dysfunction and its clinical consequences. Surprisingly, this glucose-lowering drug ameliorated the glycemic and metabolic control in GSDIb patients. Furthermore, numerous studies from big cohorts of type 2 diabetes patients showed the efficacy of empagliflozin in reducing the cardiovascular risk, the progression of kidney disease, the NAFLD and the metabolic syndrome. Beneficial effects have also been described on peripheral neuropathy in a prediabetic rat model. Increasing evidences highlight the role of empagliflozin in regulating the cellular energy sensors SIRT1/AMPK and Akt/mTOR, which leads to improvement of mitochondrial structure and function, stimulation of autophagy, decrease of oxidative stress and suppression of inflammation. Modulation of these pathways shift the oxidative metabolism from carbohydrates to lipids oxidation and results crucial in reducing insulin levels, insulin resistance, glucotoxicity and lipotoxicity. For its pleiotropic effects, empagliflozin appears to be a good candidate for drug repurposing also in other metabolic diseases presenting with hypoglycemia, organ damage, mitochondrial dysfunction and defective autophagy.
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Affiliation(s)
- Arianna Maiorana
- Division of Metabolism, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
- *Correspondence: Arianna Maiorana,
| | - Francesco Tagliaferri
- SCDU of Pediatrics, Azienda Ospedaliero-Universitaria Maggiore della Carità, University of Piemonte Orientale, Novara, Italy
| | - Carlo Dionisi-Vici
- Division of Metabolism, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
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Forycka J, Hajdys J, Krzemińska J, Wilczopolski P, Wronka M, Młynarska E, Rysz J, Franczyk B. New Insights into the Use of Empagliflozin-A Comprehensive Review. Biomedicines 2022; 10:biomedicines10123294. [PMID: 36552050 PMCID: PMC9775057 DOI: 10.3390/biomedicines10123294] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Empagliflozin is a relatively new drug that, as an inhibitor of the sodium−glucose cotransporter 2 (SGLT2), causes increased urinary glucose excretion and thus contributes to improved glycemic control, better glucose metabolism, reduced glucotoxicity and insulin resistance. Although its original use was to induce a hypoglycemic effect in patients with type 2 diabetes mellitus (T2DM), empagliflozin has also shown a number of other beneficial effects by demonstrating a nephroprotective effect, and it has proven to be a breakthrough in the treatment of heart failure (HF). Empagliflozin has been shown to reduce hospitalizations for HF and the number of deaths from cardiovascular causes. Empagliflozin treatment also reduces the incidence of renal events, including death from renal causes, as well as the risk of end-stage renal failure. Empagliflozin appears to be a fairly well-tolerated and safe drug. In patients with inadequate glycemic control, empagliflozin used in monotherapy or as an adjunct to therapy effectively lowers fasting blood glucose, postprandial blood glucose, average daily glucose levels, glycated hemoglobin A1C (HbA1C) and also leads to significant weight reduction in patients with T2DM. Unfortunately, there are some limitations, e.g., severe hypersensitivity reaction to the drug and a glomerular filtration rate (GFR) < 30 mL/min/1.73 m2. As with any drug, empagliflozin is also characterized by several side effects among which symptomatic hypotension, troublesome genital fungal infections, urinary tract infections and rare ketoacidosis are characteristic.
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Affiliation(s)
- Joanna Forycka
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Joanna Hajdys
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Julia Krzemińska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Piotr Wilczopolski
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Magdalena Wronka
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
- Correspondence: ; Tel.: +48-(042)-639-37-50
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
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Afzal U, Bilal M, Zubair M, Rasool N, Adnan Ali Shah S, Amiruddin Zakaria Z. Stereospecific/stereoselective Nickel catalyzed reductive cross-coupling: An efficient tool for the synthesis of biological active targeted molecules. JOURNAL OF SAUDI CHEMICAL SOCIETY 2022. [DOI: 10.1016/j.jscs.2022.101589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Anan G, Hirose T, Kikuchi D, Takahashi C, Endo A, Ito H, Sato S, Nakayama S, Hashimoto H, Ishiyama K, Kimura T, Takahashi K, Sato M, Mori T. Inhibition of sodium-glucose cotransporter 2 suppresses renal stone formation. Pharmacol Res 2022; 186:106524. [PMID: 36349594 DOI: 10.1016/j.phrs.2022.106524] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/24/2022] [Accepted: 10/25/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND AIMS Nephrolithiasis is a common renal disease with no effective medication. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, an anti-diabetic agent, have diuretic and anti-inflammatory properties and could prevent nephrolithiasis. Here, we investigated the potential of SGLT2 inhibition against nephrolithiasis using large-scale epidemiological data, animal models, and cell culture experiments. METHODS This study included the data of diabetic patients (n = 1,538,198) available in the Japanese administrative database and divided them according to SGLT2 inhibitor prescription status. For animal experiments, renal calcium oxalate stones were induced by ethylene glycol in Sprague-Dawley rats, and phlorizin, an SGLT1/2 inhibitor, was used for the treatment. The effects of SGLT2-specific inhibition for renal stone formation were assessed in SGLT2-deficient mice and a human proximal tubular cell line, HK-2. RESULTS Nephrolithiasis prevalence in diabetic men was significantly lower in the SGLT2 inhibitor prescription group than in the non-SGLT2 inhibitor prescription group. Phlorizin attenuated renal stone formation and downregulated the kidney injury molecule 1 (Kim1) and osteopontin (Opn) expression in rats, with unchanged water intake and urine volume. It suppressed inflammation and macrophage marker expression, suggesting the role of the SGLT2 inhibitor in reducing inflammation. SGLT2-deficient mice were resistant to glyoxylic acid-induced calcium oxalate stone formation with reduced Opn expression and renal damages. High glucose-induced upregulation of OPN and CD44 and cell surface adhesion of calcium oxalate reduced upon SGLT2-silencing in HK-2 cells. CONCLUSION Overall, our findings identified that SGLT2 inhibition prevents renal stone formation and may be a promising therapeutic approach against nephrolithiasis.
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Affiliation(s)
- Go Anan
- Department of Urology, Tohoku Medical and Pharmaceutical University, Sendai, Japan; Department of Urology, Yotsuya Medical Cube, Tokyo, Japan
| | - Takuo Hirose
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan; Division of Integrative Renal Replacement Therapy, Tohoku Medical and Pharmaceutical University, Sendai, Japan; Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Daisuke Kikuchi
- Department of Pharmacy, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan
| | - Chika Takahashi
- Division of Integrative Renal Replacement Therapy, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Akari Endo
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan; Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroki Ito
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan; Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shigemitsu Sato
- Division of Integrative Renal Replacement Therapy, Tohoku Medical and Pharmaceutical University, Sendai, Japan; Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shingo Nakayama
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Hideaki Hashimoto
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Katsuya Ishiyama
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Tomoyoshi Kimura
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Kazuhiro Takahashi
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Makoto Sato
- Department of Urology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Takefumi Mori
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan; Division of Integrative Renal Replacement Therapy, Tohoku Medical and Pharmaceutical University, Sendai, Japan
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Olagunju A, Yamani N, Kenny D, Mookadam M, Mookadam F, Unzek S. Potential for sodium-glucose cotransporter-2 inhibitors in the management of metabolic syndrome: A systematic review and meta-analysis. World J Cardiol 2022; 14:599-616. [PMID: 36483765 PMCID: PMC9724001 DOI: 10.4330/wjc.v14.i11.599] [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: 07/03/2022] [Revised: 09/17/2022] [Accepted: 10/28/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Landmark trials have established the benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2-Is) in cardiovascular disease including heart failure with reduced and preserved ejection fraction and renal diseases regardless of the presence of diabetes mellitus. However, studies evaluating the role of SGLT2-Is in metabolic syndrome (MetS) are limited.
AIM This study primarily aimed to evaluate the impact of SGLT2-Is on the components of MetS.
METHODS Two independent reviewers and an experienced librarian searched Medline, Scopus and the Cochrane central from inception to December 9, 2021 to identify placebo controlled randomized controlled trials that evaluated the impact of SGLT2-Is on the components of MetS as an endpoint. Pre- and post-treatment data of each component were obtained. A meta-analysis was performed using the RevMan (version 5.3; Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration).
RESULTS Treatment with SGLT2-Is resulted in a decrease in fasting plasma glucose (–18.07 mg/dL; 95%CI: -25.32 to –10.82), systolic blood pressure (–1.37 mmHg; 95%CI: -2.08 to –0.65), and waist circumference (–1.28 cm; 95%CI: -1.39 to –1.18) compared to placebo. The impact on high-density lipoprotein cholesterol was similar to placebo (0.01 mg/dL; 95%CI: -0.05 to 0.07).
CONCLUSION SGLT2-Is have a promising role in the management of MetS.
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Affiliation(s)
- Abdulbaril Olagunju
- Internal Medicine, Creighton University School of Medicine, Phoenix, AZ 85013, United States
| | - Naser Yamani
- Cardiology, Heart Center, University of Arizona College of Medicine-Phoenix, Banner University Medical Center, Phoenix, AZ 85006, United States
| | - Dorothy Kenny
- Internal Medicine, Creighton University School of Medicine, Phoenix, AZ 85013, United States
| | - Martina Mookadam
- Department of Family Medicine, Mayo Clinic, Scottsdale, AZ 85260, United States
| | - Farouk Mookadam
- Cardiology, Heart Center, University of Arizona College of Medicine-Phoenix, Banner University Medical Center, Phoenix, AZ 85006, United States
| | - Samuel Unzek
- Cardiology, Heart Center, University of Arizona College of Medicine-Phoenix, Banner University Medical Center, Phoenix, AZ 85006, United States
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SGLT2 Inhibitors in Type 2 Diabetes Mellitus. Heart Fail Clin 2022; 18:551-559. [DOI: 10.1016/j.hfc.2022.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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Patoulias D, Papadopoulos C, Kassimis G, Fragakis N, Vassilikos V, Karagiannis A, Doumas M. Effect of sodium-glucose co-transporter-2 inhibitors on arterial stiffness: A systematic review and meta-analysis of randomized controlled trials. Vasc Med 2022; 27:433-439. [PMID: 35754338 DOI: 10.1177/1358863x221101653] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND Arterial stiffness represents an established cardiovascular risk marker. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have significant cardio-protective effects. Herein we sought to determine the effect of SGLT-2 inhibitors on pulse wave velocity (PWV). METHODS We searched PubMed, Cochrane Library, and grey literature from inception to 7th February 2022 for randomized controlled trials (RCTs) enrolling adult subjects with or without type 2 diabetes mellitus (T2DM), assigned to a SGLT-2 inhibitor versus control and addressing their effect on PWV. We set as primary efficacy outcome the change in PWV with SGLT-2 inhibitors versus placebo or control. RESULTS We pooled data from six trials in a total of 452 enrolled participants assigned either to SGLT-2 inhibitor or control. Overall, SGLT-2 inhibitor treatment compared to control resulted in a nonsignificant decrease in PWV. Exclusion of a trial utilizing cardiac magnetic resonance imaging for the assessment of PWV demonstrated that SGLT-2 inhibitors induce a significant reduction in PWV by 0.21 m/s. When we restricted our analysis to RCTs enrolling subjects with T2DM, we observed that SGLT-2 inhibitor compared to control resulted in a significant decrease in PWV by 0.17 m/s. CONCLUSION SGLT-2 inhibitors do not decrease PWV in patients with established cardiovascular disease or cardiovascular risk factors. However, we have shown that SGLT-2 inhibitors lead to a slight, but significant decrease in PWV in patients with T2DM. The latter finding is of great value, based on the significant correlation between PWV and micro- and macro-vascular complications of T2DM.
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Affiliation(s)
- Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital 'Hippokration', Thessaloniki, Greece
| | - Christodoulos Papadopoulos
- Third Department of Cardiology, Aristotle University of Thessaloniki, General Hospital 'Hippokration', Thessaloniki, Greece
| | - George Kassimis
- Second Department of Cardiology, Aristotle University of Thessaloniki, General Hospital 'Hippokration', Thessaloniki, Greece
| | - Nikolaos Fragakis
- Third Department of Cardiology, Aristotle University of Thessaloniki, General Hospital 'Hippokration', Thessaloniki, Greece
| | - Vassilios Vassilikos
- Third Department of Cardiology, Aristotle University of Thessaloniki, General Hospital 'Hippokration', Thessaloniki, Greece
| | - Asterios Karagiannis
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital 'Hippokration', Thessaloniki, Greece
| | - Michael Doumas
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital 'Hippokration', Thessaloniki, Greece
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Kubota Y, Shimizu W. Clinical Benefits of Sodium–Glucose Cotransporter 2 Inhibitors and the Mechanisms Underlying Their Cardiovascular Effects. JACC: ASIA 2022; 2:287-293. [PMID: 36338417 PMCID: PMC9627935 DOI: 10.1016/j.jacasi.2022.03.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/15/2022] [Indexed: 11/30/2022]
Abstract
In addition to showing antidiabetic effects, sodium–glucose cotransporter 2 (SGLT2) inhibitors also reduce cardiovascular events in patients with type 2 diabetes mellitus. In major trials of cardiovascular outcomes, SGLT2 inhibitors have been shown to improve cardiovascular and renal outcomes, including reduced rehospitalization in patients with heart failure, regardless of the presence of diabetes. A recent report showed that the benefits of SGLT2 inhibitors in terms of cardiovascular deaths/admissions caused by heart failure and reduced ejection fraction were greater in Asians than in Whites. In this review, the first part demonstrates the results of recent clinical trials and their clinical implications and outlines current trials and upcoming research areas. The second part provides a general overview of the current understanding of the mechanisms of the cardiovascular benefits of SGLT2 inhibitors.
Type 2 diabetes mellitus and heart failure are closely related. SGLT2 inhibitors can reduce the incidence of cardiovascular events and heart failure. SGLT2 inhibitors can improve hemodynamics, myocardial energy supply, and sympathetic and parasympathetic nerve activities.
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Affiliation(s)
- Yoshiaki Kubota
- Address for correspondence: Dr Yoshiaki Kubota, Department of Cardiovascular Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
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Koo BK, Lim S. Metabolic Syndrome and Metabolic Dysfunction‐Associated Fatty Liver Disease. CLINICAL OBESITY IN ADULTS AND CHILDREN 2022:159-177. [DOI: 10.1002/9781119695257.ch13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Jhuo SJ, Lin TH, Lin YH, Tsai WC, Liu IH, Wu BN, Lee KT, Lai WT. Clinical Observation of SGLT2 Inhibitor Therapy for Cardiac Arrhythmia and Related Cardiovascular Disease in Diabetic Patients with Controlled Hypertension. J Pers Med 2022; 12:jpm12020271. [PMID: 35207759 PMCID: PMC8880188 DOI: 10.3390/jpm12020271] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 12/14/2022] Open
Abstract
Sodium-glucose transporter 2 (SGLT2) inhibitors are new glucose-lowering agents that have been proven to be beneficial for patients with cardiovascular diseases, heart failure, and sudden cardiac death. However, the possible protective effects of cardiac arrhythmia have not yet been clarified in clinical practice. In this study, we attempted to demonstrate the effects of SGLT2 inhibitors on cardiac arrhythmia by medical records from a single center. This retrospective study included patients diagnosed with type 2 diabetes mellitus (DM) and controlled hypertension who prescribed the indicated glucose-lowering agents based on medical records from 2016 to 2019 from Kaohsiung Medical University Hospital. These patients were divided into two groups. Group one patients were defined as patients with SGLT2 inhibitor therapy, and group two patients were defined as patients without SGLT2 inhibitor therapy. Baseline characteristics were collected from medical records. Univariate, multivariate, and match-paired statistical analyses were performed for the study endpoints. The primary study outcome was the incidence of cardiac arrhythmias, including atrial and ventricular arrhythmias, after SGLT2 inhibitor therapy. The secondary study outcomes were the incidence of stroke, heart failure, and myocardial infarction after SGLT2 inhibitor therapy. From the initial 62,704 medical records, a total of 9609 people who met our experimental design criteria were included. The mean follow-up period was 51.50 ± 4.23 months. Group one included 3203 patients who received SGLT2 inhibitors for treatment, and group two included 6406 patients who received non-SGLT2 inhibitors for treatment. Multivariate analysis showed that group one patients had significantly lower incidences of total cardiac arrhythmia (hazard ratio (HR): 0.58, 95% confidence interval (CI): 0.38–0.89, p = 0.013) and atrial fibrillation (HR: 0.56, 95% CI: 0.35–0.88, p = 0.013) than those of group two patients. The secondary outcome analysis showed that group one patients also had a significantly lower risk of stroke (HR: 0.48, 95% CI: 0.33–0.7; p < 0.001), heart failure (HR: 0.54, 95% CI: 0.41–0.7, p < 0.001), and myocardial infarction (HR: 0.47, 95% CI: 0.31–0.72, p < 0.001). A time-to-event analysis showed that treatment of type 2 DM patients with SGLT2 inhibitors could reduce the probability of total cardiac arrhythmia and related cardiovascular disease, such as atrial fibrillation, stroke, heart failure, or myocardial infarction, by 0.5%~0.8%. This databank analysis showed that SGLT2 inhibitor therapy reduced the incidence of total cardiac arrhythmia and atrial fibrillation in type 2 DM patients and decreased the incidence of related cardiovascular diseases, such as stroke, heart failure, and myocardial infarction. However, additional investigations are needed to confirm this hypothesis.
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Affiliation(s)
- Shih-Jie Jhuo
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan; (S.-J.J.); (W.-C.T.); (K.-T.L.)
- Department of Internal Medicine, Division of Cardiology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (T.-H.L.); (Y.-H.L.); (I.-H.L.); (W.-T.L.)
- Department of Internal Medicine, Department of Pharmacology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Tsung-Hsien Lin
- Department of Internal Medicine, Division of Cardiology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (T.-H.L.); (Y.-H.L.); (I.-H.L.); (W.-T.L.)
- Department of Internal Medicine, Department of Pharmacology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Yi-Hsiung Lin
- Department of Internal Medicine, Division of Cardiology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (T.-H.L.); (Y.-H.L.); (I.-H.L.); (W.-T.L.)
- Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
| | - Wei-Chung Tsai
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan; (S.-J.J.); (W.-C.T.); (K.-T.L.)
- Department of Internal Medicine, Division of Cardiology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (T.-H.L.); (Y.-H.L.); (I.-H.L.); (W.-T.L.)
- Department of Internal Medicine, Department of Pharmacology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - I-Hsin Liu
- Department of Internal Medicine, Division of Cardiology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (T.-H.L.); (Y.-H.L.); (I.-H.L.); (W.-T.L.)
| | - Bin-Nan Wu
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan; (S.-J.J.); (W.-C.T.); (K.-T.L.)
- Department of Internal Medicine, Department of Pharmacology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Correspondence: ; Tel.: +886-73121101 (ext. 7741); Fax: +886-73234845
| | - Kun-Tai Lee
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan; (S.-J.J.); (W.-C.T.); (K.-T.L.)
| | - Wen-Ter Lai
- Department of Internal Medicine, Division of Cardiology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (T.-H.L.); (Y.-H.L.); (I.-H.L.); (W.-T.L.)
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Bradley SA, Spring KJ, Beran RG, Chatzis D, Killingsworth MC, Bhaskar SMM. Role of diabetes in stroke: Recent advances in pathophysiology and clinical management. Diabetes Metab Res Rev 2022; 38:e3495. [PMID: 34530485 DOI: 10.1002/dmrr.3495] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/28/2021] [Accepted: 08/31/2021] [Indexed: 02/05/2023]
Abstract
The increasing prevalence of diabetes and stroke is a major global public health concern. Specifically, acute stroke patients, with pre-existing diabetes, pose a clinical challenge. It is established that diabetes is associated with a worse prognosis after acute stroke and the various biological factors that mediate poor recovery profiles in diabetic patients is unknown. The level of association and impact of diabetes, in the setting of reperfusion therapy, is yet to be determined. This article presents a comprehensive overview of the current knowledge of the role of diabetes in stroke, therapeutic strategies for primary and secondary prevention of cardiovascular disease and/or stroke in diabetes, and various therapeutic considerations that may apply during pre-stroke, acute, sub-acute and post-stroke stages. The early diagnosis of diabetes as a comorbidity for stroke, as well as tailored post-stroke management of diabetes, is pivotal to our efforts to limit the burden. Increasing awareness and involvement of neurologists in the management of diabetes and other cardiovascular risk factors is desirable towards improving stroke prevention and efficacy of reperfusion therapy in acute stroke patients with diabetes.
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Affiliation(s)
- Sian A Bradley
- University of New South Wales (UNSW), South Western Sydney Clinical School, Liverpool, New South Wales, Australia
- Neurovascular Imaging Laboratory, Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
| | - Kevin J Spring
- University of New South Wales (UNSW), South Western Sydney Clinical School, Liverpool, New South Wales, Australia
- NSW Brain Clot Bank, NSW Health Pathology, Sydney, New South Wales, Australia
- Medical Oncology Group, Liverpool Clinical School, Western Sydney University & Ingham Institute of Applied Medical Research, Sydney, New South Wales, Australia
| | - Roy G Beran
- University of New South Wales (UNSW), South Western Sydney Clinical School, Liverpool, New South Wales, Australia
- Department of Neurology and Neurophysiology, Liverpool Hospital and South Western Sydney Local Health District, Sydney, New South Wales, Australia
- Medical School, Griffith University, Southport, Queensland, Australia
- Sechenov Moscow First State University, Moscow, Russia
| | | | - Murray C Killingsworth
- University of New South Wales (UNSW), South Western Sydney Clinical School, Liverpool, New South Wales, Australia
- Neurovascular Imaging Laboratory, Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
- NSW Brain Clot Bank, NSW Health Pathology, Sydney, New South Wales, Australia
- Department of Anatomical Pathology, Correlatively Microscopy Facility, NSW Health Pathctology, Sydney, New South Wales, Australia
| | - Sonu M M Bhaskar
- University of New South Wales (UNSW), South Western Sydney Clinical School, Liverpool, New South Wales, Australia
- Neurovascular Imaging Laboratory, Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
- NSW Brain Clot Bank, NSW Health Pathology, Sydney, New South Wales, Australia
- Department of Neurology and Neurophysiology, Liverpool Hospital and South Western Sydney Local Health District, Sydney, New South Wales, Australia
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Saeedi M, Mehranfar F, Ghorbani F, Eskandari M, Ghorbani M, Babaeizad A. Review of pharmaceutical and therapeutic approaches for type 2 diabetes and related disorders. Recent Pat Biotechnol 2022; 16:188-213. [PMID: 35088682 DOI: 10.2174/1872208316666220128102934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 11/05/2021] [Accepted: 11/30/2021] [Indexed: 11/22/2022]
Abstract
One of the essential diseases that are increasing in the world is type 2 diabetes (T2D), which many people around the world live with this disease. Various studies have revealed that insulin resistance, lessened insulin production has been associated with T2D, and they also show that this disease can have a genetic origin and is associated with different genes such as KCNQ1, PPAR-γ, calpain-10, ADIPOR2, TCF7L2 that can be utilized as a therapeutic target. Different therapeutic approaches and strategies such as exercise and diet, pharmacological approaches, and utilization of nanoparticles in drug delivery and gene therapy can be effective in the treatment and control of T2D. Glucagon-like peptide 1 (GLP-1) and sodium glucose cotransporter-2 (SGLT2) have both been considered as drug classes in the treatment of T2D and T2D-related diseases such as cardiovascular disease and renal disease, and have considerable influences such as diminished cardiovascular mortality in individuals with T2D, ameliorate postprandial glycaemia, ameliorate fasting glycaemia, and diminish body weight on disease treatment and improvement process. In the present review article, we have made an attempt to explore the risk factors, Genes, and diseases associated with T2D, therapeutic approaches in T2D, the influences of drugs such as Dapagliflozin, Metformin, Acarbose, Januvia (Sitagliptin), and Ertugliflozin on T2D in clinical trials and animal model studies. Research in clinical trials has promising results that support the role of these drug approaches in T2D prophylaxis and ameliorate safety even though additional clinical research is still obligatory.
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Affiliation(s)
- Mohammad Saeedi
- Department of Hematology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mehranfar
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fateme Ghorbani
- Department of immunology, Semnan university of Medical sciences, Semnan, Iran
| | - Mohammadali Eskandari
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Majid Ghorbani
- Department of Hematology, Mashhad University of Medical sciences, Mashhad, Iran
| | - Ali Babaeizad
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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Joseph JJ, Deedwania P, Acharya T, Aguilar D, Bhatt DL, Chyun DA, Di Palo KE, Golden SH, Sperling LS. Comprehensive Management of Cardiovascular Risk Factors for Adults With Type 2 Diabetes: A Scientific Statement From the American Heart Association. Circulation 2022; 145:e722-e759. [PMID: 35000404 DOI: 10.1161/cir.0000000000001040] [Citation(s) in RCA: 297] [Impact Index Per Article: 99.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cardiovascular disease remains the leading cause of death in patients with diabetes. Cardiovascular disease in diabetes is multifactorial, and control of the cardiovascular risk factors leads to substantial reductions in cardiovascular events. The 2015 American Heart Association and American Diabetes Association scientific statement, "Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence," highlighted the importance of modifying various risk factors responsible for cardiovascular disease in diabetes. At the time, there was limited evidence to suggest that glucose-lowering medications reduce the risk of cardiovascular events. At present, several large randomized controlled trials with newer antihyperglycemic agents have been completed, demonstrating cardiovascular safety and reduction in cardiovascular outcomes, including cardiovascular death, myocardial infarction, stroke, and heart failure. This AHA scientific statement update focuses on (1) the evidence and clinical utility of newer antihyperglycemic agents in improving glycemic control and reducing cardiovascular events in diabetes; (2) the impact of blood pressure control on cardiovascular events in diabetes; and (3) the role of newer lipid-lowering therapies in comprehensive cardiovascular risk management in adults with diabetes. This scientific statement addresses the continued importance of lifestyle interventions, pharmacological therapy, and surgical interventions to curb the epidemic of obesity and metabolic syndrome, important precursors of prediabetes, diabetes, and comorbid cardiovascular disease. Last, this scientific statement explores the critical importance of the social determinants of health and health equity in the continuum of care in diabetes and cardiovascular disease.
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Song Y, Huang C, Sin J, Germano JDF, Taylor DJR, Thakur R, Gottlieb RA, Mentzer RM, Andres AM. Attenuation of Adverse Postinfarction Left Ventricular Remodeling with Empagliflozin Enhances Mitochondria-Linked Cellular Energetics and Mitochondrial Biogenesis. Int J Mol Sci 2021; 23:437. [PMID: 35008865 PMCID: PMC8745294 DOI: 10.3390/ijms23010437] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 12/23/2022] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin are known to reduce the risk of hospitalizations related to heart failure irrespective of diabetic state. Meanwhile, adverse cardiac remodeling remains the leading cause of heart failure and death in the USA. Thus, understanding the mechanisms that are responsible for the beneficial effects of SGLT2 inhibitors is of the utmost relevance and importance. Our previous work illustrated a connection between adverse cardiac remodeling and the regulation of mitochondrial turnover and cellular energetics using a short-acting glucagon-like peptide-1 receptor agonist (GLP1Ra). Here, we sought to determine if the mechanism of the SGLT2 inhibitor empagliflozin (EMPA) in ameliorating adverse remodeling was similar and/or to identify what differences exist, if any. To this end, we administered permanent coronary artery ligation to induce adverse remodeling in wild-type and Parkin knockout mice and examined the progression of adverse cardiac remodeling with or without EMPA treatment over time. Like GLP1Ra, we found that EMPA affords a robust attenuation of PCAL-induced adverse remodeling. Interestingly, unlike the GLP1Ra, EMPA does not require Parkin to improve/maintain mitochondria-related cellular energetics and afford its benefits against developing adverse remodeling. These findings suggests that further investigation of EMPA is warranted as a potential path for developing therapy against adverse cardiac remodeling for patients that may have Parkin and/or mitophagy-related deficiencies.
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Affiliation(s)
- Yang Song
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Chengqun Huang
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Jon Sin
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
- University of Alabama, Birmingham, AL 35294, USA
| | - Juliana de F. Germano
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - David J. R. Taylor
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Reetu Thakur
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Roberta A. Gottlieb
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Robert M. Mentzer
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
| | - Allen M. Andres
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Y.S.); (C.H.); (J.S.); (J.d.F.G.); (D.J.R.T.); (R.T.); (R.A.G.); (R.M.M.J.)
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Afzal M, Al-Abbasi FA, Nadeem MS, Alshehri S, Ghoneim MM, Imam SS, Almalki WH, Kazmi I. Sodium-Glucose Cotransporter-2 Inhibitors Improve Cardiovascular Dysfunction in Type 2 Diabetic East Asians. Metabolites 2021; 11:794. [PMID: 34822452 PMCID: PMC8622829 DOI: 10.3390/metabo11110794] [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: 09/29/2021] [Revised: 11/15/2021] [Accepted: 11/17/2021] [Indexed: 11/22/2022] Open
Abstract
In East Asians, the incidence of type 2 DM (T2DM) has increased as a result of major alterations in life. Cardiovascular problems are more likely in those with T2DM. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are novel insulin-independent antihyperglycemic drugs that limit renal glucose reabsorption and thereby improve glycemic control. They are used alone or in combination with insulin and other antihyperglycemic medications to treat diabetes, and they are also helpful in protecting against the progression of complications. This review has evaluated the available evidence not only on the efficacy of SGLT2 inhibitors in T2DM, but also on their favourable cardiovascular events in East Asians. DM is an independent risk factor for cardiovascular diseases. As a result, in addition to glycemic control in diabetes management, the therapeutic goal in East Asian diabetic patients should be to improve adverse cardiovascular outcomes. Besides establishing antidiabetic effects, several studies have reported cardioprotective benefits of SGLT2 inhibitors via numerous pathways. SGLT2 inhibitors show promising antidiabetic drugs with potential cardiovascular advantages, given that a high number of diabetic patients in East Asia have co-existing cardiovascular disorders. Despite significant positive results in favour of SGLT2, more research is needed to determine how SGLT2 inhibitors exert these impressive cardiovascular effects.
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Affiliation(s)
- Muhammad Afzal
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia;
| | - Fahad A. Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (F.A.A.-A.); (M.S.N.)
| | - Muhammad Shahid Nadeem
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (F.A.A.-A.); (M.S.N.)
| | - Sultan Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (S.S.I.)
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia;
| | - Syed Sarim Imam
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (S.S.I.)
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
| | - Imran Kazmi
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia;
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Chen Y, Qie X, Quan W, Zeng M, Qin F, Chen J, Adhikari B, He Z. Omnifarious fruit polyphenols: an omnipotent strategy to prevent and intervene diabetes and related complication? Crit Rev Food Sci Nutr 2021:1-37. [PMID: 34792409 DOI: 10.1080/10408398.2021.2000932] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus is a metabolic syndrome which cannot be cured. Recently, considerable interest has been focused on food ingredients to prevent and intervene in complications of diabetes. Polyphenolic compounds are one of the bioactive phytochemical constituents with various biological activities, which have drawn increasing interest in human health. Fruits are part of the polyphenol sources in daily food consumption. Fruit-derived polyphenols possess the anti-diabetic activity that has already been proved either from in vitro studies or in vivo studies. The mechanisms of fruit polyphenols in treating diabetes and related complications are under discussion. This is a comprehensive review on polyphenols from the edible parts of fruits, including those from citrus, berries, apples, cherries, mangoes, mangosteens, pomegranates, and other fruits regarding their potential benefits in preventing and treating diabetes mellitus. The signal pathways of characteristic polyphenols derived from fruits in reducing high blood glucose and intervening hyperglycemia-induced diabetic complications were summarized.
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Affiliation(s)
- Yao Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Xuejiao Qie
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Wei Quan
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Maomao Zeng
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Fang Qin
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Jie Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Benu Adhikari
- School of Science, RMIT University, Melbourne, Victoria, Australia
| | - Zhiyong He
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
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Mozawa K, Kubota Y, Hoshika Y, Tara S, Tokita Y, Yodogawa K, Iwasaki Y, Yamamoto T, Takano H, Tsukada Y, Asai K, Miyamoto M, Miyauchi Y, Kodani E, Maruyama M, Tanabe J, Shimizu W. Empagliflozin confers reno-protection in acute myocardial infarction and type 2 diabetes mellitus. ESC Heart Fail 2021; 8:4161-4173. [PMID: 34235875 PMCID: PMC8497324 DOI: 10.1002/ehf2.13509] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/02/2021] [Accepted: 06/24/2021] [Indexed: 11/08/2022] Open
Abstract
AIMS Although the reno-protective effects of sodium-glucose cotransporter 2 inhibitors are known in patients with heart failure or type 2 diabetes mellitus (T2DM), this effect has not been confirmed in patients with acute myocardial infarction (AMI). METHODS AND RESULTS The prospective, multicentre, randomized, double-blind, placebo-controlled EMBODY trial investigated patients with AMI and T2DM in Japan. The eligible patients included adults aged 20 years or older, diagnosed with AMI and T2DM, and who could be discharged within 2-12 weeks after the onset of AMI. One hundred and five patients were randomized (1:1) to receive once daily 10 mg empagliflozin or placebo within 2 weeks of AMI onset. In this sub-analysis, we investigated the time course of renal functional parameters such as serum creatinine levels and estimated glomerular filtration rate (eGFR) from baseline to Weeks 4, 12, and 24. Ninety-six patients (64 ± 11 years, 78 male) were included in the full analysis (n = 46 and 50 in the empagliflozin and placebo groups, respectively). We used serum creatinine and eGFR as indicators of renal function. In the placebo group, eGFR decreased from 66.14 mL/min/1.73 m2 at baseline to 62.77 mL/min/1.73 m2 by Week 24 (P = 0.023) but remained unchanged in the empagliflozin group (from 64.60 to 64.36 mL/min/1.73 m2 , P = 0.843). In the latter group, uric acid improved from 5.8 mg/dL at baseline to 4.9 mg/dL at Week 24 (P < 0.001). In the earlier analysis of 56 patients with eGFR ≥ 60 mL/min/1.73 m2 , the eGFR decreased and the serum creatinine increased from baseline to 24 weeks in the placebo group, significantly different to the empagliflozin group (-6.61 vs. +0.22 mL/min/1.73 m2 , P = 0.008 and +0.063 vs. -0.001 mg/dL, P = 0.030, respectively). The changes in serum creatinine and eGFR from baseline to Week 24 were significantly correlated with those in uric acid in the placebo group (r = 0.664, P < 0.001 and r = -0.675, P < 0.001, respectively) but not in the empagliflozin group. CONCLUSIONS Empagliflozin prevented the kidney functional decline in patients with AMI and T2DM, especially those with baseline eGFR ≥ 60 mL/min/1.73 m2 . Early administration of sodium-glucose cotransporter 2 inhibitors in these patients is considered desirable for renal protection.
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Affiliation(s)
- Kosuke Mozawa
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Yoshiaki Kubota
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Yu Hoshika
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Shuhei Tara
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Yukichi Tokita
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Kenji Yodogawa
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Yu‐ki Iwasaki
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Takeshi Yamamoto
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Hitoshi Takano
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Yayoi Tsukada
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Kuniya Asai
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Masaaki Miyamoto
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
| | - Yasushi Miyauchi
- Department of Cardiovascular MedicineNippon Medical School Chiba Hokuso HospitalChibaJapan
| | - Eitaro Kodani
- Department of Cardiovascular MedicineNippon Medical School Tama Nagayama HospitalTokyoJapan
| | - Mitsunori Maruyama
- Department of Cardiovascular MedicineNippon Medical School Musashi Kosugi HospitalTokyoJapan
| | - Jun Tanabe
- Department of Cardiovascular MedicineShizuoka Medical CenterShizuokaJapan
| | - Wataru Shimizu
- Department of Cardiovascular MedicineNippon Medical School1‐1‐5, Sendagi, Bunkyo‐kuTokyo113‐0022Japan
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SGLT-2 inhibitors reduce the risk of cerebrovascular/cardiovascular outcomes and mortality: A systematic review and meta-analysis of retrospective cohort studies. Pharmacol Res 2021; 172:105836. [PMID: 34418562 DOI: 10.1016/j.phrs.2021.105836] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/15/2021] [Accepted: 08/16/2021] [Indexed: 12/28/2022]
Abstract
Despite Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been associated with a reduced risk of heart failure in patients with type 2 diabetes mellitus (T2DM), the effect observed for other cardiovascular (CV) and cerebrovascular outcomes differed among clinical trials. Different observational studies have investigated the effects of SGLT2 inhibitors on these outcomes and mortality. The present meta-analysis aimed to assess the effects of SGLT2 inhibitors on the risk of CV (major adverse CV event - MACE, non-fatal myocardial infarction, or hospitalization for heart failure) and cerebrovascular (stroke) outcomes. A systematic review was conducted in Pubmed from January 1, 2012 to November 31, 2020. Only retrospective cohort studies including as control group users of dipeptidyl peptidase-4 (DPP-4) inhibitors or non-SGLT2 inhibitors were retained and analysed separately. A random effect meta-analysis approach was used. This study followed the PRISMA statement. Of the 158 references identified, 20 articles were selected for meta-analysis, of which 13 considered the comparison with DPP-4 inhibitors and 7 the comparison with non-SGLT2 inhibitors. The pooled intention-to-treat analysis showed a reduced risk of stroke with SGLT2 inhibitors compared to DPP-4 inhibitors (Hazard ratio HR, 0.89; 95%CI, 0.82-0.96; I2 = 25%; p = 0.25) and non-SGLT2 inhibitors (HR, 0.83; 95%CI, 0.77-0.91; I2 = 11%; p = 0.34). Finally, SGLT2 inhibitors were also associated with a reduced risk of CV outcomes and mortality in all comparisons. Our data support contemporary society recommendations to prioritise the use of SGLT2 inhibitors in patients with T2DM and at high risk for CV complications.
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Haloot J, Krokar L, Badin A. Effect of SLGT2 Inhibitors on Patients with Atrial Fibrillation. J Atr Fibrillation 2021; 14:20200502. [PMID: 34950375 PMCID: PMC8691277 DOI: 10.4022/jafib.20200502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/16/2021] [Accepted: 05/12/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND Sodium glucose cotransporter 2 (SGLT2) inhibitors have been associated with various cardiovascular benefits. There is limited data examining the effect of these medications on atrial fibrillation (AF) associated clinical outcomes. We compared ischemic stroke, acute coronary syndrome (ACS), cardioversion, and all-cause mortality outcomes in AF patients on SGLT2 inhibitors to propensity matched controls. MATERIALS AND METHODS We conducted a retrospective study with a global medical research network database. AF patients were identified via ICD codes that must have been present for at least one month. Patients on SGLT2 inhibitors were identified as those on dapagliflozin, empagliflozin, or canagliflozin for at least one month. AF patients on SGLT2 inhibitors were propensity matched to those not on SGLT2 inhibitors based on age, race, ethnicity, cardiovascular comorbidities, valvular disease, pulmonary disease, urinary diseases, cardiovascular procedures, cardiovascular medications, and anticoagulants. We examined incidence of ischemic stroke, at least one ACS episode, cardioversion, and all-cause mortality. RESULTS In 26,269 AF patients, SGLT2 inhibitors were associated with lower risk of cardioversion (HR 0.921, 95% CI 0.841 - 0.999, p = 0.0245) and all-cause mortality (HR 0.676, 95% CI 0.635 - 0.721, p < 0.0001). However, there was an association with increased risk for ischemic stroke (HR 1.081, 95% CI 1.012 - 1.154, p 0.0201). There was no clear association with ACS events. CONCLUSIONS In patients with AF, use of SGLT2 inhibitors was associated with a lower risk of cardioversion and all-cause mortality and higher probability of survival based on Kaplan-Meier analysis.
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Affiliation(s)
- Justin Haloot
- University of Texas Health San Antonio, San Antonio, TX
| | | | - Auroa Badin
- University of Texas Health San Antonio, San Antonio, TX
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Tsai WH, Chuang SM, Liu SC, Lee CC, Chien MN, Leung CH, Liu SJ, Shih HM. Effects of SGLT2 inhibitors on stroke and its subtypes in patients with type 2 diabetes: a systematic review and meta-analysis. Sci Rep 2021; 11:15364. [PMID: 34321571 PMCID: PMC8319393 DOI: 10.1038/s41598-021-94945-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/19/2021] [Indexed: 02/07/2023] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown impressive effects in reducing major vascular events in several randomized controlled trials (RCTs). The purpose of this study was to perform a meta-analysis to evaluate the effect of SGLT2 inhibitors on the risk of stroke and its subtypes. All data from prospective RCTs up to 20 October 2020 involving SGLT2 inhibitors that reported stroke events as the primary endpoint or safety in subjects with type 2 diabetes were subjected to meta-analysis. Five eligible RCTs (EMPA-REG, CANVAS, DECLARE-TIMI 58, CREDENCE and VERTIS CV) involving 46,969 participants were included. Pooled analysis of the RCTs showed no significant effect of SGLT2 inhibitors on total stroke [risk ratio (RR) = 0.95; 95% confidence interval (CI) 0.79-1.13, P = 0.585]. Subgroup analysis indicated that SGLT2 inhibitors had no significant effect against fatal stroke, non-fatal stroke, ischemic stroke or transient ischemic attack. When only hemorrhagic stroke was included, SGLT2 inhibitors were associated with a significant 50% reduction compared with placebo (RR = 0.49, 95% CI 0.30-0.82, P = 0.007). This meta-analysis shows that SGLT2 inhibitors have a neutral effect on the risk of stroke and its subtypes but a potential protective effect against hemorrhagic stroke.
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Affiliation(s)
- Wen-Hsuan Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei, 10449, Taiwan
| | - Shih-Ming Chuang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei, 10449, Taiwan. .,Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan. .,Department of Medicine, Mackay Medical Collage, New Taipei City, Taiwan.
| | - Sung-Chen Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei, 10449, Taiwan.,Department of Medicine, Mackay Medical Collage, New Taipei City, Taiwan
| | - Chun-Chuan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei, 10449, Taiwan
| | - Ming-Nan Chien
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei, 10449, Taiwan.,Department of Medicine, Mackay Medical Collage, New Taipei City, Taiwan
| | - Ching-Hsiang Leung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei, 10449, Taiwan
| | - Shu-Jung Liu
- Medical Library, MacKay Memorial Hospital, Tamsui Branch, New Taipei City, Taiwan
| | - Hong-Mou Shih
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.,Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
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Schwarzenbach M, Bernhard FE, Czerlau C, Sidler D. Chances and risks of sodium-glucose cotransporter 2 inhibitors in solid organ transplantation: A review of literatures. World J Transplant 2021; 11:254-262. [PMID: 34316450 PMCID: PMC8290999 DOI: 10.5500/wjt.v11.i7.254] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 05/17/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Solid organ transplantation offers life-saving treatment for patients with end-organ dysfunction. Patient survival and quality of life have improved over the past few decades as a result of pharmacological development, expansion of the donor pool, technological advances and standardization of practices related to transplantation. Still, transplantation is associated with cardiovascular complications, of which post-transplant diabetes mellitus (PTDM) is one of the most important. PTDM increases mortality, which is best documented in patients who have received kidney and heart transplants. PTDM results from traditional risk factors seen in patients with type 2 diabetes mellitus, but also from specific post-transplant risk factors such as metabolic side effects of immunosuppressive drugs, post-transplant viral infections and hypomagnesemia. Oral hypoglycaemic agents are the first choice for the treatment of type 2 diabetes mellitus in non-transplanted patients. However, the evidence on the safety and efficacy of oral hypoglycaemic agents in transplant recipients is limited. The favourable risk/benefit ratio, which is suggested by large-scale and long-term studies on new glucose-lowering drug classes such as glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, makes studies warranted to assess the potential role of these agents in the management of PTDM.
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Affiliation(s)
- Marlene Schwarzenbach
- Department of Nephrology and Hypertension, University Hospital Insel Bern, Bern 3010, Switzerland
| | - Flavia Elena Bernhard
- Department of Nephrology and Hypertension, University Hospital Insel Bern, Bern 3010, Switzerland
| | - Cecilia Czerlau
- Department of Nephrology and Hypertension, University Hospital Insel Bern, Bern 3010, Switzerland
| | - Daniel Sidler
- Department of Nephrology and Hypertension, University Hospital Insel Bern, Bern 3010, Switzerland
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46
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Zhai M, Du X, Liu C, Xu H. The Effects of Dapagliflozin in Patients With Heart Failure Complicated With Type 2 Diabetes: A Meta-Analysis of Placebo-Controlled Randomized Trials. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2021; 2:703937. [PMID: 36994345 PMCID: PMC10012068 DOI: 10.3389/fcdhc.2021.703937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/11/2021] [Indexed: 01/10/2023]
Abstract
BackgroundCardiovascular disease threatens the health and quality of life of individuals, particularly those with type II diabetes. Recently, some studies have reported the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing the rates of hospitalization or urgent visits, resulting in IV therapy for heart failure in patients with type 2 diabetes mellitus (T2DM).MethodsWe did a comprehensive search in electronic databases from inception through July 2020 for randomized-controlled trials, using the keywords “sodium-glucose cotransporter-2 inhibitor”, “dapagliflozin”, “heart failure”, “cardiovascular outcomes”, “major adverse cardiovascular events”, “all-cause mortality”, and “cardiovascular death”. Random-effects summary odds ratios (OR) were constructed using M-L heterogeneity model.ResultsFive trials with 5,252 patients were ultimately included. The incidence of hospitalization for heart failure (HHF) (n=4, OR=0.74; 95% CI, 0.61 to 0.88; I2 = 0%) and all-cause mortality (ACM, n=4, OR=0.76; 95% CI, 0.66 to 0.94; I2 = 0%); was reduced by dapagliflozin, respectively, in all heart failure patients, without obvious heterogeneity. The incidence of cardiovascular death in dapagliflozin was lower than that in placebo without statistically significant (CVD, n=5, OR=0.84; 95% CI, 0.69 to 1.03; I2 = 0%). In HFrEF subgroup, dapagliflozin was associated with a reduced incidence of hospitalization for heart failure (n=4, OR=0.74; 95% CI, 0.60 to 0.91; I2 = 0%), cardiovascular death (n=4, OR=0.72; 95% CI, 0.58 to 0.91; I2 = 8%), and all-cause mortality (n=3, OR=0.70; 95% CI, 0.50 to 0.99; I2 = 43%) without significant heterogeneity. In contrast, in the HFpEF subgroup, there was no difference in the incidence of cardiovascular death (n=2, OR=1.45; 95% CI, 0.95 to 2.22; I2 = 0%) and all-cause mortality (n=2, OR=1.04; 95% CI, 0.76 to 1.43; I2 = 0%) between dapagliflozin and placebo.ConclusionIn our study, dapagliflozin performed a statistical reduction in the rate of heart failure hospitalization, cardiovascular death, and all-cause mortality in patients with HFrEF and diabetes. However, in the HFpEF subgroup, dapagliflozin did not show a significant cardiovascular protective effect.
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Zhang Y, Lin X, Chu Y, Chen X, Du H, Zhang H, Xu C, Xie H, Ruan Q, Lin J, Liu J, Zeng J, Ma K, Chai D. Dapagliflozin: a sodium-glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced cardiac fibrotic remodeling by regulating TGFβ1/Smad signaling. Cardiovasc Diabetol 2021; 20:121. [PMID: 34116674 PMCID: PMC8196449 DOI: 10.1186/s12933-021-01312-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/03/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms in part, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms. METHODS Sprague-Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II (1 μM) with or without the indicated concentration (0.5, 1, 10 μM) of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes. RESULTS DAPA pretreatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA pretreatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling. CONCLUSION DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a non-glucose-lowering dependent manner.
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MESH Headings
- Angiotensin II
- Animals
- Antifibrotic Agents/pharmacology
- Benzhydryl Compounds/pharmacology
- Cells, Cultured
- Disease Models, Animal
- Fibroblasts/drug effects
- Fibroblasts/metabolism
- Fibroblasts/pathology
- Fibrosis
- Glucosides/pharmacology
- Hypertrophy, Left Ventricular/chemically induced
- Hypertrophy, Left Ventricular/metabolism
- Hypertrophy, Left Ventricular/pathology
- Hypertrophy, Left Ventricular/prevention & control
- Male
- Myocardium/metabolism
- Myocardium/pathology
- Rats, Sprague-Dawley
- Signal Transduction
- Smad Proteins/metabolism
- Sodium-Glucose Transporter 2 Inhibitors/pharmacology
- Transforming Growth Factor beta1/metabolism
- Ventricular Dysfunction, Left/chemically induced
- Ventricular Dysfunction, Left/metabolism
- Ventricular Dysfunction, Left/pathology
- Ventricular Dysfunction, Left/prevention & control
- Ventricular Function, Left/drug effects
- Ventricular Remodeling/drug effects
- Rats
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Affiliation(s)
- Yuze Zhang
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Xiaoyan Lin
- Echocardiological Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Yong Chu
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Xiaoming Chen
- Editorial Department of Chinese Journal of Hypertension, Fuzhou, 350005, China
| | - Heng Du
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Hailin Zhang
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Changsheng Xu
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Hong Xie
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Qinyun Ruan
- Echocardiological Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Jinxiu Lin
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Jie Liu
- School of Pharmacy College, Xiamen University, Xiamen, 361102, China
| | - Jinzhang Zeng
- School of Pharmacy College, Xiamen University, Xiamen, 361102, China
| | - Ke Ma
- Clinical Research Center, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.
| | - Dajun Chai
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China.
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Jhuo SJ, Liu IH, Tasi WC, Chou TW, Lin YH, Wu BN, Lee KT, Lai WT. Characteristics of Ventricular Electrophysiological Substrates in Metabolic Mice Treated with Empagliflozin. Int J Mol Sci 2021; 22:ijms22116105. [PMID: 34198942 PMCID: PMC8200966 DOI: 10.3390/ijms22116105] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 01/10/2023] Open
Abstract
Empagliflozin (EMPA) is a sodium–glucose transporter 2 (SGLT2) inhibitor that functions as a new-generation glucose-lowering agent and has been proven to be beneficial for patients with cardiovascular diseases. However, the possible benefits and mechanisms of its antiarrhythmic effects in cardiac tissue have not yet been reported. In this study, we elucidated the possible antiarrhythmic effects and mechanisms of EMPA treatment in cardiac tissues of metabolic syndrome (MS) mice. A total of 20 C57BL/6J mice (age: 8 weeks) were divided into four groups: (1) control group, mice fed a standard chow for 16 weeks; (2) MS group, mice fed a high-fat diet for 16 weeks; (3) EMPA group, mice fed a high-fat diet for 12 weeks and administered EMPA at 10 mg/kg daily for the following 4 weeks; and (4) glibenclamide (GLI) group, mice fed a high-fat diet for 12 weeks and administered GLI at 0.6 mg/kg daily for the following 4 weeks. All mice were sacrificed after 16 weeks of feeding. The parameters of electrocardiography (ECG), echocardiography, and the effective refractory period (ERP) of the left ventricle were recorded. The histological characteristics of cardiac tissue, including connexin (Cx) expression and fibrotic areas, were also evaluated. Compared with the MS group, the ECG QT interval in the EMPA group was significantly shorter (57.06 ± 3.43 ms vs. 50.00 ± 2.62 ms, p = 0.011). The ERP of the left ventricle was also significantly shorter in the EMPA group than that in the GLI group (20.00 ± 10.00 ms vs. 60.00 ± 10.00 ms, p = 0.001). The expression of Cx40 and Cx43 in ventricular tissue was significantly lower in the MS group than in the control group. However, the downregulation of Cx40 and Cx43 was significantly attenuated in the EMPA group compared with the MS and GLI groups. The fibrotic areas of ventricular tissue were also fewer in the EMPA group than that in the MS group. In this study, the ECG QT interval in the EMPA group was shorter than that in the MS group. Compared with the MS group, the EMPA group exhibited significant attenuation of downregulated connexin expression and significantly fewer fibrotic areas in ventricles. These results may provide evidence of possible antiarrhythmic effects of EMPA.
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Affiliation(s)
- Shih-Jie Jhuo
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80701, Taiwan; (S.-J.J.); (I.-H.L.); (W.-C.T.); (T.-W.C.); (Y.-H.L.); (W.-T.L.)
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - I-Hsin Liu
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80701, Taiwan; (S.-J.J.); (I.-H.L.); (W.-C.T.); (T.-W.C.); (Y.-H.L.); (W.-T.L.)
| | - Wei-Chung Tasi
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80701, Taiwan; (S.-J.J.); (I.-H.L.); (W.-C.T.); (T.-W.C.); (Y.-H.L.); (W.-T.L.)
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
- Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
| | - Te-Wu Chou
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80701, Taiwan; (S.-J.J.); (I.-H.L.); (W.-C.T.); (T.-W.C.); (Y.-H.L.); (W.-T.L.)
| | - Yi-Hsiung Lin
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80701, Taiwan; (S.-J.J.); (I.-H.L.); (W.-C.T.); (T.-W.C.); (Y.-H.L.); (W.-T.L.)
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
| | - Bin-Nan Wu
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - Kun-Tai Lee
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80701, Taiwan; (S.-J.J.); (I.-H.L.); (W.-C.T.); (T.-W.C.); (Y.-H.L.); (W.-T.L.)
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
- Correspondence:
| | - Wen-Ter Lai
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80701, Taiwan; (S.-J.J.); (I.-H.L.); (W.-C.T.); (T.-W.C.); (Y.-H.L.); (W.-T.L.)
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49
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Nassif ME, Windsor SL, Tang F, Husain M, Inzucchi SE, McGuire DK, Pitt B, Scirica BM, Austin B, Fong MW, LaRue SJ, Umpierrez G, Hartupee J, Khariton Y, Malik AO, Ogunniyi MO, Wenger NK, Kosiborod MN. Dapagliflozin effects on lung fluid volumes in patients with heart failure and reduced ejection fraction: Results from the DEFINE-HF trial. Diabetes Obes Metab 2021; 23:1426-1430. [PMID: 33606921 DOI: 10.1111/dom.14352] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/02/2021] [Accepted: 02/15/2021] [Indexed: 11/28/2022]
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular death or worsening heart failure (HF), and improve symptom burden, physical function and quality of life in patients with HF and reduced ejection fraction. The mechanisms of the HF benefits of SGLT2 inhibitors, however, remain unclear. In this substudy of the DEFINE-HF trial, patients randomized to dapagliflozin or placebo had lung fluid volumes (LFVs) measured by remote dieletric sensing at baseline and after 12 weeks of therapy. A significantly greater proportion of dapagliflozin-treated patients (as compared with placebo) experienced improvement in LFVs and fewer dapagliflozin-treated patients had no change or deterioration in LFVs after 12 weeks of treatment. To our knowledge, this is the first study to suggest a direct effect of dapagliflozin (or any SGLT2 inhibitor) on more effective "decongestion", contributing in a meaningful way to the ongoing debate regarding the mechanisms of SGLT2 inhibitor HF benefits.
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Affiliation(s)
- Michael E Nassif
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri
- University of Missouri-Kansas City, Kansas City, Missouri
| | | | - Fengming Tang
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri
| | - Mansoor Husain
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada
- University of Toronto, Toronto, Ontario, Canada
- Peter Munk Cardiac Centre, Toronto, Ontario, Canada
| | | | - Darren K McGuire
- University of Texas Southwestern Medical Center and Parkland Health and Hospital System, Dallas, Texas
| | - Bertram Pitt
- University of Michigan School of Medicine, Ann Arbor, Michigan
| | - Benjamin M Scirica
- Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Bethany Austin
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri
- University of Missouri-Kansas City, Kansas City, Missouri
| | - Michael W Fong
- Keck School of Medicine of USC, University of Southern California, Los Angeles, California
| | - Shane J LaRue
- Washington University School of Medicine, St. Louis, Missouri
| | | | - Justin Hartupee
- Washington University School of Medicine, St. Louis, Missouri
| | - Yevgeniy Khariton
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri
- University of Missouri-Kansas City, Kansas City, Missouri
| | - Ali O Malik
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri
- University of Missouri-Kansas City, Kansas City, Missouri
| | | | | | - Mikhail N Kosiborod
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri
- University of Missouri-Kansas City, Kansas City, Missouri
- The George Institute for Global Health, Sydney, New South Wales, Australia
- University of New South Wales, Sydney, New South Wales, Australia
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50
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Ferrannini G, Savarese G, Rydén L. Sodium-glucose transporter inhibition in heart failure: from an unexpected side effect to a novel treatment possibility. Diabetes Res Clin Pract 2021; 175:108796. [PMID: 33845051 DOI: 10.1016/j.diabres.2021.108796] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 12/17/2022]
Abstract
Sodium-glucose transporter-2 inhibitors (SGLT2i), originally launched as glucose-lowering drugs, have been studied in large cardiovascular outcome trials to ascertain safety. Surprisingly, these compounds reduced the risk of cardiovascular events (cardiovascular death, non-fatal myocardial and non-fatal stroke) and total mortality. The mechanisms behind this benefit are only partly understood, but a major contributor is the reduction of heart failure hospitalisations, evident already within weeks after the initiation of the SGLT2i. SGLT2 inhibition increases urinary glucose excretion, thereby improving glycaemic control in an insulin-independent manner. Moreover, SGLT2i potentially impact the cardiovascular system both indirectly via weight loss and blood pressure lowering and directly through osmotic diuresis and increased sodium excretion and presumably by improving myocardial energetics. The aim of this review is to summarise evidence from all major outcome trials investigating SGLT2i in patients with diabetes, as well as recent evidence from trials in heart failure patients without glucose perturbations, which pave the way for novel treatment of large groups of patients. The results of these studies have been taken into account in recently issued guidelines for the management of diabetes and cardiovascular disease. An important task for diabetologists, cardiologists and general practitioners is to incorporate them into clinical practice to the benefit of many patients.
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Affiliation(s)
- Giulia Ferrannini
- Department of Medicine K2, Karolinska Institutet, 171 76 Stockholm, Sweden
| | - Gianluigi Savarese
- Department of Medicine K2, Karolinska Institutet, 171 76 Stockholm, Sweden
| | - Lars Rydén
- Department of Medicine K2, Karolinska Institutet, 171 76 Stockholm, Sweden.
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