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Zhuang W, Park M, Jeong J, Kim HR, Jang Y, Seo MS, An JR, Park H, Jung WK, Choi IW, Park WS. The sodium-glucose cotransporter 2 inhibitor tofogliflozin induces vasodilation of rabbit femoral artery by activating Kv channels, the SERCA pump, and the sGC/cGMP pathway. Eur J Pharmacol 2025; 996:177595. [PMID: 40189081 DOI: 10.1016/j.ejphar.2025.177595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/21/2025] [Accepted: 04/02/2025] [Indexed: 04/11/2025]
Abstract
Tofogliflozin is a sodium-glucose cotransporter 2 inhibitor widely used to treat type 2 diabetes mellitus, but it also exhibits cardio-protective effects. This study investigated the vasodilatory action of tofogliflozin using rabbit femoral artery rings pre-contracted with phenylephrine (1 μM). The results showed the concentration-dependent induction of vasodilation by tofogliflozin, a response that remained unchanged following endothelial removal, pretreatment with the nitric oxide synthase inhibitor L-NAME (100 μM), or the inhibition of low- and intermediate-conductance Ca2+-activated K+ channels using apamin (1 μM) in combination with TRAM-34 (1 μM). Furthermore, pretreatment with the voltage-dependent K+ (Kv) channel inhibitor 4-AP (3 mM) reduced the vasodilatory effects of tofogliflozin whereas pretreatment with the ATP-sensitive K+ channel inhibitor glibenclamide (10 μM) or the large-conductance Ca2+-activated K+ channel inhibitor paxilline (1 μM) did not. Notably, our findings indicated that Kv7.X, rather than Kv1.5 or Kv2.1, is the primary Kv subtype involved in tofogliflozin-induced vasodilation. The vasodilatory effects of tofogliflozin were also significantly inhibited in femoral arterial rings pretreated with the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin (1 μM) and cyclopiazonic acid (10 μM). Tofogliflozin-induced vasodilation was unaltered in arterial rings exposed to the adenylyl cyclase inhibitor SQ 22536 (50 μM), the protein kinase A (PKA) inhibitor KT 5720 (1 μM), and the protein kinase G inhibitor KT 5823 (1 μM) whereas it was effectively reduced by the soluble guanylyl cyclase (sGC) inhibitor ODQ (10 μM). These findings suggest that tofogliflozin-induced vasodilation is mediated by the activation of the SERCA pump, the sGC/cGMP pathway, and Kv channels.
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Affiliation(s)
- Wenwen Zhuang
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea
| | - Minju Park
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea
| | - Junsu Jeong
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea
| | - Hye Ryung Kim
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea
| | - YeEun Jang
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea
| | - Mi Seon Seo
- Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, 27478, South Korea
| | - Jin Ryeol An
- Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, 27478, South Korea
| | - Hongzoo Park
- Institute of Medical Sciences, Department of Urology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea
| | - Won-Kyo Jung
- Department of Biomedical Engineering, and Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan, 48513, South Korea
| | - Il-Whan Choi
- Department of Microbiology, College of Medicine, Inje University, Busan, 48516, South Korea
| | - Won Sun Park
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea.
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Mghaieth Zghal F, Abbassi M, Silini A, Ben Halima M, Jebberi Z, Daly F, Ouali S, Farhati A, Ben Mansour N, Boudiche S, Mourali MS. Impact of sodium-glucose cotransporter inhibitors in acute coronary syndrome patients on endothelial function and atherosclerosis related-biomarkers: ATH-SGLT2i pilot study. Medicine (Baltimore) 2024; 103:e40536. [PMID: 39813066 PMCID: PMC11596703 DOI: 10.1097/md.0000000000040536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 10/25/2024] [Indexed: 01/16/2025] Open
Abstract
Little is known about the effects of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on atherosclerosis. We aimed to determine if a 90-day intake of Dapagliflozin could improve atherosclerosis biomarkers (namely endothelial function assessed by flow-mediated dilatation [FMD] and carotid intima-media thickness [CIMT]) in diabetic and non-diabetic acute coronary syndrome (ACS) patients when initiated in the early in-hospital phase. ATH-SGLT2i was a prospective, single-center, observational trial that included 113 SGLT2i naive patients who were admitted for ACS and who were prescribed Dapagliflozin at a fixed dose of 10 mg during their hospital stay for either type 2 diabetes or for heart failure. After 90 days of follow-up, subjects who had a continuous intake of Dapagliflozin formed the SGLT2i group, while patients who did not take Dapagliflozin formed the non-SGLT2i group. In each of these main study groups, we considered diabetic and non-diabetic subgroups. The primary endpoint was the difference in between baseline and 90 days in FMD (∆FMD) and in FMD rate (∆FMD%). The secondary outcome was change in CIMT (∆CIMT). We enrolled 54 patients in the SGLT2i group aged 59 ± 9 years (70.4% males) which 30 were diabetics, and 59 in the non-SGLT2i group aged 63 ± 11 years (78% males) which 34 were diabetics. After 90 days, ∆FMD and ∆ FMD% were higher in the SGLT2i group in comparison with the non-SGLT2i group (0.05 ± 0.15 vs -0.05 ± 0.11, P < .001 and 1.78 ± 3.63 vs -0.88 ± 4, P < .001). Within the SGLT2i group, the improvement of FMD% was higher in non-diabetic patients (2.85 ± 3.46 vs 0.9 ± 3.59, P = .05). Multivariate analysis showed that Dapagliflozin intake was independently associated with FMD% improvement (HR = 2.24). After 90 days, CIMT showed no significant difference between the SGLT2i and the non-SGLT2i groups. In this pilot study, a 90-day intake of Dapagliflozin at the fixed dose of 10 mg started in the acute phase of an ACS, was associated with endothelial function improvement in diabetic and non-diabetic patients.
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Affiliation(s)
- Fathia Mghaieth Zghal
- Department of Cardiology, Rabta Teaching Hospital, University of Medicine Tunis, Tunis, Tunisia
- Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Manel Abbassi
- Department of Cardiology, Rabta Teaching Hospital, University of Medicine Tunis, Tunis, Tunisia
- Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Ahlem Silini
- Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
- National Institute of Public Health, Tunis, Tunisia
| | - Manel Ben Halima
- Department of Cardiology, Rabta Teaching Hospital, University of Medicine Tunis, Tunis, Tunisia
- Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Zeynab Jebberi
- Department of Cardiology, Rabta Teaching Hospital, University of Medicine Tunis, Tunis, Tunisia
- Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Foued Daly
- Department of Cardiology, Rabta Teaching Hospital, University of Medicine Tunis, Tunis, Tunisia
- Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Sana Ouali
- Department of Cardiology, Rabta Teaching Hospital, University of Medicine Tunis, Tunis, Tunisia
- Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Abdeljelil Farhati
- Department of Cardiology, Rabta Teaching Hospital, University of Medicine Tunis, Tunis, Tunisia
- Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Nadia Ben Mansour
- Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
- National Institute of Public Health, Tunis, Tunisia
| | - Selim Boudiche
- Department of Cardiology, Rabta Teaching Hospital, University of Medicine Tunis, Tunis, Tunisia
- Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Mohamed Sami Mourali
- Department of Cardiology, Rabta Teaching Hospital, University of Medicine Tunis, Tunis, Tunisia
- Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
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Barkas F, Sener YZ, Golforoush PA, Kheirkhah A, Rodriguez-Sanchez E, Novak J, Apellaniz-Ruiz M, Akyea RK, Bianconi V, Ceasovschih A, Chee YJ, Cherska M, Chora JR, D'Oria M, Demikhova N, Kocyigit Burunkaya D, Rimbert A, Macchi C, Rathod K, Roth L, Sukhorukov V, Stoica S, Scicali R, Storozhenko T, Uzokov J, Lupo MG, van der Vorst EPC, Porsch F. Advancements in risk stratification and management strategies in primary cardiovascular prevention. Atherosclerosis 2024; 395:117579. [PMID: 38824844 DOI: 10.1016/j.atherosclerosis.2024.117579] [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: 03/20/2024] [Revised: 04/29/2024] [Accepted: 05/14/2024] [Indexed: 06/04/2024]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide, highlighting the urgent need for advancements in risk assessment and management strategies. Although significant progress has been made recently, identifying and managing apparently healthy individuals at a higher risk of developing atherosclerosis and those with subclinical atherosclerosis still poses significant challenges. Traditional risk assessment tools have limitations in accurately predicting future events and fail to encompass the complexity of the atherosclerosis trajectory. In this review, we describe novel approaches in biomarkers, genetics, advanced imaging techniques, and artificial intelligence that have emerged to address this gap. Moreover, polygenic risk scores and imaging modalities such as coronary artery calcium scoring, and coronary computed tomography angiography offer promising avenues for enhancing primary cardiovascular risk stratification and personalised intervention strategies. On the other hand, interventions aiming against atherosclerosis development or promoting plaque regression have gained attention in primary ASCVD prevention. Therefore, the potential role of drugs like statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, omega-3 fatty acids, antihypertensive agents, as well as glucose-lowering and anti-inflammatory drugs are also discussed. Since findings regarding the efficacy of these interventions vary, further research is still required to elucidate their mechanisms of action, optimize treatment regimens, and determine their long-term effects on ASCVD outcomes. In conclusion, advancements in strategies addressing atherosclerosis prevention and plaque regression present promising avenues for enhancing primary ASCVD prevention through personalised approaches tailored to individual risk profiles. Nevertheless, ongoing research efforts are imperative to refine these strategies further and maximise their effectiveness in safeguarding cardiovascular health.
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Affiliation(s)
- Fotios Barkas
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.
| | - Yusuf Ziya Sener
- Department of Internal Medicine, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | | | - Azin Kheirkhah
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Elena Rodriguez-Sanchez
- Division of Cardiology, Department of Medicine, Department of Physiology, and Molecular Biology Institute, UCLA, Los Angeles, CA, USA
| | - Jan Novak
- 2(nd) Department of Internal Medicine, St. Anne's University Hospital in Brno and Faculty of Medicine of Masaryk University, Brno, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Maria Apellaniz-Ruiz
- Genomics Medicine Unit, Navarra Institute for Health Research - IdiSNA, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Pamplona, Spain
| | - Ralph Kwame Akyea
- Centre for Academic Primary Care, School of Medicine, University of Nottingham, United Kingdom
| | - Vanessa Bianconi
- Department of Medicine and Surgery, University of Perugia, Italy
| | - Alexandr Ceasovschih
- Internal Medicine Department, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania
| | - Ying Jie Chee
- Department of Endocrinology, Tan Tock Seng Hospital, Singapore
| | - Mariia Cherska
- Cardiology Department, Institute of Endocrinology and Metabolism, Kyiv, Ukraine
| | - Joana Rita Chora
- Unidade I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal; Universidade de Lisboa, Faculdade de Ciências, BioISI - Biosystems & Integrative Sciences Institute, Lisboa, Portugal
| | - Mario D'Oria
- Division of Vascular and Endovascular Surgery, Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Nadiia Demikhova
- Sumy State University, Sumy, Ukraine; Tallinn University of Technology, Tallinn, Estonia
| | | | - Antoine Rimbert
- Nantes Université, CNRS, INSERM, l'institut du Thorax, Nantes, France
| | - Chiara Macchi
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università Degli Studi di Milano, Milan, Italy
| | - Krishnaraj Rathod
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; Barts Interventional Group, Barts Heart Centre, St. Bartholomew's Hospital, London, United Kingdom
| | - Lynn Roth
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
| | - Vasily Sukhorukov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Petrovsky National Research Centre of Surgery, Moscow, Russia
| | - Svetlana Stoica
- "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania; Institute of Cardiovascular Diseases Timisoara, Timisoara, Romania
| | - Roberto Scicali
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Tatyana Storozhenko
- Cardiovascular Center Aalst, OLV Clinic, Aalst, Belgium; Department of Prevention and Treatment of Emergency Conditions, L.T. Malaya Therapy National Institute NAMSU, Kharkiv, Ukraine
| | - Jamol Uzokov
- Republican Specialized Scientific Practical Medical Center of Therapy and Medical Rehabilitation, Tashkent, Uzbekistan
| | | | - Emiel P C van der Vorst
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074, Aachen, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074, Aachen, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, 80336, Munich, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, 52074, Aachen, Germany
| | - Florentina Porsch
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
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Zhang T, Gao X, Chen T, Zhang H, Zhang X, Xin Y, Shi D, Du Y, Xu L, Zhou Y. Longitudinal assessment of coronary plaque regression related to sodium-glucose cotransporter-2 inhibitor using coronary computed tomography angiography. Cardiovasc Diabetol 2024; 23:267. [PMID: 39039597 PMCID: PMC11264370 DOI: 10.1186/s12933-024-02368-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 07/17/2024] [Indexed: 07/24/2024] Open
Abstract
BACKGROUND Sodium-Glucose Cotransporter-2 Inhibitor (SGLT2i) is a novel oral drug for treating type 2 diabetes mellitus (T2DM) with demonstrated cardiovascular benefits. Previous studies in apolipoprotein E knockout mice have shown that SGLT2i is associated with attenuated progression of atherosclerosis. However, whether this effect extends to T2DM patients with coronary atherosclerosis in real-world settings remains unknown. METHODS In this longitudinal cohort study using coronary computed tomography angiography (CCTA), T2DM patients who underwent ≥ 2 CCTA examinations at our center between 2019 and 2022 were screened. Eligible patients had multiple study plaques, defined as non-obstructive stenosis at baseline and not intervened during serial CCTAs. Exclusion criteria included a CCTA time interval < 12 months, prior SGLT2i treatment, or initiation/discontinuation of SGLT2i during serial CCTAs. Plaque volume (PV) and percent atheroma volume (PAV) were measured for each study plaque using CCTA plaque analysis software. Patients and plaques were categorized based on SGLT2i therapy and compared using a 1:1 propensity score matching (PSM) analysis. RESULTS The study included 236 patients (mean age 60.5 ± 9.5 years; 69.1% male) with 435 study plaques (diameter stenosis ≥ 50%, 31.7%). Following SGLT2i treatment for a median duration of 14.6 (interquartile range: 13.0, 20.0) months, overall, non-calcified, and low-attenuation PV and PAV were significantly decreased, while calcified PV and PAV were increased (all p < 0.001). Meanwhile, reductions in overall PV, non-calcified PV, overall PAV, and non-calcified PAV were significantly greater in SGLT2i-treated compared to non-SGLT2i-treated plaques (all p < 0.001). PSM analysis showed that SGLT2i treatment was associated with higher reductions in overall PV (- 11.77 mm3 vs. 4.33 mm3, p = 0.005), non-calcified PV (- 16.96 mm3 vs. - 1.81 mm3, p = 0.017), overall PAV (- 2.83% vs. 3.36%, p < 0.001), and non-calcified PAV (- 4.60% vs. 0.70%, p = 0.003). These findings remained consistent when assessing annual changes in overall and compositional PV and PAV. Multivariate regression models demonstrated that SGLT2i therapy was associated with attenuated progression of overall or non-calcified PV or PAV, even after adjusting for cardiovascular risk factors, medications, and baseline overall or non-calcified PV or PAV, respectively (all p < 0.05). The effect of SGLT2i on attenuating non-calcified plaque progression was consistent across subgroups (all p for interaction > 0.05). CONCLUSIONS In this longitudinal CCTA cohort of T2DM patients, SGLT2i therapy markedly regressed coronary overall PV and PAV, mainly result from a significant reduction in non-calcified plaque.
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Affiliation(s)
- Tianhao Zhang
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Key Laboratory of Precision Medicine of Coronary Atherosclerotic Disease, Clinical center for coronary heart disease, Capital Medical University, Beijing, 100029, China
| | - Xuelian Gao
- Department of Radiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Disease, Capital Medical University, Beijing, 100029, China
| | - Tianlong Chen
- Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, 100029, China
| | - Hongkai Zhang
- Department of Radiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Disease, Capital Medical University, Beijing, 100029, China
| | - Xiaoming Zhang
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Key Laboratory of Precision Medicine of Coronary Atherosclerotic Disease, Clinical center for coronary heart disease, Capital Medical University, Beijing, 100029, China
| | - Yu Xin
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Key Laboratory of Precision Medicine of Coronary Atherosclerotic Disease, Clinical center for coronary heart disease, Capital Medical University, Beijing, 100029, China
| | - Dongmei Shi
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Key Laboratory of Precision Medicine of Coronary Atherosclerotic Disease, Clinical center for coronary heart disease, Capital Medical University, Beijing, 100029, China
| | - Yu Du
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Key Laboratory of Precision Medicine of Coronary Atherosclerotic Disease, Clinical center for coronary heart disease, Capital Medical University, Beijing, 100029, China.
| | - Lei Xu
- Department of Radiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Disease, Capital Medical University, Beijing, 100029, China.
| | - Yujie Zhou
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Key Laboratory of Precision Medicine of Coronary Atherosclerotic Disease, Clinical center for coronary heart disease, Capital Medical University, Beijing, 100029, China.
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Tao SB, Lu X, Ye ZW, Tong NW. Update on evidence-based clinical application of sodium-glucose cotransporter inhibitors: Insight to uncommon cardiovascular disease scenarios in diabetes. World J Diabetes 2024; 15:1461-1476. [PMID: 39099824 PMCID: PMC11292321 DOI: 10.4239/wjd.v15.i7.1461] [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: 02/20/2024] [Revised: 04/28/2024] [Accepted: 05/29/2024] [Indexed: 07/08/2024] Open
Abstract
In this paper, we concentrate on updating the clinical research on sodium-glucose cotransporter inhibitors (SGLTis) for patients with type 2 diabetes who have heart failure with a preserved injection fraction, acute heart failure, atrial fibrillation, primary prevention of atherosclerotic cardiovascular disease/cardiovascular disease, and acute myocardial infarction. We searched the data of randomized controlled trials and meta-analyses of SGLTis in patients with diabetes from PubMed between January 1, 2020 and April 6, 2024 for our review. According to our review, certain SGLTis (empagliflozin, dapagliflozin, canagliflozin, and tofogliflozin), but not sodium-glucose cotransporter 1 inhibitor (SGLT1i), exhibit relatively superior clinical safety and effectiveness for treating the abovementioned diseases. Proper utilization of SGLTis in these patients can foster clinical improvement and offer an alternative medication option. However, clinical trials involving SGLTis for certain diseases have relatively small sample sizes, brief intervention durations, and conclusions based on weak evidence, necessitating additional data. These findings are significant and valuable for providing a more comprehensive reference and new possibilities for the clinical utilization and scientific exploration of SGLTis.
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Affiliation(s)
- Shi-Bing Tao
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Research Centre for Diabetes and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Endocrinology and Metabolism, Ziyang Central Hospital, Ziyang 641300, Sichuan Province, China
| | - Xi Lu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Research Centre for Diabetes and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zi-Wei Ye
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Nan-Wei Tong
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Research Centre for Diabetes and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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Katakami N, Mita T, Sato Y, Watada H, Shimomura I. Changes in serum levels of liver-related parameters, uric acid, and hemoglobin in patients with type 2 diabetes mellitus under treatment with tofogliflozin-a post-hoc analysis of the UTOPIA study. Diabetol Int 2024; 15:379-388. [PMID: 39101158 PMCID: PMC11291786 DOI: 10.1007/s13340-024-00693-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 01/08/2024] [Indexed: 08/06/2024]
Abstract
Aims/Introduction The aim of the study was to evaluate the effects of tofogliflozin, a selective sodium-glucose cotransporter 2 inhibitor, on circulating levels of hepatic enzymes, uric acid and hemoglobin levels in patients with type 2 diabetes mellitus (T2DM). Materials and methods We evaluated longitudinal changes in circulating aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), uric acid, and hemoglobin levels in tofogliflozin (n = 169) and conventional treatment groups (n = 170) using data obtained from the UTOPIA trial, a randomized prospective study conducted to evaluate the efficacy of tofogliflozin in preventing atherosclerosis. Results Within 104 weeks, tofogliflozin treatment, but not conventional treatment, significantly reduced AST, ALT, and γ-GTP levels. This reduction was significantly greater in the tofogliflozin group than in the conventional group. Stratified analysis showed that, in patients with obesity (defined as body mass index (BMI) ≥ 25.0 kg/m2), significant differences were observed in AST, ALT, and γ-GTP changes from baseline to 104 weeks between treatment groups. However, in patients without obesity, there were no significant differences in AST and γ-GTP changes from baseline to 104 weeks between treatment groups. Multivariable regression analysis showed that changes in BMI and HbA1c levels were independently associated with changes in AST, ALT, and γ-GTP levels. The reduction of uric acid and the increase of hemoglobin from baseline to 104 weeks were significantly greater in the tofogliflozin group than in the conventional group. Conclusions The beneficial effects of tofogliflozin on circulating levels of hepatic enzymes, uric acid, and Hb lasted for 2 years in patients with T2DM. Clinical trial registration UMIN000017607 (https://www.umin.ac.jp/icdr/index.html). Supplementary Information The online version contains supplementary material available at 10.1007/s13340-024-00693-x.
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Affiliation(s)
- Naoto Katakami
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871 Japan
| | - Tomoya Mita
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-Ku, Tokyo 113-8421 Japan
| | - Yasunori Sato
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, 45 Shinanomachi, Shinjuku-Ku, Tokyo 160-8582 Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-Ku, Tokyo 113-8421 Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871 Japan
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Buttice L, Ghani M, Suthakar J, Gnanalingham S, Carande E, Kennedy BWC, Pitcher A, Gamble JHP, Ahmad M, Lewis A, Jüni P, Rider OJ, Stephens JW, Bray JJH. The effect of sodium-glucose cotransporter-2 inhibitors on inflammatory biomarkers: A meta-analysis of randomized controlled trials. Diabetes Obes Metab 2024; 26:2706-2721. [PMID: 38602398 DOI: 10.1111/dom.15586] [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: 12/13/2023] [Revised: 03/22/2024] [Accepted: 03/23/2024] [Indexed: 04/12/2024]
Abstract
AIMS To conduct a meta-analysis of randomized controlled trials (RCTs) to assess the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors on inflammatory biomarkers. METHODS Medline, Embase and the Cochrane Library were searched for RCTs investigating the effect of SGLT2 inhibitors on inflammatory biomarkers, adipokine profiles and insulin sensitivity. RESULTS Thirty-eight RCTs were included (14 967 participants, 63.3% male, mean age 62 ± 8.6 years) with a median (interquartile range) follow-up of 16 (12-24) weeks. Meta-analysis showed that SGLT2 inhibitors significantly improved adiponectin, interleukin-6, tumour necrosis factor receptor-1 (vs. placebo alone: standardized mean difference [SMD] 0.34 [95% confidence interval {CI} 0.23, 0.45], mean difference [MD] -0.85 pg/mL [95% CI -1.32, -0.38], SMD -0.13 [95% CI -0.20, -0.06], respectively), leptin and homeostatic model assessment of insulin resistance index (vs. CONTROL SMD -0.20 [95% CI -0.33, -0.07], MD -0.83 [95% CI -1.32, -0.33], respectively). There were no significant changes in C-reactive protein (CRP), tumour necrosis factor-α, plasminogen activator inhibitor-1, fibroblast growth factor-21 or monocyte chemoattractant protein-1. CONCLUSIONS Our analysis shows that SGLT2 inhibitors likely improve adipokine biomarkers and insulin sensitivity, but there is little evidence that SGLT2 inhibitors improve other inflammatory biomarkers including CRP.
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Affiliation(s)
| | | | | | | | - Elliott Carande
- Grange University Hospital, Cwmbran, UK
- Institute of Life Sciences 2, Swansea Bay University Health Board and Swansea University Medical School, Swansea, UK
| | | | - Alex Pitcher
- Oxford Heart Centre, John Radcliffe Hospital, Oxford, UK
| | | | | | - Andrew Lewis
- Oxford Heart Centre, John Radcliffe Hospital, Oxford, UK
- Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Peter Jüni
- Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK
| | - Oliver J Rider
- Oxford Heart Centre, John Radcliffe Hospital, Oxford, UK
- Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Jeffrey W Stephens
- Institute of Life Sciences 2, Swansea Bay University Health Board and Swansea University Medical School, Swansea, UK
- Diabetes Research Group, School of Medicine, Swansea University, Swansea, UK
| | - Jonathan J H Bray
- University College London (UCL), London, UK
- Institute of Life Sciences 2, Swansea Bay University Health Board and Swansea University Medical School, Swansea, UK
- Oxford Heart Centre, John Radcliffe Hospital, Oxford, UK
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Imada T, Katakami N, Watanabe H, Nishina S, Sasaki S, Takahara M, Shimomura I, Yamamoto T. Effect of sodium-glucose cotransporter 2 inhibitors on serum low-density lipoprotein cholesterol in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig 2024; 15:843-850. [PMID: 38459768 PMCID: PMC11215694 DOI: 10.1111/jdi.14179] [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: 08/23/2023] [Revised: 01/21/2024] [Accepted: 02/23/2024] [Indexed: 03/10/2024] Open
Abstract
AIMS/INTRODUCTION We aimed to evaluate factors that influence changes in blood low-density lipoprotein cholesterol (LDL-C) levels after treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors in Japanese patients with type 2 diabetes. MATERIALS AND METHODS We retrospectively analyzed clinical data of outpatients newly initiated on SGLT2 inhibitors (n = 176) and other oral antidiabetic drugs (n = 227). The patients were classified into four subgroups according to statin administration and baseline LDL-C levels (<120 or ≥120 mg/dL). Clinical characteristics were compared among the subgroups. Multivariate analysis was carried out to identify factors contributing to changes in LDL-C. RESULTS The median follow-up period was 13.0 weeks (range 11.9-14.1 weeks, min 8 weeks, maximum 16 weeks) in the SGLT2i group, and 12.0 weeks (range 10.0-14.0 weeks, min 8 weeks, maximum 16 weeks) in the control group. Both groups showed a significant decrease in LDL-C (SGLT2i group -3.8 ± 24.7 mg/dL, control group -3.4 ± 15.0 mg/dL). Multivariate regression analyses showed that in both groups, the change in LDL-C depended on statin use and baseline LDL-C levels. Stratified analyses showed that LDL-C level was significantly decreased in statin users with baseline LDL-C ≥120 mg/dL (from 148.9 ± 33.5 to 109.3 ± 17.9 mg/dL, P = 0.002), and significantly increased in statin non-users with baseline LDL-C <120 mg/dL (from 96.3 ± 27.3 to 104.7 ± 24.8 mg/dL, P = 0.002). These changes were more characteristic for SGLT2 inhibitors than for other oral antidiabetic drugs (P for interaction = 0.010 and <0.001, respectively). CONCLUSIONS LDL-C levels and statin medication at baseline influence changes in LDL-C after SGLT2 inhibitors treatment in Japanese patients with type 2 diabetes.
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Affiliation(s)
- Tasuku Imada
- Department of Diabetes and EndocrinologyKansai‐Rosai HospitalAmagasaki CityHyogoJapan
- Department of Metabolic MedicineOsaka University Graduate School of MedicineSuita CityOsakaJapan
| | - Naoto Katakami
- Department of Metabolic MedicineOsaka University Graduate School of MedicineSuita CityOsakaJapan
| | - Hirotaka Watanabe
- Department of Metabolic MedicineOsaka University Graduate School of MedicineSuita CityOsakaJapan
| | - Shuhei Nishina
- Department of Diabetes and EndocrinologyKansai‐Rosai HospitalAmagasaki CityHyogoJapan
| | - Shugo Sasaki
- Department of Metabolic MedicineOsaka University Graduate School of MedicineSuita CityOsakaJapan
| | - Mitsuyoshi Takahara
- Department of Diabetes Care MedicineOsaka University Graduate School of MedicineSuita CityOsakaJapan
| | - Iichiro Shimomura
- Department of Metabolic MedicineOsaka University Graduate School of MedicineSuita CityOsakaJapan
| | - Tsunehiko Yamamoto
- Department of Diabetes and EndocrinologyKansai‐Rosai HospitalAmagasaki CityHyogoJapan
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Stachteas P, Karakasis P, Patoulias D, Clemenza F, Fragakis N, Rizzo M. The effect of sodium-glucose co-transporter-2 inhibitors on markers of subclinical atherosclerosis. Ann Med 2024; 55:2304667. [PMID: 38233735 PMCID: PMC10798275 DOI: 10.1080/07853890.2024.2304667] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 12/19/2023] [Indexed: 01/19/2024] Open
Abstract
BACKGROUND Despite the widespread use of classical cholesterol-lowering drugs to mitigate the adverse impacts of dyslipidaemia on atherosclerosis, many patients still face a substantial residual risk of developing atherosclerotic cardiovascular disease (CVD). This risk is partially attributed to non-traditional pathophysiological pathways. Latest evidence suggests that sodium glucose co-transporter-2 (SGLT2) inhibitors are beneficial for patients suffering from type 2 diabetes mellitus (T2DM) or established CVD by reducing morbidity and mortality. However, the underlying mechanisms of this benefit have not been clearly elucidated. It has been hypothesized that one possible mechanism could be the attenuation of subclinical atherosclerosis (SA) progression. AIM The objective of this narrative review is to examine the present evidence concerning the impact of SGLT2 inhibitors on markers of SA. RESULTS The current evidence on the efficacy of SGLT2 on SA, endothelial function and arterial stiffness remains controversial. Findings from observational and randomized studies are quite heterogeneous; however, they converge that the antiatherosclerotic activity of SGLT2 inhibitors is not strong enough to be widely used for prevention of atherosclerosis progression in patients with or without T2DM. CONCLUSIONS Further research is needed to investigate the underlying mechanisms and the possible beneficial impact of SGLT2i on primary and secondary CVD prevention through attenuation of premature atherosclerosis progression.
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Affiliation(s)
- Panagiotis Stachteas
- Second Department of Cardiology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paschalis Karakasis
- Second Department of Cardiology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Patoulias
- Outpatient Department of Cardiometabolic Medicine, Second Department of Cardiology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Francesco Clemenza
- Department for the Study and Treatment of Cardiothoracic Diseases and for Cardiothoracic Transplants, Cardiology Unit, IRCCS – ISMETT, Palermo, Italy
| | - Nikolaos Fragakis
- Second Department of Cardiology, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Outpatient Department of Cardiometabolic Medicine, Second Department of Cardiology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Manfredi Rizzo
- Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), School of Medicine, University of Palermo, Palermo, Italy
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10
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AKHANLI P, HEPŞEN S, ARSLAN İE, DÜĞER H, BOSTAN H, KIZILGÜL M, UÇAN B, ÇAKAL E. Impact of 24-week dapagliflozin treatment on body weight, body composition, and cardiac risk indicators of patients with type-2 diabetes mellitus. Turk J Med Sci 2023; 53:1178-1184. [PMID: 38813008 PMCID: PMC10763806 DOI: 10.55730/1300-0144.5683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 10/26/2023] [Accepted: 08/11/2023] [Indexed: 05/31/2024] Open
Abstract
Background/aim To reveal the impacts of dapagliflozin, a sodium glucose transporter-2 inhibitor (SGLT-2i), on body weight and body composition, cardiovascular risk indices, and carotid intima-media thickness (CIMT). Materials and methods The data of patients with type-2 diabetes mellitus (T2DM) who applied to Department of Endocrinology and Metabolic Disorders between September 2019 and 2020, and had started dapagliflozin treatment along with their current medications were recorded retrospectively. Body weights, body compositions measured through bioelectrical impedance, and CIMT with T2DM receiving SGLT-2i treatment and medication were measured at weeks 1, 12, and 24 of 42. The visceral adiposity index (VAI), lipid accumulation product (LAP), and atherogenic index of plasma (AIP) were used to determine the lipid measurements and anthropometric values. Results The mean change in the total body weight and total fat mass was -2.96 and -1.97 kg, respectively (p < 0.001). There was a reduction in total fat mass of 1.23 kg (from 31.4 to 29.3 kg, p < 0.001) and in body fat percentage of 2.5% (from 35.8% to 34.4%, p < 0.001) in the first 12 weeks. A mild increase was observed in both the total fat mass and body fat percentage between weeks 12 and 24, which was not statistically significant (p = 0.783 and p = 0.925, respectively), whereas there was a statistically significant reduction in high-sensitive C-reactive protein (hsCRP), AIP, and CIMT values (p = 0.006, p = 0.035, and p = 0.007, respectively). No changes were observed in the VAI and LAP values (p = 0.985 and p = 0.636, respectively). Conclusion It was observed that dapagliflozin not only contributes to weight and fat loss but also has positive impacts on cardiovascular and atherosclerotic indicators.
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Affiliation(s)
- Pınar AKHANLI
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Sema HEPŞEN
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - İsmail Emre ARSLAN
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Hakan DÜĞER
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Hayri BOSTAN
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Muhammed KIZILGÜL
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Bekir UÇAN
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Erman ÇAKAL
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
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Zhang S, Qi Z, Wang Y, Song D, Zhu D. Effect of sodium-glucose transporter 2 inhibitors on sarcopenia in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2023; 14:1203666. [PMID: 37465122 PMCID: PMC10351980 DOI: 10.3389/fendo.2023.1203666] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/16/2023] [Indexed: 07/20/2023] Open
Abstract
Objective Sarcopenia has been recognized as the third category of disabling complications in patients with type 2 diabetes mellitus(T2DM), in addition to micro- and macrovascular complications. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are innovative glucose-lowering treatments that have been shown to reduce body weight and enhance cardiovascular and renal outcomes. However, there is vigilance that SGLT2 inhibitors should be taken cautiously because they target skeletal muscle and may raise the risk of sarcopenia. Herein, we conducted a meta-analysis of randomized controlled trials to evaluate the effects of SGLT2 inhibitors on sarcopenia in patients with T2DM. Method Relevant studies were obtained from PubMed, Embase, Medicine, Cochrane, and Web of Science databases to determine eligible studies until February 2023, without any language restrictions. A random effects model was utilized irrespective of heterogeneity, and the I2 statistic was used to evaluate study heterogeneity. The differences in results were measured using the weighted average difference (WMD) of the continuous data, along with a 95% confidence interval (CI). Results A total of 25 randomized controlled trials with 2,286 participants were included. SGLT2 inhibitors significantly reduced weight-related changes and fat-related changes, including body weight(BW) (WMD= -2.74, 95% CI: -3.26 to -2.23, P<0.01), body mass index(BMI) (WMD= -0.72, 95% CI: -0.95 to -0.49, P<0.01), waist circumference(WC) (WMD= -1.60, 95% CI: -2.99 to -0.22, P=0.02), fat mass(FM)(WMD= -1.49, 95% CI: -2.18 to -0.80, P<0.01), percentage body fat(PBF) (WMD= -1.28, 95% CI: -1.83 to -0.74, P<0.01), visceral fat area(VFA)(WMD= -19.52, 95% CI: -25.90 to -13.14, P<0.01), subcutaneous fat area(SFA)(WMD= -19.11, 95% CI: -31.18 to -7.03, P=0.002), In terms of muscle-related changes, lean mass(LM)(WMD= -0.80, 95% CI: -1.43 to -0.16, P=0.01), and skeletal muscle mass(SMM) (WMD= -0.38, 95% CI: -0.65 to -0.10, P=0.007), skeletal muscle index(SMI) (WMD= -0.12, 95% CI: -0.22 to -0.02, P=0.02)were also significantly reduced. In addition, body water likewise decreased significantly (WMD=-0.96, 95% CI: -1.68 to -0.23, P=0.009). Conclusions As one of the most widely used hypoglycemic, SGLT2 inhibitors have beneficial effects on FM and BW weight loss in T2DM, such as BW, BMI, WC, FM, PBF, VFA, and SFA. However, the negative influence on muscle mass paralleled the reduction in FM and BW, and the consequent increased risk of sarcopenia warrants high attention, especially as patients are already predisposed to physical frailty. Clinical Trial Registration https://www.crd.york.ac.uk/prospero/#myprospero, identifier PROSPERO (No.CRD 42023396278).
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Affiliation(s)
- Sha Zhang
- Department of Pharmacy, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhan Qi
- Department of Pharmacy, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yidong Wang
- Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Danfei Song
- Department of Pharmacy, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Deqiu Zhu
- Department of Pharmacy, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
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12
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Katakami N, Mita T, Yoshii H, Shiraiwa T, Yasuda T, Okada Y, Kurozumi A, Hatazaki M, Kaneto H, Osonoi T, Yamamoto T, Kuribayashi N, Maeda K, Yokoyama H, Kosugi K, Ohtoshi K, Hayashi I, Sumitani S, Tsugawa M, Ryomoto K, Kato K, Nakamura T, Kawashima S, Sato Y, Watada H, Shimomura I. Tofogliflozin long-term effects on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes mellitus lacking a history of cardiovascular disease: a 2-year extension study of the UTOPIA trial. Cardiovasc Diabetol 2023; 22:143. [PMID: 37349722 PMCID: PMC10286339 DOI: 10.1186/s12933-023-01879-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 06/05/2023] [Indexed: 06/24/2023] Open
Abstract
BACKGROUND This study aimed to assess the long-term effects of tofogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes lacking an apparent history of cardiovascular disease. METHODS This was a prospective observational 2-year extension study of the "Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)" trial, a 2-year randomized intervention study. The primary endpoints represented changes in the carotid intima-media thickness (IMT). Secondary endpoints included brachial-ankle pulse wave velocity (baPWV) and biomarkers for glucose metabolism, lipid metabolism, renal function, and cardiovascular risks. RESULTS The mean IMT of the common carotid artery (IMT-CCA) significantly decreased in both the tofogliflozin (- 0.067 mm, standard error 0.009, p < 0.001) and conventional treatment groups (- 0.080 mm, SE 0.009, p < 0.001) throughout the follow-up period; however, no significant intergroup differences in the changes (0.013 mm, 95% confidence interval (CI) - 0.012 to 0.037, p = 0.32) were observed in a mixed-effects model for repeated measures. baPWV significantly increased in the conventional treatment group (82.7 ± 210.3 cm/s, p = 0.008) but not in the tofogliflozin group (- 17.5 ± 221.3 cm/s, p = 0.54), resulting in a significant intergroup difference in changes (- 100.2 cm/s, 95% CI - 182.8 to - 17.5, p = 0.018). Compared to the conventional treatment group, tofogliflozin significantly improved the hemoglobin A1c and high-density lipoprotein cholesterol levels, body mass index, abdominal circumference, and systolic blood pressure. The frequencies of total and serious adverse events did not vary significantly between the groups. CONCLUSIONS Tofogliflozin was not associated with improved inhibition of carotid wall thickening but exerted long-term positive effects on various cardiovascular risk factors and baPWV while showing a good safety profile.
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Affiliation(s)
- Naoto Katakami
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871 Japan
- Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871 Japan
| | - Tomoya Mita
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Hidenori Yoshii
- Department of Medicine, Diabetology & Endocrinology, Juntendo Tokyo Koto Geriatric Medical Center, Koto-ku, Tokyo, 136-0075 Japan
| | - Toshihiko Shiraiwa
- Shiraiwa Medical Clinic, 4-10-24 Hozenji, Kashiwara, Osaka 582-0005 Japan
| | - Tetsuyuki Yasuda
- Department of Endocrinology and Metabolism, Osaka Police Hospital, 10-31, Kitayama-Cho, Tennoji-ku, Osaka, 543-0035 Japan
| | - Yosuke Okada
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555 Japan
| | - Akira Kurozumi
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555 Japan
| | - Masahiro Hatazaki
- Department of Diabetes and Endocrinology, Osaka General Medical Center, 3-1-56, Bandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558 Japan
| | - Hideaki Kaneto
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192 Japan
| | - Takeshi Osonoi
- Nakakinen Clinic, 745-5, Nakadai, Naka, Ibaraki 311-0113 Japan
| | - Tsunehiko Yamamoto
- Diabetes and Endocrinology, Kansai Rosai Hospital, 3-1-69, Inabaso, Amagasaki, Hyogo Japan
| | | | - Kazuhisa Maeda
- Kitasenri Maeda Clinic, 4-119, Furuedai, Suita, Osaka 565-0874 Japan
| | - Hiroki Yokoyama
- Jiyugaoka Medical Clinic, West 6, South 6-4-3, Obihiro, Hokkaido 080-0016 Japan
| | - Keisuke Kosugi
- Kosugi Medical Clinic, 3-9, Tamatsukurimoto-Cho, Tennoji-ku, Osaka, 543-0014 Japan
| | - Kentaro Ohtoshi
- Otoshi Medical Clinic, 8-47, KakudachoOsaka Kita-ku, Osaka, 530-0017 Japan
| | - Isao Hayashi
- Hayashi Clinic, 3-9-23, Koshienguchi, Nishinomiya, Hyogo 663-8113 Japan
| | - Satoru Sumitani
- Center for Diabetes and Endocrinology, Nippon Life Hospital, 2-1-54 Enokojima, Nishi-ku, Osaka, 550-0006 Japan
- Present Address: Department of Diabetology and Endocrinology, Pref Osaka Saiseikai Izuo Hospital, 3-4-5 Kitamura, Taisho, Osaka 551-0032 Japan
| | - Mamiko Tsugawa
- Department of Endocrinology and Metabolism, Ikeda Municipal Hospital, 3-1-18, Jonan, Ikeda, Osaka 563-8510 Japan
- Present Address: Department of Diabetes and Endocrinology, Meiwa Hospital, 4-31 Agenaruo, Nishinomiya, Hyogo 663-8186 Japan
| | - Kayoko Ryomoto
- Center for Diabetes Mellitus, Osaka Rosai Hospital, 1179-3 Nagasone-Cho, Kita-ku, Sakai, Osaka 591-8025 Japan
| | - Ken Kato
- Diabetes Center, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka, 540-0006 Japan
| | - Tadashi Nakamura
- Department of Internal Medicine, Kawasaki Hospital, 3-3-1, Higashiyamacho, Kobe Hyogo-ku, Hyogo, 652-0042 Japan
| | - Satoshi Kawashima
- Kanda Naika Clinic, 5-21-3, Hannancho, Osaka Abeno-ku, Osaka, 545-0021 Japan
| | - Yasunori Sato
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, 45 Shinanomachi Shinjuku-ku, Tokyo, 160-8582 Japan
| | - Hirotaka Watada
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871 Japan
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Nani A, Carrara F, Paulesu CME, Dalle Fratte C, Padroni M, Enisci S, Bilancio MC, Romio MS, Bertuzzi F, Pintaudi B. Association of Sodium-Glucose Cotransporter 2 Inhibitors with Osteomyelitis and Other Lower Limb Safety Outcomes in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. J Clin Med 2023; 12:3958. [PMID: 37373652 DOI: 10.3390/jcm12123958] [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: 04/29/2023] [Revised: 06/04/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Our aim was to evaluate osteomyelitis and other major lower limb safety outcomes (i.e., peripheral artery disease or PAD, ulcers, atraumatic fractures, amputations, symmetric polyneuropathy, and infections) in patients affected by type 2 diabetes mellitus (T2DM) and treated with sodium-glucose cotransporter 2 inhibitors (SGLT2-is). We thus performed a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing SGLT2-is at approved doses for T2DM with a placebo or standard of care. MEDLINE, Embase, and Cochrane CENTRAL were searched through August 2022. Separate intention-to-treat analyses were implemented for each molecule to calculate Mantel-Haenszel risk ratios (RRMH) with 95% confidence intervals (CIs) through a random-effects model. We processed data from 42 RCTs for a total of 29,491 and 23,052 patients, respectively assigned to SGLT2-i and comparator groups. SGLT2-is showed a pooled neutral effect on osteomyelitis, PAD, fractures, and symmetric polyneuropathy, whereas slightly deleterious sway on ulcers (RRMH 1.39 [1.01-1.91]), amputations (RRMH 1.27 [1.04-1.55]), and infections (RRMH 1.20 [1.02-1.40]). In conclusion, SGLT2-is appear to not significantly interfere with the onset of osteomyelitis, PAD, lower limb fractures, or symmetric polyneuropathy, even though the number of these events proved consistently higher in the investigational groups; otherwise, local ulcers, amputations, and overall infections may be favoured by their employment. This study is registered with the Open Science Framework (OSF).
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Affiliation(s)
- Alessandro Nani
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Federica Carrara
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
- Hospital Pharmacy, Humanitas Gavazzeni, 24125 Bergamo, Italy
| | | | - Chiara Dalle Fratte
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Matteo Padroni
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Silvia Enisci
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Maria Concetta Bilancio
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Maria Silvia Romio
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
| | | | - Basilio Pintaudi
- Department of Diabetology, Niguarda Hospital, 20162 Milan, Italy
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Kourtidou C, Rafailidis V, Varouktsi G, Kanakis E, Liakopoulos V, Vyzantiadis TA, Savopoulos C, Marinaki S, Stangou M, Tziomalos K. Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Markers of Vascular Damage. J Pers Med 2023; 13:536. [PMID: 36983717 PMCID: PMC10052523 DOI: 10.3390/jpm13030536] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/12/2023] [Accepted: 03/16/2023] [Indexed: 03/19/2023] Open
Abstract
BACKGROUND Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular morbidity and delay the progression of kidney disease in patients with type 2 diabetes mellitus (T2DM). However, the mechanisms underpinning these benefits are not entirely clear. More specifically, it is uncertain whether these agents exert cardiorenal protective effects through a direct action on the vascular wall. The aim of the present study was to evaluate the effects of SGLT2 inhibitors on markers of subclinical vascular damage. METHODS In total, 40 adult patients with T2DM and glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 and age- and gender-matched patients with T2DM and GFR > 60 mL/min/1.73 m2 were consecutively enrolled. Indices of arterial stiffness (pulse wave velocity, augmentation index (AIx), AIx adjusted to a heart rate of 75 beats/min (Alx@75) and central systolic, diastolic, pulse and mean pressure), carotid atherosclerosis (stenosis, intima-media thickness (cIMT) and maximal plaque thickness) and peripheral arterial disease (ankle brachial index (ABI)) were determined. The chi-squared and Mann-Whitney U-test were used to detect differences in categorical and continuous variables between groups, respectively. RESULTS In total, 15 patients were treated with SGLT2 inhibitors and 25 patients were not receiving these agents. Serum low-density lipoprotein cholesterol levels were lower in the former whereas other cardiovascular risk factors, the prevalence of established cardiovascular disease, anthropometric and demographic characteristics, and vital signs did not differ between the 2 groups. The AIx was lower in patients treated with SGLT2 inhibitors (21.9 ± 11.3 vs. 29.7 ± 12% in patients not treated with SGLT2 inhibitors; p < 0.05). The AIx@75 was also lower in the former (21.3 ± 10.9 and 32.6 ± 11.3%, respectively, p < 0.005). Other markers of arterial stiffness were similar in the 2 groups. In addition, markers of carotid atherosclerosis and the ABI did not differ between patients treated and not treated with SGLT2 inhibitors. CONCLUSIONS Treatment with SGLT2 inhibitors appears to reduce arterial stiffness. Accordingly, these agents might improve cardiovascular outcomes not only in patients with T2DM and established cardiorenal disease but also in lower-risk patients.
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Affiliation(s)
- Christodoula Kourtidou
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
| | - Vasileios Rafailidis
- Department of Radiology, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
| | - Garyfallia Varouktsi
- Department of Nephrology, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
| | - Efthimios Kanakis
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
| | - Vassilios Liakopoulos
- Department of Nephrology, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
| | | | - Christos Savopoulos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
| | - Smaragdi Marinaki
- Department of Nephrology and Renal Transplantation, Medical School, National and Kapodistrian University of Athens, Laiko Hospital, 11527 Athens, Greece
| | - Maria Stangou
- Department of Nephrology, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, 54642 Thessaloniki, Greece
| | - Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
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Tanaka A, Sata M, Okada Y, Teragawa H, Eguchi K, Shimabukuro M, Taguchi I, Matsunaga K, Kanzaki Y, Yoshida H, Ishizu T, Ueda S, Kitakaze M, Murohara T, Node K, Murohara T, Kitakaze M, Nishio Y, Inoue T, Ohishi M, Kario K, Sata M, Shimabukuro M, Shimizu W, Jinnouchi H, Taguchi I, Tomiyama H, Maemura K, Suzuki M, Ando S, Eguchi K, Kamiya H, Sakamoto T, Teragawa H, Nanasato M, Matsuhisa M, Ako J, Aso Y, Ishihara M, Kitagawa K, Yamashina A, Ishizu T, Ikehara Y, Ueda S, Takamori A, Tanaka A, Mori M, Yamaguchi K, Asaka M, Kaneko T, Sakuma M, Toyoda S, Nasuno T, Kageyama M, Teruo J, Toshie I, Kishi H, Yamada H, Kusunose K, Fukuda D, Yagi S, Yamaguchi K, Ise T, Kawabata Y, Kuroda A, Akasaki Y, Kurano M, Hoshide S, Komori T, Kabutoya T, Ogata Y, Koide Y, Kawano H, Ikeda S, Fukae S, Koga S, Higashi Y, Kishimoto S, Kajikawa M, Maruhashi T, Kubota Y, Shibata Y, Kuriyama N, Nakamura I, Hironori K, Takase B, Orita Y, Oshita C, Uchimura Y, Yoshida R, Yoshida Y, Suzuki H, Ogura Y, Maeda M, Takenaka M, Hayashi T, Hirose M, Hisauchi I, Kadokami T, Nakamura R, et alTanaka A, Sata M, Okada Y, Teragawa H, Eguchi K, Shimabukuro M, Taguchi I, Matsunaga K, Kanzaki Y, Yoshida H, Ishizu T, Ueda S, Kitakaze M, Murohara T, Node K, Murohara T, Kitakaze M, Nishio Y, Inoue T, Ohishi M, Kario K, Sata M, Shimabukuro M, Shimizu W, Jinnouchi H, Taguchi I, Tomiyama H, Maemura K, Suzuki M, Ando S, Eguchi K, Kamiya H, Sakamoto T, Teragawa H, Nanasato M, Matsuhisa M, Ako J, Aso Y, Ishihara M, Kitagawa K, Yamashina A, Ishizu T, Ikehara Y, Ueda S, Takamori A, Tanaka A, Mori M, Yamaguchi K, Asaka M, Kaneko T, Sakuma M, Toyoda S, Nasuno T, Kageyama M, Teruo J, Toshie I, Kishi H, Yamada H, Kusunose K, Fukuda D, Yagi S, Yamaguchi K, Ise T, Kawabata Y, Kuroda A, Akasaki Y, Kurano M, Hoshide S, Komori T, Kabutoya T, Ogata Y, Koide Y, Kawano H, Ikeda S, Fukae S, Koga S, Higashi Y, Kishimoto S, Kajikawa M, Maruhashi T, Kubota Y, Shibata Y, Kuriyama N, Nakamura I, Hironori K, Takase B, Orita Y, Oshita C, Uchimura Y, Yoshida R, Yoshida Y, Suzuki H, Ogura Y, Maeda M, Takenaka M, Hayashi T, Hirose M, Hisauchi I, Kadokami T, Nakamura R, Kanda J, Matsunaga K, Hoshiga M, Sohmiya K, Kanzaki Y, Koyosue A, Uehara H, Miyagi N, Chinen T, Nakamura K, Nago C, Chiba S, Hatano S, Gima Y, Abe M, Ajioka M, Asano H, Nakashima Y, Osanai H, Kanbara T, Sakamoto Y, Oguri M, Ohguchi S, Takahara K, Izumi K, Yasuda K, Kudo A, Machii N, Morimoto R, Bando Y, Okumura T, Kondo T, Miura SI, Shiga Y, Mirii J, Sugihara M, Arimura T, Nakano J, Sakamoto T, Kodama K, Ohte N, Sugiura T, Wakami K, Takemoto Y, Yoshiyama M, Shuto T, Fukumoto K, Okada Y, Tanaka K, Sonoda S, Tokutsu A, Otsuka T, Uemura F, Koikawa K, Miyazaki M, Umikawa M, Narisawa M, Furuta M, Minami H, Doi M, Sugimoto K, Suzuki S, Kurozumi A, Nishio K. Effect of ipragliflozin on carotid intima-media thickness in patients with type 2 diabetes: a multicenter, randomized, controlled trial. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2023; 9:165-172. [PMID: 36308299 PMCID: PMC9892869 DOI: 10.1093/ehjcvp/pvac059] [Show More Authors] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/13/2022] [Accepted: 10/24/2022] [Indexed: 11/11/2022]
Abstract
AIMS To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. METHODS AND RESULTS In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0-10.0% (42-86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), -0.0155-0.0182] mm and 0.0015 (95% CI, -0.0155-0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of -0.0001 mm (95% CI, -0.0191-0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [-0.1% (95% CI, -0.2-0.1); P = 0.359]. CONCLUSION Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.
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Affiliation(s)
- Atsushi Tanaka
- Corresponding authors: Tel: +81-952-34-2364, Fax +81-952-34-2089,
| | - Masataka Sata
- Department of Cardiovascular Medicine, Tokushima University Hospital, 2-50-1 Kuramoto-machi, Tokushima, Tokushima, 770-8503, Japan
| | - Yosuke Okada
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku Kitakyushu, 807-8556, Japan
| | - Hiroki Teragawa
- Department of Cardiovascular Medicine, JR Hiroshima Hospital, 3-1-36 Futabanosato, Higashi-ku, Hiroshima, 732-0057, Japan
| | - Kazuo Eguchi
- Department of General Internal Medicine, Saitama Red Cross Hospital, 1-5 Shintoshin, Chuo-ku, Saitama, 330-0081, Japan
| | - Michio Shimabukuro
- Department of Diabetes, Endocrinology, and Metabolism, Fukushima Medical University, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Isao Taguchi
- Department of Cardiology, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minamikoshigaya, Koshigaya, 343-8555, Japan
| | - Kazuo Matsunaga
- Department of Internal Medicine, Imari-Arita Kyoritsu Hospital, 860 Ninoseko, Matsuura, Saga, 849-4141, Japan
| | - Yumiko Kanzaki
- Department of Cardiology, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Hisako Yoshida
- Department of Medical Statistics, Osaka Metropolitan University, 1-4-3 Asahimachi, Abeno-ku, Osaka, Osaka, 545-8585, Japan
| | - Tomoko Ishizu
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, 2-1-1 Amakubo, Tsukuba, 305-8576, Japan
| | - Shinichiro Ueda
- Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus, 207 Uehara, Nishihara, 903-0215, Okinawa, Japan
| | - Masafumi Kitakaze
- Hanwa Daini Senboku Hospital, 3176 Fukaikitamachi, Naka-ku, Sakai, 599-8271, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumaicho, Showa-ku Nagoya, 466-0065, Japan
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Yanai H, Adachi H, Hakoshima M, Katsuyama H. Glucagon-Like Peptide 1 Receptor Agonists Versus Sodium-Glucose Cotransporter 2 Inhibitors for Atherosclerotic Cardiovascular Disease in Patients With Type 2 Diabetes. Cardiol Res 2023; 14:12-21. [PMID: 36896226 PMCID: PMC9990545 DOI: 10.14740/cr1459] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 02/11/2023] [Indexed: 02/27/2023] Open
Abstract
Beyond improving hemoglobin A1c (HbA1c) in adults with type 2 diabetes, glucagon-like peptide 1 receptor agonists (GLP-1RA) have been approved for reducing risk of major adverse cardiovascular events (MACE) with established cardiovascular disease (CVD) or multiple CV risk factors. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) also reduced the risk for the primary composite CV outcome in patients with type 2 diabetes at high risk for CV events. In the American Diabetes Association (ADA) and European Association of Study in Diabetes (EASD) consensus report 2022, there is the description "In people with established atherosclerotic CVD (ASCVD) or with a high risk for ASCVD, GLP-1RA were prioritized over SGLT2i"; however, the evidence supporting such statement is limited. Therefore, we studied the superiority of GLP-1RA over SGLT2i for prevention of ASCVD from various viewpoints. We could not find a meaningful difference in the risk reduction in three-point MACE (3P-MACE), mortality due to any cause, mortality due to CV cause and nonfatal myocardial infarction between GLP-1RA and SGLT2i trials. The risk of nonfatal stroke decreased in all five GLP-1RA trials; however, two of three SGLT2i trials showed an increase in risk of nonfatal stroke. The risk of hospitalization for heart failure (HHF) decreased in all three SGLT2i trials, and one GLP-1RA trial showed an increase in risk of HHF. The risk reduction of HHF in SGLT2i trials was greater than that in GLP-1RA trials. These findings were consistent with current systematic reviews and meta-analyses. The risk reduction of 3P-MACE was significantly and negatively correlated with changes in HbA1c (R = -0.861, P = 0.006) and body weight (R = -0.895, P = 0.003) in GLP-1RA and SGLT2i trials. The studies using SGLT2i failed to reduce carotid intima media thickness (cIMT), the surrogate marker for atherosclerosis; however, several studies using GLP-1RA successfully reduced cIMT in patients with type 2 diabetes. Compared with SGLT2i, GLP-1RA had a higher probability of decreasing serum triglyceride. GLP-1RA have multiple vascular biological anti-atherogenic properties.
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Affiliation(s)
- Hidekatsu Yanai
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
| | - Hiroki Adachi
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
| | - Mariko Hakoshima
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
| | - Hisayuki Katsuyama
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
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Tornyos D, Meuer M, Lukács R, El Alaoui El Abdallaoui O, Kupó P, Faludi R, Komócsi A. Cardiovascular outcomes in patients treated with sodium-glucose transport protein 2 inhibitors, a network meta-analysis of randomized trials. Front Cardiovasc Med 2022; 9:1041200. [PMID: 36545024 PMCID: PMC9760750 DOI: 10.3389/fcvm.2022.1041200] [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] [Received: 09/10/2022] [Accepted: 11/11/2022] [Indexed: 12/07/2022] Open
Abstract
Background Gliflozins altering the sodium-glucose transport protein 2 (SGLT2) in the nephron, represent alone or in combination a promising treatment option for patients with type II diabetes mellitus. In addition to glucose control, these drugs provide benefits including reduced risk of long-term cardiovascular (CV) and renal complications. Several trials evaluated gliflozins in patients with various degrees of cardiac dysfunction with heterogeneous results. Objectives We aimed to perform a comprehensive analysis of the effect of gliflozins on CV outcomes. Methods Systematic searches of electronic databases were conducted until September 2022. Multiple treatment network meta-analysis was performed in R. Random-effects model was used to combine risk estimates across trials calculating risk ratio (RR) with 95% confidence intervals as summary statistics. The primary endpoint of interest was the rate of heart failure-related hospitalization (HHF) and the composite of HHF with CV mortality (HHF + CVD). Secondary outcomes included major adverse cardiac events (MACE), CV- and overall mortality, myocardial infarction (MI), and stroke. Results Twenty-nine studies randomizing 88,418 patients were identified. Gliflozins reduced the risk of HHF (RR: 0.72 [0.69; 0.76]) and HHF + CVD (RR: 0.78 [0.75; 0.82]). The risk of MACE and its component also improved significantly except for stroke. The network analyses did not explore major differences among the individual substances. The only exception was sotagliflozin which appeared to be more effective regarding HHF + CVD, stroke, and MI compared to ertugliflozin, in HHF + CVD and stroke compared to dapagliflozin, and in stroke endpoint compared to empagliflozin. Conclusion Our meta-analysis supports a group effect of gliflozins beneficial in a wide spectrum of patients with a risk of heart failure (HF) development. In addition to the improvement of HF-related outcomes, the risk of major adverse events is also reduced with SGLT2 inhibition. Systematic review registration [www.ClinicalTrials.gov], identifier [CRD42022358078].
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Wang D, Liu J, Zhong L, Li S, Zhou L, Zhang Q, Li M, Xiao X. The effect of sodium-glucose cotransporter 2 inhibitors on biomarkers of inflammation: A systematic review and meta-analysis of randomized controlled trials. Front Pharmacol 2022; 13:1045235. [PMID: 36467062 PMCID: PMC9717685 DOI: 10.3389/fphar.2022.1045235] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 10/26/2022] [Indexed: 10/27/2023] Open
Abstract
Aims: Inflammatory biomarkers may play vital roles in the pathophysiology of diabetes and diabetic cardiorenal complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have a potential cardiovascular and renal protective effect in type 2 diabetes. The aim of this meta-analysis was to quantify the effects of SGLT2 inhibitors on biomarkers of inflammation in randomized controlled trials (RCTs). Methods: PubMed, Cochrane Library, EMBASE, and Web of Science were searched for eligible RCTs of adults with type 2 diabetes (T2D) with no time limit (updated to 12 October 2022). The biomarkers selected included C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, leptin, adiponectin, ferritin, plasminogen activator inhibitor (PAI)-1, and vascular cell adhesion molecule-1. Data were analyzed using a random-effect model in Review Manager 5.4. Results: Thirty-four studies with 6,261 patients (68.6% male) were eligible for this meta-analysis. The mean age of the participants was 62.57(±11.13) years old, and the median treatment duration length with follow-up was 24 weeks. Generally, the included trials were of good methodological quality. The meta-analysis revealed that ferritin levels were significantly reduced in SGLT2 inhibitor treatment groups versus placebo or standard diabetes therapies (SMD: -1.21; 95% CI: -1.91, -0.52, p < 0.001). The effects of CRP (SMD: 0.25; 95% CI: -0.47, -0.03, p = 0.02) and leptin (SMD: -0.22; 95% CI: -0.43, -0.01, p = 0.04) were reduced, and the effects of adiponectin were improved (SMD: 0.28; 95% CI: 0.15, 0.41, p < 0.001) in placebo-controlled studies. PAI-1 levels were significantly reduced in studies controlled for diabetes therapies (SMD: -0.38; 95% CI: -0.61, -0.15, p = 0.001). Conclusion: This analysis provides strong evidence supporting anti-inflammatory effects of SGLT2 inhibitors in T2D subjects. The mechanisms and possible targets for the inflammation reducing and cardiorenal protective properties of SGLT2 inhibitors remain to be explored.
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Affiliation(s)
- Dongmei Wang
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jieying Liu
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ling Zhong
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Shunhua Li
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Liyuan Zhou
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Qian Zhang
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Ming Li
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xinhua Xiao
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Yan ST, Sun J, Gu ZY, Miao XY, Ma LC, Sun BR, Fu XM, Liu HZ, Yang G, Fang FS, Li H. The bidirectional association of C-peptide with cardiovascular risk in nondiabetic adults and patients with newly diagnosed type 2 diabetes mellitus: a retrospective cohort study. Cardiovasc Diabetol 2022; 21:201. [PMID: 36192784 PMCID: PMC9531486 DOI: 10.1186/s12933-022-01636-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 09/21/2022] [Indexed: 11/26/2022] Open
Abstract
Background Recent literature reported the biological role of C-peptide, but this role is still controversial and unclear. The primary aim of this study was to investigate associations between C-peptide and cardiovascular biomarkers as well as events. Methods A total of 55636 participants who had a health examination from 2017 to 2021 were included. Of them, 6727 participants visited the hospital at least twice. Cardiovascular biomarkers like high-sensitivity C-reactive protein (hs-CRP) and high-sensitivity cardiac troponin T (hs-cTnT) were measured and their relationships with fasting C-peptide were evaluated for all participants. Cardiovascular events were obtained during the last visit and their associations with C-peptide were evaluated for those participants who visited the hospital at least twice. Results Among the included participants, 11.1% had a previous type 2 diabetes mellitus (T2DM). In the participants without previous T2DM, the relationships between fasting C-peptide and hs-CRP and hs-cTnT were negative if the value of fasting C-peptide was < 1.4 ng/mL and positive if the value was ≥ 1.4 ng/mL. These relationships remained significant after adjusting for hemoglobin A1c, insulin resistance index, and its interaction with C-peptide, even if the participants were stratified by glucose metabolism status or levels of insulin resistance index. Hazard ratios of cardiovascular events were first decreased and then increased with the increasing of baseline C-peptide levels, though these associations became unsignificant using the multivariate Cox regression model. Unlike the participants without previous T2DM, the associations of C-peptide with cardiovascular biomarkers and events were not significant in the patients with previous T2DM. Conclusions The associations of C-peptide with cardiovascular biomarkers and events were different between the participants without previous T2DM and those with previous T2DM. The effect of C-peptide on cardiovascular risk may be bidirectional, play a benefit role at a low level, and play a harmful role at a high level in the nondiabetic adults and the patients with newly diagnosed T2DM. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-022-01636-z.
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Affiliation(s)
- Shuang-Tong Yan
- Department of Geriatric Endocrinology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Jing Sun
- Health Management Institute, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Zhao-Yan Gu
- Department of Geriatric Endocrinology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Xin-Yu Miao
- Department of Geriatric Endocrinology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Li-Chao Ma
- Department of Geriatric Endocrinology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Ban-Ruo Sun
- Department of Geriatric Endocrinology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Xiao-Min Fu
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Hong-Zhou Liu
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Guang Yang
- Department of Geriatric Nephrology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Fu-Sheng Fang
- Department of Health Care, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
| | - Hong Li
- Health Management Institute, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
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Han G, Li H, Guo H, Yi C, Yu B, Lin Y, Zheng B, He D. The roles and mechanisms of miR-26 derived from exosomes of adipose-derived stem cells in the formation of carotid atherosclerotic plaque. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1134. [PMID: 36388831 PMCID: PMC9652556 DOI: 10.21037/atm-22-4247] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 10/18/2022] [Indexed: 10/04/2023]
Abstract
Background This study explored the serum concentrations of miR-26 in patients with carotid atherosclerosis (CAS) and defined the roles and mechanisms of miR-26 derived from the exosomes of adipose-derived stem cells (ADSC-exos). Methods The carotid artery width was diagnosed by ultrasound examination in patients with different degrees of CAS. The serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in patients were detected by biochemistry. The serum levels of miR-26 were determined by quantitative polymerase chain reaction (qPCR). A model of CAS in ApoE-/- mice fed with a rich-fat diet was established to analyze the regulatory effects of serum miR-26 on blood lipids in mice. Adipose mesenchymal stem cell lines transfected with miR-26 were established. The regulatory relationship between the expression levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β, and the expression levels of miR-26 in the supernatant of each group of cells was determined by qPCR. The ADSC-exos were extracted from ADSCs and injected into model mice through the tail vein. The therapeutic effect of ADSCs expressing miR-26 on model mice was evaluated by detecting the levels of inflammatory factors and blood lipids in the serum of the mice. Results The degree of atherosclerosis (AS) was positively associated with the intima-media thickness (IMT) of the carotid artery. The serum levels of miR-26 in patients were inversely correlated with the levels of blood lipids (TC, TG, and LDL-C), and positively correlated with HDL-C levels. Similarly, in the CAS mouse model, the serum levels of miR-26 were inversely correlated with the levels of blood lipids (TC, TG, and LDL-C), and positively correlated with HDL-C level. In ADSCs transfected with miR-26, the miR-26 expression in the cell supernatant was negatively regulated by the expression of inflammatory factors, TNF-α, IL-6, and IL-1β, in the cell supernatant. ADSC-exos expressing miR-26 has positive effects on correcting blood lipids and inflammatory factors in the mouse model of CAS. Conclusions miR-26 has an active role in CAS and may be a novel target for the treatment of CAS in the future.
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Affiliation(s)
- Guochao Han
- Department of Electrophysiology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Hui Li
- Department of Electrophysiology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Hongyan Guo
- Department of Biochemistry, Qiqihar Medical University, Qiqihar, China
| | - Chao Yi
- Department of Neurosurgery, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Beiguang Yu
- Department of Electrophysiology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Yuan Lin
- Department of Electrophysiology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Bingjie Zheng
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dongruo He
- Department of Electrophysiology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
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21
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Iwamoto M, Kubota T, Sakurai Y, Wada N, Shioda S, Yamauchi T, Kadowaki T, Kubota N. The sodium-glucose co-transporter 2 inhibitor tofogliflozin suppresses atherosclerosis through glucose lowering in ApoE-deficient mice with streptozotocin-induced diabetes. Pharmacol Res Perspect 2022; 10:e00971. [PMID: 35707828 PMCID: PMC9201373 DOI: 10.1002/prp2.971] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 04/23/2022] [Accepted: 04/25/2022] [Indexed: 11/11/2022] Open
Abstract
Epidemiological and animal studies have revealed that sodium-glucose cotransporter 2 (SGLT2) inhibitors suppress cardiovascular events in subjects with type 2 diabetes and atherosclerosis in animal models of diabetes. However, it still remains unclear if the anti-atherosclerotic effect of SGLT2 inhibitors is entirely dependent on their glucose-lowering effect. Tofogliflozin, a highly specific SGLT2 inhibitor, was administrated to apolipoprotein-E-deficient (ApoEKO) with streptozotocin (STZ)-induced diabetes and nondiabetic ApoEKO mice. After 6 weeks, samples were collected to investigate the histological changes and peritoneal macrophage inflammatory cytokine levels. Tofogliflozin suppressed atherosclerosis in the diabetic ApoEKO mice. The atherosclerosis lesion areas and accumulation of macrophages in these areas were reduced by tofogliflozin treatment. The expression levels of interleukin (IL)-1β and IL-6 in the peritoneal macrophages were significantly suppressed in the tofogliflozin-treated diabetic ApoEKO mice. Tofogliflozin treatment failed to inhibit atherosclerosis in the nondiabetic ApoEKO mice. No significant difference in the anti-atherosclerotic effects of insulin and tofogliflozin was observed between diabetic ApoEKO mice with equivalent degrees of glycemic control achieved with the two treatments. Insulin treatment significantly reduced the IL-1β and IL-6 expression levels in the peritoneal macrophages of the diabetic ApoEKO mice. Significant decrease of the LPS-stimulated IL-1β concentrations was also observed in the conditioned medium of the peritoneal macrophages collected from insulin- and tofogliflozin-treated diabetic ApoEKO mice. These results suggest that tofogliflozin suppresses atherosclerosis by improving glucose intolerance associated with inhibition of inflammation. Tofogliflozin suppresses atherosclerosis in ApoEKO mice with STZ-induced diabetes via its glucose-lowering effect.
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Affiliation(s)
- Masahiko Iwamoto
- Department of Diabetes and Metabolic DiseasesGraduate School of MedicineThe University of TokyoTokyoJapan
- Division of Diabetes and MetabolismThe Institute of Medical ScienceAsahi Life FoundationTokyoJapan
| | - Tetsuya Kubota
- Department of Diabetes and Metabolic DiseasesGraduate School of MedicineThe University of TokyoTokyoJapan
- Division of Diabetes and MetabolismThe Institute of Medical ScienceAsahi Life FoundationTokyoJapan
- Department of Clinical NutritionNational Institutes of Biomedical InnovationHealth and Nutrition (NIBIOHN)TokyoJapan
- Laboratory for Intestinal EcosystemRIKEN Center for Integrative Medical Sciences (IMS)KanagawaJapan
- Intestinal Microbiota ProjectKanagawa Institute of Industrial Science and Technology EbinaKanagawaJapan
- Division of Cardiovascular MedicineToho University Ohashi Medical CenterTokyoJapan
| | - Yoshitaka Sakurai
- Department of Diabetes and Metabolic DiseasesGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Nobuhiro Wada
- Department of Diabetes and Metabolic DiseasesGraduate School of MedicineThe University of TokyoTokyoJapan
- Department of Clinical NutritionNational Institutes of Biomedical InnovationHealth and Nutrition (NIBIOHN)TokyoJapan
| | - Seiji Shioda
- Global Research Center for Innovative Life SciencePeptide Drug InnovationSchool of Pharmacy and Pharmaceutical SciencesHoshi UniversityTokyoJapan
| | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic DiseasesGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic DiseasesGraduate School of MedicineThe University of TokyoTokyoJapan
- Toranomon HospitalTokyoJapan
| | - Naoto Kubota
- Department of Diabetes and Metabolic DiseasesGraduate School of MedicineThe University of TokyoTokyoJapan
- Department of Clinical Nutrition TherapyThe University of TokyoTokyoJapan
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22
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Adam CA, Anghel R, Marcu DTM, Mitu O, Roca M, Mitu F. Impact of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors on Arterial Stiffness and Vascular Aging-What Do We Know So Far? (A Narrative Review). Life (Basel) 2022; 12:803. [PMID: 35743834 PMCID: PMC9224553 DOI: 10.3390/life12060803] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 05/23/2022] [Accepted: 05/25/2022] [Indexed: 11/23/2022] Open
Abstract
Vascular aging, early vascular aging or supernormal vascular aging are concepts used for estimating the cardiovascular risk at a certain age. From the famous line of Thomas Sydenham that "a man is as old as his arteries" to the present day, clinical studies in the field of molecular biology of the vasculature have demonstrated the active role of vascular endothelium in the onset of cardiovascular diseases. Arterial stiffness is an important cardiovascular risk factor associated with the occurrence of cardiovascular events and a high risk of morbidity and mortality, especially in the presence of diabetes. Sodium-glucose cotransporter 2 inhibitors decrease arterial stiffness and vascular resistance by decreasing endothelial cell activation, stimulating direct vasorelaxation and ameliorating endothelial dysfunction or expression of pro-atherogenic cells and molecules.
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Affiliation(s)
- Cristina Andreea Adam
- Clinical Rehabilitation Hospital, Cardiovascular Rehabilitation Clinic, Pantelimon Halipa Street nr. 14, 700661 Iaşi, Romania; (C.A.A.); (R.A.); (M.R.); (F.M.)
| | - Razvan Anghel
- Clinical Rehabilitation Hospital, Cardiovascular Rehabilitation Clinic, Pantelimon Halipa Street nr. 14, 700661 Iaşi, Romania; (C.A.A.); (R.A.); (M.R.); (F.M.)
- Department of Internal Medicine, University of Medicine and Pharmacy, Grigore T. Popa, University Street nr. 16, 700115 Iaşi, Romania
| | - Dragos Traian Marius Marcu
- Department of Internal Medicine, University of Medicine and Pharmacy, Grigore T. Popa, University Street nr. 16, 700115 Iaşi, Romania
| | - Ovidiu Mitu
- Department of Internal Medicine, University of Medicine and Pharmacy, Grigore T. Popa, University Street nr. 16, 700115 Iaşi, Romania
- Sf. Spiridon Clinical Emergency Hospital, Independence Boulevard nr. 1, 700111 Iasi, Romania
| | - Mihai Roca
- Clinical Rehabilitation Hospital, Cardiovascular Rehabilitation Clinic, Pantelimon Halipa Street nr. 14, 700661 Iaşi, Romania; (C.A.A.); (R.A.); (M.R.); (F.M.)
- Department of Internal Medicine, University of Medicine and Pharmacy, Grigore T. Popa, University Street nr. 16, 700115 Iaşi, Romania
| | - Florin Mitu
- Clinical Rehabilitation Hospital, Cardiovascular Rehabilitation Clinic, Pantelimon Halipa Street nr. 14, 700661 Iaşi, Romania; (C.A.A.); (R.A.); (M.R.); (F.M.)
- Department of Internal Medicine, University of Medicine and Pharmacy, Grigore T. Popa, University Street nr. 16, 700115 Iaşi, Romania
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23
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Ma CX, Ma XN, Guan CH, Li YD, Mauricio D, Fu SB. Cardiovascular disease in type 2 diabetes mellitus: progress toward personalized management. Cardiovasc Diabetol 2022; 21:74. [PMID: 35568946 PMCID: PMC9107726 DOI: 10.1186/s12933-022-01516-6] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/28/2022] [Indexed: 01/10/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the main cause of death among patients with type 2 diabetes mellitus (T2DM), particularly in low- and middle-income countries. To effectively prevent the development of CVDs in T2DM, considerable effort has been made to explore novel preventive approaches, individualized glycemic control and cardiovascular risk management (strict blood pressure and lipid control), together with recently developed glucose-lowering agents and lipid-lowering drugs. This review mainly addresses the important issues affecting the choice of antidiabetic agents and lipid, blood pressure and antiplatelet treatments considering the cardiovascular status of the patient. Finally, we also discuss the changes in therapy principles underlying CVDs in T2DM.
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Affiliation(s)
- Cheng-Xu Ma
- Department of Endocrinology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, Gansu, 730000, People's Republic of China.,The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Xiao-Ni Ma
- Department of Endocrinology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, Gansu, 730000, People's Republic of China.,The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Cong-Hui Guan
- Department of Endocrinology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, Gansu, 730000, People's Republic of China.,The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Ying-Dong Li
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, China
| | - Dídac Mauricio
- Department of Endocrinology & Nutrition, CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, 08041, Barcelona, Spain.
| | - Song-Bo Fu
- Department of Endocrinology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, Gansu, 730000, People's Republic of China. .,The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China.
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24
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Tharmaraja T, Ho JS, Sia CH, Lim NA, Chong YF, Lim AY, Rathakrishnan RR, Yeo LL, Sharma VK, Tan BY. Sodium-glucose cotransporter 2 inhibitors and neurological disorders: a scoping review. Ther Adv Chronic Dis 2022; 13:20406223221086996. [PMID: 35432846 PMCID: PMC9006360 DOI: 10.1177/20406223221086996] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 02/24/2022] [Indexed: 01/24/2023] Open
Abstract
Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic medications with a favourable cardiovascular, renal and overall safety profile. Given the limited treatment options available for neurological disorders, it is important to determine whether the pleiotropic effects of SGLT2i can be utilised in their prevention and management. Methods All articles published before 20 March 2021 were systematically searched in MEDLINE, EMBASE, Scopus, Web of Science, APA PsycINFO and ClinicalTrials.gov. Overall, 1395 titles were screened, ultimately resulting in 160 articles being included in the qualitative analysis. Screening and data extraction were conducted by two independent authors and studies were excluded if they were not an original research study. Findings Of the 160 studies, 134 addressed stroke, 19 cognitive impairment, 4 epilepsy and 4 movement disorders, encompassing a range from systematic reviews and randomised controlled trials to bioinformatic and animal studies. Most animal studies demonstrated significant improvements in behavioural and neurological deficits, which were reflected in beneficial changes in neurovascular units, synaptogenesis, neurotransmitter levels and target receptors' docking energies. The evidence from the minority clinical literature was conflicting and many studies did not reach statistical significance. Interpretation SGLT2i may exert neurological benefits through three mechanisms: reduction in cardiovascular risk factors, augmentation of ketogenesis and anti-inflammatory pathways. Most clinical studies were observational, meaning that a causal relationship could not be established, while randomised controlled trials were heterogeneous and powered to detect cardiovascular or renal outcomes. We suggest that a longitudinal study should be conducted and specifically powered to detect neurological outcomes.
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Affiliation(s)
- Thahesh Tharmaraja
- Intensive Care Unit, University College Hospital, University College London Hospitals NHS Foundation Trust, London, UK
| | - Jamie S.Y. Ho
- Intensive Care Unit, Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK
| | - Ching-Hui Sia
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Nicole-Ann Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yao Feng Chong
- Division of Neurology, Department of Medicine, National University Health System, Singapore
| | - Amanda Y.L. Lim
- Division of Endocrinology, Department of Medicine, National University Health System, Singapore
| | - Rahul R. Rathakrishnan
- Division of Neurology, Department of Medicine, National University Health System, Singapore
| | - Leonard L.L. Yeo
- Division of Neurology, Department of Medicine, National University Health System, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, 1E Kent Ridge Road Level 11, 119228 Singapore
| | - Vijay K. Sharma
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Neurology, Department of Medicine, National University Health System, Singapore
| | - Benjamin Y.Q. Tan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Neurology, Department of Medicine, National University Health System, Singapore
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25
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SGLT2 inhibitor dapagliflozin prevents atherosclerotic and cardiac complications in experimental type 1 diabetes. PLoS One 2022; 17:e0263285. [PMID: 35176041 PMCID: PMC8853531 DOI: 10.1371/journal.pone.0263285] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 01/17/2022] [Indexed: 02/07/2023] Open
Abstract
Introduction Cardiovascular disease (CVD) is two to five times more prevalent in diabetic patients and is the leading cause of death. Therefore, identification of novel therapeutic strategies that reduce the risk of CVD is a research priority. Clinical trials showed that reduction in the relative risk of heart failure by sodium-glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects, however, the molecular mechanisms are still elusive. Here we investigated the role of SGLT2i dapagliflozin (DAPA) in the prevention of diabetes-induced cardiovascular complications. Methods Type 1 diabetes was induced with streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with DAPA (1 mg/bwkg/day, po.). Results DAPA decreased blood glucose levels (D: 37±2.7 vs. D+DAPA: 18±5.6 mmol/L; p<0.05) and prevented metabolic decline. Aortic intima-media thickening was mitigated by DAPA. DAPA abolished cardiac hypertrophy, and myocardial damage. Cardiac inflammation and fibrosis were also moderated after DAPA treatment. Conclusions These data support the preventive and protective role of SGLT2i in diabetes-associated cardiovascular disease. SGLT2i may provide novel therapeutic strategy to hinder the development of cardiovascular diseases in type 1 diabetes, thereby improve the outcomes.
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26
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Katakami N, Mita T, Maeda N, Sato Y, Watada H, Shimomura I. Evaluation of the effect of tofogliflozin on the tissue characteristics of the carotid wall-a sub-analysis of the UTOPIA trial. Cardiovasc Diabetol 2022; 21:19. [PMID: 35123483 PMCID: PMC8817596 DOI: 10.1186/s12933-022-01451-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/25/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Since sodium-glucose cotransporter 2 (SGLT2) inhibitors have a pleiotropic antiatherogenic effect, they are expected to attenuate the progression of atherosclerosis. However, whether SGLT2 inhibitors affect the tissue characteristics of the human arterial wall remains unclear. This study aimed to evaluate the effects of tofogliflozin, a selective SGLT2 inhibitor, on the tissue characteristics of the human arterial wall in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD). METHODS The present study was a post hoc analysis based on data obtained from the Using Tofogliflozin for Possible Better Intervention against Atherosclerosis for Type 2 Diabetes Patients (UTOPIA) trial, which was a multicenter prospective, randomized, open-label, blinded-endpoint study conducted to evaluate the efficacy of tofogliflozin in preventing the progression of atherosclerosis in patients with T2DM. We evaluated the longitudinal change in the ultrasonic tissue characteristics of the carotid wall using gray-scale median (GSM), an established index of ultrasonic tissue characteristics. The right and left intima-medial areas were delineated, and the GSM values were evaluated (right GSM-CCA and left GSM-CCA). The average values of the right and left carotid arteries were defined as "mean GSM-CCA value." RESULTS In a mixed-effects model for repeated measures, mean GSM-CCA, along with the right and left GSM-CCA values, did not significantly change in either the tofogliflozin (n = 168) or conventional treatment group (n = 169). In addition, the tofogliflozin and conventional treatment groups did not significantly differ regarding the change of the mean GSM-CCA (mean difference [95% CI] - 1.24[- 3.87, 1.38], P = 0.35), along with the right (mean difference [95% CI] - 2.33[- 5.70, 1.05], P = 0.18) and the left GSM-CCA (mean difference [95% CI] - 0.29 [- 3.53, 2.95], P = 0.86) values. Similar findings were obtained even after adjusting for traditional cardiovascular risk factors and/or the administration of drugs at baseline. CONCLUSIONS The tissue characteristics of the carotid arterial wall did not change in either the tofogliflozin or conventional treatment group during the 104-week treatment period, and there was no significant difference between the treatment groups. Clinical trial registration UMIN000017607 ( https://www.umin.ac.jp/icdr/index.html ).
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Affiliation(s)
- Naoto Katakami
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Tomoya Mita
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Norikazu Maeda
- Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yasunori Sato
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, 45 Shinanomachi Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hirotaka Watada
- Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
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27
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Pahud de Mortanges A, Salvador D, Laimer M, Muka T, Wilhelm M, Bano A. The Role of SGLT2 Inhibitors in Atherosclerosis: A Narrative Mini-Review. Front Pharmacol 2021; 12:751214. [PMID: 34803693 PMCID: PMC8602558 DOI: 10.3389/fphar.2021.751214] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/01/2021] [Indexed: 01/10/2023] Open
Abstract
Objective: Sodium glucose cotransporter 2 inhibitors (SGLT2-is) are antidiabetic drugs that improve glycemic control by limiting urinary glucose reuptake in the proximal tubule. SGLT2-is might suppress atherosclerotic processes and ameliorate the prognosis of patients with diabetes mellitus diagnosed with or at high risk of atherosclerotic cardiovascular disease (ASCVD). In this mini review, we examine the role of SGLT2-is in the development and progression of atherosclerosis throughout its spectrum, from subclinical atherosclerosis to ASCVD. Data Sources—PubMed and Google Scholar were searched for publications related to SGLT2-is and atherosclerosis. All types of articles were considered, including clinical trials, animal studies, in vitro observations, and reviews and meta-analyses. Data were examined according to their impact and clinical relevance. Synopsis of Content—We first review the underlying mechanisms of SGLT2-is on the development and progression of atherosclerosis, including favorable effects on lipid metabolism, reduction of systemic inflammation, and improvement of endothelial function. We then discuss the putative impact of SGLT2-is on the formation, composition, and stability of atherosclerotic plaque. Furthermore, we evaluate the effects of SGLT2-is in subclinical atherosclerosis assessed by carotid intima media thickness and pulse wave velocity. Subsequently, we summarize the effects of SGLT2-is in ASCVD events, including ischemic stroke, angina pectoris, myocardial infarction, revascularization, and peripheral artery disease, as well as major adverse cardiovascular events, cardiovascular mortality, heart failure, and chronic kidney disease. Moreover, we examine factors that could modify the role of SGLT2-is in atherosclerosis, including sex, age, diabetes, glycemic control, ASCVD, and SGLT2-i compounds. Additionally, we propose future directions that can improve our understanding of SGLT2-is and atherosclerosis.
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Affiliation(s)
| | - Dante Salvador
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.,Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Markus Laimer
- Department of Diabetes, Endocrinology, Nutritional Medicine, and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Taulant Muka
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Matthias Wilhelm
- Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Arjola Bano
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.,Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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28
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Onyali CB, Anim-Koranteng C, Shah HE, Bhawnani N, Ethirajulu A, Alkasabera A, Mostafa JA. Role of Selective Sodium-Glucose Co-Transporter-2 Inhibitors in Managing Cardio-Renal Complications in Type 2 Diabetes Mellitus: Beyond Glycemic Control. Cureus 2021; 13:e17452. [PMID: 34603858 PMCID: PMC8475743 DOI: 10.7759/cureus.17452] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/26/2021] [Indexed: 12/30/2022] Open
Abstract
Chronic kidney disease (CKD) and cardiovascular complications are the leading causes of death in type 2 diabetes mellitus. Apart from the standard therapy, which includes angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), lipid-lowering medication, and anti-platelet therapy, the new group of drugs termed the 'sodium-glucose co-transporter-2 (SGLT2) inhibitors' have shown promising results in managing complications arising from the cardiovascular and renal systems in diabetics. This article attempts to highlight the role and mechanism of action of this class of drugs. We reviewed 127 articles and analyses of randomized controlled trials using several drugs in the SGLT2 inhibitor family (sotagliflozin, canagliflozin, dapagliflozin, tofogliflozin) over the past five years, out of which 58 met the criteria and aim of the study. These articles were retrieved from PubMed, Google Scholar, and Medline data sources and assessed for quality using the assessment of multiple systematic reviews (AMSTAR) checklist and Cochrane risk-of-bias tool. Results from the review showed significant benefits in reducing progressive renal decline, blood pressure control, heart failure hospitalization, death from renal or cardiovascular complications, myocardial infarction, and stroke. This benefit is also seen in non-diabetic patients, hence postulating that these effects may not be solely due to glycemic control. There are several mechanisms with which it achieves this benefit with the most significant being its role on intraglomerular pressure. Other pathways include blood pressure control, natriuresis, ventricular remodeling, erythropoiesis, lipid metabolism, plasma volume, and electrolyte imbalance. It is clear that the role of SGLT2 inhibitors isn’t limited to glycemic control and they can achieve a wide array of functions by affecting different systems. More studies need to be done to completely understand this medication to improve the quality of life in diabetic and non-diabetic patients living with CKD and cardiovascular complications. The pharmacokinetics of this drug could also help set the basis for newer medications.
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Affiliation(s)
- Chike B Onyali
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | | | - Hira E Shah
- Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nitin Bhawnani
- Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Aarthi Ethirajulu
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Almothana Alkasabera
- General Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Jihan A Mostafa
- Psychiatry/Cognitive Behavioural Psychotherapy, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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Katakami N, Mita T, Yoshii H, Shiraiwa T, Yasuda T, Okada Y, Torimoto K, Umayahara Y, Kaneto H, Osonoi T, Yamamoto T, Kuribayashi N, Maeda K, Yokoyama H, Kosugi K, Ohtoshi K, Hayashi I, Sumitani S, Tsugawa M, Ryomoto K, Taki H, Nakamura T, Kawashima S, Sato Y, Watada H, Shimomura I. The Influence of Tofogliflozin on Treatment-Related Quality of Life in Patients with Type 2 Diabetes Mellitus. Diabetes Ther 2021; 12:2499-2515. [PMID: 34357559 PMCID: PMC8385006 DOI: 10.1007/s13300-021-01125-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/19/2021] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION Treatment-related quality of life (QOL) is an important aspect of diabetes management. We evaluated the influence of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, tofogliflozin, on treatment-related QOL in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS This is the prespecified subanalysis study of the "Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)" trial. Treatment-related QOL was evaluated at baseline, week 26, week 52, and week 104 after the initiation of the study using the Diabetes Therapy-Related QOL questionnaire (DTR-QOL). Among the 340 patients in the original UTOPIA study, a total of 252 patients (127, tofogliflozin group; 125, conventional treatment group) who completed the DTR-QOL questionnaire at baseline were the study subjects of the current subanalysis. RESULTS The tofogliflozin and conventional treatment groups exhibited almost comparable baseline clinical characteristics, while the use of antihypertensive drugs and lipid-lowering agents was significantly lower in the tofogliflozin treatment group than in the conventional treatment group. Tofogliflozin treatment increased the total score of DTR-QOL7 from baseline (P < 0.001), while conventional treatment did not change it. There were statistically significant differences in delta change in the total DTR-QOL7 score and DTR-QOL7 Q4, Q5, Q6, and Q7 scores from the baseline to week 104 between the treatment groups. Delta changes in HbA1c (Spearman's correlation coefficient, ρ = - 0.30, P < 0.001), fasting blood glucose (ρ = - 0.16, P = 0.031), BMI (ρ = - 0.19, P = 0.008), and waist circumference (ρ = - 0.17, P = 0.024) at week 104 were negatively associated with delta change in the total QOL7 score. CONCLUSIONS Our data indicated that tofogliflozin treatment improved treatment-related QOL compared to conventional treatment in Japanese patients with T2DM, in accordance with the improvement of major cardiovascular risk factors. TRIAL REGISTRATION UMIN000017607.
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Affiliation(s)
- Naoto Katakami
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
- Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Tomoya Mita
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hidenori Yoshii
- Department of Medicine, Diabetology and Endocrinology, Juntendo Tokyo Koto Geriatric Medical Center, Koto-ku, Tokyo, 136-0075, Japan
| | - Toshihiko Shiraiwa
- Shiraiwa Medical Clinic, 4-10-24 Hozenji, Kashiwara, Osaka, 582-0005, Japan
| | - Tetsuyuki Yasuda
- Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31, Kitayama-cho, Tennoji-ku, Osaka, 543-0035, Japan
| | - Yosuke Okada
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Keiichi Torimoto
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Yutaka Umayahara
- Department of Diabetes and Endocrinology, Osaka General Medical Center, 3-1-56, Bandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan
| | - Hideaki Kaneto
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan
| | - Takeshi Osonoi
- Nakakinen Clinic, 745-5, Nakadai, Naka, Ibaraki, 311-0113, Japan
| | - Tsunehiko Yamamoto
- Diabetes and Endocrinology, Kansai Rosai Hospital, 3-1-69, Inabaso, Amagasaki, Hyogo, Japan
| | | | - Kazuhisa Maeda
- Kitasenri Maeda Clinic, 4-119, Furuedai, Suita, Osaka, 565-0874, Japan
| | - Hiroki Yokoyama
- Jiyugaoka Medical Clinic, West 6, South 6-4-3, Obihiro, Hokkaido, 080-0016, Japan
| | - Keisuke Kosugi
- Kosugi Medical Clinic, 3-9, Tamatsukurimoto-cho, Tennoji-ku, Osaka, 543-0014, Japan
| | - Kentaro Ohtoshi
- Otoshi Medical Clinic, 8-47, Kakudacho, Osaka Kita-ku, Osaka, 530-0017, Japan
| | - Isao Hayashi
- Hayashi Clinic, 3-9-23, Koshienguchi, Nishinomiya, Hyogo, 663-8113, Japan
| | - Satoru Sumitani
- Center for Diabetes and Endocrinology, Nippon Life Hospital, 2-1-54 Enokojima, Nishi-ku, Osaka, 550-0006, Japan
| | - Mamiko Tsugawa
- Department of Endocrinology and Metabolism, Ikeda Municipal Hospital, 3-1-18, Jonan, Ikeda, Osaka, 563-8510, Japan
| | - Kayoko Ryomoto
- Center for Diabetes Mellitus, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Kita-ku, Sakai, Osaka, 591-8025, Japan
| | - Hideki Taki
- Diabetes Center, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan
| | - Tadashi Nakamura
- Department of Internal Medicine, Kawasaki Hospital, 3-3-1, Higashiyamacho, Hyogo-ku, Kobe, Hyogo, 652-0042, Japan
| | - Satoshi Kawashima
- Kanda Naika Clinic, 5-21-3, Hannancho, Osaka Abeno-ku, Osaka, 545-0021, Japan
| | - Yasunori Sato
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, 45 Shinanomachi Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
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Gitto M, Vrachatis DA, Condorelli G, Papathanasiou K, Reimers B, Deftereos S, Stefanini GG. Potential Therapeutic Benefits of Sodium-Glucose Cotransporter 2 Inhibitors in the Context of Ischemic Heart Failure: A State-Of-The-Art Review. Cardiovasc Hematol Agents Med Chem 2021; 20:90-102. [PMID: 34370645 DOI: 10.2174/1871525719666210809121016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/25/2021] [Accepted: 07/15/2021] [Indexed: 11/22/2022]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of anti-diabetic agents that block the reabsorption of glucose in the proximal convoluted tubule of the nephron, thereby contributing to glycosuria and lowering blood glucose levels. SGLT2 inhibitors have been associated with improved cardiovascular outcomes in patients with diabetes, including a reduced risk of cardiovascular death and hospitalizations for heart failure. Recently, DAPA-HF and EMPEROR REDUCED trials showed the beneficial cardiovascular effect of SGLT2 inhibitors in patients with heart failure with consistently reduced ejection fraction (HFrEF) regardless of the presence of diabetes. Moreover, some exploratory studies suggested that these drugs improve Left Ventricular (LV) systolic function and oppose LV adverse remodeling in patients with HFrEF. However, the exact mechanisms that mediated for this benefit are not fully understood. Beyond glycemic control, enhanced natriuresis, increased erythropoiesis, improved endothelial function, changes in myocardial metabolism, anti-inflammatory and anti-oxidative properties may all play an active role in SGLT2 inhibitors' cardiovascular benefits. A deep understanding of the pathophysiological interplay is key to define which HF phenotype could benefit more from SGLT2 inhibitors. Current clinical evidence on the comparison of different HF etiologies is limited to posthoc subgroup analysis of DAPA-HF and EMPEROR-REDUCED, which showed similar outcomes in patients with or without ischemic HF. On the other hand, in earlier studies of patients suffering from diabetes, rates of classic ischemic endpoints, such as myocardial infarction, stroke or coronary revascularization, did not differ between patients treated with SGLT2 inhibitors or placebo. The aim of this review is to discuss whether SGLT2 inhibitors may improve prognosis in patients with ischemic HF, not only in terms of reducing re-hospitalizations and improving left ventricular function but also by limiting coronary artery disease progression and ischemic burden.
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Affiliation(s)
- Mauro Gitto
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
| | - Dimitrios A Vrachatis
- 2nd Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | - Gianluigi Condorelli
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
| | | | - Bernhard Reimers
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
| | - Spyridon Deftereos
- 2nd Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | - Giulio G Stefanini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
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Xiao L, Nie X, Cheng Y, Wang N. Sodium-Glucose Cotransporter-2 Inhibitors in Vascular Biology: Cellular and Molecular Mechanisms. Cardiovasc Drugs Ther 2021; 35:1253-1267. [PMID: 34273091 DOI: 10.1007/s10557-021-07216-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/07/2021] [Indexed: 12/16/2022]
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are new antidiabetic drugs that reduce hyperglycemia by inhibiting the glucose reabsorption in renal proximal tubules. Clinical studies have shown that SGLT2 inhibitors not only improve glycemic control but also reduce major adverse cardiovascular events (MACE, cardiovascular and total mortality, fatal or nonfatal myocardial infarction or stroke) and hospitalization for heart failure (HF), and improve outcome in chronic kidney disease. These cardiovascular and renal benefits have now been confirmed in both diabetes and non-diabetes patients. The precise mechanism(s) responsible for the protective effects are under intensive investigation. This review examines current evidence on the cardiovascular benefits of SGLT2 inhibitors, with a special emphasis on the vascular actions and their potential mechanisms.
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Affiliation(s)
- Lei Xiao
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xin Nie
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Yanyan Cheng
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Nanping Wang
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, and Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, 100191, China.
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Shi N, Shi Y, Xu J, Si Y, Yang T, Zhang M, Ng DM, Li X, Xie F. SGLT-2i and Risk of Malignancy in Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. Front Public Health 2021; 9:668368. [PMID: 34164370 PMCID: PMC8215266 DOI: 10.3389/fpubh.2021.668368] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/03/2021] [Indexed: 12/25/2022] Open
Abstract
Background: Currently, the association between sodium-glucose cotransporter 2 inhibitor (SGLT-2i) and malignancy risk has yet to be fully elucidated. This meta-analysis aimed to determine the relationship between SGLT-2i and malignancy risk in type 2 diabetes (T2D) patients. Methods: We searched PubMed, ScienceDirect, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science to identify randomized controlled trials (RCTs) published up to August 2020 related to T2D patients treated with SGLT-2i vs. placebo or other hypoglycemic agents. The meta-analysis's primary outcome was malignancies' incidence, and the results were evaluated using risk ratio (RR) and 95% confidence interval (CI). Results: We reviewed 76 articles (77 RCTs), comprising 45,162 and 43,811 patients in SGLT-2i and control groups, respectively. Compared with the control group, SGLT-2i had no significant association with augmented overall malignancy risk in T2D patients (RR = 1.05, 95% CI = 0.97–1.14, P = 0.20), but ertugliflozin may upsurge the risk (RR = 1.80, 95% CI = 1.02–3.17, P = 0.04). Compared with active hypoglycemic agents, dapagliflozin may increase (RR = 2.71, 95% CI = 1.46–6.43, P = 0.02) and empagliflozin may decrease (RR = 0.67, 95% CI = 0.45–0.98, P = 0.04) the malignancy risk. Compared with placebo, empagliflozin may exhibit risk increase (RR = 1.25, 95% CI = 1.05–1.49, P = 0.01), primarily in digestive system (RR = 1.48, 95% CI = 0.99–2.21, P = 0.05). Conclusions: Our results proposed that in diverse comparisons, ertugliflozin and dapagliflozin seemed to increase the malignancy risk in T2D patients. Empagliflozin may cause malignancy risk reduction compared with active hypoglycemic agents but increase overall risk primarily in the digestive system compared with placebo. In short, the relationship between SGLT-2i and malignancy in T2D patients remains unclear.
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Affiliation(s)
- Nanjing Shi
- Department of Endocrinology, Affiliated Hangzhou First People' Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yetan Shi
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jingsi Xu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuexiu Si
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Tong Yang
- Department of Tumor High Intensity Focused Ultrasound Therapy, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Mengting Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | | | - Xiangyuan Li
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Fei Xie
- Department of Endocrinology, Ningbo Yinzhou No. 2 Hospital, Ningbo, China
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Liu Z, Ma X, Ilyas I, Zheng X, Luo S, Little PJ, Kamato D, Sahebkar A, Wu W, Weng J, Xu S. Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics. Theranostics 2021; 11:4502-4515. [PMID: 33754074 PMCID: PMC7977463 DOI: 10.7150/thno.54498] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 01/17/2021] [Indexed: 02/06/2023] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are new oral drugs for the therapy of patients with type 2 diabetes mellitus (T2DM). Research in the past decade has shown that drugs of the SGLT2i class, such as empagliflozin, canagliflozin, and dapagliflozin, have pleiotropic effects in preventing cardiovascular diseases beyond their favorable impact on hyperglycemia. Of clinical relevance, recent landmark cardiovascular outcome trials have demonstrated that SGLT2i reduce major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular death in T2DM patients with/without cardiovascular diseases (including atherosclerotic cardiovascular diseases and various types of heart failure). The major pharmacological action of SGLT2i is through inhibiting glucose re-absorption in the kidney and thus promoting glucose excretion. Studies in experimental models of atherosclerosis have shown that SGLT2i ameliorate the progression of atherosclerosis by mechanisms including inhibition of vascular inflammation, reduction in oxidative stress, reversing endothelial dysfunction, reducing foam cell formation and preventing platelet activation. Here, we summarize the anti-atherosclerotic actions and mechanisms of action of SGLT2i, with an aim to emphasize the clinical utility of this class of agents in preventing the insidious cardiovascular complications accompanying diabetes.
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Affiliation(s)
- Zhenghong Liu
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xiaoxuan Ma
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Iqra Ilyas
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xueying Zheng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Sihui Luo
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Peter J. Little
- Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, QLD 4575, Australia
- School of Pharmacy, Pharmacy Australia Centre of Excellence, the University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Danielle Kamato
- School of Pharmacy, Pharmacy Australia Centre of Excellence, the University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Weiming Wu
- Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, China
| | - Jianping Weng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Suowen Xu
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Yu YW, Zhao XM, Wang YH, Zhou Q, Huang Y, Zhai M, Zhang J. Effect of sodium-glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis. Cardiovasc Diabetol 2021; 20:25. [PMID: 33494751 PMCID: PMC7836497 DOI: 10.1186/s12933-020-01209-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/27/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Although the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular events have been reported in patients with type 2 diabetes mellitus (T2DM) with or without heart failure (HF), the impact of SGLT2i on cardiac remodelling remains to be established. METHODS We searched the PubMed, Embase, Cochrane Library and Web of Science databases up to November 16th, 2020, for randomized controlled trials reporting the effects of SGLT2i on parameters of cardiac structure, cardiac function, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level or the Kansas City Cardiomyopathy Questionnaire (KCCQ) score in T2DM patients with or without chronic HF. The effect size was expressed as the mean difference (MD) or standardized mean difference (SMD) and its 95% confidence interval (CI). Subgroup analyses were performed based on the stage A-B or stage C HF population and HF types. RESULTS Compared to placebo or other antidiabetic drugs, SGLT2i showed no significant effects on left ventricular mass index, left ventricular end diastolic volume index, left ventricular end systolic volume index, or left atrial volume index. SGLT2i improved left ventricular ejection fraction only in the subgroup of HF patients with reduced ejection fraction (MD 3.16%, 95% CI 0.11 to 6.22, p = 0.04; I2 = 0%), and did not affect the global longitudinal strain in the overall analysis including stage A-B HF patients. SGLT2i showed benefits in the E/e' ratio (MD - 0.45, 95% CI - 0.88 to - 0.03, p = 0.04; I2 = 0%), plasma NT-proBNP level (SMD - 0.09, 95% CI - 0.16 to - 0.03, p = 0.004; I2 = 0%), and the KCCQ score (SMD 3.12, 95% CI 0.76 to 5.47, p = 0.01; I2 = 0%) in the overall population. CONCLUSION The use of SGLT2i was associated with significant improvements in cardiac diastolic function, plasma NT-proBNP level, and the KCCQ score in T2DM patients with or without chronic HF, but did not significantly affect cardiac structural parameters indexed by body surface area. The LVEF level was improved only in HF patients with reduced ejection fraction.
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Affiliation(s)
- Yi-Wen Yu
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Xue-Mei Zhao
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Yun-Hong Wang
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Qiong Zhou
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Yan Huang
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Mei Zhai
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Jian Zhang
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
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Effect of tofogliflozin on arterial stiffness in patients with type 2 diabetes: prespecified sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial. Cardiovasc Diabetol 2021; 20:4. [PMID: 33397376 PMCID: PMC7784389 DOI: 10.1186/s12933-020-01206-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 12/24/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Tofogliflozin, an SGLT2 inhibitor, is associated with favorable metabolic effects, including improved glycemic control and serum lipid profile and decreased body weight, visceral adipose tissue, and blood pressure (BP). This study evaluated the effects of tofogliflozin on the brachial-ankle pulse wave velocity (baPWV) in patients with type 2 diabetes (T2DM) without a history of apparent cardiovascular disease. METHODS The using tofogliflozin for possible better intervention against atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. As one of the prespecified secondary outcomes, changes in baPWV over 104 weeks were evaluated in 154 individuals (80 in the tofogliflozin group and 74 in the conventional treatment group) who completed baPWV measurement at baseline. RESULTS In a mixed-effects model, the progression in the right, left, and mean baPWV over 104 weeks was significantly attenuated with tofogliflozin compared to that with conventional treatment (- 109.3 [- 184.3, - 34.3] (mean change [95% CI] cm/s, p = 0.005; - 98.3 [- 172.6, - 24.1] cm/s, p = 0.010; - 104.7 [- 177.0, - 32.4] cm/s, p = 0.005, respectively). Similar findings were obtained even after adjusting the mixed-effects models for traditional cardiovascular risk factors, including body mass index (BMI), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, systolic blood pressure (SBP), hypertension, smoking, and/or administration of drugs, including hypoglycemic agents, antihypertensive agents, statins, and anti-platelets, at baseline. The findings of the analysis of covariance (ANCOVA) models, which included the treatment group, baseline baPWV, and traditional cardiovascular risk factors, resembled those generated by the mixed-effects models. CONCLUSIONS Tofogliflozin significantly inhibited the increased baPWV in patients with T2DM without a history of apparent cardiovascular disease, suggesting that tofogliflozin suppressed the progression of arterial stiffness. Trial Registration UMIN000017607. Registered 18 May 2015. ( https://www.umin.ac.jp/icdr/index.html ).
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