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An X, Sun W, Wen Z, Duan L, Zhang Y, Kang X, Ji H, Sun Y, Jiang L, Zhao X, Gao Q, Lian F. Comparison of the efficacy and safety of GLP-1 receptor agonists on cardiovascular events and risk factors: A review and network meta-analysis. Diabetes Obes Metab 2025; 27:1735-1751. [PMID: 39910752 DOI: 10.1111/dom.16228] [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: 09/11/2024] [Revised: 01/07/2025] [Accepted: 01/21/2025] [Indexed: 02/07/2025]
Abstract
OBJECTIVE This study aims to systematically evaluate and perform a systematic review and network meta-analysis comparing the comprehensive cardiovascular protective effects of various glucagon-like peptide-1 receptor agonists (GLP-1RAs), focusing on cardiovascular events and risk factors. METHODS We searched PubMed, Embase, Cochrane Library and Web of Science from inception to December 15, 2024. Included studies were published randomized controlled trials (RCTs) comparing GLP-1RAs to placebo or other GLP-1RAs. Missing data were standardized, and network meta-analysis was performed using Stata 17.0. Study heterogeneity, publication bias and evidence quality were assessed using the Cochrane Risk of Bias tool and Confidence in Network Meta-Analysis (CINeMA). RESULTS As of December 15, 2024, a total of 18 313 articles were retrieved. Based on the inclusion and exclusion criteria, 156 high-quality studies were included, incorporating 144 782 patients and 14 different GLP-1RAs. The network meta-analysis demonstrated low heterogeneity, ensuring the reliability of the results. Comprehensive analysis revealed the following: Efpeglenatide was the most effective in reducing major adverse cardiovascular events. Oral semaglutide shows more significant advantages in reducing all-cause mortality and cardiovascular mortality. Orforglipron excelled in glycaemic control and weight reduction. SC-Semaglutide showed the greatest efficacy in lowering both systolic blood pressure and diastolic blood pressure, Liraglutide showed the greatest efficacy in lowering total cholesterol, Noiiglutide in triglycerides and Taspoglutide in low-density lipoprotein cholesterol, but no GLP-1RAs in high-density lipoprotein cholesterol. GLP-1RAs did not significantly increase the incidence of adverse events, but Orforglipron and Taspoglutide significantly increased the incidence of gastrointestinal adverse events compared with placebo. CONCLUSION This study compared the cardiovascular benefits of different GLP-1RAs, including reductions in cardiovascular events and improvements in multiple cardiovascular risk factors. However, due to limitations in the quantity and quality of the included studies, the conclusions should be interpreted with caution. Future large-scale, high-quality clinical trials are needed to validate these findings and further optimize comprehensive cardiovascular management strategies for patients.
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Affiliation(s)
- Xuedong An
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - WenJie Sun
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhige Wen
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - LiYun Duan
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - YueHong Zhang
- Fangshan Hospital Beijing University of Chinese Medicine, Beijing, China
| | - Xiaomin Kang
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Hangyu Ji
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuting Sun
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Linlin Jiang
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuefei Zhao
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Qing Gao
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengmei Lian
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
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Wang Y, Chen J, Zheng Y, Jiang J, Wang L, Wu J, Zhang C, Luo M. Glucose metabolite methylglyoxal induces vascular endothelial cell pyroptosis via NLRP3 inflammasome activation and oxidative stress in vitro and in vivo. Cell Mol Life Sci 2024; 81:401. [PMID: 39269632 PMCID: PMC11399538 DOI: 10.1007/s00018-024-05432-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/21/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024]
Abstract
Methylglyoxal (MGO), a reactive dicarbonyl metabolite of glucose, plays a prominent role in the pathogenesis of diabetes and vascular complications. Our previous studies have shown that MGO is associated with increased oxidative stress, inflammatory responses and apoptotic cell death in endothelial cells (ECs). Pyroptosis is a novel form of inflammatory caspase-1-dependent programmed cell death that is closely associated with the activation of the NOD-like receptor 3 (NLRP3) inflammasome. Recent studies have shown that sulforaphane (SFN) can inhibit pyroptosis, but the effects and underlying mechanisms by which SFN affects MGO-induced pyroptosis in endothelial cells have not been determined. Here, we found that SFN prevented MGO-induced pyroptosis by suppressing oxidative stress and inflammation in vitro and in vivo. Our results revealed that SFN dose-dependently prevented MGO-induced HUVEC pyroptosis, inhibited pyroptosis-associated biochemical changes, and attenuated MGO-induced morphological alterations in mitochondria. SFN pretreatment significantly suppressed MGO-induced ROS production and the inflammatory response by inhibiting the NLRP3 inflammasome (NLRP3, ASC, and caspase-1) signaling pathway by activating Nrf2/HO-1 signaling. Similar results were obtained in vivo, and we demonstrated that SFN prevented MGO-induced oxidative damage, inflammation and pyroptosis by reversing the MGO-induced downregulation of the NLRP3 signaling pathway through the upregulation of Nrf2. Additionally, an Nrf2 inhibitor (ML385) noticeably attenuated the protective effects of SFN on MGO-induced pyroptosis and ROS generation by inhibiting the Nrf2/HO-1 signaling pathway, and a ROS scavenger (NAC) and a permeability transition pore inhibitor (CsA) completely reversed these effects. Moreover, NLRP3 inhibitor (MCC950) and caspase-1 inhibitor (VX765) further reduced pyroptosis in endothelial cells that were pretreated with SFN. Collectively, these findings broaden our understanding of the mechanism by which SFN inhibits pyroptosis induced by MGO and suggests important implications for the potential use of SFN in the treatment of vascular diseases.
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Affiliation(s)
- Yanan Wang
- Basic Medicine Research Innovation Center for Cardiometabolic DiseasesMinistry of EducationLaboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China
- Clinical Research Center (CRC), Clinical Pathology Center (CPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, Chongqing University, Wanzhou, Chongqing, China
| | - Jinxiang Chen
- Basic Medicine Research Innovation Center for Cardiometabolic DiseasesMinistry of EducationLaboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China
| | - Youkun Zheng
- Basic Medicine Research Innovation Center for Cardiometabolic DiseasesMinistry of EducationLaboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China
| | - Jun Jiang
- Department of General Surgery (Thyroid Surgery), the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, Sichuan, China
| | - Liqun Wang
- Basic Medicine Research Innovation Center for Cardiometabolic DiseasesMinistry of EducationLaboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China
| | - Jianbo Wu
- Basic Medicine Research Innovation Center for Cardiometabolic DiseasesMinistry of EducationLaboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China
| | - Chunxiang Zhang
- Basic Medicine Research Innovation Center for Cardiometabolic DiseasesMinistry of EducationLaboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
| | - Mao Luo
- Basic Medicine Research Innovation Center for Cardiometabolic DiseasesMinistry of EducationLaboratory for Cardiovascular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
- Municipal Key Laboratory of Thrombosis and Vascular Biology, Luzhou, Sichuan, China.
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Li M, Chen L, Liu X, Wu Y, Chen X, Chen H, Zhong Y, Xu Y. The investigation of potential mechanism of Fuzhengkangfu Decoction against Diabetic myocardial injury based on a combined strategy of network pharmacology, transcriptomics, and experimental verification. Biomed Pharmacother 2024; 177:117048. [PMID: 38959606 DOI: 10.1016/j.biopha.2024.117048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/16/2024] [Accepted: 06/26/2024] [Indexed: 07/05/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Diabetic cardiomyopathy (DCM) is a cardiac condition resulting from myocardial damage caused by diabetes mellitus (DM), currently lacking specific therapeutic interventions. Fuzhengkangfu decoction (FZK) plays an important role in the prevention and treatment of various cardiovascular diseases. However, the efficacy and potential mechanisms of FZK are not fully understood. This study aims to investigate the protective effect and mechanisms of FZK against DCM. METHODOLOGIES Rats were given a high-calorie diet along with a low dosage of streptozotocin (STZ) to establish a rat model of DCM. The diabetic rats received FZK or normal saline subcutaneously for 12 weeks. Echocardiography was conducted to evaluate their heart function characteristics. Rat heart morphologies were assessed using Sirius Red staining and H&E staining. Transcriptome sequencing analysis and network pharmacology were used to reveal possible targets and mechanisms. Molecular docking was conducted to validate the association between the primary components of FZK and the essential target molecules. Finally, both in vitro and in vivo studies were conducted on the cardioprotective properties and mechanism of FZK. RESULTS According to the results of network pharmacology, FZK may prevent DCM by reducing oxidative stress and preventing apoptosis. Transcriptomics confirmed that FZK protected against DCM-induced myocardial fibrosis and remodelling, as predicted by network pharmacology, and suggested that FZK regulated the expression of oxidative stress and apoptosis-related proteins. Integrating network pharmacology and transcriptome analysis results revealed that the AGE-RAGE signalling pathway-associated MMP2, SLC2A1, NOX4, CCND1, and CYP1A1 might be key targets. Molecular docking showed that Poricoic acid A and 5-O-Methylvisammioside had the highest docking activities with these targets. We further conducted in vivo experiments, and the results showed that FZK significantly attenuated left ventricular remodelling, reduced myocardial fibrosis, and improved cardiac contractile function. And, our study demonstrated that FZK effectively reduced oxidative stress and apoptosis of cardiomyocytes. The data showed that Erk, NF-κB, and Caspase 3 phosphorylation was significantly inhibited, and Bcl-2/Bax was significantly increased after FZK treatment. In vitro, FZK significantly reduced AGEs-induced ROS increase and apoptosis in cardiomyocytes. Furthermore, FZK significantly inhibited the phosphorylation of Erk and NF-κB proteins and decreased the expression of MMP2. All the results confirmed that FZK inhibited the activation of the Erk/NF-κB pathway in AGE-RAGE signalling and alleviated oxidative stress and apoptosis of cardiomyocytes. In summary, we verified that FZK protects against DCM by inhibiting myocardial apoptotic remodelling through the suppression of the AGE-RAGE signalling pathway. CONCLUSION In conclusion, our research indicates that FZK demonstrates anti-cardiac dysfunction properties by reducing oxidative stress and cardiomyocyte apoptosis through the AGE-RAGE pathway in DCM, showing potential for therapeutic use.
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Affiliation(s)
- Miaofu Li
- Department of Cardiology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Liuying Chen
- Department of Cardiology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Xiaohua Liu
- Department of Cardiology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yirong Wu
- Department of Cardiology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Xuechun Chen
- Department of Cardiology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Huimin Chen
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yigang Zhong
- Department of Cardiology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yizhou Xu
- Department of Cardiology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
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Zhang X, van der Vorst EPC. High-Density Lipoprotein Modifications: Causes and Functional Consequences in Type 2 Diabetes Mellitus. Cells 2024; 13:1113. [PMID: 38994965 PMCID: PMC11240616 DOI: 10.3390/cells13131113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/22/2024] [Accepted: 06/24/2024] [Indexed: 07/13/2024] Open
Abstract
High-density lipoprotein (HDL) is a group of small, dense, and protein-rich lipoproteins that play a role in cholesterol metabolism and various cellular processes. Decreased levels of HDL and HDL dysfunction are commonly observed in individuals with type 2 diabetes mellitus (T2DM), which is also associated with an increased risk for cardiovascular disease (CVD). Due to hyperglycemia, oxidative stress, and inflammation that develop in T2DM, HDL undergoes several post-translational modifications such as glycation, oxidation, and carbamylation, as well as other alterations in its lipid and protein composition. It is increasingly recognized that the generation of HDL modifications in T2DM seems to be the main cause of HDL dysfunction and may in turn influence the development and progression of T2DM and its related cardiovascular complications. This review provides a general introduction to HDL structure and function and summarizes the main modifications of HDL that occur in T2DM. Furthermore, the potential impact of HDL modifications on the pathogenesis of T2DM and CVD, based on the altered interactions between modified HDL and various cell types that are involved in glucose homeostasis and atherosclerotic plaque generation, will be discussed. In addition, some perspectives for future research regarding the T2DM-related HDL modifications are addressed.
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Affiliation(s)
- Xiaodi Zhang
- 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
| | - 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
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, 52074 Aachen, Germany
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), 80336 Munich, Germany
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Kim M, Ha KH, Lee J, Park S, Oh KS, Bae DH, Lee JH, Kim SM, Choi WG, Hwang KK, Kim DW, Cho MC, Kim DJ, Bae JW. Lower Atrial Fibrillation Risk With Sodium-Glucose Cotransporter 2 Inhibitors Than With Dipeptidyl Peptidase-4 Inhibitors in Individuals With Type 2 Diabetes: A Nationwide Cohort Study. Korean Circ J 2024; 54:256-267. [PMID: 38654455 PMCID: PMC11109837 DOI: 10.4070/kcj.2023.0234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 01/22/2024] [Accepted: 02/13/2024] [Indexed: 04/26/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Accumulating evidence shows that sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce adverse cardiovascular outcomes. However, whether SGLT2i, compared with other antidiabetic drugs, reduce the new development of atrial fibrillation (AF) is unclear. In this study, we compared SGLT2i with dipeptidyl peptidase-4 inhibitors (DPP-4is) in terms of reduction in the risk of AF in individuals with type 2 diabetes. METHODS We included 42,786 propensity score-matched pairs of SGLT2i and DPP-4i users without previous AF diagnosis using the Korean National Health Insurance Service database between May 1, 2016, and December 31, 2018. RESULTS During a median follow-up of 1.3 years, SGLT2i users had a lower incidence of AF than DPP-4i users (1.95 vs. 2.65 per 1,000 person-years; hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.55-0.97; p=0.028]). In individuals without heart failure, SGLT2i users was associated with a decreased risk of AF incidence (HR, 0.70; 95% CI, 0.52-0.94; p=0.019) compared to DPP-4i users. However, individuals with heart failure, SGLT2i users was not significantly associated with a change in risk (HR, 1.04; 95% CI, 0.44-2.44; p=0.936). CONCLUSIONS In this nationwide cohort study of individuals with type 2 diabetes, treatment with SGLT2i was associated with a lower risk of AF compared with treatment with DPP-4i.
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Affiliation(s)
- Min Kim
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
| | - Kyoung Hwa Ha
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea
| | - Junyoung Lee
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
| | - Sangshin Park
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
| | - Kyeong Seok Oh
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
| | - Dae-Hwan Bae
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
| | - Ju Hee Lee
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
| | - Sang Min Kim
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
| | - Woong Gil Choi
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
| | - Kyung-Kuk Hwang
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
- Department of Cardiology, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Dong-Woon Kim
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
- Department of Cardiology, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Myeong-Chan Cho
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
- Department of Cardiology, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea.
| | - Jang-Whan Bae
- Department of Cardiology, Chungbuk National University Hospital, Cheongju, Korea
- Department of Cardiology, Chungbuk National University College of Medicine, Cheongju, Korea.
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Li Y, Liu Y, Cui J, Zhu M, Wang W, Chen K, Huang L, Liu Y. Oral-gut microbial transmission promotes diabetic coronary heart disease. Cardiovasc Diabetol 2024; 23:123. [PMID: 38581039 PMCID: PMC10998415 DOI: 10.1186/s12933-024-02217-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: 12/25/2023] [Accepted: 03/27/2024] [Indexed: 04/07/2024] Open
Abstract
BACKGROUND Diabetes is a predominant driver of coronary artery disease worldwide. This study aims to unravel the distinct characteristics of oral and gut microbiota in diabetic coronary heart disease (DCHD). Simultaneously, we aim to establish a causal link between the diabetes-driven oral-gut microbiota axis and increased susceptibility to diabetic myocardial ischemia-reperfusion injury (MIRI). METHODS We comprehensively investigated the microbial landscape in the oral and gut microbiota in DCHD using a discovery cohort (n = 183) and a validation chohort (n = 68). Systematically obtained oral (tongue-coating) and fecal specimens were subjected to metagenomic sequencing and qPCR analysis, respectively, to holistically characterize the microbial consortia. Next, we induced diabetic MIRI by administering streptozotocin to C57BL/6 mice and subsequently investigated the potential mechanisms of the oral-gut microbiota axis through antibiotic pre-treatment followed by gavage with specific bacterial strains (Fusobacterium nucleatum or fecal microbiota from DCHD patients) to C57BL/6 mice. RESULTS Specific microbial signatures such as oral Fusobacterium nucleatum and gut Lactobacillus, Eubacterium, and Roseburia faecis, were identified as potential microbial biomarkers in DCHD. We further validated that oral Fusobacterium nucleatum and gut Lactobacillus are increased in DCHD patients, with a positive correlation between the two. Experimental evidence revealed that in hyperglycemic mice, augmented Fusobacterium nucleatum levels in the oral cavity were accompanied by an imbalance in the oral-gut axis, characterized by an increased coexistence of Fusobacterium nucleatum and Lactobacillus, along with elevated cardiac miRNA-21 and a greater extent of myocardial damage indicated by TTC, HE, TUNEL staining, all of which contributed to exacerbated MIRI. CONCLUSION Our findings not only uncover dysregulation of the oral-gut microbiota axis in diabetes patients but also highlight the pivotal intermediary role of the increased abundance of oral F. nucleatum and gut Lactobacillus in exacerbating MIRI. Targeting the oral-gut microbiota axis emerges as a potent strategy for preventing and treating DCHD. Oral-gut microbial transmission constitutes an intermediate mechanism by which diabetes influences myocardial injury, offering new insights into preventing acute events in diabetic patients with coronary heart disease.
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Affiliation(s)
- Yiwen Li
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, 100078, China
| | - Yanfei Liu
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Jing Cui
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Mengmeng Zhu
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Wenting Wang
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Keji Chen
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Luqi Huang
- China Academy of Chinese Medical Sciences, Beijing, 100078, China
| | - Yue Liu
- National Clinical Research Center for TCM Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, China.
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Vinci MC, Costantino S, Damiano G, Rurali E, Rinaldi R, Vigorelli V, Sforza A, Carulli E, Pirola S, Mastroiacovo G, Raucci A, El-Osta A, Paneni F, Pompilio G. Persistent epigenetic signals propel a senescence-associated secretory phenotype and trained innate immunity in CD34 + hematopoietic stem cells from diabetic patients. Cardiovasc Diabetol 2024; 23:107. [PMID: 38553774 PMCID: PMC10981360 DOI: 10.1186/s12933-024-02195-1] [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: 12/17/2023] [Accepted: 03/11/2024] [Indexed: 04/01/2024] Open
Abstract
BACKGROUND Diabetes-induced trained immunity contributes to the development of atherosclerosis and its complications. This study aimed to investigate in humans whether epigenetic signals involved in immune cell activation and inflammation are initiated in hematopoietic stem/progenitor cells (HSPCs) and transferred to differentiated progeny. METHODS AND RESULTS High glucose (HG)-exposure of cord blood (CB)-derived HSPCs induced a senescent-associated secretory phenotype (SASP) characterized by cell proliferation lowering, ROS production, telomere shortening, up-regulation of p21 and p27genes, upregulation of NFkB-p65 transcription factor and increased secretion of the inflammatory cytokines TNFα and IL6. Chromatin immunoprecipitation assay (ChIP) of p65 promoter revealed that H3K4me1 histone mark accumulation and methyltransferase SetD7 recruitment, along with the reduction of repressive H3K9me3 histone modification, were involved in NFkB-p65 upregulation of HG-HSPCs, as confirmed by increased RNA polymerase II engagement at gene level. The differentiation of HG-HSPCs into myeloid cells generated highly responsive monocytes, mainly composed of intermediate subsets (CD14hiCD16+), that like the cells from which they derive, were characterized by SASP features and similar epigenetic patterns at the p65 promoter. The clinical relevance of our findings was confirmed in sternal BM-derived HSPCs of T2DM patients. In line with our in vitro model, T2DM HSPCs were characterized by SASP profile and SETD7 upregulation. Additionally, they generated, after myeloid differentiation, senescent monocytes mainly composed of proinflammatory intermediates (CD14hiCD16+) characterized by H3K4me1 accumulation at NFkB-p65 promoter. CONCLUSIONS Hyperglycemia induces marked chromatin modifications in HSPCs, which, once transmitted to the cell progeny, contributes to persistent and pathogenic changes in immune cell function and composition.
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Affiliation(s)
- Maria Cristina Vinci
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Via C. Parea 4, 20138, Milan, Italy.
| | - Sarah Costantino
- Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich and University of Zürich, Zurich, Switzerland
- University Heart Center, University Hospital Zurich, Zurich, Switzerland
| | - Giulia Damiano
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Via C. Parea 4, 20138, Milan, Italy
| | - Erica Rurali
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Via C. Parea 4, 20138, Milan, Italy
| | - Raffaella Rinaldi
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Via C. Parea 4, 20138, Milan, Italy
| | - Vera Vigorelli
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Via C. Parea 4, 20138, Milan, Italy
| | - Annalisa Sforza
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Via C. Parea 4, 20138, Milan, Italy
| | - Ermes Carulli
- Dipartimento Di Scienze Cliniche E Di Comunità, Università Di Milano, Milan, Italy
- Doctoral Programme in Translational Medicine, Università Di Milano, 20122, Milan, Italy
| | - Sergio Pirola
- Department of Cardiac Surgery, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | | | - Angela Raucci
- Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Assam El-Osta
- Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia
| | - Francesco Paneni
- Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich and University of Zürich, Zurich, Switzerland.
- University Heart Center, University Hospital Zurich, Zurich, Switzerland.
| | - Giulio Pompilio
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Via C. Parea 4, 20138, Milan, Italy
- Department of Biomedical, Surgical and Dental Sciences, Università Degli Studi di Milano, Milan, Italy
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Zhao N, Yu X, Zhu X, Song Y, Gao F, Yu B, Qu A. Diabetes Mellitus to Accelerated Atherosclerosis: Shared Cellular and Molecular Mechanisms in Glucose and Lipid Metabolism. J Cardiovasc Transl Res 2024; 17:133-152. [PMID: 38091232 DOI: 10.1007/s12265-023-10470-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 11/23/2023] [Indexed: 02/28/2024]
Abstract
Diabetes is one of the critical independent risk factors for the progression of cardiovascular disease, and the underlying mechanism regarding this association remains poorly understood. Hence, it is urgent to decipher the fundamental pathophysiology and consequently provide new insights into the identification of innovative therapeutic targets for diabetic atherosclerosis. It is now appreciated that different cell types are heavily involved in the progress of diabetic atherosclerosis, including endothelial cells, macrophages, vascular smooth muscle cells, dependence on altered metabolic pathways, intracellular lipids, and high glucose. Additionally, extensive studies have elucidated that diabetes accelerates the odds of atherosclerosis with the explanation that these two chronic disorders share some common mechanisms, such as endothelial dysfunction and inflammation. In this review, we initially summarize the current research and proposed mechanisms and then highlight the role of these three cell types in diabetes-accelerated atherosclerosis and finally establish the mechanism pinpointing the relationship between diabetes and atherosclerosis.
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Affiliation(s)
- Nan Zhao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, 10 You'anmen Outer West 1st Street, Beijing, 100069, China
| | - Xiaoting Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, 10 You'anmen Outer West 1st Street, Beijing, 100069, China
| | - Xinxin Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, 10 You'anmen Outer West 1st Street, Beijing, 100069, China
| | - Yanting Song
- Department of Pathology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing, 100029, China
| | - Fei Gao
- Department of Cardiology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing, 100029, China
| | - Baoqi Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, 10 You'anmen Outer West 1st Street, Beijing, 100069, China.
- Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, 100069, China.
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, 10 You'anmen Outer West 1st Street, Beijing, 100069, China.
- Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, 100069, China.
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Hao J, Zhou J, Hu S, Zhang P, Wu H, Yang J, Zhao B, Liu H, Lin H, Chi J, Lou D. RTA 408 ameliorates diabetic cardiomyopathy by activating Nrf2 to regulate mitochondrial fission and fusion and inhibiting NF-κB-mediated inflammation. Am J Physiol Cell Physiol 2024; 326:C331-C347. [PMID: 38047307 DOI: 10.1152/ajpcell.00467.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 12/05/2023]
Abstract
Diabetic cardiomyopathy (dCM) is a major complication of diabetes; however, specific treatments for dCM are currently lacking. RTA 408, a semisynthetic triterpenoid, has shown therapeutic potential against various diseases by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. We established in vitro and in vivo models using high glucose toxicity and db/db mice, respectively, to simulate dCM. Our results demonstrated that RTA 408 activated Nrf2 and alleviated various dCM-related cardiac dysfunctions, both in vivo and in vitro. Additionally, it was found that silencing the Nrf2 gene eliminated the cardioprotective effect of RTA 408. RTA 408 ameliorated oxidative stress in dCM mice and high glucose-exposed H9C2 cells by activating Nrf2, inhibiting mitochondrial fission, exerting anti-inflammatory effects through the Nrf2/NF-κB axis, and ultimately suppressing apoptosis, thereby providing cardiac protection against dCM. These findings provide valuable insights for potential dCM treatments.NEW & NOTEWORTHY We demonstrated first that the nuclear factor erythroid 2-related factor 2 (Nrf2) activator RTA 408 has a protective effect against diabetic cardiomyopathy. We found that RTA 408 could stimulate the nuclear entry of Nrf2 protein, regulate the mitochondrial fission-fusion balance, and redistribute p65, which significantly alleviated the oxidative stress level in cardiomyocytes, thereby reducing apoptosis and inflammation, and protecting the systolic and diastolic functions of the heart.
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Affiliation(s)
- Jinjin Hao
- Department of Endocrinology, Shaoxing People's Hospital, Shaoxing, China
| | - Jiedong Zhou
- College of Medicine, Shaoxing University, Shaoxing, China
| | - Songqing Hu
- Zhejiang University School of Medicine, Hangzhou, China
| | - Peipei Zhang
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Haowei Wu
- Zhejiang University School of Medicine, Hangzhou, China
| | - Juntao Yang
- College of Medicine, Shaoxing University, Shaoxing, China
| | - Bingjie Zhao
- College of Medicine, Shaoxing University, Shaoxing, China
| | - Hanxuan Liu
- College of Medicine, Shaoxing University, Shaoxing, China
| | - Hui Lin
- The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Jufang Chi
- Department of Cardiology, Zhuji People's Hospital, Shaoxing, China
| | - Dajun Lou
- Department of Endocrinology, Shaoxing People's Hospital, Shaoxing, China
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Hirsh BJ, Hirsch JS, Hmoud H, Weintraub S, Cha A, Lesser M, Huang X, Xie YYS, Nahrwold R, Joshua J, Scanlon J, Galella T, Singh V, Gianos E. A system approach to improving guideline-directed therapy for cardio-renal-metabolic conditions: The "beyond diabetes" initiative. Am J Prev Cardiol 2023; 16:100608. [PMID: 37822579 PMCID: PMC10562667 DOI: 10.1016/j.ajpc.2023.100608] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/29/2023] [Accepted: 09/24/2023] [Indexed: 10/13/2023] Open
Abstract
Objective Despite demonstrating improvements in cardiovascular disease, kidney disease, and survival outcomes, guideline-directed antihyperglycemic medications such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like-peptide-1 receptor agonists (GLP1-RA), are underutilized. Many obstacles constrain their use including lack of systematic provider and patient education, concern for medication side effects, and patient affordability. Methods We designed a multimodality, systems-based approach to address these challenges with the goal of increasing medication utilization across the largest healthcare system in New York State. This multispecialty collaborative included provider and patient education, an electronic health record-enabled platform to identify eligible patients, and access to pharmacists for medication guidance and addressing insurance coverage barriers. Surveys were administered following grand rounds lectures and knowledge-based questionnaires were given before and after case-based sessions for housestaff, with results analyzed using a two-sided Student's t-test. Rates of first prescriptions of SGLT2i/GLP1-RA in combined and individual analyses were compared between the pre- and post-education periods (6 months prior to 3/31/2021 and 6 months post 8/19/2021), and the change in prescriptions per 100 eligible-visits was assessed using the incidence density approach. Results Among grand rounds participants, 69.3% of respondents said they would make changes to their clinical practice. Knowledge increased by 14.7% (p-value <0.001) among housestaff following case-based sessions. An increase in SGLT2i/GLP1-RA prescribing was noted for eligible patients among internal medicine, cardiology, nephrology, and endocrinology providers, from 11.9 per 100 eligible visits in the pre-education period to 14.8 in the post-education period (absolute increase 2.9 [24.4%], incidence risk ratio 1.24 [95% CI 1.18-1.31]; p-value <0.001). Increases in prescribing rates were also seen among individual medical specialties. Conclusions Our "Beyond Diabetes" initiative showed an improvement in provider knowledge-base and was associated with a modest, but statistically significant increase in the use of SGLT2i and GLP1-RA throughout our healthcare system.
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Affiliation(s)
- Benjamin J. Hirsh
- Department of Cardiology, Sandra Atlas Bass Heart Hospital, Manhasset, NY, United States
- Department of Cardiology, Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, Hempstead, NY, United States
| | - Jamie S. Hirsch
- Division of Kidney Diseases and Hypertension, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Institute of Health System Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- North Shore University Hospital, Manhasset, NY, United States
| | - Hosam Hmoud
- Lenox Hill Hospital, New York, NY, United States
| | | | - Agnes Cha
- Department of Ambulatory Pharmacy Services, Northwell Health, Lake Success, NY, United States
| | - Martin Lesser
- Institute of Health System Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Biostatistics Unit, Office of Academic Affairs, Northwell Health, New York, NY, United States
| | - Xueqi Huang
- Biostatistics Unit, Office of Academic Affairs, Northwell Health, New York, NY, United States
| | - Yan Yan Sally Xie
- Division of Endocrinology, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Rachel Nahrwold
- Department of Cardiology, Lenox Hill Hospital, New York, NY, United States
| | - John Joshua
- Global Strategic Partnerships, Northwell Health, New York, NY, United States
| | - Jennifer Scanlon
- Global Strategic Partnerships, Northwell Health, New York, NY, United States
| | - Thomas Galella
- Department of Healthcare Delivery Analytics, Northwell Health, New York, NY, United States
| | - Varinder Singh
- Department of Cardiology, Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, Hempstead, NY, United States
- Department of Cardiology, Lenox Hill Hospital, New York, NY, United States
| | - Eugenia Gianos
- Department of Cardiology, Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, Hempstead, NY, United States
- Department of Cardiology, Lenox Hill Hospital, New York, NY, United States
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11
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Boutsikos I, Beltsios E, Schmack B, Pantazopoulos I, Chatzis DG. Sodium Glucose Co-Transporter 2 Inhibitors and the Cardiovascular System: Current Knowledge and Future Expectations. Heart Int 2023; 17:12-18. [PMID: 38419717 PMCID: PMC10898587 DOI: 10.17925/hi.2023.17.2.12] [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: 06/25/2023] [Accepted: 09/26/2023] [Indexed: 03/02/2024] Open
Abstract
Diabetic cardiomyopathy is a well-recognized clinical entity and reflects a complex relationship between metabolic substrates and myocardial function. Sodium glucose co-transporter 2 (SGLT2) inhibitors are antidiabetic agents that are found to exert multiple cardioprotective effects. Large clinical trials showed their beneficial effects on patients with heart failure, reducing the rates of rehospitalizations and improving kidney function. The aim of this review is to summarize the latest evidence in the literature regarding the multiple effects of SGLT2 inhibitors on patients across the spectrum of cardiovascular diseases.
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Affiliation(s)
- Ioannis Boutsikos
- Department of Therapeutics, Alexandra General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleftherios Beltsios
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Bastian Schmack
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Ioannis Pantazopoulos
- Department of Emergency Medicine, Medical School, University of Thessaly, Larissa, Greece
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Wang K, Sun S, Zhang G, Lu Z, Chen H, Fan X, Gu C, Pan X, Lin Q, Chen O, Cai L, Dai X, Wang X, Lu C, Yan X, Tan Y. CXCR7 Agonist TC14012 Improves Angiogenic Function of Endothelial Progenitor Cells via Activating Akt/eNOS Pathway and Promotes Ischemic Angiogenesis in Diabetic Limb Ischemia. Cardiovasc Drugs Ther 2023; 37:849-863. [PMID: 35471717 PMCID: PMC10926281 DOI: 10.1007/s10557-022-07337-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/18/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE Endothelial progenitor cells (EPCs) play a critical role in repairing damaged vessels and triggering ischemic angiogenesis, but their number is reduced and function is impaired under diabetic conditions. Improving EPC function has been considered a promising strategy to ameliorate diabetic vascular complications. In the present study, we aim to investigate whether and how CXCR7 agonist TC14012 promotes the angiogenic function of diabetic EPCs. METHODS High glucose (HG) treatment was used to mimic the hyperglycemia in diabetes. Tube formation, cell scratch recovery and transwell assay, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and cleaved-caspase3 expression were used to evaluate the angiogenic capability, cell migration, and apoptosis of EPCs, respectively. Hind limb ischemia (HLI) model was used to appraise the ability of TC14012 in promoting diabetic ischemic angiogenesis in vivo. RESULTS HG treatment impaired EPC tube formation and migration, and induced EPC apoptosis and oxidative damage, while TC14012 rescued tube formation and migration, and prevented HG-induced apoptosis and oxidative damage of EPCs. Furthermore, these beneficial effects of TC14012 on EPCs were attenuated by specific siRNAs against CXCR7, validating that CXCR7 is a functional target of TC14012 in EPCs. Mechanistic studies demonstrated that HG treatment reduced CXCR7 expression in EPCs, and impaired Akt and endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production; similarly, these signal impairments in HG-exposed EPCs could be rescued by TC14012. However, the protective effects of TC14012 on tube formation and migration, Akt and eNOS phosphorylation, and NO production in HG-treated EPCs were almost completely abolished by siRNAs against CXCR7 or Akt specific inhibitor wortmannin. More importantly, in vivo study showed that TC14012 administration enhanced blood perfusion recovery and angiogenesis in the ischemic hind limb and increased the EPC number in peripheral circulation of db/db mice, demonstrating the capability of TC14012 in promoting EPC mobilization and ischemia angiogenic function. CONCLUSION TC14012 can prevent EPCs from HG-induced dysfunction and apoptosis, improve eNOS activity and NO production via CXCR7/Akt signal pathway, and promote EPC mobilization and diabetic ischemia angiogenesis.
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Affiliation(s)
- Kai Wang
- Department of Pediatrics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, 570 South Preston Street, Baxter-I Building Suite 304E, Louisville, KY, 40202, USA
| | - Shiyue Sun
- Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Guigui Zhang
- Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zixian Lu
- Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Hui Chen
- Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xia Fan
- Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Chunjie Gu
- Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xiaohong Pan
- Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qian Lin
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, 570 South Preston Street, Baxter-I Building Suite 304E, Louisville, KY, 40202, USA
| | - Oscar Chen
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, 570 South Preston Street, Baxter-I Building Suite 304E, Louisville, KY, 40202, USA
| | - Lu Cai
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, 570 South Preston Street, Baxter-I Building Suite 304E, Louisville, KY, 40202, USA
| | - Xiaozhen Dai
- School of Biosciences and Technology, Chengdu Medical College, Chengdu, Sichuan, China
| | - Xiao Wang
- Department of Obstetrics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chaosheng Lu
- Department of Pediatrics, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaoqing Yan
- Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
| | - Yi Tan
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, 570 South Preston Street, Baxter-I Building Suite 304E, Louisville, KY, 40202, USA.
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Hommels TM, Hermanides RS, Fabris E, Kedhi E. Exploring new insights in coronary lesion assessment and treatment in patients with diabetes mellitus: the impact of optical coherence tomography. Cardiovasc Diabetol 2023; 22:123. [PMID: 37226183 DOI: 10.1186/s12933-023-01844-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 04/28/2023] [Indexed: 05/26/2023] Open
Abstract
In this review, we summarise new insights into diagnostic approaches and treatment strategies for coronary artery disease (CAD) in patients with diabetes mellitus (DM). Despite the improvements in therapy, the clinical management of DM patients remains challenging as they develop more extensive CAD at a younger age and consistently have worse clinical outcomes than non-DM patients. Current diagnostic modalities as well as revascularisation treatments mainly focus on ischemic lesions. However, the impact of plaque morphology and composition are emerging as strong predictors of adverse cardiac events even in the absence of identified ischemia. In particular, the presence of vulnerable plaques such as thin-cap fibroatheroma (TCFA) lesions has been identified as a very strong predictor of future adverse events. This emphasises the need for an approach combining both functional and morphological methods in the assessment of lesions. In particular, optical coherence tomography (OCT) has proven to be a valuable asset by truly identifying TCFAs. New treatment strategies should consist of individualised and advanced medical regimens and may evolve towards plaque sealing through percutaneous treatment.
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Affiliation(s)
| | | | - Enrico Fabris
- Cardiovascular Department, University of Trieste, Trieste, Italy
| | - Elvin Kedhi
- Division of Cardiology and Structural Heart Diseases, Medical University of Silesia, Poniatowskiego 15, 40-055, Katowice, Poland.
- Department of Cardiology, Hôpital Erasme, Université libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.
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d'Aiello A, Bonanni A, Vinci R, Pedicino D, Severino A, De Vita A, Filomia S, Brecciaroli M, Liuzzo G. Meta-Inflammation and New Anti-Diabetic Drugs: A New Chance to Knock Down Residual Cardiovascular Risk. Int J Mol Sci 2023; 24:ijms24108643. [PMID: 37239990 DOI: 10.3390/ijms24108643] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/28/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Type 2 diabetes mellitus (DM) represents, with its macro and microvascular complications, one of the most critical healthcare issues for the next decades. Remarkably, in the context of regulatory approval trials, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) proved a reduced incidence of major adverse cardiovascular events (MACEs), i.e., cardiovascular death and heart failure (HF) hospitalizations. The cardioprotective abilities of these new anti-diabetic drugs seem to run beyond mere glycemic control, and a growing body of evidence disclosed a wide range of pleiotropic effects. The connection between diabetes and meta-inflammation seems to be the key to understanding how to knock down residual cardiovascular risk, especially in this high-risk population. The aim of this review is to explore the link between meta-inflammation and diabetes, the role of newer glucose-lowering medications in this field, and the possible connection with their unexpected cardiovascular benefits.
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Affiliation(s)
- Alessia d'Aiello
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Alice Bonanni
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Ramona Vinci
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Daniela Pedicino
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Anna Severino
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Antonio De Vita
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Simone Filomia
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Mattia Brecciaroli
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Giovanna Liuzzo
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
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Aktas G, Atak Tel BM, Tel R, Balci B. Treatment of type 2 diabetes patients with heart conditions. Expert Rev Endocrinol Metab 2023; 18:255-265. [PMID: 37078758 DOI: 10.1080/17446651.2023.2204941] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 04/17/2023] [Indexed: 04/21/2023]
Abstract
INTRODUCTION While type 2 diabetes mellitus (T2DM) increases the risk of cardiac complications, diabetes treatment choices may increase or decrease the rates of cardiac events. In the present review, we comprehensively discussed the treatment options of diabetic subjects with cardiac conditions. AREAS COVERED Current evidence related to diabetes treatment in cardiac situations has been reviewed. Clinical trials and meta-analyses on cardiac safety of anti-diabetic medicines are discussed. Treatment choices with proven benefits and those at least without associated increased cardiac risk were drawn from clinical trials; meta-analyses and cardiac safety studies in the recent medical literature were the basis of the suggestions in the present review. EXPERT OPINION We can suggest that hypoglycemia and extreme hyperglycemia should be avoided in acute ischemic heart conditions. Certain diabetic treatment options, especially sodium-glucose cotransporter-2 (SGLT2) inhibitors, can reduce overall cardiovascular mortality and hospitalization due to heart failure. Therefore, we suggest that physicians should choose SGLT2 inhibitors as the first-line treatment option in diabetic patients with heart failure or those who have a high risk of heart failure development. T2DM increases the risk of atrial fibrillation (AF), and metformin and pioglitazone seem to reduce the risk of AF in diabetic population.
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Affiliation(s)
- Gulali Aktas
- Department of Internal Medicine, Abant Izzet Baysal University Hospital, Bolu, Turkey
| | | | - Ramiz Tel
- Izzet Baysal State Hospital, Department of Emergency, Bolu, Turkey
| | - Buse Balci
- Department of Internal Medicine, Abant Izzet Baysal University Hospital, Bolu, Turkey
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Kuang Z, Hou N, Kan C, Han F, Qiu H, Sun X. The protective effects of SGLT-2 inhibitors, GLP-1 receptor agonists, and RAAS blockers against renal injury in patients with type 2 diabetes. Int Urol Nephrol 2023; 55:617-629. [PMID: 36036316 DOI: 10.1007/s11255-022-03355-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 08/21/2022] [Indexed: 10/15/2022]
Abstract
Diabetic kidney disease is one of the most severe complications of type 2 diabetes mellitus. Patients with diabetic kidney disease have a worse prognosis in terms of mortality and morbidity, compared with patients who have diabetes alone. Strict control of blood pressure and blood glucose is the primary method for prevention of initial kidney damage and delaying further progression of existing damage. Other management approaches include the use of exogenous drugs that can effectively protect the kidneys from diabetes, such as sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers. These drugs may protect against kidney injury through various molecular mechanisms. This review focuses on renal impairment in patients with type 2 diabetes; it discusses the direct and indirect effects of sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers on diabetic kidney disease. Finally, it discusses the effects of combination treatment with two or three types of drugs in patients with chronic kidney disease.
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Affiliation(s)
- Zengguang Kuang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Ningning Hou
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China
| | - Chengxia Kan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Hongyan Qiu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China.
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China.
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China.
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China.
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.
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Clinical cardiovascular phenotypes and the pattern of future events in patients with type 2 diabetes. Clin Res Cardiol 2023; 112:215-226. [PMID: 35396632 DOI: 10.1007/s00392-022-02016-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/29/2022] [Indexed: 02/07/2023]
Abstract
IMPORTANCE Updated guidelines on diabetes recommend targeting sodium-glucose cotransporter-2 inhibitors (SGLT2i) at patients at risk of heart failure (HF) and glucagon-like peptide-1 receptor agonists (GLP1-RA) at those at greater risk of atherothrombotic events. OBJECTIVE We estimated the risk of different cardiovascular events in patients with type 2 diabetes (T2D) and newly established cardiovascular disease. DESIGN, SETTING AND PARTICIPANTS Patients with T2D and newly established cardiovascular disease from 1998 to 2016 were identified using Danish healthcare registers and divided into one of four phenotype groups: (1) HF, (2) ischemic heart disease (IHD), (3) transient ischemic stroke (TIA)/ischemic stroke, and (4) peripheral artery disease (PAD). The absolute 5-year risk of the first HF- or atherothrombotic event occurring after inclusion was calculated, along with the risk of death. MAIN OUTCOMES AND MEASURES The main outcome was the first event of either HF or an atherothrombotic event (IHD, TIA/ischemic stroke or PAD) in patients with T2D and new-onset cardiovascular disease. RESULTS Of the 37,850 patients included, 40% were female and the median age was 70 years. Patients with HF were at higher 5-year risk of a subsequent HF event (17.9%; 95% confidence interval (CI) 17.1-18.8%) than an atherothrombotic event (15.8%; 15.0-16.6%). Patients with IHD were at higher risk of a subsequent atherothrombotic event (24.6%; 23.9-25.3%) than developing HF, although the risk of HF was still substantial (10.6%; 10.2-11.1%). Conversely, patients with PAD were at low risk of developing HF (4.4%; 3.8-5.1%) but at high risk of developing an atherothrombotic event (15.9%; 14.9-17.1%). Patients with TIA/ischemic stroke had the lowest risk of HF (3.2%; 2.9-3.6%) and the highest risk of an atherothrombotic event (20.6%; 19.8-21.4). CONCLUSIONS In T2D, a patient's cardiovascular phenotype can help predict the pattern of future cardiovascular events.
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Zhou YD, Liang FX, Tian HR, Luo D, Wang YY, Yang SR. Mechanisms of gut microbiota-immune-host interaction on glucose regulation in type 2 diabetes. Front Microbiol 2023; 14:1121695. [PMID: 36891383 PMCID: PMC9986296 DOI: 10.3389/fmicb.2023.1121695] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 01/31/2023] [Indexed: 02/22/2023] Open
Abstract
Intestinal absorption of food is one of the sources of glucose. Insulin resistance and impaired glucose tolerance caused by lifestyle and diet are the precursors of type 2 diabetes. Patients with type 2 diabetes have trouble controlling their blood sugar levels. For long-term health, strict glycemic management is necessary. Although it is thought to be well correlated with metabolic diseases like obesity, insulin resistance, and diabetes, its molecular mechanism is still not completely understood. Disturbed microbiota triggers the gut immune response to reshape the gut homeostasis. This interaction not only maintains the dynamic changes of intestinal flora, but also preserves the integrity of the intestinal barrier. Meanwhile, the microbiota establishes a systemic multiorgan dialog on the gut-brain and gut-liver axes, intestinal absorption of a high-fat diet affects the host's feeding preference and systemic metabolism. Intervention in the gut microbiota can combat the decreased glucose tolerance and insulin sensitivity linked to metabolic diseases both centrally and peripherally. Moreover, the pharmacokinetics of oral hypoglycemic medications are also influenced by gut microbiota. The accumulation of drugs in the gut microbiota not only affects the drug efficacy, but also changes the composition and function of them, thus may help to explain individual therapeutic variances in pharmacological efficacy. Regulating gut microbiota through healthy dietary patterns or supplementing pro/prebiotics can provide guidance for lifestyle interventions in people with poor glycemic control. Traditional Chinese medicine can also be used as complementary medicine to effectively regulate intestinal homeostasis. Intestinal microbiota is becoming a new target against metabolic diseases, so more evidence is needed to elucidate the intricate microbiota-immune-host relationship, and explore the therapeutic potential of targeting intestinal microbiota.
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Affiliation(s)
- Yu-Dian Zhou
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hebei, China
| | - Feng-Xia Liang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hebei, China
| | - Hao-Ran Tian
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hebei, China
| | - Dan Luo
- Department of Respiratory Wuhan No.1 Hospital, Wuhan, Hebei, China
| | - Ya-Yuan Wang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hebei, China
| | - Shu-Rui Yang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hebei, China
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19
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Thomsen RW, Christensen LWB, Kahlert J, Knudsen JS, Ustyugova A, Sandgaard S, Holmgaard P, Ehlers LH, Sørensen HT. Healthcare Resource Utilization and Costs for Empagliflozin Versus Glucagon-Like Peptide-1 Receptor Agonists in Routine Clinical Care in Denmark. Diabetes Ther 2022; 13:1891-1906. [PMID: 36315384 PMCID: PMC9663772 DOI: 10.1007/s13300-022-01323-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/21/2022] [Indexed: 12/04/2022] Open
Abstract
INTRODUCTION The sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin has shown reductions in major adverse cardiac events similar to glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, evidence is limited about how these therapies compare regarding overall healthcare resource utilization and costs in routine clinical care. METHODS We conducted a comparative cohort study based on linked prospective healthcare databases for the entire population of Denmark during 2015-2018. We included 13,747 new users of empagliflozin and 13,249 new users of GLP-1RAs. Propensity scores were applied to balance potential confounders across the two treatment groups through inverse probability treatment weighting (IPTW). We assessed directly referable costs per person-year associated with healthcare resource utilization (inpatient, emergency room, and outpatient clinic hospital care, primary care health services, and prescription medication costs at pharmacies) among drug initiators while on-treatment. RESULTS The two IPTW cohorts were well balanced at baseline (median age 61 years, 60% men, diabetes duration 6.7 years, 19% with pre-existing ischemic heart disease, 8% with pre-existing cerebrovascular disease), with similar healthcare costs in the previous year. During follow-up, average on-treatment costs per person-year were very similar among empagliflozin and GLP-1 RA initiators for the following services: inpatient hospitalizations (13,565 DKK versus 13,275 DKK), hospital outpatient clinic visits (12,007 DKK versus 12,152 DKK), emergency room visits (370 DKK versus 399 DKK), and primary care services (4108 DKK versus 4302 DKK). Total costs for any prescription drugs were clearly lower for empagliflozin initiators than for GLP-1 RA initiators (8946 DKK versus 14,029 DKK). In sum, overall healthcare costs on-treatment were lower for empagliflozin initiators (38,995 DKK per person-year) than for GLP-1RA initiators (44,157 DKK per person-year). CONCLUSIONS In this nationwide population-based cohort study, average healthcare costs after drug initiation and while on treatment were lower for empagliflozin initiators than for GLP-1RAs initiators, driven by lower drug costs. REGISTRATION The study protocol and analysis plan have been registered on the website of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) ( http://www.encepp.eu/encepp/viewResource.htm?id=37726 , first protocol registration 4 June 2019), and on clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT03993132 , first posted 20 June 2019).
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Affiliation(s)
- Reimar W Thomsen
- Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Olof Palmes Allé 43-45, 8200, Aarhus N, Denmark.
| | - Lotte W B Christensen
- Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Olof Palmes Allé 43-45, 8200, Aarhus N, Denmark
| | - Johnny Kahlert
- Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Olof Palmes Allé 43-45, 8200, Aarhus N, Denmark
| | - Jakob S Knudsen
- Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Olof Palmes Allé 43-45, 8200, Aarhus N, Denmark
| | | | | | | | - Lars H Ehlers
- Nordic Institute of Health Economics, Aarhus, Denmark
| | - Henrik T Sørensen
- Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Olof Palmes Allé 43-45, 8200, Aarhus N, Denmark
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20
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Yildiz M, Lavie CJ, Morin DP, Oktay AA. The complex interplay between diabetes mellitus and atrial fibrillation. Expert Rev Cardiovasc Ther 2022; 20:707-717. [PMID: 35984314 DOI: 10.1080/14779072.2022.2115357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
INTRODUCTION : A growing body of evidence suggests that diabetes mellitus (DM) is associated with an increased risk of new-onset atrial fibrillation (AF) and contributes to suboptimal arrhythmia control and poor prognosis in patients with AF. The high prevalence of AF among patients with DM is primarily attributed to common risk factors, shared pathophysiological mechanisms, and associated atrial remodeling and autonomic dysfunction. AREAS COVERED : This comprehensive review covers the current data on the role of DM in the development and prognosis of AF. In addition, we review the impact of anti-DM medications on AF prevention and the role of anticoagulation in patients with coexisting DM and AF. EXPERT OPINION : DM is independently associated with new-onset AF, and the coexistence of these two conditions contributes to poor outcomes, from reduced quality of life to increased risks of thromboembolic events, heart failure, and mortality. Despite this strong link, the current evidence is insufficient to recommend routine screening for AF in patients with DM. Although some observations exist on preventing AF with anti-DM medications, randomized controlled trials are warranted to explore the proposed benefits of novel anti-DM medicines in reducing the risk of incident AF.
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Affiliation(s)
- Mehmet Yildiz
- The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati, OH
| | - Carl J Lavie
- John Ochsner Heart and Vascular Institute, Ochsner Clinical School-The University of Queensland School of Medicine, New Orleans, LA
| | - Daniel P Morin
- John Ochsner Heart and Vascular Institute, Ochsner Clinical School-The University of Queensland School of Medicine, New Orleans, LA
| | - Ahmet Afsin Oktay
- The Heart and Vascular Institute, Rush University Medical Center, Chicago, IL
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21
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Lee SJ, Choi DW, Kim C, Suh Y, Hong SJ, Ahn CM, Kim JS, Kim BK, Ko YG, Choi D, Park EC, Jang Y, Nam CM, Hong MK. Prolonged dual antiplatelet therapy after drug-eluting stent implantation in patients with diabetes mellitus: A nationwide retrospective cohort study. Front Cardiovasc Med 2022; 9:954704. [PMID: 36035946 PMCID: PMC9403781 DOI: 10.3389/fcvm.2022.954704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 06/29/2022] [Indexed: 11/13/2022] Open
Abstract
Background Optimal duration of dual antiplatelet therapy (DAPT) in patients with diabetes mellitus (DM) who have undergone drug-eluting stent (DES) implantation is not clearly established. This study sought to impact of DAPT duration on real-world clinical outcome in patients with or without DM. Methods Using a nationwide cohort database, we investigate the association between DAPT duration and clinical outcome between 1 and 3 years after percutaneous coronary intervention (PCI). Primary outcome was all-cause death. Secondary outcomes were cardiovascular death, myocardial infarction, and composite bleeding events. After weighting, 90,100 DES-treated patients were included; 29,544 patients with DM and 60,556 without DM; 31,233 patients with standard DAPT (6–12 months) and 58,867 with prolonged DAPT (12–24 months). Results The incidence of all-cause death was significantly lower in patients with prolonged DAPT [8.3% vs. 10.5% in those with standard DAPT, hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.72–0.84] in diabetic patients and non-diabetic patients (4.5% vs. 5.0% in those with standard DAPT, HR 0.89, 95% CI 0.83–0.96). The incidence of composite bleeding events was 5.7% vs. 5.4%, respectively, (HR 1.07, 95% CI 0.96–1.18) in diabetic patients and 5.6% vs. 5.0%, respectively, in non-diabetic patients (HR 1.13, 95% CI 1.05–1.21). There was a significant interaction between the presence of DM and DAPT duration for all-cause death (p for interaction, pint = 0.01) that further favored prolonged DAPT in diabetic patients. However, there was no significant interaction between the presence of DM and DAPT duration for composite bleeding events (pint = 0.38). Conclusions This study showed that prolonged rather than standard DAPT might be clinically beneficial in diabetic patients with DES implantation. Trial registration ClinicalTrial.gov (NCT04715594).
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Affiliation(s)
- Seung-Jun Lee
- Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Dong-Woo Choi
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Cancer Big Data Center, National Cancer Center, National Cancer Control Institute, Goyang, South Korea
| | - Choongki Kim
- Ewha Womans University College of Medicine, Seoul Hospital, Seoul, South Korea
| | - Yongsung Suh
- Myongji Hospital, Hanyang University College of Medicine, Goyang, South Korea
| | - Sung-Jin Hong
- Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Chul-Min Ahn
- Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Jung-Sun Kim
- Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Byeong-Keuk Kim
- Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Young-Guk Ko
- Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Donghoon Choi
- Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Eun-Cheol Park
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Yangsoo Jang
- CHA Bundang Medical Center, CHA University College of Medicine, Seongnam, South Korea
| | - Chung-Mo Nam
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: Myeong-Ki Hong
| | - Myeong-Ki Hong
- Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea
- Chung-Mo Nam
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22
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Bhandari N, Newman JD, Berger JS, Smilowitz NR. Diabetes mellitus and outcomes of lower extremity revascularization for peripheral artery disease. EUROPEAN HEART JOURNAL. QUALITY OF CARE & CLINICAL OUTCOMES 2022; 8:298-306. [PMID: 33351089 PMCID: PMC9630873 DOI: 10.1093/ehjqcco/qcaa095] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/09/2020] [Accepted: 12/16/2020] [Indexed: 01/03/2023]
Abstract
AIMS The impact of diabetes mellitus (DM) on outcomes of lower extremity revascularization (LER) for peripheral artery disease (PAD) is uncertain. We characterized associations between DM and post-procedural outcomes in PAD patients undergoing LER. METHODS AND RESULTS Adults undergoing surgical or endovascular LER were identified from the 2014 Nationwide Readmissions Database. DM was defined by ICD-9 diagnosis codes and sub-classified based on the presence or absence of complications (poor glycaemic control or end-organ damage). Major adverse cardiovascular and limb events (MACLEs) were defined as the composite of death, myocardial infarction, ischaemic stroke, or major limb amputation during the index hospitalization for LER. For survivors, all-cause 6-month hospital readmission was determined. Among 39 441 patients with PAD hospitalized for LER, 50.8% had DM. The composite of MACLE after LER was not different in patients with and without DM after covariate adjustment, but patients with DM were more likely to require major limb amputation [5.5% vs. 3.2%, P < 0.001; adjusted odds ratio (aOR) 1.22, 95% confidence interval (CI) 1.03-1.44] and hospital readmission (59.2% vs. 41.3%, P < 0.001; aOR 1.44, 95% CI 1.34-1.55). Of 20 039 patients with DM hospitalized for LER, 55.7% had DM with complications. These patients were more likely to have MACLE after LER (11.1% vs. 5.2%, P < 0.001; aOR 1.56 95% CI 1.28-1.89) and require hospital readmission (61.1% vs. 47.2%, P < 0.001; aOR 1.41 95% CI 1.27-1.57) than patients with uncomplicated DM. CONCLUSIONS DM is present in ≈50% of patients undergoing LER for PAD and is an independent risk factor for major limb amputation and 6-month hospital readmission.
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Affiliation(s)
- Nipun Bhandari
- Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 423 East 23rd Street, Room 12020-W, New York, NY 10010, USA
| | - Jonathan D Newman
- Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 423 East 23rd Street, Room 12020-W, New York, NY 10010, USA
| | - Jeffrey S Berger
- Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 423 East 23rd Street, Room 12020-W, New York, NY 10010, USA
- Department of Surgery, New York University School of Medicine, 550 1st Ave, New York, NY 10016, USA
| | - Nathaniel R Smilowitz
- Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 423 East 23rd Street, Room 12020-W, New York, NY 10010, USA
- Division of Cardiology, Department of Medicine, Veterans Affairs New York Harbor Health Care System, 423 E 23rd St, New York, NY 10010, USA
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23
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Haudum CW, Kolesnik E, Colantonio C, Mursic I, Url-Michitsch M, Tomaschitz A, Glantschnig T, Hutz B, Lind A, Schweighofer N, Reiter C, Ablasser K, Wallner M, Tripolt NJ, Pieske-Kraigher E, Madl T, Springer A, Seidel G, Wedrich A, Zirlik A, Krahn T, Stauber R, Pieske B, Pieber TR, Verheyen N, Obermayer-Pietsch B, Schmidt A. Cohort profile: 'Biomarkers of Personalised Medicine' (BioPersMed): a single-centre prospective observational cohort study in Graz/Austria to evaluate novel biomarkers in cardiovascular and metabolic diseases. BMJ Open 2022; 12:e058890. [PMID: 35393327 PMCID: PMC8991072 DOI: 10.1136/bmjopen-2021-058890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
PURPOSE Accumulating evidence points towards a close relationship between cardiovascular, endocrine and metabolic diseases. The BioPersMed Study (Biomarkers of Personalised Medicine) is a single-centre prospective observational cohort study with repetitive examination of participants in 2-year intervals. The aim is to evaluate the predictive impact of various traditional and novel biomarkers of cardiovascular, endocrine and metabolic pathways in asymptomatic individuals at risk for cardiovascular and/or metabolic disease. PARTICIPANTS Between 2010 and 2016, we recruited 1022 regional individuals into the study. Subjects aged 45 years or older presenting with at least one traditional cardiovascular risk factor or manifest type 2 diabetes mellitus (T2DM) were enrolled. The mean age of the participants was 57±8 years, 55% were female, 18% had T2DM, 33% suffered from arterial hypertension, 15% were smokers, 42% had hyperlipidaemia, and only 26% were at low cardiovascular risk according to the Framingham 'Systematic COronary Risk Evaluation'. FINDINGS TO DATE Study procedures during screening and follow-up visits included a physical examination and comprehensive cardiovascular, endocrine, metabolic, ocular and laboratory workup with biobanking of blood and urine samples. The variety of assessed biomarkers allows a full phenotyping of individuals at cardiovascular and metabolic risk. Preliminary data from the cohort and relevant biomarker analyses were already used as control population for genomic studies in local and international research cooperation. FUTURE PLANS Participants will undergo comprehensive cardiovascular, endocrine and metabolic examinations for the next decades and clinical outcomes will be adjudicated prospectively.
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Affiliation(s)
- Christoph Walter Haudum
- Center for Biomarker Research in Medicine, Graz, Austria
- Department of Internal Medicine, Medical University, Graz, Austria
| | - Ewald Kolesnik
- Department of Internal Medicine, Medical University and University Heart Center, Graz, Austria
| | - Caterina Colantonio
- Department of Internal Medicine, Medical University and University Heart Center, Graz, Austria
| | - Ines Mursic
- Department of Internal Medicine, Medical University, Graz, Austria
| | - Marion Url-Michitsch
- Department of Internal Medicine, Medical University and University Heart Center, Graz, Austria
| | - Andreas Tomaschitz
- Department of Internal Medicine, Medical University and University Heart Center, Graz, Austria
| | - Theresa Glantschnig
- Department of Internal Medicine, Medical University and University Heart Center, Graz, Austria
| | - Barbara Hutz
- Department of Internal Medicine, Medical University, Graz, Austria
| | - Alice Lind
- Department of Internal Medicine, Medical University, Graz, Austria
| | | | - Clemens Reiter
- Department of Internal Medicine, Medical University and University Heart Center, Graz, Austria
- Department of Radiology, Medizinische Universitat, Graz, Austria
| | - Klemens Ablasser
- Department of Internal Medicine, Medical University and University Heart Center, Graz, Austria
| | - Markus Wallner
- Department of Internal Medicine, Medical University and University Heart Center, Graz, Austria
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | | | | | - Tobias Madl
- Gottfried Schatz Research Center, Medical University, Graz, Austria
- BioTechMed, Graz, Austria
| | - Alexander Springer
- Gottfried Schatz Research Center, Medical University, Graz, Austria
- BioTechMed, Graz, Austria
| | - Gerald Seidel
- Department of Ophthalmology, Medical University, Graz, Austria
| | - Andreas Wedrich
- Department of Ophthalmology, Medizinische Universitat, Graz, Austria
| | - Andreas Zirlik
- Department of Internal Medicine, Medical University and University Heart Center, Graz, Austria
| | - Thomas Krahn
- Department of Internal Medicine, Medical University, Graz, Austria
- Department of Pharmacology and Personalised Medicine, Maastricht University, Maastricht, The Netherlands
| | - Rudolf Stauber
- Department of Internal Medicine, Medizinische Universitat, Graz, Austria
| | - Burkert Pieske
- Department of Internal Medicine and Cardiology, Charité University Medicine, Berlin, Germany
| | - Thomas R Pieber
- Center for Biomarker Research in Medicine, Graz, Austria
- Department of Internal Medicine, Medical University, Graz, Austria
| | - Nicolas Verheyen
- Department of Internal Medicine, Medical University and University Heart Center, Graz, Austria
| | | | - Albrecht Schmidt
- Department of Internal Medicine, Medical University and University Heart Center, Graz, Austria
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24
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Mazin I, Chernomordik F, Fefer P, Matetzky S, Beigel R. The Impact of Novel Anti-Diabetic Medications on CV Outcomes: A New Therapeutic Horizon for Diabetic and Non-Diabetic Cardiac Patients. J Clin Med 2022; 11:1904. [PMID: 35407513 PMCID: PMC9000034 DOI: 10.3390/jcm11071904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/17/2022] [Accepted: 03/27/2022] [Indexed: 01/27/2023] Open
Abstract
It is estimated that in the past two decades the number of patients diagnosed with diabetes mellites (DM) has doubled. Despite significant progress in the treatment of cardiovascular disease (CVD), including novel anti-platelet agents, effective lipid-lowering medications, and advanced revascularization techniques, patients with DM still are least twice as likely to die of cardiovascular causes compared with their non-diabetic counterparts, and current guidelines define patients with DM at the highest risk for atherosclerotic cardiovascular disease and major adverse cardiovascular events (MACE). Over the last few years, there has been a breakthrough in anti-diabetic therapeutics, as two novel anti-diabetic classes have demonstrated cardiovascular benefit with consistently reduced MACE, and for some agents, also improvement in heart failure status as well as reduced cardiovascular and all-cause mortality. These include the sodium-glucose cotransporter-2 inhibitors and the glucagon-like peptide-1 receptor agonists. The benefits of these medications are thought to be derived not only from their anti-diabetic effect but also from additional mechanisms. The purpose of this review is to provide the everyday clinician a detailed review of the various agents within each class with regard to their specific characteristics and the effects on MACE and cardiovascular outcomes.
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Affiliation(s)
- Israel Mazin
- Department of Cardiology, The Cardiovascular Division, Sheba Medical Center, Tel-Hashomer, The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 5265601, Israel; (F.C.); (P.F.); (S.M.); (R.B.)
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25
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Rafaqat S, Rafaqat S, Rafaqat S. Pathophysiological aspects of insulin resistance in Atrial Fibrillation: novel therapeutic approaches. INTERNATIONAL JOURNAL OF ARRHYTHMIA 2022. [DOI: 10.1186/s42444-021-00057-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract
Background
Insulin resistance is associated with metabolic disorders including diabetes, obesity, hypertension, and inflammation which are the risk factors for Atrial Fibrillation. Many studies have reported that type 2 diabetes and AF are related and also their prevalence is increasing globally. Moreover, insulin resistance begins the type 2 diabetes.
Main body
This review explains the pathophysiological aspects of insulin resistance in AF patients and discusses the drugs that are used to manage insulin resistance including Biguanides (metformin), thiazolidinediones (TZDs) [Pioglitazone, rosiglitazone], Sodium-glucose cotransporter 2 (SGLT2) inhibitors, Concentrated Insulin Products, Dipeptidyl peptidase-4 (DPP-4) Inhibitors, Glucagon-like peptide 1 (GLP-1) receptor Agonists, Pramlintide, Sulfonylureas, Meglitinides, α-Glucosidase Inhibitors, Colesevelam, Bromocriptine. This review will highlight a few major drugs that played a significant role in AF patients. For this purpose, many databases were used for reviewing the literature and keywords are used such as Insulin Resistance, Pathophysiology, Atrial Fibrillation, and Drugs.
Conclusion
This review article concludes that insulin resistance is related to AF. It also provides an outlook on the recent pathophysiological aspects of insulin resistance in AF; however, more studies are needed to clarify the management of insulin resistance in AF patients to prevent the development of type 2 diabetes.
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26
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Shi FH, Yue J, Jiang YH, Yang ML, Gu ZC, Ma J, Li H. Sodium-Glucose Co-Transporter 2 Inhibitors Use Improves the Satisfaction With Anti-diabetic Agent Treatment: A Questionnaire-based Propensity Score-matched Study. Front Pharmacol 2022; 12:787704. [PMID: 35177981 PMCID: PMC8844021 DOI: 10.3389/fphar.2021.787704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 12/20/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Specific safety issues with sodium-glucose co-transporter-2 (SGLT2) inhibitors such as infection, fractures, worsening of renal function and euglycemic ketoacidosis have been raised. Concerns about adverse events might limit the use of this drug class. The satisfaction with SGLT2 inhibitors treatment in Chinese patients with type 2 diabetes mellitus (T2DM) is unknown. Material and Methods: Patients with T2DM who visited the hospital between October 2019 and June 2020 were included in this retrospective analysis. Patients were divided into SGLT2 inhibitors used group or not. The Satisfaction with Oral Anti-Diabetic Agent Scale (SOADAS) questionnaire and self-reported AEs were obtained at 3 months of follow-up. Propensity score matching (PSM) was performed to adjust for confounding factors. Univariate and multivariable linear regression models were used to explore potential risk factors associated with overall satisfaction. Results: A total of 145 T2DM patients were included, with 76 SGLT2 inhibitors users and 69 non-users. Patients administered with SGLT2 inhibitors presented with increased overall satisfaction (mean [SE]: 22.8 [0.67] vs. 20.6 [0.64], p = 0.016) and overall satisfaction rate (n [%]: 40 [52.6%] vs 21 [30.4%], p = 0.007) when compared to other anti-diabetic agents. The use of SGLT2 inhibitors significantly improved satisfaction of glycemic control ability (mean [SE]:3.9 [0.12] vs. 3.5 [0.12], p = 0.027), diabetic symptom’s control ability (3.5 [0.15] vs. 3.0 [0.15], p = 0.027), glycemic control speed (3.9 [0.11] vs. 3.4 [0.12], p = 0.011), medication tolerability (3.9 [0.10] vs. 3.5 [0.12], p = 0.012), and overall satisfaction (4.0 [0.11] vs. 3.6 [0.12], p = 0.037), but it did not improve satisfaction of medication effect on bodyweight (3.8 [0.11] vs. 3.4 [0.11], p = 0.166). After adjusting confounding factors (47 patients for each group), consistent results were obtained. No significant differences of self-reported clinical AEs were observed between SGLT2 inhibitors users and non-users. Multivariable regression analyses verified that the use of SGLT2 inhibitors was associated with increased levels of satisfaction. Conclusions: The use of SGLT2 inhibitors was associated with increased levels of satisfaction in T2DM patients, but not associated with overall clinical safety. Self-reported AEs were not related to the satisfaction with the use of anti-diabetic agents.
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Affiliation(s)
- Fang-Hong Shi
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiang Yue
- Department of Endocrinology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi-Hong Jiang
- Department of Endocrinology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming-Lan Yang
- Department of Endocrinology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi-Chun Gu
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Ma
- Department of Endocrinology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Li
- Department of Pharmacy, Clinical Research Center, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Palano MT, Cucchiara M, Gallazzi M, Riccio F, Mortara L, Gensini GF, Spinetti G, Ambrosio G, Bruno A. When a Friend Becomes Your Enemy: Natural Killer Cells in Atherosclerosis and Atherosclerosis-Associated Risk Factors. Front Immunol 2022; 12:798155. [PMID: 35095876 PMCID: PMC8793801 DOI: 10.3389/fimmu.2021.798155] [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: 10/19/2021] [Accepted: 12/14/2021] [Indexed: 12/15/2022] Open
Abstract
Atherosclerosis (ATS), the change in structure and function of arteries with associated lesion formation and altered blood flow, is the leading cause of cardiovascular disease, the number one killer worldwide. Beyond dyslipidemia, chronic inflammation, together with aberrant phenotype and function of cells of both the innate and adaptive immune system, are now recognized as relevant contributors to atherosclerosis onset and progression. While the role of macrophages and T cells in atherosclerosis has been addressed in several studies, Natural Killer cells (NKs) represent a poorly explored immune cell type, that deserves attention, due to NKs’ emerging contribution to vascular homeostasis. Furthermore, the possibility to re-polarize the immune system has emerged as a relevant tool to design new therapies, with some succesfull exmples in the field of cancer immunotherapy. Thus, a deeper knowledge of NK cell pathophysiology in the context of atherosclerosis and atherosclerosis-associated risk factors could help developing new preventive and treatment strategies, and decipher the complex scenario/history from “the risk factors for atherosclerosis” Here, we review the current knowledge about NK cell phenotype and activities in atherosclerosis and selected atherosclerosis risk factors, namely type-2 diabetes and obesity, and discuss the related NK-cell oriented environmental signals.
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Affiliation(s)
- Maria Teresa Palano
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milano, Italy
| | - Martina Cucchiara
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Matteo Gallazzi
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Federica Riccio
- Laboratory of Cardiovascular Physiopathology-Regenerative Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milano, Italy
| | - Lorenzo Mortara
- Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Gian Franco Gensini
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milano, Italy
| | - Gaia Spinetti
- Laboratory of Cardiovascular Physiopathology-Regenerative Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milano, Italy
| | | | - Antonino Bruno
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milano, Italy
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28
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Mahtta D, Ramsey DJ, Lee MT, Chen L, Al Rifai M, Akeroyd JM, Vaughan EM, Matheny ME, Santo KRDE, Navaneethan SD, Lavie CJ, Birnbaum Y, Ballantyne CM, Petersen LA, Virani SS. Utilization Rates of SGLT2 Inhibitors and GLP-1 Receptor Agonists and Their Facility-Level Variation Among Patients With Atherosclerotic Cardiovascular Disease and Type 2 Diabetes: Insights From the Department of Veterans Affairs. Diabetes Care 2022; 45:372-380. [PMID: 35015080 PMCID: PMC8914426 DOI: 10.2337/dc21-1815] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/17/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE There is mounting evidence regarding the cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) among patients with atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes mellitus (T2DM). There is paucity of data assessing real-world practice patterns for these drug classes. We aimed to assess utilization rates of these drug classes and facility-level variation in their use. RESEARCH DESIGN AND METHODS We used the nationwide Veterans Affairs (VA) health care system data set from 1 January 2020 to 31 December 2020 and included patients with established ASCVD and T2DM. Among these patients, we assessed the use of SGLT2i and GLP-1 RA and the facility-level variation in their use. Facility-level variation was computed using median rate ratios (MRR), a measure of likelihood that two random facilities differ in use of SGLT2i and GLP-1 RA in patients with ASCVD and T2DM. RESULTS Among 537,980 patients with ASCVD and T2DM across 130 VA facilities, 11.2% of patients received an SGLT2i while 8.0% of patients received a GLP-1 RA. Patients receiving these cardioprotective glucose-lowering drug classes were on average younger and had a higher proportion of non-Hispanic Whites. Overall, median (10th-90th percentile) facility-level rates were 14.92% (9.31-22.50) for SGLT2i and 10.88% (4.44-17.07) for GLP-1 RA. There was significant facility-level variation among SGLT2i use-MRRunadjusted: 1.41 (95% CI 1.35-1.47) and MRRadjusted: 1.55 (95% CI 1.46 -1.63). Similar facility-level variation was observed for use of GLP-1 RA-MRRunadjusted: 1.34 (95% CI 1.29-1.38) and MRRadjusted: 1.78 (95% CI 1.65-1.90). CONCLUSIONS Overall utilization rates of SGLT2i and GLP-1 RA among eligible patients are low, with significantly higher residual facility-level variation in the use of these drug classes. Our results suggest opportunities to optimize their use to prevent future adverse cardiovascular events among these patients.
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Affiliation(s)
- Dhruv Mahtta
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX.,Health Policy, Quality & Informatics Program, Michael E. DeBakey Veterans Affairs Medical Center Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety, Houston, TX
| | - David J Ramsey
- Health Policy, Quality & Informatics Program, Michael E. DeBakey Veterans Affairs Medical Center Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety, Houston, TX
| | - Michelle T Lee
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX.,Health Policy, Quality & Informatics Program, Michael E. DeBakey Veterans Affairs Medical Center Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety, Houston, TX
| | - Liang Chen
- Health Policy, Quality & Informatics Program, Michael E. DeBakey Veterans Affairs Medical Center Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety, Houston, TX
| | - Mahmoud Al Rifai
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Julia M Akeroyd
- Health Policy, Quality & Informatics Program, Michael E. DeBakey Veterans Affairs Medical Center Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety, Houston, TX
| | - Elizabeth M Vaughan
- Division of General Internal Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX.,Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Michael E Matheny
- Geriatrics Research Education and Clinical Care, Tennessee Valley Healthcare System VA, Nashville, TN.,Departments of Biomedical Informatics, Biostatistics, and Medicine, Vanderbilt University Medical Center, Nashville, TN
| | | | - Sankar D Navaneethan
- Section of Nephrology and Institute of Clinical and Translational Research, Baylor College of Medicine, Houston, TX.,Section of Nephrology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX
| | - Carl J Lavie
- 10Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA
| | - Yochai Birnbaum
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Christie M Ballantyne
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX.,Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Laura A Petersen
- Health Policy, Quality & Informatics Program, Michael E. DeBakey Veterans Affairs Medical Center Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety, Houston, TX.,11Section of Health Services Research, Baylor College of Medicine, Houston, TX
| | - Salim S Virani
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX.,Health Policy, Quality & Informatics Program, Michael E. DeBakey Veterans Affairs Medical Center Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety, Houston, TX.,Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX.,10Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA.,12Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX
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29
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Berger JS, Kornblith LZ, Gong MN, Reynolds HR, Cushman M, Cheng Y, McVerry BJ, Kim KS, Lopes RD, Atassi B, Berry S, Bochicchio G, de Oliveira Antunes M, Farkouh ME, Greenstein Y, Hade EM, Hudock K, Hyzy R, Khatri P, Kindzelski A, Kirwan BA, Baumann Kreuziger L, Lawler PR, Leifer E, Lopez-Sendon Moreno J, Lopez-Sendon J, Luther JF, Nigro Maia L, Quigley J, Sherwin R, Wahid L, Wilson J, Hochman JS, Neal MD. Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non-Critically Ill Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA 2022; 327:227-236. [PMID: 35040887 PMCID: PMC8767444 DOI: 10.1001/jama.2021.23605] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/13/2021] [Indexed: 12/17/2022]
Abstract
Importance Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19. Objective To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19. Design, Setting, and Participants An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021. Interventions Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = 293) or a therapeutic dose of heparin only (usual care) (n = 269) in a 1:1 ratio for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. Main Outcomes and Measures The composite primary outcome was organ support-free days evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and, for those who survived to hospital discharge, the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization (range, -1 to 21 days; higher scores indicate less organ support and better outcomes). The primary safety outcome was major bleeding by 28 days as defined by the International Society on Thrombosis and Hemostasis. Results Enrollment of non-critically ill patients was discontinued when the prespecified criterion for futility was met. All 562 patients who were randomized (mean age, 52.7 [SD, 13.5] years; 41.5% women) completed the trial and 87% received a therapeutic dose of heparin by the end of study day 1. In the P2Y12 inhibitor group, ticagrelor was used in 63% of patients and clopidogrel in 37%. The median number of organ support-free days was 21 days (IQR, 20-21 days) among patients in the P2Y12 inhibitor group and was 21 days (IQR, 21-21 days) in the usual care group (adjusted odds ratio, 0.83 [95% credible interval, 0.55-1.25]; posterior probability of futility [defined as an odds ratio <1.2], 96%). Major bleeding occurred in 6 patients (2.0%) in the P2Y12 inhibitor group and in 2 patients (0.7%) in the usual care group (adjusted odds ratio, 3.31 [95% CI, 0.64-17.2]; P = .15). Conclusions and Relevance Among non-critically ill patients hospitalized for COVID-19, the use of a P2Y12 inhibitor in addition to a therapeutic dose of heparin, compared with a therapeutic dose of heparin only, did not result in an increased odds of improvement in organ support-free days within 21 days during hospitalization. Trial Registration ClinicalTrials.gov Identifier: NCT04505774.
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Affiliation(s)
| | | | | | | | - Mary Cushman
- College of Medicine, University of Vermont, Burlington
| | - Yu Cheng
- University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | | | | | - Bassel Atassi
- OSF Little Company of Mary Medical Center, Evergreen Park, Illinois
| | | | | | | | | | | | | | - Kristin Hudock
- University of Cincinnati Medical Center, Cincinnati, Ohio
| | | | - Pooja Khatri
- University of Cincinnati Medical Center, Cincinnati, Ohio
| | | | | | | | | | - Eric Leifer
- National Heart, Lung, and Blood Institute, Bethesda, Maryland
| | | | | | | | - Lilia Nigro Maia
- Fundação Faculdade Regional De Medicina De São José Do Rio Preto, São José do Rio Preto, Brazil
| | | | | | - Lana Wahid
- Duke University Hospital, Durham, North Carolina
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30
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Triposkiadis F, Xanthopoulos A, Parissis J, Butler J, Farmakis D. Pathogenesis of chronic heart failure: cardiovascular aging, risk factors, comorbidities, and disease modifiers. Heart Fail Rev 2022; 27:337-344. [DOI: 10.1007/s10741-020-09987-z] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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31
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Nashawi M, Ahmed MS, Amin T, Abualfoul M, Chilton R. Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy. World J Cardiol 2021; 13:676-694. [PMID: 35070111 PMCID: PMC8716977 DOI: 10.4330/wjc.v13.i12.676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/02/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) have been substantiated by multiple clinical trials, resulting in increased interest in the multifarious pathways by which their mechanisms act. The principal effect of SGLT2i (-flozin drugs) can be appreciated in their ability to block the SGLT2 protein within the kidneys, inhibiting glucose reabsorption, and causing an associated osmotic diuresis. This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter. These include aberrant mitochondrial metabolism and oxidative stress burden, endothelial cell dysfunction, pernicious neurohormonal activation, and the development of inimical hemodynamics. Positive outcomes within these domains have been validated with SGLT2i administration. However, by modulating the sodium-glucose cotransporter in the proximal tubule (PT), SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention. Phosphatemia, even at physiologic levels, poses a risk in cardiovascular disease burden, more so in patients with type 2 diabetes mellitus (T2DM). There also exists an association between phosphatemia and renal impairment, the latter hampering cardiovascular function through an array of physiologic roles, such as fluid regulation, hormonal tone, and neuromodulation. Moreover, increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels, also detrimental to homeostatic cardiometabolic function. A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature. Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia, we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease, as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects. Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.
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Affiliation(s)
- Mouhamed Nashawi
- Department of Internal Medicine, Baylor Scott and White All Saints Medical Center, Fort Worth, TX 76132, United States.
| | - Mahmoud S Ahmed
- Division of Medicine-Cardiology, UT Health San Antonio, San Antonio, TX 78229, United States
| | - Toka Amin
- Division of Medicine-Cardiology, UT Health San Antonio, San Antonio, TX 78229, United States
| | - Mujahed Abualfoul
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Dallas, TX 75203, United States
| | - Robert Chilton
- Department of Internal Medicine, Methodist Dallas Medical Center, Dallas, TX 75203, United States
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32
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Lin DSH, Lee JK, Hung CS, Chen WJ. The efficacy and safety of novel classes of glucose-lowering drugs for cardiovascular outcomes: a network meta-analysis of randomised clinical trials. Diabetologia 2021; 64:2676-2686. [PMID: 34536085 DOI: 10.1007/s00125-021-05529-w] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/23/2021] [Indexed: 01/10/2023]
Abstract
AIMS/HYPOTHESIS Several cardiovascular outcome trials on sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been released recently, including trials enrolling patients with congestive heart failure (CHF) and chronic kidney disease (CKD). Comparisons of the efficacy and safety of SGLT2i, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) thus require an update. Assessments in patient subgroups, i.e., as stratified by age or the presence of CHF, CKD or atherosclerotic cardiovascular disease (ASCVD), are also currently lacking. METHODS We searched the PubMed, Embase and Cochrane databases for relevant studies published up until 5 December 2020. RCTs comparing SGLT2i, GLP-1RA and DPP-4i with placebo (or other controls) or with each other with cardiovascular (CV) or renal outcomes were eligible for inclusion. The primary efficacy endpoint was 3-point major adverse cardiovascular events (3P-MACE), which are defined as CV death, non-fatal myocardial infarction and non-fatal ischaemic stroke. All-cause mortality, hospitalisation for heart failure (HHF) and composite renal outcomes were also analysed. Pre-specified subgroup analyses of 3P-MACE were also performed. RESULTS A total of 21 trials with 170,930 participants were included in this network meta-analysis. Both GLP-1RA and SGLT2i were associated with lower risks of 3P-MACE than placebo (RR 0.89, 95% CI 0.84, 0.94 and RR 0.88, 95% CI 0.83, 0.94, respectively). GLP-1RA and SGLT2i were also associated with lower risks of 3P-MACE than DPP-4i (RR 0.89, 95% CI 0.82, 0.98 and RR 0.89, 95% CI 0.81, 0.97, respectively). A comparison between SGLT2i and GLP-1RA demonstrated no difference in their risks of 3P-MACE (RR 0.99, 95% CI 0.91, 1.08). Only GLP-1RA was associated with a lower risk of stroke compared with placebo (RR 0.85, 95% CI 0.76, 0.94). SGLT2i is superior to GLP-1RA in reducing HHF (RR 0.76, 95% CI 0.68, 0.84) and renal outcomes (RR 0.78, 95% CI 0.65, 0.93). Subgroup analyses indicated that the benefits of SGLT2i and GLP-1RA were more pronounced in elderly patients, white and Asian patients, those with established ASCVD and those with longer durations of diabetes mellitus and worse glycaemic control. CONCLUSIONS/INTERPRETATION SGLT2i and GLP-1RA are superior to DPP-4i in terms of CV and renal outcomes. GLP-1RA is the only drug class that reduces the risk of stroke. SGLT2i is superior in reducing HHF and renal outcomes. Therefore, the choice between SGLT2i and GLP-1RA should be individualised according to patient profiles. PROSPERO REGISTRATION NUMBER CRD42020206600.
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Affiliation(s)
- Donna Shu-Han Lin
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan
- Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Jen-Kuang Lee
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Laboratory Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Sheng Hung
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
- Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan.
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
- Telehealth Center, National Taiwan University Hospital, Taipei, Taiwan.
| | - Wen-Jone Chen
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan
- Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Emergency Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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Edgar L, Akbar N, Braithwaite AT, Krausgruber T, Gallart-Ayala H, Bailey J, Corbin AL, Khoyratty TE, Chai JT, Alkhalil M, Rendeiro AF, Ziberna K, Arya R, Cahill TJ, Bock C, Laurencikiene J, Crabtree MJ, Lemieux ME, Riksen NP, Netea MG, Wheelock CE, Channon KM, Rydén M, Udalova IA, Carnicer R, Choudhury RP. Hyperglycemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis. Circulation 2021; 144:961-982. [PMID: 34255973 PMCID: PMC8448412 DOI: 10.1161/circulationaha.120.046464] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 06/23/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND Cardiovascular risk in diabetes remains elevated despite glucose-lowering therapies. We hypothesized that hyperglycemia induces trained immunity in macrophages, promoting persistent proatherogenic characteristics. METHODS Bone marrow-derived macrophages from control mice and mice with diabetes were grown in physiological glucose (5 mmol/L) and subjected to RNA sequencing (n=6), assay for transposase accessible chromatin sequencing (n=6), and chromatin immunoprecipitation sequencing (n=6) for determination of hyperglycemia-induced trained immunity. Bone marrow transplantation from mice with (n=9) or without (n=6) diabetes into (normoglycemic) Ldlr-/- mice was used to assess its functional significance in vivo. Evidence of hyperglycemia-induced trained immunity was sought in human peripheral blood mononuclear cells from patients with diabetes (n=8) compared with control subjects (n=16) and in human atherosclerotic plaque macrophages excised by laser capture microdissection. RESULTS In macrophages, high extracellular glucose promoted proinflammatory gene expression and proatherogenic functional characteristics through glycolysis-dependent mechanisms. Bone marrow-derived macrophages from diabetic mice retained these characteristics, even when cultured in physiological glucose, indicating hyperglycemia-induced trained immunity. Bone marrow transplantation from diabetic mice into (normoglycemic) Ldlr-/- mice increased aortic root atherosclerosis, confirming a disease-relevant and persistent form of trained innate immunity. Integrated assay for transposase accessible chromatin, chromatin immunoprecipitation, and RNA sequencing analyses of hematopoietic stem cells and bone marrow-derived macrophages revealed a proinflammatory priming effect in diabetes. The pattern of open chromatin implicated transcription factor Runt-related transcription factor 1 (Runx1). Similarly, transcriptomes of atherosclerotic plaque macrophages and peripheral leukocytes in patients with type 2 diabetes were enriched for Runx1 targets, consistent with a potential role in human disease. Pharmacological inhibition of Runx1 in vitro inhibited the trained phenotype. CONCLUSIONS Hyperglycemia-induced trained immunity may explain why targeting elevated glucose is ineffective in reducing macrovascular risk in diabetes and suggests new targets for disease prevention and therapy.
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Affiliation(s)
- Laurienne Edgar
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | - Naveed Akbar
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | - Adam T. Braithwaite
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | - Thomas Krausgruber
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (T.K., A.F.R., C.B.)
| | - Héctor Gallart-Ayala
- Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden (H.G.-A., C.E.W.)
- Department of Respiratory Medicine and Allergy (H.G.-A., C.E.W.), Karolinska University Hospital, Stockholm, Sweden
| | - Jade Bailey
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | - Alastair L. Corbin
- The Kennedy Institute of Rheumatology, University of Oxford, UK (A.L.C., T.E.K., I.A.U.)
| | - Tariq E. Khoyratty
- The Kennedy Institute of Rheumatology, University of Oxford, UK (A.L.C., T.E.K., I.A.U.)
| | - Joshua T. Chai
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | - Mohammad Alkhalil
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | - André F. Rendeiro
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (T.K., A.F.R., C.B.)
| | - Klemen Ziberna
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | - Ritu Arya
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | - Thomas J. Cahill
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | - Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (T.K., A.F.R., C.B.)
- Institute of Artificial Intelligence and Decision Support, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Austria (C.B.)
| | - Jurga Laurencikiene
- Department of Medicine (H7) (J.L., M.R.), Karolinska University Hospital, Stockholm, Sweden
| | - Mark J. Crabtree
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | | | - Niels P. Riksen
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands (N.P.R.., M.G.N.)
| | - Mihai G. Netea
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands (N.P.R.., M.G.N.)
- Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Germany (M.G.N.)
| | - Craig E. Wheelock
- Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden (H.G.-A., C.E.W.)
- Department of Respiratory Medicine and Allergy (H.G.-A., C.E.W.), Karolinska University Hospital, Stockholm, Sweden
| | - Keith M. Channon
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | - Mikael Rydén
- Department of Medicine (H7) (J.L., M.R.), Karolinska University Hospital, Stockholm, Sweden
| | - Irina A. Udalova
- The Kennedy Institute of Rheumatology, University of Oxford, UK (A.L.C., T.E.K., I.A.U.)
| | - Ricardo Carnicer
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
| | - Robin P. Choudhury
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK (L.E., N.A., A.T.B., J.B., J.T.C., M.A., K.Z., R.A., T.J.C., M.J.C., K.M.C., R.C., R.P.C.)
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Cordero A, Rodríguez-Mañero M, Bertomeu-González V, García-Acuña JM, Baluja A, Agra-Bermejo R, Álvarez-Álvarez B, Cid B, Zuazola P, González-Juanatey JR. Insuficiencia cardiaca de novo tras un síndrome coronario agudo en pacientes sin insuficiencia cardiaca ni disfunción ventricular izquierda. Rev Esp Cardiol 2021. [DOI: 10.1016/j.recesp.2020.03.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Zhang Y, Li S, Cao Z, Cheng Y, Xu C, Yang H, Sun L, Jiao H, Wang J, Li WD, Wang Y. A network analysis framework of genetic and nongenetic risks for type 2 diabetes. Rev Endocr Metab Disord 2021; 22:461-469. [PMID: 32926312 DOI: 10.1007/s11154-020-09585-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/26/2020] [Indexed: 12/25/2022]
Abstract
Both genetic and nongenetic factors have been found to be associated with type 2 diabetes, however, the correlation between them is still unclear. In the present study, we aimed to fully decipher the nongenetic and genetic factor association network for type 2 diabetes. We identified risk factors for type 2 diabetes by systematically searching for related meta-analyses and genome-wide association studies (GWAS) database. Among a total of 27,822 studies screened, 202 articles were eligible, from which 174 nongenetic factors and 210 genetic factors associated with type 2 diabetes were identified. Then, we obtained 584 associations between the nongenetic and genetic factors of type 2 diabetes, based on which a risk factor association network was conducted. The nongenetic factors could be classified into seven categories according to the Global Burden of Diseases (GBD). Of these seven categories of nongenetic factors, five were found to be correlated with genes associated with type 2 diabetes, including environmental risks, behavioral risks, metabolic risks, related disease of type 2 diabetes, and treatments. Specifically, air pollutants of environmental risks, alcohol using of behavioral risks, obesity of metabolic risks, rheumatoid arthritis of related disease risk, and simvastatin of treatment was correlated with the largest number of genes. In summary, the correlation between genetic factors and nongenetic factors identified in this study indicates that there is a common phenotype-genotype association in type 2 diabetes, with the combinations of genotypes ("genetic signature") clustering in phenotypes related to type 2 diabetes. Thus, we should take a systematic approach to explore the relationship of various factors for type 2 diabetes, as well as other noncommunicable diseases.
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Affiliation(s)
- Yuan Zhang
- School of Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Shu Li
- School of Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Zhi Cao
- School of Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Yangyang Cheng
- School of Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Chenjie Xu
- School of Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Hongxi Yang
- School of Public Health, Tianjin Medical University, Tianjin, 300070, China
| | - Li Sun
- School of Public Health, Tianjin Medical University, Tianjin, 300070, China
- School of Nursing, Tianjin Medical University, Tianjin, China
| | - Hongxiao Jiao
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Ju Wang
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, China
| | - Wei-Dong Li
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
| | - Yaogang Wang
- School of Public Health, Tianjin Medical University, Tianjin, 300070, China.
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Thomsen RW, Knudsen JS, Kahlert J, Baggesen LM, Lajer M, Holmgaard PH, Vedin O, Ustyugova A, Sørensen HT. Cardiovascular Events, Acute Hospitalizations, and Mortality in Patients With Type 2 Diabetes Mellitus Who Initiate Empagliflozin Versus Liraglutide: A Comparative Effectiveness Study. J Am Heart Assoc 2021; 10:e019356. [PMID: 34032121 PMCID: PMC8483550 DOI: 10.1161/jaha.120.019356] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background In cardiovascular outcome trials, the sodium glucose cotransporter 2 inhibitor empagliflozin and glucagon‐like peptide‐1 (GLP‐1) receptor agonist liraglutide caused similar reductions in major adverse cardiac events (MACE). We compared clinical outcomes in routine clinical care. Methods and Results EMPLACE (Cardiovascular and Renal Outcomes, and Mortality in Danish Patients with Type 2 Diabetes Who Initiate Empagliflozin Versus GLP‐1RA: A Danish Nationwide Comparative Effectiveness Study) is an ongoing nationwide population‐based comparative effectiveness cohort study in Denmark. For the present study, we included 14 498 new users of empagliflozin and 12 706 new users of liraglutide, 2015 to 2018. Co‐primary outcomes were expanded major adverse cardiac events (stroke, myocardial infarction, unstable angina, coronary revascularization, hospitalization for heart failure [HHF], or all‐cause death); HHF or all‐cause death; and first HHF or first initiation of loop‐diuretic therapy. Secondary outcomes included all‐cause hospitalization or death. We applied propensity score balancing and Cox regression to compute adjusted hazard ratios (aHRs) in on‐treatment (OT) and intention‐to‐treat (ITT) analyses. Cohorts were well balanced at baseline (median age 61 years, 59% men, diabetes mellitus duration 6.6 years, 30% with preexisting cardiovascular disease). During mean follow‐up of 1.1 years in OT and 1.5 years in ITT analyses, empagliflozin versus liraglutide was associated with a similar rate of expanded major adverse cardiac events (OT aHR, 1.02; 95% CI, 0.91–1.14; ITT aHR, 1.06; 95% CI, 0.96–1.17), and HHF or all‐cause death (OT aHR, 0.97; 95% CI, 0.85–1.11; ITT aHR, 1.02; 95% CI, 0.91–1.14); and a decreased rate of a first incident HHF or loop‐diuretic initiation (OT aHR, 0.80; 95% CI, 0.68–0.94; ITT aHR, 0.87; 95% CI, 0.76–1.00), and of all‐cause hospitalization or death (OT aHR, 0.93; 95% CI, 0.89–0.98; ITT aHR, 0.93; 95% CI, 0.90–0.97). Conclusions Empagliflozin and liraglutide initiators had comparable rates of expanded major adverse cardiac events, and HHF or all‐cause death, whereas empagliflozin initiators had a lower rate of a first HHF or loop‐diuretic initiation.
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Affiliation(s)
- Reimar W Thomsen
- Department of Clinical Epidemiology Aarhus University Hospital Aarhus Denmark
| | - Jakob S Knudsen
- Department of Clinical Epidemiology Aarhus University Hospital Aarhus Denmark
| | - Johnny Kahlert
- Department of Clinical Epidemiology Aarhus University Hospital Aarhus Denmark
| | - Lisbeth M Baggesen
- Department of Clinical Epidemiology Aarhus University Hospital Aarhus Denmark
| | | | | | - Ola Vedin
- Boehringer Ingelheim AB Stockholm Sweden
| | | | - Henrik T Sørensen
- Department of Clinical Epidemiology Aarhus University Hospital Aarhus Denmark
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Russo G, Monami M, Perseghin G, Avogaro A, Perrone Filardi P, Senni M, Borghi C, Maggioni AP. The "Early Treatment" Approach Reducing Cardiovascular Risk in Patients with Type 2 Diabetes: A Consensus From an Expert Panel Using the Delphi Technique. Diabetes Ther 2021; 12:1445-1461. [PMID: 33768493 PMCID: PMC8099991 DOI: 10.1007/s13300-021-01045-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/02/2021] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION There is no consensus on the optimal therapeutic approach to adopt in patients with newly diagnosed type 2 diabetes mellitus (T2DM) to prevent cardiovascular disease (CVD). The study aimed to gather an expert consensus on the hypoglycemic treatment and CV risk management in patients with newly diagnosed T2DM through the Delphi methodology. METHODS To address this issue, a list of 30 statements concerning the definition of "early T2DM patient", early treatment, CV risk in T2DM, treat-to-benefit approach, and indications for treatment with glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter 2 (SGLT2) inhibitors was developed. Using a two-round Delphi methodology, the survey was distributed to 80 Italian diabetes specialists who rated their level of agreement with each statement on a 5-point Likert scale. Consensus was predefined as more than 66% of the panel agreeing/disagreeing with any given statement. RESULTS A total of 27/30 statements achieved consensus. A patient was defined as "early" according to pathophysiological or clinical interpretation, and/or the timing of the diagnosis. There was agreement on the importance to reach the lowest possible HbA1c level, since diagnosis, also using combination therapy with hypoglycemic drugs with a proven CV benefit. There was a consensus that a treat-to-benefit approach involves the addition of a glucose-lowering agent with proven CV benefits to metformin since diagnosis. The use of GLP-1RAs and SGLT2 inhibitors was considered a key strategy in this approach and the benefits were recognized also for patients with T2DM without established CVD. GLP-1RAs should be used at an earlier stage than SGLT2 inhibitors to prevent CVD, especially in patients with evidence of subclinical atherosclerotic disease. CONCLUSION This Delphi consensus recognized the importance to adopt a tailored hypoglycemic treatment of patients with T2DM according to their CVD risk and the key role of glucose-lowering agents with proven CV efficacy, GLP-1RAs and SGLT2 inhibitors, in the context of an early treat-to-benefit approach.
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Affiliation(s)
- Giuseppina Russo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
| | - Matteo Monami
- Unit of Diabetology and Metabolic Disease, Careggi Teaching Hospital and University of Florence, Florence, Italy
| | - Gianluca Perseghin
- Department of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy
| | - Angelo Avogaro
- Department of Medicine, Section of Diabetes and Metabolic Diseases, University of Padova, Padova, Italy
| | - Pasquale Perrone Filardi
- Department of Advanced Biomedical Sciences, Federico II University of Naples and Mediterranea Cardio Center Clinic of Naples, Naples, Italy
| | - Michele Senni
- Division of Cardiology, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Claudio Borghi
- Medical and Surgery Sciences Department, Dyslipidemia and Atherosclerosis Research Unit, Alma Mater Studiorum University of Bologna, Bologna, Italy
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Choudhury RP, Edgar L, Rydén M, Fisher EA. Diabetes and Metabolic Drivers of Trained Immunity. Arterioscler Thromb Vasc Biol 2021; 41:1284-1290. [PMID: 33657881 PMCID: PMC10069665 DOI: 10.1161/atvbaha.120.314211] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Accumulating evidence shows how diverse physiological functions, such as metabolism, immunity, tissue homeostasis, and hematopoiesis, are intricately and profoundly intertwined at multiple levels. This brief review will present evidence from a rapidly expanding field of immunometabolism, highlighting how cells that are relevant to processes at play in determining vascular health and disease can be programmed by changes in their metabolic environment. It will focus on how such changes can be imprinted or trained, particularly through epigenetic modifications, such that adaptations driven by metabolic signals can cause persistent changes in cell function, even after the original stimulus has been corrected or removed. Recognition of these processes and elucidation of the mechanisms underlying them stand to have far-reaching implications for the diagnosis and treatment of diabetes and related metabolic states.
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Affiliation(s)
- Robin P. Choudhury
- Radcliffe Department of Medicine, University of Oxford, United Kingdom (R.P.C., L.E.)
| | - Laurienne Edgar
- Radcliffe Department of Medicine, University of Oxford, United Kingdom (R.P.C., L.E.)
- Novo Nordisk A/S, Gatwick, United Kingdom (L.E.)
| | - Mikael Rydén
- Department of Medicine (H7), Karolinska Institute, C2-94, Karolinska University Hospital, Huddinge, Stockholm, Sweden (M.R.)
| | - Edward A. Fisher
- Department of Medicine, NYU Grossman School of Medicine, NY (E.A.F.)
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Zheng W, Li T, Wei J, Zhang Y, Zuo Q, Lin Y. Identification of miR-145 as a regulator of the cardiomyocyte inflammatory response and oxidative stress under hyperglycemia. Exp Ther Med 2021; 21:467. [PMID: 33763154 PMCID: PMC7983182 DOI: 10.3892/etm.2021.9898] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 10/23/2020] [Indexed: 12/14/2022] Open
Abstract
The current study aimed to explore the effects of microRNA (miR)-145 on the inflammatory response and oxidative stress (OS) in high glucose (HG)-induced cardiomyocytes, as well as the specific mechanism underlying this action. H9c2 cells were treated with 33 mmol/l glucose (HG group) or cotreated with 24.5 mmol/l mannitol and 5.5 mmol/l glucose (hypertonic group), and the expression levels of miR-145 and ADP ribosylation factor 6 (ARF6) were detected. The cells were transfected with pcDNA3.1-ARF6, miR-145 mimics or corresponding negative controls prior to the assessment of cell survival rate. Levels of lactate dehydrogenase (LDH), reactive oxygen species (ROS) and malondialdehyde (MDA), as well as the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and the levels of IL-6, TNF-α and monocyte chemoattractant protein-1 (MCP-1) were subsequently determined. The apoptotic rate of H9c2 cells was examined by flow cytometry. The interaction between miR-145-ARF6 was predicted and confirmed by luciferase reporter assays. In the HG group, miR-145 expression was significantly decreased and ARF6 expression significantly increased compared with controls. Furthermore, the levels of inflammatory factors (IL-6, TNF-α and MCP-1), LDH, ROS and MDA were significantly elevated in the HG group compared with controls. Significantly decreased SOD, CAT and GPx activities and significantly increased numbers of apoptotic cells were observed in the HG group compared with controls. The cells transfected with miR-145 mimics exhibited significantly decreased LDH, ROS and MDA levels, significantly increased antioxidant enzyme activities and significantly decreased apoptotic rates compared with controls, while the opposite results were observed in cells transfected with pcDNA3.1-ARF6. Moreover, co-transfection with miR-145 mimics and pcDNA3.1-ARF6 exacerbated the inflammatory response and OS injury in HG-induced cardiomyocytes compared with cells transfected with miR-145 mimics alone. Furthermore, miR-145 negatively targeted ARF6. miR-145 attenuated the HG-induced inflammatory response and OS injury in cardiomyocytes by negatively regulating ARF6, which may contribute to providing a theoretical basis for the treatment of diabetic cardiomyopathy.
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Affiliation(s)
- Wan Zheng
- Department of Cardiovascular Internal Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Tianfa Li
- Department of Cardiovascular Internal Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Junping Wei
- Department of Cardiovascular Internal Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Yuanyuan Zhang
- Department of Cardiovascular Internal Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Qi Zuo
- Department of Cardiovascular Internal Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Yun Lin
- Department of Cardiovascular Internal Medicine, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
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Matei LL, Siliste C, Vinereanu D. Modifiable Risk Factors and Atrial Fibrillation: the Quest for a Personalized Approach. MAEDICA 2021; 16:88-96. [PMID: 34221161 PMCID: PMC8224718 DOI: 10.26574/maedica.2020.16.1.88] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Background:Atrial fibrillation (AF) is the most common tachyarrhythmia, affecting up to 4% of the general population. Susceptibility to AF episodes can be explained by various risk factors (RF) that alter the substrate of the left atrium. Association between several RF and AF development and recurrence has been demonstrated in several studies. Areas of uncertainty: Treatment strategies depend on patients' characteristics and comorbidities. Medical literature and consensus documents recommend an integrated approach, but also identify evidence gaps in treating patients with severe comorbidities. Data sources: Literature search was performed using PubMed electronic database. We used the following terms as key words: atrial fibrillation, risk factors, comorbidities, primary prevention, secondary prevention. Results: Active intervention helps control the burden of AF and increase the chances of a positive outcome on the long term. Aggressive control and individualized treatment of most prevalent modifiable risk factors can reduce the risk of atrial fibrillation. Optimization of treatment strategy should be performed periodically, since RF and comorbidities are dynamic and often evolve. Conclusion:Personalized strategies should be applied to each patient after careful assessment of individual risk. A personalized approach is indicated to both reduce the burden of AF and improve symptoms, quality of life and survival. Close attention to details is required to avoid disease and therapy related complications in the presence of comorbidities.
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Affiliation(s)
| | - Calin Siliste
- "Carol Davila" University of Medicine and Pharmacy Bucharest, Romania
| | - Dragos Vinereanu
- "Carol Davila" University of Medicine and Pharmacy Bucharest, Romania
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Grover A, Sharma K, Gautam S, Gautam S, Gulati M, Singh SK. Diabetes and Its Complications: Therapies Available, Anticipated and Aspired. Curr Diabetes Rev 2021; 17:397-420. [PMID: 33143627 DOI: 10.2174/1573399816666201103144231] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/26/2020] [Accepted: 09/12/2020] [Indexed: 11/22/2022]
Abstract
Worldwide, diabetes ranks among the ten leading causes of mortality. Prevalence of diabetes is growing rapidly in low and middle income countries. It is a progressive disease leading to serious co-morbidities, which results in increased cost of treatment and over-all health system of the country. Pathophysiological alterations in Type 2 Diabetes (T2D) progressed from a simple disturbance in the functioning of the pancreas to triumvirate to ominous octet to egregious eleven to dirty dozen model. Due to complex interplay of multiple hormones in T2D, there may be multifaceted approach in its management. The 'long-term secondary complications' in uncontrolled diabetes may affect almost every organ of the body, and finally may lead to multi-organ dysfunction. Available therapies are inconsistent in maintaining long term glycemic control and their long term use may be associated with adverse effects. There is need for newer drugs, not only for glycemic control but also for prevention or mitigation of secondary microvascular and macrovascular complications. Increased knowledge of the pathophysiology of diabetes has contributed to the development of novel treatments. Several new agents like Glucagon Like Peptide - 1 (GLP-1) agonists, Dipeptidyl Peptidase IV (DPP-4) inhibitors, amylin analogues, Sodium-Glucose transport -2 (SGLT- 2) inhibitors and dual Peroxisome Proliferator-Activated Receptor (PPAR) agonists are available or will be available soon, thus extending the range of therapy for T2D, thereby preventing its long term complications. The article discusses the pathophysiology of diabetes along with its comorbidities, with a focus on existing and novel upcoming antidiabetic drugs which are under investigation. It also dives deep to deliberate upon the novel therapies that are in various stages of development. Adding new options with new mechanisms of action to the treatment armamentarium of diabetes may eventually help improve outcomes and reduce its economic burden.
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Affiliation(s)
- Anu Grover
- Ipca Laboratories, Mumbai - 400063, India
| | - Komal Sharma
- Bhupal Nobles' Institute of Pharmaceutical Sciences, Udaipur, India
| | - Suresh Gautam
- Department of Biochemistry, Pacific Institute of Medical Sciences, Udaipur, India
| | - Srishti Gautam
- Ravinder Nath Tagore Medical College and Maharana Bhupal Govt. Hospital, Udaipur, India
| | - Monica Gulati
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab- 144411, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab- 144411, India
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Dorcely B, Nitis J, Schwartzbard A, Newman JD, Goldberg IJ, Sum M. A Case Report: Euglycemic Diabetic Ketoacidosis Presenting as Chest Pain in a Patient on a Low Carbohydrate Diet. Curr Diabetes Rev 2021; 17:243-246. [PMID: 32178617 PMCID: PMC8020366 DOI: 10.2174/1573399816666200316112709] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 02/21/2020] [Accepted: 02/24/2020] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Sodium-glucose cotransporter-2 [SGLT2] inhibitors reduce cardiovascular events and mortality in patients with diabetes, particularly patients with established cardiovascular disease. Euglycemic diabetic ketoacidosis [euDKA], a complication of SGLT2 therapy, can be exacerbated by a low carbohydrate diet. CASE REPORT A 61-year-old man with a history of type 2 diabetes, taking an SGLT2 inhibitor empagliflozin 10 mg orally daily, presented to the emergency room with a 2-day history of nausea and chest pain. A week prior to presentation, he had started a ketogenic diet. He was initially admitted with a diagnosis of acute coronary syndrome. On initial assessment in the emergency room, his cardiac enzymes were normal and there were no ischemic changes in his ECG. As there was concern for unstable angina, he underwent cardiac catheterization, which showed a known total occlusion with collaterals and arteries with a non-obstructive disease without any evidence of acute plaque rupture. His baseline laboratory assessments revealed an elevated anion gap of 17, increased urinary and plasma ketones, and metabolic acidosis. His plasma glucose level was 84 mg/dL. The diagnosis of euDKA was made, and treatment with intravenous fluids and insulin was initiated. His chest pain and nausea subsequently resolved. CONCLUSION We present a case of euDKA triggered by a ketogenic diet while on SGLT2 inhibitor therapy presenting as chest pain. The recognition of euDKA is important in the context of increased SGLT2 use for the management of cardiovascular risk for patients with diabetes.
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Affiliation(s)
- Brenda Dorcely
- Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
- Address correspondence to this author at the Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA; Tel: 212-263-8077l; Fax: 212-481-1355;
| | - Juliana Nitis
- Vagelos College of Physicians and Surgeons-Columbia University, New York, NY 10032, USA
| | - Arthur Schwartzbard
- Center for Prevention of Cardiovascular Disease, New York University School of Medicine, New York, NY, 10016, USA
| | - Jonathan D. Newman
- Center for Prevention of Cardiovascular Disease, New York University School of Medicine, New York, NY, 10016, USA
| | - Ira J. Goldberg
- Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
| | - Melissa Sum
- Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
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Hecking M, Sharif A, Eller K, Jenssen T. Management of post-transplant diabetes: immunosuppression, early prevention, and novel antidiabetics. Transpl Int 2021; 34:27-48. [PMID: 33135259 PMCID: PMC7839745 DOI: 10.1111/tri.13783] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/20/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) shows a relationship with risk factors including obesity and tacrolimus-based immunosuppression, which decreases pancreatic insulin secretion. Several of the sodium-glucose-linked transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) dramatically improve outcomes of individuals with type 2 diabetes with and without chronic kidney disease, which is, as heart failure and atherosclerotic cardiovascular disease, differentially affected by both drug classes (presumably). Here, we discuss SGLT2is and GLP1-RAs in context with other PTDM management strategies, including modification of immunosuppression, active lifestyle intervention, and early postoperative insulin administration. We also review recent studies with SGLT2is in PTDM, reporting their safety and antihyperglycemic efficacy, which is moderate to low, depending on kidney function. Finally, we reference retrospective case reports with GLP1-RAs that have not brought forth major concerns, likely indicating that GLP1-RAs are ideal for PTDM patients suffering from obesity. Although our article encompasses PTDM after solid organ transplantation in general, data from kidney transplant recipients constitute the largest proportion. The PTDM research community still requires data that treating and preventing PTDM will improve clinical conditions beyond hyperglycemia. We therefore suggest that it is time to collaborate, in testing novel antidiabetics among patients of all transplant disciplines.
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Affiliation(s)
- Manfred Hecking
- Department of Internal Medicine IIIClinical Division of Nephrology & DialysisMedical University of ViennaViennaAustria
| | - Adnan Sharif
- Department of Nephrology and TransplantationQueen Elizabeth HospitalBirminghamUK
| | - Kathrin Eller
- Clinical Division of NephrologyMedical University of GrazGrazAustria
| | - Trond Jenssen
- Department of Organ TransplantationOslo University HospitalRikshospitaletOsloNorway
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Ilias I, Thomopoulos C, Michalopoulou H, Bazoukis G, Tsioufis C, Makris T. Antidiabetic drugs and blood pressure changes. Pharmacol Res 2020; 161:105108. [PMID: 32738493 DOI: 10.1016/j.phrs.2020.105108] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 05/30/2020] [Accepted: 07/24/2020] [Indexed: 12/14/2022]
Abstract
New era antidiabetic drugs are characterized by cardiovascular safety, including specific outcome benefits observed in randomized clinical trials (RCTs). It has been postulated that the favorable effects of new antidiabetic agents are related both to better control of blood pressure (BP) levels and to activation of multiple anti-atherosclerotic properties. In this review, we aimed to assess whether antidiabetic drugs have a pressor effect in glucose control and outcome-oriented RCTs, and to summarize the activated pathophysiological mechanisms relevant to BP control following the use of different antidiabetic drug classes. We also tried to determine which, if any, are the BP-lowering effects of more intense vs less intense glucose-lowering strategy irrespectively of trial antidiabetic regimen. To provide more robust results and evidence-based argumentation, a meta-analysis of placebo-controlled antidiabetic drug RCTs was undertaken to estimate the ongoing BP reduction for all considered and each separate drug class alone. This quantitative synthesis might be helpful for the clinician 1) to select or avoid the use of some classes of antidiabetic agents with a potential favorable or adverse pressor effect, respectively 2) to organize the overall drug regimen in patients with diabetes mellitus and minimize side effects because of concomitant use of drugs with established pressor effect (i.e. antihypertensive agents). This review was also organized to indicate whether BP change associated with different antidiabetic treatments may explain the specific macrovascular outcome benefits. Between all antidiabetic drugs including exogenous insulin, only sodium-glucose cotransporter 2 inhibitors produce a clinically important BP-lowering effect, but this BP reduction alone cannot explain the observed cardiovascular benefit.
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Affiliation(s)
- Ioannis Ilias
- Department of Endocrinology, Helena Venizelou Hospital, Athens, Greece
| | | | | | - George Bazoukis
- Second Department of Cardiology, Evangelismos Hospital, Athens, Greece
| | - Costas Tsioufis
- First Cardiology Clinic, Hippokration Hospital, Athens University, Athens, Greece
| | - Thomas Makris
- Department of Cardiology, Helena Venizelou Hospital, Athens, Greece
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Kobalava ZD, Kokhan EV. [Semaglutide for the Management of type 2 Diabetes: Clinical Evidence, Cardioprotective Effects, and Guidelines]. KARDIOLOGIYA 2020; 60:122-133. [PMID: 33131483 DOI: 10.18087/cardio.2020.9.n1274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 07/29/2020] [Indexed: 11/18/2022]
Abstract
Cardiovascular diseases remain a leading cause for unfavorable outcomes, including death, in patients with type 2 diabetes mellitus (DM2). In the recent decade, novel drugs, including glucagon-like peptide-1 receptor agonists (GPP-1-RA) and sodium-glucose cotransporter-2 inhibitors, have convincingly demonstrated their ability to reduce risk of cardiovascular complications in patients with DM2. This review discusses one of GPP-1-RA, semaglutide, with a special focus on the evidence-based data on its use, cardioprotective properties, and algorithms of administration consistent with current clinical recommendations.
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Affiliation(s)
- Zh D Kobalava
- Peoples' Friendship University of Russia (RUDN University), Moscow
| | - E V Kokhan
- Peoples' Friendship University of Russia (RUDN University), Moscow
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Qiu M, Ding LL, Zhang M, Lin JH, Wei XB, Huang H. GLP-1RAs and SGLT2is Reduce Cardiovascular Events Independent of Reductions of Systolic Blood Pressure and Body Weight: A Meta-Analysis with Meta-Regression. Diabetes Ther 2020; 11:2429-2440. [PMID: 32852698 PMCID: PMC7509017 DOI: 10.1007/s13300-020-00912-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION The impact of reduction of systolic blood pressure or body weight on reduction of cardiovascular events during the treatment with glucagon-like peptide 1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter 2 inhibitors (SGLT2is) for type 2 diabetes is unclear. METHODS We searched Embase and PubMed. We performed meta-analysis using hazard ratio (HR) and 95% confidence interval (CI) as effect size stratified by drug class on six endpoints of interest, which were major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), cardiovascular death (CVD), myocardial infarction (MI), stroke, and all-cause death (ACD). We performed meta-regression to assess the difference between GLP-1RAs and SGLT2is, and the impact of reduction of systolic blood pressure or body weight on reduction of cardiovascular events. RESULTS We included 11 randomized trials. Compared with placebo, SGLT2is reduced HHF by 32% (HR 0.68, 95% CI 0.60-0.76) whereas GLP-1RAs reduced HHF by only 9% (HR 0.91, 95% CI 0.83-0.99). The benefit from SGLT2is on HHF was significantly greater than that from GLP-1RAs (Psubgroup = 0.004). GLP-1RAs reduced stroke by 16% (HR 0.84, 95% CI 0.76-0.93) whereas SGLT2is did not reduce stroke (HR 0.96, 95% CI 0.82-1.12). GLP-1RAs and SGLT2is similarly reduced MACE by 12%, CVD by 15%, MI by 9%, and ACD by 13%. The effects of systolic blood pressure reduction and body weight reduction on the logarithms of HRs of GLP-1RAs or SGLT2is vs. placebo as for reducing six endpoints of interest were not statistically significant (β ranged from - 0.145 to 0.269, and P ranged from 0.211 to 0.941). CONCLUSIONS GLP-1RAs and SGLT2is lead to similar benefits on MACE, CVD, MI, and ACD in adults with type 2 diabetes. The benefit from SGLT2is on HHF is greater than that from GLP-1RAs, while GLP-1RAs vs. placebo significantly reduce stroke whereas SGLT2is do not. The two drug classes reduce cardiovascular events independent of reductions of systolic blood pressure and body weight.
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Affiliation(s)
- Mei Qiu
- Department of General Medicine, Shenzhen Longhua District Central Hospital, Shenzhen, 518110, China.
| | - Liang-Liang Ding
- Department of Endocrinology, First Affiliated Hospital of Yangtze University, Jingzhou, 434000, China
| | - Miao Zhang
- Department of Nephrology, Shenzhen Hospital of Beijing University of Chinese Medicine, Shenzhen, 518116, China
| | - Jin-Hao Lin
- Department of Gastroenterology, Shenzhen Hospital of Beijing University of Chinese Medicine, Shenzhen, 518116, China
| | - Xu-Bin Wei
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650000, China
| | - Hua Huang
- Department of Neurology, Hankou Hospital of Wuhan City, Wuhan, 430312, China
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Consoli A, Czupryniak L, Duarte R, Jermendy G, Kautzky-Willer A, Mathieu C, Melo M, Mosenzon O, Nobels F, Papanas N, Roman G, Schnell O, Sotiropoulos A, Stehouwer CDA, Tack CJ, Woo V, Fadini GP, Raz I. Positioning sulphonylureas in a modern treatment algorithm for patients with type 2 diabetes: Expert opinion from a European consensus panel. Diabetes Obes Metab 2020; 22:1705-1713. [PMID: 32476244 DOI: 10.1111/dom.14102] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/15/2020] [Accepted: 05/27/2020] [Indexed: 12/21/2022]
Abstract
The large number of pharmacological agents available to treat type 2 diabetes (T2D) makes choosing the optimal drug for any given patient a complex task. Because newer agents offer several advantages, whether and when sulphonylureas (SUs) should still be used to treat T2D is controversial. Published treatment guidelines and recommendations should govern the general approach to diabetes management. However, expert opinions can aid in better understanding local practices and in formulating individual choices. The current consensus paper aims to provide additional guidance on the use of SUs in T2D. We summarize current local treatment guidelines in European countries, showing that SUs are still widely proposed as second-line treatment after metformin and are often ranked at the same level as newer glucose-lowering medications. Strong evidence now shows that sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with low hypoglycaemia risk, promote weight loss, and exert a positive impact on vascular, cardiac and renal endpoints. Thus, using SUs in place of SGLT-2is and GLP-1RAs may deprive patients of key advantages and potentially important cardiorenal benefits. In subjects with ascertained cardiovascular disease or at very high cardiovascular risk, SGLT-2is and/or GLP-1RAs should be used as part of diabetes management, in the absence of contraindications. Routine utilization of SUs as second-line agents continues to be acceptable in resource-constrained settings.
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Affiliation(s)
| | - Leszek Czupryniak
- Department of Diabetology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Rui Duarte
- Associação Protectora dos Diabéticos de Portugal (APDP), Lisbon, Portugal
| | | | - Alexandra Kautzky-Willer
- Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Unit of Gender Medicine, Medical University of Vienna, Vienna, Austria
| | | | - Miguel Melo
- Department of Endocrinology, Diabetes and Metabolism, University and Hospital Center of Coimbra, Coimbra, Portugal
- Medical Faculty, University of Coimbra, Coimbra, Portugal
| | - Ofri Mosenzon
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Hebrew University Hospital, The Faculty of Medicine, Jerusalem, Israel
| | | | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Gabriela Roman
- "Iuliu Hatieganu" University of Medicine & Pharmacy, Clinical Centre of Diabetes, Nutrition, Metabolic Diseases, Cluj-Napoca, Romania
| | - Oliver Schnell
- Forschergruppe Diabetes e.V., Helmholtz Centre, Munich, Germany
| | | | - Coen D A Stehouwer
- Department of Internal Medicine and Cardiovascular Research Institute (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Cees J Tack
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Vincent Woo
- Section of Endocrinology and Metabolism, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | | | - Itamar Raz
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Hebrew University Hospital, The Faculty of Medicine, Jerusalem, Israel
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Choudhury RP. Transient Intermittent Hyperglycemia-Enhanced Myelopoiesis and Atherosclerosis. Circ Res 2020; 127:893-895. [DOI: 10.1161/circresaha.120.317797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Robin P. Choudhury
- From the Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, United Kingdom
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Zhu XS, Zhou HY, Yang F, Zhang HS, Ma KZ. miR-381-3p inhibits high glucose-induced vascular smooth muscle cell proliferation and migration by targeting HMGB1. J Gene Med 2020; 23:e3274. [PMID: 32902022 DOI: 10.1002/jgm.3274] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 09/02/2020] [Accepted: 09/02/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Hyperglycemia increases the risk of many cardiovascular diseases (CVD), and the dysregulation of proliferation and migration in vascular smooth muscle cells (VSMCs) also participates in the pathogenesis of CVD. miR-381-3p is known to suppress the proliferation and migration of multiple human cell types. Nevertheless, the function of miR-381-3p in VSMCs remains largely indistinct. METHODS A quantitative real-time polymerase chain reaction (qRT-PCR) was employed to investigate miR-381-3p expression in high-glucose-induced VSMCs. Inflammatory cytokines tumor necrosis factor-α, interleukin-1β and interleukin-6, as well as oxidative stress markers SOD and MDA, were determined by an enzyme-linked immunosorbent assay. Reactive oxygen species generation was examined using a 2,7'-dichlorofluorescein kit. The proliferation, migration and apoptosis of VSMCs were monitored by 3-(4,5-dimethylthiazl2-yl)-2,5-diphenyltetazolium bromide (MTT), transwell and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays. The TargetScan database (http://www.targetscan.org) was employed to seek the potential target gene of miR-381-3p. Interaction between miR-381-3p and HMGB1 was determined by a qRT-PCR, western blotting and a luciferase reporter assay. RESULTS miR-381-3p expression was significantly reduced in a VSMCs dysfunction model induced by high-glucose in a dose- and time-dependent manner. Transfection of miR-381-3p mimics suppressed the inflammation, oxidative stress, proliferation and migration of VSMCs, whereas apoptosis of VSMCs was promoted, and the transfection of miR-381-3p inhibitors had the opposite effect. Mechanistically, HMGB1, an important factor in inflammation response, was confirmed as a target gene of miR-381-3p. CONCLUSIONS miR-381-3p targets HMGB1 to suppress the inflammation, oxidative stress, proliferation and migration of high-glucose-induced VSMCs by targeting HMGB1.
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Affiliation(s)
- Xiao-Shan Zhu
- Department of Cardiology, Xiangyang Central Hospital, Affliated Hospital of Hubei College of Arts and Science, Xiangyang City, Hubei Province, 441021, China
| | - Han-Yun Zhou
- Department of Cardiology, Xiangyang Central Hospital, Affliated Hospital of Hubei College of Arts and Science, Xiangyang City, Hubei Province, 441021, China
| | - Feng Yang
- Department of Cardiology, Xiangyang Central Hospital, Affliated Hospital of Hubei College of Arts and Science, Xiangyang City, Hubei Province, 441021, China
| | - Hong-Shen Zhang
- Department of Cardiology, Xiangyang Central Hospital, Affliated Hospital of Hubei College of Arts and Science, Xiangyang City, Hubei Province, 441021, China
| | - Ke-Zhong Ma
- Department of Cardiology, Xiangyang Central Hospital, Affliated Hospital of Hubei College of Arts and Science, Xiangyang City, Hubei Province, 441021, China
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50
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Muzurović E, Mikhailidis DP. Impact of glucagon-like peptide 1 receptor agonists and sodium-glucose transport protein 2 inhibitors on blood pressure and lipid profile. Expert Opin Pharmacother 2020; 21:2125-2135. [DOI: 10.1080/14656566.2020.1795132] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Emir Muzurović
- Department of Internal Medicine, Endocrinology Section, Clinical Center of Montenegro, Podgorica, Montenegro
- University of Montenegro Faculty of Medicine, Podgorica, Montenegro
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK
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