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Mariscal M, Testai FD. Emerging Treatments for Obesity: the Role of GLP1 Receptor Agonists on Stroke. Curr Neurol Neurosci Rep 2025; 25:36. [PMID: 40397216 PMCID: PMC12095380 DOI: 10.1007/s11910-025-01423-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/01/2025] [Indexed: 05/22/2025]
Abstract
PURPOSE Stroke is a leading cause of disability and mortality worldwide. It has been estimated that more than 90% of the risk of stroke is associated with modifiable factors, including diabetes, hypertension, obesity, and heart disease. Glucagon-like peptide 1 receptor agonists (GLP1RAs) have been shown to have a beneficial effect on these major risk factors. In this review, we discuss the evidence supporting the use of GLP1RAs on brain health, particularly in relation to stroke prevention. RECENT FINDINGS The results of multiple randomized clinical trials demonstrate that, among patients with type 2 diabetes, GLP1RAs reduce body weight and improve glucose levels and lipid metabolism. In high-risk populations, GLP1RAs also reduce the risk of major adverse cardiovascular events, including all stroke and non-fatal stroke. Mechanistically, GLP1RAs have a beneficial effect on different stroke risk factors, support microvascular function, and reduce inflammation and oxidative stress. GLP1RAs are recommended for the primary prevention of stroke in patients with diabetes and elevated cardiovascular risk.
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Affiliation(s)
- Melissa Mariscal
- Neurology and Rehabilitation, University of Illinois Chicago, 912 S Wood St, Chicago, IL, 60612, USA.
| | - Fernando D Testai
- Neurology and Rehabilitation, University of Illinois Chicago, 912 S Wood St, Chicago, IL, 60612, USA
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Xia Y, Liang A, Wang M, Zhang J. Risk analysis of the association between EASIX and all-cause mortality in critical ill patients with atrial fibrillation: a retrospective study from MIMIC-IV database. Eur J Med Res 2025; 30:344. [PMID: 40301954 PMCID: PMC12039053 DOI: 10.1186/s40001-025-02621-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Accepted: 04/21/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND The Endothelial Activation and Stress Index (EASIX) is a recognized marker of vascular endothelial health but has limited application in patients with atrial fibrillation (AF). This study aimed to explore the association between EASIX and prognosis in critically ill patients with AF. METHODS The patient's data were extracted from Medical Information Mart for Intensive Care IV(MIMIC-IV) database. EASIX was calculated as lactate dehydrogenase (U/L) × creatinine (mg/dL)/platelets (109 cells/L) and log2-transformed for statistical analysis. The Boruta algorithm and Least Absolute Shrinkage and Selection Operator (Lasso) Regression were used for feature selection. Multivariable logistic regression and Cox proportional hazard models were employed to assess EASIX as a risk factor, with nonlinear relationships evaluated using restricted cubic spline curves. The area under the receiver operating characteristic curve (AUC) was utilized to compare the predictive performance of EASIX with the Sequential Organ Failure Assessment (SOFA) score and the CHA₂DS₂-VASc score. Furthermore, Kaplan-Meier survival analysis based on EASIX quartiles (with Q1 as the reference) and stratified analyses were conducted to further explore these associations. RESULTS A total of 4896 patients with complete data were included. In-hospital, 28-day, and 365-day all-cause mortality rates were26.04%, 29.25%, and 49.75%, respectively. The median EASIX was 5.64 (4.56, 6.84). Higher EASIX was significantly associated with increased in-hospital, short-term, and long-term all-cause mortality after multivariable adjustment. Patients in quartiles Q2, Q3, and Q4 had significantly higher mortality than those in Q1, showing a clear trend. Kaplan-Meier analysis confirmed that patients with higher EASIX scores had significantly lower survival. The AUC showed that the performance of EASIX in predicting both short-term and long-term all-cause mortality was comparable to the SOFA and higher than the CHA₂DS₂-VASc score. Stratified analyses indicated that the association remained robust across subgroups, accounting for various underlying conditions and hospital interventions. CONCLUSIONS EASIX is a reliable predictor of both short- and long-term mortality in critically ill patients with AF. Future prospective studies are necessary to confirm its broader applicability in other populations.
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Affiliation(s)
- Yu Xia
- Department of Burn and Trauma Medicine, First Naval Hospital of Southern Theater Command, Zhanjiang, China
| | - Anfeng Liang
- Trauma Center, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Mei Wang
- Department of Emergency Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jianlin Zhang
- Department of Emergency Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
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Chen Y, Wang L, Zhou Y, Wang Y, Qin W, Wang M, Liu B, Tian Q, Xu H, Shen H, Zheng C. Exendin-4 improves cerebral ischemia by relaxing microvessels, rapidly increasing cerebral blood flow after reperfusion. Basic Res Cardiol 2025; 120:423-441. [PMID: 40121575 DOI: 10.1007/s00395-025-01096-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: 11/19/2024] [Revised: 01/08/2025] [Accepted: 01/09/2025] [Indexed: 03/25/2025]
Abstract
Intravenous thrombolysis remains the cornerstone for restoring cerebral reperfusion post-stroke. Despite recombinant tissue plasminogen activator (rtPA) achieving arterial reperfusion within 6 h, persistent microcirculatory blood flow reduction often hampers recovery. Exendin-4, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has demonstrated potential for improving stroke outcomes, though its mechanisms remain partially unclear. This study investigated the role of Exendin-4 in restoring microcirculatory blood flow post-stroke. Using ischemic stroke models in 8-week-old male C57BL/6j mice, induced by transient middle cerebral artery occlusion or bilateral common carotid artery ligation, Exendin-4 (150 μg/kg) was administered intravenously. Infarct size and neurological deficits were evaluated using TTC staining and neurological severity scores. Real-time cerebral blood flow (CBF) and microvascular changes were measured with laser speckle imaging and two-photon microscopy. Mechanistic studies employed immunofluorescence and infrared differential interference contrast microscopy. Our findings demonstrated that Exendin-4 significantly reduced infarct size and improved neurological outcomes, independent of blood glucose levels. Immunofluorescence revealed GLP-1 receptor expression in arteriolar smooth muscle cells, endothelial cells, and pericytes. Exendin-4 enhanced microvascular blood flow via vasodilation, confirmed through real-time imaging. In vitro, Exendin-4 relaxed pre-constricted vessels, an effect that was abolished by eNOS and adenylate cyclase (AC) inhibitors. However, guanylate cyclase (GC) inhibition failed to block Exendin-4-induced vasodilation, suggesting a non-cGMP-dependent NO pathway may be involved. Furthermore, prostaglandin E2 (PGE2) signaling via EP4 receptors was identified as a critical contributor to Exendin-4's vasodilatory effect, highlighting the involvement of multiple signaling pathways. These findings suggest that Exendin-4 preserves cerebral microcirculation through a multifaceted mechanism involving GLP-1R-mediated AC-cAMP signaling, PGE2-EP4 signaling, and a non-cGMP-dependent NO pathway. This study positions GLP-1 receptor agonists as promising therapeutic candidates for enhancing cerebral microcirculation and improving outcomes following stroke.
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Affiliation(s)
- Yujie Chen
- Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Lei Wang
- Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Yutong Zhou
- Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Yuguang Wang
- Department of Orthopedics, Characteristic Medical Center of Chinese People's Armed Police Force, Tianjin, China
| | - Wei Qin
- Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Mingxiao Wang
- Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Bo Liu
- Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Qian Tian
- Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Huisen Xu
- Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Hui Shen
- Department of Cellular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
| | - Chen Zheng
- Department of Physiology, Zhuhai Campus of Zunyi Medical University, Zhuhai, Guangdong, China.
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Vear A, Heneka MT, Clemmensen C. Incretin-based therapeutics for the treatment of neurodegenerative diseases. Nat Metab 2025; 7:679-696. [PMID: 40211045 DOI: 10.1038/s42255-025-01263-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 03/06/2025] [Indexed: 04/12/2025]
Abstract
Neurodegenerative diseases (NDDs) represent a heterogeneous group of disorders characterized by progressive neuronal loss, which results in significant deficits in memory, cognition, motor skills, and sensory functions. As the prevalence of NDDs rises, there is an urgent unmet need for effective therapies. Current drug development approaches primarily target single pathological features of the disease, which could explain the limited efficacy observed in late-stage clinical trials. Originally developed for the treatment of obesity and diabetes, incretin-based therapies, particularly long-acting GLP-1 receptor (GLP-1R) agonists and GLP-1R-gastric inhibitory polypeptide receptor (GIPR) dual agonists, are emerging as promising treatments for NDDs. Despite limited conclusive preclinical evidence, their pleiotropic ability to reduce neuroinflammation, enhance neuronal energy metabolism and promote synaptic plasticity positions them as potential disease-modifying NDD interventions. In anticipation of results from larger clinical trials, continued advances in next-generation incretin mimetics offer the potential for improved brain access and enhanced neuroprotection, paving the way for incretin-based therapies as a future cornerstone in the management of NDDs.
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Affiliation(s)
- Anika Vear
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Michael T Heneka
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
- Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany
- Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Christoffer Clemmensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
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Gera A, Latif F, Borra V, Naz S, Mittal V, Ayoobkhan FS, Kumar T, Wajid Z, Deb N, Prasad T, Mattumpuram J, Jaiswal V. Efficacy of glucagon-like peptide-1 receptor agonists for prevention of stroke among patients with and without diabetes: A meta-analysis with the SELECT and FLOW trails. IJC HEART & VASCULATURE 2025; 57:101638. [PMID: 40165866 PMCID: PMC11957674 DOI: 10.1016/j.ijcha.2025.101638] [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: 08/22/2024] [Revised: 01/09/2025] [Accepted: 02/19/2025] [Indexed: 04/02/2025]
Abstract
Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown a reduction in major adverse cardiovascular events (MACE) among patients with type 2 diabetes mellitus (T2DM). However, its efficacy on cerebrovascular events is yet to be well established among diabetic and non diabetic patients. Objective We sought to evaluate the efficacy of GLP-1 RAs on stroke risk among its different types in patients with and without Diabetes. Methods We performed a systematic literature search on PubMed, EMBASE, and ClinicalTrials.gov for relevant randomized controlled trials (RCTs) from inspection until 15th July 2024, without any language restrictions. Odds ratios (OR) and 95 % confidence intervals (CI) were pooled using a random-effect model, and a p-value of < 0.05 was considered statistically significant. Results A total of 11 RCTs with 85,373 patients were included (43,339 in GLP-1 RA and 42,034 in the placebo group) in the analysis. The mean age of the patients in GLP-1 RAs and the placebo groups was 63.5 and 63.1 years, respectively. Pooled analysis of primary and secondary endpoints showed that GLP-1 RAs significantly reduced the risk of incidence of stroke by 15 % (OR, 0.85(95 %CI: 0.77-0.93), P < 0.001) and nonfatal stroke by 13 % (OR, 0.87(95 %CI: 0.79-0.95), P < 0.001) compared with placebo. However, the risk of fatal stroke (OR, 0.94(95 %CI: 0.75-1.17), P = 0.56) was comparable between both groups of patients. Similarly, the risk of serious adverse events such as cerebrovascular accident (OR, 0.75(95 %CI: 0.57-1.00), P = 0.05), hemorrhagic stroke (OR, 0.82(95 %CI: 0.42-1.60), P = 0.57, and ischemic stroke (OR, 0.85(95 %CI: 0.64-1.13), P = 0.26) was comparable between GLP-1RAs and placebo. Conclusion Treatment with GLP-1 receptor agonists has beneficial effects in reducing the risk of stroke, and nonfatal stroke in patients with and without diabetes. However, no such effect was observed for fatal stroke.
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Affiliation(s)
- Asmita Gera
- Department of Internal Medicine, Tianjin Medical University, Wuqing District, Tianjin 301700, China
| | - Fakhar Latif
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Vamsikalyan Borra
- Department of Internal Medicine, The University of Texas Rio Grande Valley, Edinburg, Texas, USA
| | - Sidra Naz
- The University of Texas, MD Anderson Cancer Center, Texas, USA
| | - Vivek Mittal
- Department of Internal Medicine, Trinity Health Oakland/Wayne State University, MI, USA
| | | | - Tushar Kumar
- Department of Cardiothoracic and Abdominal Radiology, University of Washington, Seattle, Washington, USA
| | - Zarghoona Wajid
- Hennepin Healthcare/University of Minnesota, S8, Minneapolis, MN 55415, USA
| | - Novonil Deb
- Department of Medicine, North Bengal Medical College, West Bengal, India
| | - Tanisha Prasad
- Department of Medicine, Royal College of Surgeons, Dublin, Ireland
| | - Jishanth Mattumpuram
- Division of Cardiology, University of Louisville School of Medicine, KY 40202, United States
| | - Vikash Jaiswal
- Department of Cardiovascular Research, Larkin Community Hospital, South Miami, FL, USA
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Martin SS, Aday AW, Allen NB, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Bansal N, Beaton AZ, Commodore-Mensah Y, Currie ME, Elkind MSV, Fan W, Generoso G, Gibbs BB, Heard DG, Hiremath S, Johansen MC, Kazi DS, Ko D, Leppert MH, Magnani JW, Michos ED, Mussolino ME, Parikh NI, Perman SM, Rezk-Hanna M, Roth GA, Shah NS, Springer MV, St-Onge MP, Thacker EL, Urbut SM, Van Spall HGC, Voeks JH, Whelton SP, Wong ND, Wong SS, Yaffe K, Palaniappan LP. 2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation 2025; 151:e41-e660. [PMID: 39866113 DOI: 10.1161/cir.0000000000001303] [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] [Indexed: 01/28/2025]
Abstract
BACKGROUND The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2025 AHA Statistical Update is the product of a full year's worth of effort in 2024 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. This year's edition includes a continued focus on health equity across several key domains and enhanced global data that reflect improved methods and incorporation of ≈3000 new data sources since last year's Statistical Update. RESULTS Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
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Haran K, Johnson CE, Smith P, Venable Z, Kranyak A, Bhutani T, Jeon C, Liao W. Impact of GLP-1 Receptor Agonists on Psoriasis and Cardiovascular Comorbidities: A Narrative Review. PSORIASIS (AUCKLAND, N.Z.) 2024; 14:143-152. [PMID: 39564576 PMCID: PMC11575455 DOI: 10.2147/ptt.s485061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 10/28/2024] [Indexed: 11/21/2024]
Abstract
Psoriasis is an immune-mediated skin disease known to be associated with a higher risk of cardiometabolic comorbidities such as hypertension, myocardial infarction, and stroke. GLP-1 receptor agonists (GLP-1RAs) are medications approved to treat type 2 diabetes mellitus and obesity and have been reported to improve psoriasis. As more psoriasis patients start GLP-1RAs for approved indications, it is of interest to understand the impact of GLP-1RAs on both psoriasis and associated cardiovascular risk. In this review, we examine the effect of GLP-1RAs on psoriasis and cardiovascular comorbidities-defined as hypertension, stroke, and myocardial infarction. The majority of case reports and prospective cohort studies found GLP-1RAs improved psoriasis, while two randomized controlled trials showed conflicting results. For cardiovascular disease, most studies found GLP-1RAs reduced systolic blood pressure, total stroke, and myocardial mortality. These results suggest that GLP-1RAs may be a particularly promising treatment for psoriasis patients with diabetes or obesity comorbidities, offering both cardioprotective benefits and potential improvement in psoriatic symptoms.
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Affiliation(s)
- Kathryn Haran
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Chandler E Johnson
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Payton Smith
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Zoë Venable
- Department of Dermatology, Golden State Dermatology, Berkeley, CA, USA
| | - Allison Kranyak
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Tina Bhutani
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Caleb Jeon
- Department of Dermatology, Golden State Dermatology, Berkeley, CA, USA
| | - Wilson Liao
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
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Karonova TL, Murasheva AV, Timkina NV, Fuks OS, Shlyakhto EV. Comparative study of the neuroprotective potential of semaglutide injectable preparations in experimental ischemic stroke. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2024:163-170. [DOI: 10.21518/ms2024-404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2024]
Abstract
Introduction. Stroke remains one of the major causes of death in type diabetes mellitus (DM). Injectable form of glucagon-like peptide-1 receptor agonist semaglutide, Ozempic® decreases the stroke risk. In Russia there appeared a biosimilar Semavic® but its effects on the brain are not yet studied.Aim. To compare neuroprotective properties of Semavic® and Ozempic® while used before ischemic stroke in rats without DM.Materials and methods. The study was conducted in male Wistar rats that were divided into the following groups: “Control” (n = 10) – 0.9% NaCl, “MET” (n = 9) – metformin 200 mg/kg once daily per os, “Ozempic” (n = 10) – Ozempic® 0.012 mg/kg s.c. once daily, “Semavic” (n = 9) – Semavic® 0.012 mg/kg s.c. once daily. After 7 days ischemic stroke was modelled, after 48 hour of reperfusion neurological deficit and brain damage volume were evaluated. Glycemia was measured on the 3rd, 7th days as well as during and after ischemia.Results. None of the study drugs caused hypoglycemia including in poststroke period. Neurological deficit in “MET” group did not differ from that in the “Control” (11.00 [6.50; 12.50] and 10.0 [6.25; 12.00] scores). Both semaglutide drugs caused comparable improvement in neurological status (14.00 [12.00; 18.00] and 14.00 [11.00; 18.00] scores in “Ozempic” and “Semavic” groups). Brain necrosis volume in “Control” group was 16.60 [13.40; 28.58] %. All the study drugs had infarct-limiting effect but brain damage volume in “Ozempic” (6.00 [4.32; 8.44] %) and “Semavic” (7.69 [2.99; 11.33] %) was smaller than in “MET” group (13.07 [8.67; 29.94] %). There were no differences between semaglutide drugs.Conclusions. Biosimilar Semavic® and original Ozempic® demonstrate comparable neuroprotective effect while used in animals without DM prior to ischemic stroke modelling. This protective effect is not due to the drugs’ influence on glycemic profile.
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Affiliation(s)
| | | | | | - O. S. Fuks
- Almazov National Medical Research Centre
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Warren S, McKee S, Yakiwchuk E. Geriatric Pharmacotherapy Case Series: Medications for Diabetes-A Focus on Secondary Stroke Prevention. Sr Care Pharm 2024; 39:350-359. [PMID: 39358879 DOI: 10.4140/tcp.n.2024.350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
This report addresses evidence for efficacy of diabetes medications with a focus on stroke risk reduction. The cardiovascular benefits of SGLT-2 inhibitors and GLP-1 receptor agonists have been well-established; however, clinical trials to date have examined composite cardiovascular endpoints that include, but do not specifically focus on, stroke. The purpose of this case review is to examine the evidence for the various diabetes medications in reducing the risk for stroke. This literature review was inspired by a patient seen in a geriatric day hospital program with diabetes and a history of multiple strokes. Our goal was to select a diabetes management regimen that would provide both glycemic control and stroke risk reduction. As diabetes and cerebrovascular disease commonly coexist and are important contributors to morbidity and mortality in older individuals, appropriate management must incorporate both current evidence as well as consideration for patient-specific factors that may influence the treatment plan. This patient case illustrates the importance of both.
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Affiliation(s)
- Sabrina Warren
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Shayla McKee
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Erin Yakiwchuk
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Adamou A, Barkas F, Milionis H, Ntaios G. Glucagon-like peptide-1 receptor agonists and stroke: A systematic review and meta-analysis of cardiovascular outcome trials. Int J Stroke 2024; 19:876-887. [PMID: 38676552 DOI: 10.1177/17474930241253988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2024]
Abstract
BACKGROUND In patients surviving stroke, approximately 15% and 60% exhibit concurrent diabetes mellitus and overweight/obesity, respectively, necessitating heightened secondary prevention efforts. Despite glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrating improved outcomes for those with diabetes mellitus or obesity, their underutilization persists among eligible individuals. This systematic review and meta-analysis investigated the impact of GLP-1 RAs on stroke risk. The findings aim to optimize the implementation of this therapeutic strategy in patients surviving stroke with diabetes mellitus or obesity. METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we systematically reviewed MEDLINE and Scopus until 15 November 2023. Eligible studies included randomized cardiovascular outcome trials (CVOTs) with individuals, with or without type 2 diabetes, randomized to either GLP-1 RA or placebo. The outcomes were total strokes, non-fatal strokes, and fatal strokes. Analyses were conducted using RevMan 5.4.1. RESULTS Among 1369 screened studies, 11 were eligible, encompassing 82,140 participants (34.6% women) with a cumulative follow-up of 247,596 person-years. In the GLP-1 RAs group, the stroke rate was significantly lower compared to placebo (RR: 0.85, 95% CI: 0.77-0.93; NNT: 200), showing no heterogeneity or interaction with administration frequency (daily vs weekly). In addition, the GLP-1 RAs group exhibited a significantly lower rate of non-fatal strokes compared to placebo (RR: 0.87, 95% CI: 0.79-0.95; NNT: 250), with no heterogeneity or interaction based on administration frequency, route (oral vs subcutaneous), or diabetes presence. CONCLUSION In this meta-analysis of 11 CVOTs with 82,140 participants, GLP-1 RAs demonstrated a 16% relative reduction in stroke risk compared to placebo. This finding may increase implementation of GLP-1 RAs by stroke specialists in individuals with stroke and comorbid diabetes mellitus or obesity. DATA ACCESS STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Affiliation(s)
- Anastasia Adamou
- Department of Internal Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
- First Department of Propaedeutic Internal Medicine, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Fotios Barkas
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Haralampos Milionis
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - George Ntaios
- Department of Internal Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
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11
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Yu Z, Liu X, Feng X, Zhang X, Gao R. Causal relationship between novel antidiabetic drugs and ischemic stroke: a drug-targeted Mendelian randomization study. Front Cardiovasc Med 2024; 11:1449185. [PMID: 39380626 PMCID: PMC11458414 DOI: 10.3389/fcvm.2024.1449185] [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: 06/14/2024] [Accepted: 09/11/2024] [Indexed: 10/10/2024] Open
Abstract
Background The escalating global economic burden of ischemic stroke poses a significant public health challenge amid global aging trends. The broad therapeutic efficacy of new antidiabetic drugs may offer new options in the prevention and treatment of ischemic stroke. Consistent conclusions regarding the relationship between novel antidiabetic agents and the risk of ischemic stroke remain elusive, and the causal relationship deserves further investigation. Materials and methods Three novel antidiabetic drug targets were selected, and cis-expression quantitative trait loci (cis-eQTL) were screened as instrumental variables. Genetic association data for ischemic stroke were obtained from the Genome-wide Association Study (GWAS) database. Mendelian randomization (MR) analysis, facilitated by R software, calculated MR estimates for each single nucleotide polymorphism (SNP), and meta-analysis was performed using five methods. To ensure robustness, sensitivity analyses, heterogeneity analyses, horizontal pleiotropy analyses, and co-localization analyses were conducted for significant MR associations. Results Three eQTLs for antidiabetic drug genes served as instrumental variables, utilizing a GWAS dataset comprising 34,217 cases and 406,111 controls for ischemic stroke. Genetic variants in glucagon-like peptide-1 receptor agonists (GLP-1 RA) targets exhibited a positive correlation with ischemic stroke risk (OR 1.06, 95% CI 1.04-1.08, P = 0.000), while genetic variation in dipeptidyl peptidase 4 inhibitors (DPP-4i) targets showed a negative association with ischemic stroke risk (OR 0.93, 95% CI 0.89-0.97, P = 0.003). Sensitivity analyses supported robust conclusions, revealing no heterogeneity or horizontal pleiotropy. Conclusion This study found that GLP-1 RA and DPP-4i were associated with an increased risk of ischemic stroke by MR analysis. Although sensitivity analyses provide support for this result, it contradicts previous knowledge. Therefore, the results of this study still need to treated with caution. Updated and more in-depth GWAS data and high-quality real-world data are expected to validate the results.
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Affiliation(s)
- Zongliang Yu
- Beijing University of Chinese Medicine, Beijing, China
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xinyi Liu
- Beijing University of Chinese Medicine, Beijing, China
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xue Feng
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaonan Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Rui Gao
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Симаненкова АВ, Фукс ОС, Тимкина НВ, Суфиева ДА, Кирик ОВ, Коржевский ДЭ, Власов ТД, Каронова ТЛ. [Highly selective sodium-glucose co-transporter type 2 inhibitor empagliflozin as means of brain protection in conditions of chronic brain dyscirculation]. PROBLEMY ENDOKRINOLOGII 2024; 70:44-56. [PMID: 39302864 PMCID: PMC11551795 DOI: 10.14341/probl13336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/24/2023] [Accepted: 11/28/2023] [Indexed: 09/22/2024]
Abstract
BACKGROUND Chronic brain dyscirculation is one of the frequent type 2 diabetes mellitus (DM) complications and leads to patients' disability. Sodium-glucose co-transporter type 2 inhibitors (SGLT-2i) have been proven to have advantages for cardiovascular system, but their effect on the central nervous system (CNS) has not been studied enough. AIM To study empagliflozin effect on CNS damage functional and laboratory parameters in patients with type 2 DM and, under experimental conditions, to investigate the mechanisms of the drug neurotropic effect. MATERIALS AND METHODS The clinical part of the study included patients with type 2 DM on metformin monotherapy (n=39). Patients with a target glycated hemoglobin level formed the "MET" group (n=19), in patients with a non-target glycated hemoglobin level empagliflozin was co-administered for the following 6 months (the "MET+EMPA" group, n=20). Healthy volunteers comprised the control group (n=16). The cognitive status and neuron-specific enolase (NSE) and neurofilament light chains (NLC) concentration were studied. DM was modeled in rats, thereafter the rats were treated with empagliflozin for 8 weeks. Microglia activation was assessed using anti-Iba-1 antibodies and morphological changes in neurons when stained by the Nissl method. RESULTS Both in the "MET+EMPA" and the "MET" groups cognitive deficits were observed, according to the Montreal Cognitive Assessment (MOCA) (24.0 (23.0; 27.0) and 25.0 (21.0; 27.0) points) and the Mini-Mental State Examination (MMSE) (23.75 (23.0; 27.0) and 25.0 (21.0; 27.0) points). Empagliflozin therapy led to the cognitive status normalization after 6 months (26.5 (24.0; 27.0) points according to the MOCA scale and 27.5 (24.0; 28.0) points according to the MMSE). Initially, all patients had a significant increase of NSE (3.60 (2.66; 3.76) ng/ml in the "MET" group, 3.22 (2.94; 3.54) ng/ml in the "MET+EMPA» group, 2.72 (2.13; 2.72) ng/ml in the «Control» group) and NLC (4.50 (3.31; 5.56) ng/ml in the «MET» group, 5, 25 (3.75; 6.25) ng/ml in the «MET+EMPA» group comparing with 3.50 (2.25; 3.50) ng/ml in the «Control» group). Empagliflozin therapy led to a significant decrease in NLC already after 3 months (3.80 (3.25; 3.87) ng/ml), without significant influence on the NSE level. In the experiment, DM was characterized by an increased number of activated microgliocytes and destructured neurons and a decreased number of neurons with a normal structure. Empagliflozin therapy was accompanied by a decrease in the number of immunopositive microgliocytes in the CA1 zone of the hippocampus and an increase in the number of structured neurons. CONCLUSION Type 2 diabetes mellitus is characterized by functional and biochemical changes in the central nervous system even under satisfactory glycemic control. Therapy with empagliflozin has a neuroprotective effect, manifested in an improvement in cognitive status and a decrease in NLC level. Empagliflozin reduces neuronal damage and abnormal microglial activation.
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Affiliation(s)
- А. В. Симаненкова
- Национальный медицинский исследовательский центр им. В.А. Алмазова; Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова
| | - О. С. Фукс
- Национальный медицинский исследовательский центр им. В.А. Алмазова
| | - Н. В. Тимкина
- Национальный медицинский исследовательский центр им. В.А. Алмазова; Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова
| | | | | | | | - Т. Д. Власов
- Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова
| | - Т. Л. Каронова
- Национальный медицинский исследовательский центр им. В.А. Алмазова; Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова
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13
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Stefanou MI, Theodorou A, Malhotra K, Aguiar de Sousa D, Katan M, Palaiodimou L, Katsanos AH, Koutroulou I, Lambadiari V, Lemmens R, Giannopoulos S, Alexandrov AV, Siasos G, Tsivgoulis G. Risk of major adverse cardiovascular events and stroke associated with treatment with GLP-1 or the dual GIP/GLP-1 receptor agonist tirzepatide for type 2 diabetes: A systematic review and meta-analysis. Eur Stroke J 2024; 9:530-539. [PMID: 38400569 PMCID: PMC11418422 DOI: 10.1177/23969873241234238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
INTRODUCTION Mounting evidence suggests that glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) attenuate cardiovascular-risk in type-2 diabetes (T2DM). Tirzepatide is the first-in-class, dual glucose-dependent-insulinotropic-polypeptide GIP/GLP-1 RA approved for T2DM. PATIENTS AND METHODS A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate: (i) the incidence of major adverse cardiovascular events (MACE); and (ii) incidence of stroke, fatal, and nonfatal stroke in T2DM-patients treated with GLP-1 or GIP/GLP-1 RAs (vs placebo). RESULTS Thirteen RCTs (9 and 4 on GLP-1 RAs and tirzepatide, respectively) comprising 65,878 T2DM patients were included. Compared to placebo, GLP-1RAs or GIP/GLP-1 RAs reduced MACE (OR: 0.87; 95% CI: 0.81-0.94; p < 0.01; I2 = 37%), all-cause mortality (OR: 0.88; 95% CI: 0.82-0.96; p < 0.01; I2 = 21%) and cardiovascular-mortality (OR: 0.88; 95% CI: 0.80-0.96; p < 0.01; I2 = 14%), without differences between GLP-1 versus GIP/GLP-1 RAs. Additionally, GLP-1 RAs reduced the odds of stroke (OR: 0.84; 95% CI: 0.76-0.93; p < 0.01; I2 = 0%) and nonfatal stroke (OR: 0.85; 95% CI: 0.76-0.94; p < 0.01; I2 = 0%), whereas no association between fatal stroke and GLP-1RAs was uncovered (OR: 0.80; 95% CI: 0.61-1.05; p = 0.105; I2 = 0%). In secondary analyses, GLP-1 RAs prevented ischemic stroke (OR: 0.74; 95% CI: 0.61-0.91; p < 0.01; I2 = 0%) and MACE-recurrence, but not hemorrhagic stroke (OR: 0.92; 95% CI: 0.51-1.66; p = 0.792; I2 = 0%). There was no association between GLP-1RAs or GIP/GLP-1 RAs and fatal or nonfatal myocardial infarction. DISCUSSION AND CONCLUSION GLP-1 and GIP/GLP-1 RAs reduce cardiovascular-risk and mortality in T2DM. While there is solid evidence that GLP-1 RAs significantly attenuate the risk of ischemic stroke in T2DM, dedicated RCTs are needed to evaluate the efficacy of novel GIP/GLP-1 RAs for primary and secondary stroke prevention.
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Affiliation(s)
- Maria-Ioanna Stefanou
- Second Department of Neurology, “Attikon” University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Aikaterini Theodorou
- Second Department of Neurology, “Attikon” University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Konark Malhotra
- Department of Neurology, Allegheny Health Network, Pittsburgh, PA, USA
| | - Diana Aguiar de Sousa
- Stroke Center, Centro Hospitalar Universitário Lisboa Central and Institute of Anatomy, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Mira Katan
- Department of Neurology, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Lina Palaiodimou
- Second Department of Neurology, “Attikon” University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Aristeidis H Katsanos
- Division of Neurology, McMaster University/Population Health Research Institute, Hamilton, ON, Canada
| | - Ioanna Koutroulou
- Second Department of Neurology, Aristotle University of Thessaloniki, School of Medicine, AHEPA University Hospital, Thessaloniki, Greece
| | - Vaia Lambadiari
- Second Department of Internal Medicine, “Attikon” University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Robin Lemmens
- Department of Neurology, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium
| | - Sotirios Giannopoulos
- Second Department of Neurology, “Attikon” University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Andrei V Alexandrov
- Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Gerasimos Siasos
- Third Department of Cardiology, Sotiria Thoracic Diseases General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Tsivgoulis
- Second Department of Neurology, “Attikon” University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Hastrup S, Hedegaard JN, Andersen G, Rungby J, Johnsen SP. Glucagonlike peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors in ischemic strokes with diabetes 2. Eur J Neurol 2024; 31:e16329. [PMID: 38715389 PMCID: PMC11235957 DOI: 10.1111/ene.16329] [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: 02/01/2024] [Revised: 03/30/2024] [Accepted: 04/19/2024] [Indexed: 07/07/2024]
Abstract
BACKGROUND AND PURPOSE Cardiovascular outcome trials demonstrate that glucagonlike peptide-1 receptor agonists (GLP-1RAs) reduce the risk of major adverse cardiovascular events in patients with type 2 diabetes (T2D), whereas dipeptidyl peptidase-4 inhibitors (DPP-4is) have not shown cardiovascular benefits. We compared acute ischemic stroke (AIS) with T2D treated with either a GLP-1RA or DPP-4i prior to the index stroke. METHODS This national cohort study included AIS patients with T2D from 2017 to 2020 in Denmark who were users of a GLP-1RA or DPP-4i. To be categorized as a user, we required at least 12 months of exposure and no concurrent treatment with another newer glucose-lowering medication during the last 3 months prior to the index stroke. GLP-1RA users were compared to users of DPP-4i while adjusting for the calendar year of index stroke, age, sex, comorbidity, and socioeconomic factors. RESULTS The study included 1567 AIS events with T2D; 593 were users of GLP-1RA and 974 of DPP-4i. The absolute risk of a very severe stroke was 2.4% (95% confidence interval [CI] = 1.2-3.7) in GLP-1RA users and 6.1% (95% CI = 4.6-7.7) in DPP-4i users. The corresponding adjusted risk ratio (aRR) of GLP-1RA versus DPP-4i was 0.49 (95% CI = 0.24-1.00). The aRRs of 30-day and 365-day mortality were 0.55 (95% CI = 0.32-0.94) and 0.72 (95% CI = 0.53-0.98), respectively. CONCLUSIONS The risk of a very severe stroke as well as the 30-day and 365-day poststroke mortality rates were lower among the AIS patients with comorbid T2D receiving GLP-1RA prior to the index stroke compared to those receiving DPP-4i. Hence, GLP-1RA may improve stroke outcomes in comparison with DPP-4i.
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Affiliation(s)
- Sidsel Hastrup
- Danish Stroke Centre, NeurologyAarhus University HospitalAarhusDenmark
| | - Jakob Nebeling Hedegaard
- Danish Centre for Health Services Research, Department of Clinical MedicineAalborg UniversityAalborgDenmark
| | - Grethe Andersen
- Danish Stroke Centre, NeurologyAarhus University HospitalAarhusDenmark
- Department of Clinical Medicine, HealthAarhus UniversityAarhusDenmark
| | - Jørgen Rungby
- Steno Diabetes Centre CopenhagenHerlevDenmark
- Department of EndocrinologyBispebjerg University HospitalCopenhagenDenmark
| | - Soren Paaske Johnsen
- Danish Centre for Health Services Research, Department of Clinical MedicineAalborg UniversityAalborgDenmark
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Muir RT, Smith EE. The Spectrum of Cerebral Small Vessel Disease: Emerging Pathophysiologic Constructs and Management Strategies. Neurol Clin 2024; 42:663-688. [PMID: 38937035 DOI: 10.1016/j.ncl.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2024]
Abstract
Cerebral small vessel disease (CSVD) is a spectrum of disorders that affect small arterioles, venules, cortical and leptomeningeal vessels, perivascular spaces, and the integrity of neurovascular unit, blood brain barrier, and surrounding glia and neurons. CSVD is an important cause of lacunar ischemic stroke and sporadic hemorrhagic stroke, as well as dementia-which will constitute some of the most substantive population and public health challenges over the next century. This article provides an overview of updated pathophysiologic frameworks of CSVD; discusses common and underappreciated clinical and neuroimaging manifestations of CSVD; and reviews emerging genetic risk factors linked to sporadic CSVD.
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Affiliation(s)
- Ryan T Muir
- Calgary Stroke Program, Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 1N4, Canada
| | - Eric E Smith
- Calgary Stroke Program, Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
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16
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Rajagopal D, Al Rashid S, Prasad M, Fareed M. Unveiling the Potential Role of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Offering Protection of the Cardiovascular, Renal, and Neural Systems: An Updated Narrative Review. Cureus 2024; 16:e65910. [PMID: 39219906 PMCID: PMC11365716 DOI: 10.7759/cureus.65910] [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: 06/30/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists have drawn a lot of interest lately for their therapeutic advantages over controlling blood sugar levels in the management of type 2 diabetes mellitus (T2DM). This review aims to provide an overview of the research that has been done on the neuroprotective, renoprotective, and cardioprotective effects of GLP-1 receptor agonists. Studies suggest that these medicines could provide protective benefits beyond glucose regulation, possibly reducing the risks of cardiovascular and renal issues; mechanisms underlying these advantages are still not fully understood. The review emphasizes how crucial it is to conduct more studies to determine the clinical significance and underlying mechanisms of these protective benefits. Improved knowledge of GLP-1 receptor agonists may result in T2DM treatment plans that improve neurological, cardiovascular, and renal function in addition to blood sugar control. Therefore, further research is necessary to fully understand the potential of GLP-1 receptor agonists in providing comprehensive protection against complications related to T2DM.
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Affiliation(s)
- Divya Rajagopal
- Department of Pharmacology, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, IND
| | - Sulthan Al Rashid
- Department of Pharmacology, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, IND
| | - Monisha Prasad
- Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, IND
| | - Mohammad Fareed
- Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, IND
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Mamedov M, Druk I, Arabidze G, Akhundova K. Macrovascular and microvascular complications of type 2 diabetes mellitus. RUSSIAN JOURNAL OF PREVENTIVE MEDICINE 2024; 27:94. [DOI: 10.17116/profmed20242708194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2024]
Abstract
Type 2 diabetes mellitus was declared a pandemic by the World Health Organization in the beginning of XXI century. The global prevalence of diabetes in the 20—79 age group in 2021 was 10.5% (537 million people) and may increase up to 12.2% (784 million people) in 2045. Russia is among the top ten countries in the world with a high prevalence of diabetes. Type 2 diabetes mellitus is known to be an important risk factor for atherosclerotic cardiovascular diseases such as ischemic heart disease, stroke and peripheral arterial disease. Along with this, detection and correction of microvascular complications (retinopathy, cardiac autonomic neuropathy and chronic kidney disease) are relevant tasks of clinical practice.
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Affiliation(s)
- M.N. Mamedov
- National Medical Research Center for Therapy and Preventive Medicine
| | | | - G.G. Arabidze
- Russian Medical Academy of Continuous Professional Education
| | - Kh.R. Akhundova
- National Medical Research Center for Therapy and Preventive Medicine
- Russian Medical Academy of Continuous Professional Education
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18
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Yang DR, Wang MY, Zhang CL, Wang Y. Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications. Front Endocrinol (Lausanne) 2024; 15:1359255. [PMID: 38645427 PMCID: PMC11026568 DOI: 10.3389/fendo.2024.1359255] [Citation(s) in RCA: 35] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 03/08/2024] [Indexed: 04/23/2024] Open
Abstract
Diabetic vascular complications are prevalent and severe among diabetic patients, profoundly affecting both their quality of life and long-term prospects. These complications can be classified into macrovascular and microvascular complications. Under the impact of risk factors such as elevated blood glucose, blood pressure, and cholesterol lipids, the vascular endothelium undergoes endothelial dysfunction, characterized by increased inflammation and oxidative stress, decreased NO biosynthesis, endothelial-mesenchymal transition, senescence, and even cell death. These processes will ultimately lead to macrovascular and microvascular diseases, with macrovascular diseases mainly characterized by atherosclerosis (AS) and microvascular diseases mainly characterized by thickening of the basement membrane. It further indicates a primary contributor to the elevated morbidity and mortality observed in individuals with diabetes. In this review, we will delve into the intricate mechanisms that drive endothelial dysfunction during diabetes progression and its associated vascular complications. Furthermore, we will outline various pharmacotherapies targeting diabetic endothelial dysfunction in the hope of accelerating effective therapeutic drug discovery for early control of diabetes and its vascular complications.
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Affiliation(s)
- Dong-Rong Yang
- Department of Endocrinology and Metabolism, Shenzhen University General Hospital, Shenzhen, Guangdong, China
- Department of Pathophysiology, Shenzhen University Medical School, Shenzhen, Guangdong, China
| | - Meng-Yan Wang
- Department of Pathophysiology, Shenzhen University Medical School, Shenzhen, Guangdong, China
| | - Cheng-Lin Zhang
- Department of Pathophysiology, Shenzhen University Medical School, Shenzhen, Guangdong, China
| | - Yu Wang
- Department of Endocrinology and Metabolism, Shenzhen University General Hospital, Shenzhen, Guangdong, China
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Kim JS, Lee G, Park KI, Oh SW. Comparative Effect of Glucose-Lowering Drugs for Type 2 Diabetes Mellitus on Stroke Prevention: A Systematic Review and Network Meta-Analysis. Diabetes Metab J 2024; 48:312-320. [PMID: 38273787 PMCID: PMC10995485 DOI: 10.4093/dmj.2022.0421] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 04/20/2023] [Indexed: 01/27/2024] Open
Abstract
BACKGRUOUND There is still a lack of research on which diabetic drugs are more effective in preventing stroke. Our network metaanalysis aimed to compare cerebrovascular benefits among glucose-lowering treatments. METHODS We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry for clinical trials from inception through May 25, 2021. We included both prespecified cerebrovascular outcomes and cerebrovascular events reported as severe adverse events. Subgroup analyses were conducted by stroke subtype, publication type, age of patients, baseline glycosylated hemoglobin (HbA1c), duration of type 2 diabetes mellitus, and cardiovascular risks. RESULTS Of 2,861 reports and 1,779 trials screened, 79 randomized controlled trials comprising 206,387 patients fulfilled the inclusion criteria. In the pairwise meta-analysis, the use of glucagon-like peptide-1 (GLP-1) agonist was associated with a lower risk of total stroke compared with placebo (relative risk [RR], -0.17; 95% confidence interval [CI], -0.27 to -0.07). In the network meta- analysis, only the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitor was associated with a reduction of total stroke, compared with placebo (RR, 0.81; 95% CI, 0.67 to 0.98). In the subgroup analyses, the use of SGLT-2 inhibitor and GLP-1 agonist was associated with a lower risk of stroke in those with high HbA1c (≥8.0) and low-risk of cardiovascular disease, respectively. CONCLUSION SGLT-2 inhibitors and GLP-1 agonists were shown to be beneficial for stroke prevention in patients with type 2 diabetes mellitus.
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Affiliation(s)
- Ji Soo Kim
- International Healthcare Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeongsil Lee
- Esther Formula Medical Food R&D Center, Seoul, Korea
| | - Kyung-Il Park
- Department of Neurology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea
| | - Seung-Won Oh
- Department of Family Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul National University College of Medicine, Seoul, Korea
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Vercalsteren E, Karampatsi D, Buizza C, Nyström T, Klein T, Paul G, Patrone C, Darsalia V. The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice. Cardiovasc Diabetol 2024; 23:88. [PMID: 38424560 PMCID: PMC10905950 DOI: 10.1186/s12933-024-02174-6] [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: 10/02/2023] [Accepted: 02/19/2024] [Indexed: 03/02/2024] Open
Abstract
Type-2 diabetes (T2D) worsens stroke recovery, amplifying post-stroke disabilities. Currently, there are no therapies targeting this important clinical problem. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are potent anti-diabetic drugs that also efficiently reduce cardiovascular death and heart failure. In addition, SGLT2i facilitate several processes implicated in stroke recovery. However, the potential efficacy of SGLT2i to improve stroke recovery in T2D has not been investigated. Therefore, we determined whether a post-stroke intervention with the SGLT2i Empagliflozin could improve stroke recovery in T2D mice. T2D was induced in C57BL6J mice by 8 months of high-fat diet feeding. Hereafter, animals were subjected to transient middle cerebral artery occlusion and treated with vehicle or the SGLTi Empagliflozin (10 mg/kg/day) starting from 3 days after stroke. A similar study in non diabetic mice was also conducted. Stroke recovery was assessed using the forepaw grip strength test. To identify potential mechanisms involved in the Empagliflozin-mediated effects, several metabolic parameters were assessed. Additionally, neuronal survival, neuroinflammation, neurogenesis and cerebral vascularization were analyzed using immunohistochemistry/quantitative microscopy. Empagliflozin significantly improved stroke recovery in T2D but not in non-diabetic mice. Improvement of functional recovery was associated with lowered glycemia, increased serum levels of fibroblast growth factor-21 (FGF-21), and the normalization of T2D-induced aberration of parenchymal pericyte density. The global T2D-epidemic and the fact that T2D is a major risk factor for stroke are drastically increasing the number of people in need of efficacious therapies to improve stroke recovery. Our data provide a strong incentive for the potential use of SGLT2i for the treatment of post-stroke sequelae in T2D.
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Affiliation(s)
- Ellen Vercalsteren
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83, Stockholm, Sweden.
| | - Dimitra Karampatsi
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83, Stockholm, Sweden
| | - Carolina Buizza
- Translational Neurology Group, Department of Clinical Science, Wallenberg Neuroscience Center and Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
| | - Thomas Nyström
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83, Stockholm, Sweden
| | - Thomas Klein
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Gesine Paul
- Translational Neurology Group, Department of Clinical Science, Wallenberg Neuroscience Center and Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
| | - Cesare Patrone
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83, Stockholm, Sweden.
| | - Vladimer Darsalia
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83, Stockholm, Sweden.
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21
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Sohn M, Frias JP, Lim S. Cardiovascular efficacy and safety of antidiabetic agents: A network meta-analysis of randomized controlled trials. Diabetes Obes Metab 2023; 25:3560-3577. [PMID: 37649320 DOI: 10.1111/dom.15251] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/18/2023] [Accepted: 08/03/2023] [Indexed: 09/01/2023]
Abstract
AIM An important characteristic of glucose-lowering therapies (GLTs) is their ability to prevent cardiovascular complications. We aimed to investigate the cardiorenal efficacy and general safety of GLTs. MATERIALS AND METHODS Multicentre, randomized, clinical trials that included over 100 participants comparing antidiabetic agents with a placebo or a different antidiabetic agent and reporting major adverse cardiovascular events (MACEs), or primarily reporting heart failure, were searched in the PubMed, Embase and Cochrane databases. Data were extracted independently for random-effects network meta-analyses to calculate the hazard ratio estimates. RESULTS Forty-three trials that compared nine types of GLTs were included in the present analysis. The risk of three-point MACE was reduced in the presence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and thiazolidinedione therapy compared with the placebo, dipeptidyl peptidase-4 inhibitors, or insulin therapy. GLP-1 RAs were favourable for cardiovascular and renal outcomes. SGLT-2is reduced renal outcomes by ~40%, which was superior to other GLTs. Thiazolidinedione therapy increased the risks of hospitalization for heart failure and had no benefits on mortality. Adverse events leading to drug discontinuation were higher with GLP-1 RAs and thiazolidinediones than placebo. CONCLUSIONS GLP-1 RAs, SGLT-2is and thiazolidinediones reduced three-point MACE compared with other GLTs. Each drug class had unique advantages and disadvantages.
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Affiliation(s)
- Minji Sohn
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Juan P Frias
- National Research Institute, Metro Medical Mall, Los Angeles, California, USA
| | - Soo Lim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
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22
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Lima do Vale MR, Buckner L, Mitrofan CG, Tramontt CR, Kargbo SK, Khalid A, Ashraf S, Mouti S, Dai X, Unwin D, Bohn J, Goldberg L, Golubic R, Ray S. A synthesis of pathways linking diet, metabolic risk and cardiovascular disease: a framework to guide further research and approaches to evidence-based practice. Nutr Res Rev 2023; 36:232-258. [PMID: 34839838 DOI: 10.1017/s0954422421000378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Cardiovascular disease (CVD) is the most common non-communicable disease occurring globally. Although previous literature has provided useful insights into the important role that diet plays in CVD prevention and treatment, understanding the causal role of diets is a difficult task considering inherent and introduced weaknesses of observational (e.g. not properly addressing confounders and mediators) and experimental research designs (e.g. not appropriate or well designed). In this narrative review, we organised current evidence linking diet, as well as conventional and emerging physiological risk factors, with CVD risk, incidence and mortality in a series of diagrams. The diagrams presented can aid causal inference studies as they provide a visual representation of the types of studies underlying the associations between potential risk markers/factors for CVD. This may facilitate the selection of variables to be considered and the creation of analytical models. Evidence depicted in the diagrams was systematically collected from studies included in the British Nutrition Task Force report on diet and CVD and database searches, including Medline and Embase. Although several markers and disorders linked to conventional and emerging risk factors for CVD were identified, the causal link between many remains unknown. There is a need to address the multifactorial nature of CVD and the complex interplay between conventional and emerging risk factors with natural and built environments, while bringing the life course into the spotlight.
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Affiliation(s)
| | - Luke Buckner
- NNEdPro Global Centre for Nutrition and Health, Cambridge, UK
| | | | | | | | - Ali Khalid
- NNEdPro Global Centre for Nutrition and Health, Cambridge, UK
| | - Sammyia Ashraf
- NNEdPro Global Centre for Nutrition and Health, Cambridge, UK
| | - Saad Mouti
- University of California Berkeley, Consortium for Data Analytics in Risk, Berkeley, CA, USA
| | - Xiaowu Dai
- University of California Berkeley, Consortium for Data Analytics in Risk, Berkeley, CA, USA
| | | | - Jeffrey Bohn
- University of California Berkeley, Consortium for Data Analytics in Risk, Berkeley, CA, USA
- Swiss Re Institute, Zürich, Switzerland
| | - Lisa Goldberg
- University of California Berkeley, Consortium for Data Analytics in Risk, Berkeley, CA, USA
| | - Rajna Golubic
- NNEdPro Global Centre for Nutrition and Health, Cambridge, UK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Diabetes Trials Unit, University of Oxford, Oxford, UK
| | - Sumantra Ray
- NNEdPro Global Centre for Nutrition and Health, Cambridge, UK
- University of Ulster, School of Biomedical Sciences, Coleraine, UK
- University of Cambridge, School of the Humanities and Social Sciences, Cambridge, UK
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23
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Banerjee M, Pal R, Mukhopadhyay S, Nair K. GLP-1 Receptor Agonists and Risk of Adverse Cerebrovascular Outcomes in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Clin Endocrinol Metab 2023; 108:1806-1812. [PMID: 36800286 DOI: 10.1210/clinem/dgad076] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/26/2023] [Accepted: 02/06/2023] [Indexed: 02/18/2023]
Abstract
CONTEXT The effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on ischemic/hemorrhagic stroke and transient ischemic attacks (TIA) in type 2 diabetes mellitus (T2DM) remains undetermined. OBJECTIVE To pool effects of GLP-1RAs on adverse cerebrovascular outcomes and investigate impact of baseline variables on these effects. METHODS PubMed, Embase, Web of Science, Cochrane Library, and clinical trial registry websites were searched for randomized controlled trials (RCTs) ≥24 weeks duration in adults with T2DM (PROSPERO: CRD42022331547). Adjudicated cerebrovascular events in GLP-1RA treatment vs control arms were pooled together to calculate risk ratios (RR) using fixed-effects model. Subgroup analysis was performed based on individual drugs, treatment duration, and baseline patient characteristics. Quality of evidence was assessed using GRADE framework. RESULTS We identified 28 RCTs involving 74 148 patients (57% male; median [range], age 58 [52-67] years, BMI 32 [25.4-37.2] kg/m2, T2DM duration 9 [3.5-15.4] years, treatment duration 52 [24-259] weeks). GLP-1RA use in T2DM was associated with significantly decreased risk of adverse cerebrovascular outcomes vs placebo/active comparator (RR, 0.83; 95% CI, 0.76-0.91; I2 = 0%). Pooling data from cardiovascular outcome trials (n = 8), GLP-1RA treatment vs placebo was associated with reduced risk of nonfatal stroke (RR, 0.85; 95% CI, 0.76-0.94; I2 = 0%) but not fatal stroke (RR, 0.80; 95% CI, 0.61-1.05; I2 = 0%). GLP-1RA use was associated with reduced risk of ischemic stroke (RCTs = 12; RR, 0.73; 95% CI, 0.60-0.89; I2 = 0%), composite of ischemic stroke/TIA (RCTs = 16; RR, 0.76; 95% CI, 0.65-0.90; I2 = 0%), but not hemorrhagic stroke (RCTs = 3; RR, 0.92; 95% CI, 0.51-1.64; I2 = 0%). Treatment benefits differed according to baseline eGFR and diabetes duration (P interaction < .1). Benefits were statistically significant for dulaglutide, subcutaneous/oral semaglutide (P < .05). Sensitivity analysis, excluding shorter-acting lixisenatide, eliminated the heterogeneity between individual GLP-1RA effects. CONCLUSION GLP-1RAs, particularly longer-acting formulations, reduced ischemic cerebrovascular events in T2DM. Observed benefits were significantly higher in patients with shorter T2DM duration and higher eGFR.
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Affiliation(s)
- Mainak Banerjee
- Department of Endocrinology, Institute of Post Graduate Medical Education and Research, Kolkata 700020, India
| | - Rimesh Pal
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Satinath Mukhopadhyay
- Department of Endocrinology, Institute of Post Graduate Medical Education and Research, Kolkata 700020, India
| | - Kirthana Nair
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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24
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Longo M, Di Meo I, Caruso P, Francesca Muscio M, Scappaticcio L, Maio A, Ida Maiorino M, Bellastella G, Signoriello G, Knop FK, Rosaria Rizzo M, Esposito K. Circulating levels of endothelial progenitor cells are associated with better cognitive function in older adults with glucagon-like peptide 1 receptor agonist-treated type 2 diabetes. Diabetes Res Clin Pract 2023; 200:110688. [PMID: 37116797 DOI: 10.1016/j.diabres.2023.110688] [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: 01/16/2023] [Revised: 04/12/2023] [Accepted: 04/21/2023] [Indexed: 04/30/2023]
Abstract
AIMS To evaluate cognitive function in subjects with type 2 diabetes (T2D) treated with glucagon-like peptide 1 receptor agonist (GLP-1RA) plus metformin or metformin alone and its association with endothelial progenitor cells (EPCs). METHODS Adults with T2D treated with GLP-1RA plus metformin (GLP-1RA + MET) or MET alone for at least 12 months were included. Montreal Cognitive Assessment test (MoCA), Mini-Mental State Examination (MMSE), Mini Nutritional Assessment (MNA) and disability tests were administered. Circulating levels of seven EPCs phenotypes were measured by flow cytometry. RESULTS A total of 154 elderly patients were included, of whom 78 in GLP-1RA + MET group and 76 in MET group. The GLP-1RA + MET group showed better cognitive function as indicated by a significant higher MoCA and MMSE scores, and higher levels of CD34+ CD133+, CD133+ KDR+, and CD34+ CD133+ KDR+ as compared with MET group. The number of CD34+ CD133+ KDR+ cells was an independent predictor of higher MoCA, MMSE and MNA scores. CONCLUSIONS People with T2D on GLP-1RA + MET treatment had better cognitive function and higher circulating levels of EPCs as compared with those on MET alone warranting further studies to understand the interrelationship between EPCs, GLP-RA treatment and cognitive health.
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Affiliation(s)
- Miriam Longo
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy.
| | - Irene Di Meo
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Geriatrics and Internal Medicine, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Paola Caruso
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Francesca Muscio
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Geriatrics and Internal Medicine, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Lorenzo Scappaticcio
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Antonietta Maio
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Ida Maiorino
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Bellastella
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Signoriello
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Maria Rosaria Rizzo
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Geriatrics and Internal Medicine, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Katherine Esposito
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Division of Endocrinology and Metabolic Diseases, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
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25
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Gastaldi G, Lucchini B, Thalmann S, Alder S, Laimer M, Brändle M, Wiesli P, Lehmann R. Swiss recommendations of the Society for Endocrinology and Diabetes (SGED/SSED) for the treatment of type 2 diabetes mellitus (2023). Swiss Med Wkly 2023; 153:40060. [PMID: 37011604 DOI: 10.57187/smw.2023.40060] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023] Open
Abstract
As a first step, the authors emphasise lifestyle changes (increased physical activity, stopping smoking), blood pressure control, and lowering cholesterol). The initial medical treatment should always be a combination treatment with metformin and a sodium-glucose transporter 2 (SGLT-2) inhibitor or a glucagon-like 1 peptide (GLP-1) receptor agonist. Metformin is given first and up-titrated, followed by SGLT-2 inhibitors or GLP-1 receptor agonists. In persons with type 2 diabetes, if the initial double combination is not sufficient, a triple combination (SGLT-2 inhibitor, GLP-1 receptor agonist, and metformin) is recommended. This triple combination has not been officially tested in cardiovascular outcome trials, but there is more and more real-world experience in Europe and in the USA that proves that the triple combination with metformin, SGLT-2 inhibitor, and GLP-1 receptor agonist is the best treatment to reduce 3-point MACE, total mortality, and heart failure as compared to other combinations. The treatment with sulfonylurea is no longer recommended because of its side effects and higher mortality compared to the modern treatment with SGLT-2 inhibitors and GLP-1 receptor agonists. If the triple combination is not sufficient to reduce the HbA1c to the desired target, insulin treatment is necessary. A quarter of all patients with type 2 diabetes (sometimes misdiagnosed) require insulin treatment. If insulin deficiency is the predominant factor at the outset of type 2 diabetes, the order of medications has to be reversed: insulin first and then cardio-renal protective medications (SGLT-2 inhibitors, GLP-1 receptor agonists).
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Affiliation(s)
- Giacomo Gastaldi
- Endocrinology and Diabetes, University Hospital Geneva, Geneva, Switzerland
| | - Barbara Lucchini
- Endocrinology and Diabetes, Regional Hospital Locarno, Locarno, Switzerland
| | | | | | - Markus Laimer
- Endocrinology and Diabetes, University Hospital Berne, Berne, Switzerland
| | - Michael Brändle
- Internal Medicine, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Peter Wiesli
- Internal Medicine and Endocrinology and Diabetes, Cantonal Hospital Frauenfeld, Frauenfeld, Switzerland
| | - Roger Lehmann
- Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zürich, Zürich, Switzerland
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26
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Dihoum A, Rena G, Pearson ER, Lang CC, Mordi IR. Metformin: evidence from preclinical and clinical studies for potential novel applications in cardiovascular disease. Expert Opin Investig Drugs 2023; 32:291-299. [PMID: 36972373 DOI: 10.1080/13543784.2023.2196010] [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] [Indexed: 03/29/2023]
Abstract
INTRODUCTION For a long time, metformin has been the first-line treatment for glycaemic control in type 2 diabetes, however, the results of recent cardiovascular outcome trials of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have caused many to question metformin's position in the guidelines. Although there are several plausible mechanisms by which metformin might have beneficial cardiovascular effects, for example its anti-inflammatory effects and metabolic properties, and numerous observational data suggesting improved cardiovascular outcomes with metformin use, the main randomised clinical trial data for metformin was published over 20 years ago. Nevertheless, the overwhelming majority of participants in contemporary type 2 diabetes trials were prescribed metformin. AREAS COVERED In this review we will summarise the potential mechanisms of cardiovascular benefit with metformin, before discussing clinical data in individuals with or without diabetes. EXPERT OPINION Metformin may have some cardiovascular benefit in patients with and without diabetes, however the majority of clinical trials were small and are before the use SGLT2 inhibitors and GLP1-RAs. Larger contemporary randomised trials with metformin evaluating its cardiovascular benefit are warranted.
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Affiliation(s)
- Adel Dihoum
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, United Kingdom
| | - Graham Rena
- Division of Cellular Medicine, University of Dundee, Dundee, United Kingdom
| | - Ewan R Pearson
- Division of Population Health and Genomics, University of Dundee, Dundee, United Kingdom
| | - Chim C Lang
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, United Kingdom
| | - Ify R Mordi
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, United Kingdom
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27
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Piccini S, Favacchio G, Panico C, Morenghi E, Folli F, Mazziotti G, Lania AG, Mirani M. Time-dependent effect of GLP-1 receptor agonists on cardiovascular benefits: a real-world study. Cardiovasc Diabetol 2023; 22:69. [PMID: 36966321 PMCID: PMC10039680 DOI: 10.1186/s12933-023-01800-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 03/13/2023] [Indexed: 03/27/2023] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in cardiovascular outcome trials in type 2 diabetes mellitus. However, the most convincing evidence was obtained in subjects with established cardiovascular (CV) disease. We analyzed the determinants of GLP-1 RA-mediated CV protection in a real-world population of persons with type 2 diabetes with and without a history of CV events with long-term follow-up. METHODS Retrospective cohort study of 550 individuals with type 2 diabetes (395 in primary CV prevention, 155 in secondary CV prevention), followed at a single center after the first prescription of a GLP-1 RA between 2009 and 2019. CV and metabolic outcomes were assessed. RESULTS Median duration of follow-up was 5.0 years (0.25-10.8) in primary prevention and 3.6 years (0-10.3) in secondary prevention, with a median duration of treatment of 3.2 years (0-10.8) and 2.5 years (0-10.3) respectively. In the multivariable Cox regression model considering GLP-1 RA treatment as a time-dependent covariate, in the primary prevention group, changes in BMI and glycated hemoglobin did not have an impact on MACE risk, while age at the time of GLP-1 initiation (HR 1.08, 95% CI 1.03-1.14, p = 0.001) and GLP-1 RA cessation by time (HR 3.40, 95% CI 1.82-6.32, p < 0.001) increased the risk of MACE. Regarding the secondary prevention group, only GLP-1 RA cessation by time (HR 2.71, 95% CI 1.46-5.01, p = 0.002) increased the risk of MACE. With respect to those who withdrew treatment, subjects who continued the GLP-1 RA had significantly greater weight loss and lower glycated hemoglobin levels during follow-up. CONCLUSIONS In this real-world type 2 diabetes population, discontinuation of GLP-1 RA treatment was associated to a higher risk of major cardiovascular events, in both subjects with and without a history of CV events.
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Affiliation(s)
- Sara Piccini
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
- Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Giuseppe Favacchio
- Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Cristina Panico
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
- Department of Cardiology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Emanuela Morenghi
- Biostatistic Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Franco Folli
- Endocrinology and Metabolism, Department of Health Science, Università Degli Studi di Milano, Milan, Italy
| | - Gherardo Mazziotti
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
- Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Andrea Gerardo Lania
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
- Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Marco Mirani
- Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy.
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28
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Khedagi A, Hoke C, Kelsey M, Coviello A, Jones WS, Jackson LR, Patel MR, McGarrah RW, Pagidipati NJ, Shah NP. Call to action: Understanding the differences in the use of SGLT-2 inhibitors and GLP-1 receptor agonists. Am J Prev Cardiol 2023; 13:100477. [PMID: 36915710 PMCID: PMC10006446 DOI: 10.1016/j.ajpc.2023.100477] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/14/2023] [Accepted: 02/21/2023] [Indexed: 03/05/2023] Open
Abstract
Cardiovascular disease remains one of the most prominent global health problems and has been demonstrated to disproportionally affect certain communities. Despite an increasing collective effort to improve health inequalities, a multitude of disparities continue to affect cardiovascular outcomes. Among the most prominent disparities within cardiovascular disease prevention are with the use and distribution of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. Several landmark trials have demonstrated the efficacy of these novel agents, not only in cardiovascular disease prevention among those with diabetes, but also in heart failure and chronic kidney disease. However, the use of these agents remains limited by disparities in certain racial/ethnic, sex, and socioeconomic groups. This review works to highlight and understand these differences on the use and prescribing patterns of pivotal agents in cardiovascular disease prevention, SGLT-2 inhibitors and GLP-1 agonists. Our aim is to enrich understanding and to inspire efforts to end disparities in cardiovascular morbidity and mortality due to race, sex and income inequality.
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Affiliation(s)
- Apurva Khedagi
- Department of Medicine, Duke University School of Medicine, Durham, NC
| | - Cara Hoke
- Division of Cardiology, Duke University School of Medicine, Durham, NC
| | - Michelle Kelsey
- Division of Cardiology, Duke University School of Medicine, Durham, NC
| | - Andrea Coviello
- Division of Endocrinology, Metabolism, and Nutrition, Duke University School of Medicine
| | - W. Schuyler Jones
- Division of Cardiology, Duke University School of Medicine, Durham, NC
| | - Larry R. Jackson
- Division of Cardiology, Duke University School of Medicine, Durham, NC
| | - Manesh R Patel
- Division of Cardiology, Duke University School of Medicine, Durham, NC
| | - Rob W. McGarrah
- Division of Cardiology, Duke University School of Medicine, Durham, NC
| | - Neha J Pagidipati
- Division of Cardiology, Duke University School of Medicine, Durham, NC
| | - Nishant P. Shah
- Division of Cardiology, Duke University School of Medicine, Durham, NC
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29
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Nowell J, Blunt E, Edison P. Incretin and insulin signaling as novel therapeutic targets for Alzheimer's and Parkinson's disease. Mol Psychiatry 2023; 28:217-229. [PMID: 36258018 PMCID: PMC9812772 DOI: 10.1038/s41380-022-01792-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 09/06/2022] [Accepted: 09/09/2022] [Indexed: 01/20/2023]
Abstract
Despite an ever-growing prevalence and increasing economic burden of Alzheimer's disease (AD) and Parkinson's disease (PD), recent advances in drug development have only resulted in minimally effective treatment. In AD, along with amyloid and tau phosphorylation, there is an associated increase in inflammation/glial activation, a decrease in synaptic function, an increase in astrocyte activation, and a state of insulin resistance. In PD, along with α-synuclein accumulation, there is associated inflammation, synaptic dysfunction, dopaminergic neuronal loss, and some data to suggest insulin resistance. Therapeutic strategies for neurodegenerative disorders have commonly targeted individual pathological processes. An effective treatment might require either utilization of multiple drugs which target the individual pathological processes which underlie the neurodegenerative disease or the use of a single agent which could influence multiple pathological processes. Insulin and incretins are compounds with multiple effects on neurodegenerative processes. Preclinical studies have demonstrated that GLP-1 receptor agonists reduce neuroinflammation, reduce tau phosphorylation, reduce amyloid deposition, increase synaptic function, and improve memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. Currently, phase 2 and phase 3 trials are underway in AD and PD populations. Here, we provide a comprehensive review of the therapeutic potential of incretin mimetics and insulin in AD and PD.
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Affiliation(s)
- Joseph Nowell
- grid.7445.20000 0001 2113 8111Division of Neurology, Department of Brain Sciences, Imperial College London, London, UK
| | - Eleanor Blunt
- grid.7445.20000 0001 2113 8111Division of Neurology, Department of Brain Sciences, Imperial College London, London, UK
| | - Paul Edison
- Division of Neurology, Department of Brain Sciences, Imperial College London, London, UK. .,School of Medicine, Cardiff University, Cardiff, UK.
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30
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Vergès B, Aboyans V, Angoulvant D, Boutouyrie P, Cariou B, Hyafil F, Mohammedi K, Amarenco P. Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms. Cardiovasc Diabetol 2022; 21:242. [PMID: 36380358 PMCID: PMC9667639 DOI: 10.1186/s12933-022-01686-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/18/2022] [Indexed: 11/16/2022] Open
Abstract
Several randomized controlled trials have demonstrated the benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on ischemic stroke in patients with diabetes. In this review, we summarize and discuss the potential mechanisms of stroke protection by GLP-1RAs. GLP-1RAs exert multiple anti-atherosclerotic effects contributing to stroke prevention such as enhanced plaque stability, reduced vascular smooth muscle proliferation, increased nitric oxide, and improved endothelial function. GLP-1RAs also lower the risk of stroke by reducing traditional stroke risk factors including hyperglycemia, hypertension, and dyslipidemia. Independently of these peripheral actions, GLP-1RAs show direct cerebral effects in animal stroke models, such as reduction of infarct volume, apoptosis, oxidative stress, neuroinflammation, excitotoxicity, blood-brain barrier permeability, and increased neurogenesis, neuroplasticity, angiogenesis, and brain perfusion. Despite these encouraging findings, further research is still needed to understand more thoroughly the mechanisms by which GLP-1RAs may mediate stroke protection specifically in the human diabetic brain.
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Affiliation(s)
- Bruno Vergès
- grid.5613.10000 0001 2298 9313Department of Endocrinology, Diabetes and Metabolic Disorders, Dijon University Hospital, INSERM Unit, LNC-UMR 1231, University of Burgundy, Dijon, France
| | - Victor Aboyans
- Department of Cardiology, EpiMaCT - INSERM UMR, Dupuytren University Hospital, Limoges University, 1094 & IRD 270, Limoges, France
| | - Denis Angoulvant
- EA4245 Transplantation, Immunity & Inflammation, Department of Cardiology, University of Tours, Tours University Hospital, Tours, France
| | - Pierre Boutouyrie
- Paris Cardiovascular Research CenterUMR-970Department of Pharmacology, INSERM, Georges-Pompidou European Hospital, Paris City University, Paris, France
| | - Bertrand Cariou
- grid.462318.aUniversity of Nantes, Nantes University Hospital Centre, CNRS, INSERM, L’institut du Thorax, Nantes, France
| | - Fabien Hyafil
- grid.414093.b0000 0001 2183 5849Department of Nuclear Medicine, DMU IMAGINA, Georges-Pompidou European Hospital, APHP, Paris City University, Paris, France
| | - Kamel Mohammedi
- grid.412041.20000 0001 2106 639XDepartment of Endocrinology, Diabetes, and Nutrition, University of Bordeaux, INSERM U1034, Pessac, France
| | - Pierre Amarenco
- Neurology and Stroke Center, SOS-TIA Clinic, Bichat Hospital, University of Paris, Paris, France
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Ölmestig J, Marlet IR, Vilsbøll T, Rungby J, Rostrup E, Lambertsen KL, Kruuse C. A single dose of exenatide had no effect on blood flow velocity in the middle cerebral artery in elderly healthy volunteers: Randomized, placebo-controlled, double-blind clinical trial. Front Aging Neurosci 2022; 14:899389. [PMID: 36636739 PMCID: PMC9831269 DOI: 10.3389/fnagi.2022.899389] [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: 03/18/2022] [Accepted: 07/04/2022] [Indexed: 01/26/2023] Open
Abstract
Background and aims Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RA) are widely used for the treatment of type 2 diabetes, and recent studies indicate that they may be cardio- and neuroprotective. The safety and effect of a single dose of exenatide, a short-acting GLP-1RA, on cerebral and peripheral arterial function remain unknown. Methods In this randomized, double-blind pilot trial, we assigned elderly healthy volunteers without diabetes and no previous history of stroke to receive a single dose of subcutaneous exenatide (5 μg) or placebo. Primary outcome was immediate changes over time in blood flow velocity of the middle cerebral arteries (VMCA) assessed by repeated transcranial Doppler measurements. Secondary outcomes were changes in peripheral arterial function with finger plethysmography, ankle-brachial index (ABI), and inflammatory- and endothelial-specific biomarkers. Results Healthy volunteers (13 women and 17 men) were included: (mean ± standard deviation) age: 62 ± 8 years; body weight: 79.6 ± 12.7 kg; VMCA: 65.3 ± 10.7 cm/s; fasting plasma glucose: 5.5 ± 0.5 mmol/L; HbA1c: 33.9 ± 4.1 mmol/mol (5.3 ± 0.38%). No differences between exenatide and placebo group were seen regarding VMCA (p = 0.058), systolic ABI (p = 0.71), plethysmography (p = 0.45), tumor necrosis factor (p = 0.33), interleukin-6 (p = 0.11), interleukin-1β (p = 0.34), vascular cell adhesion molecule 1 (p = 0.73), intercellular adhesion molecule 1 (p = 0.74), or E-selectin (p = 0.31). No severe adverse events were observed. Conclusion A single dose of exenatide did not change cerebral blood flow velocity or peripheral vessel function in elderly healthy volunteers. The medication was safe to use in persons without diabetes allowing us to investigate this drug further in search of the neuroprotective mechanisms. Clinical Trial Registration https://clinicaltrials.gov, Identifier NCT02838589.
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Affiliation(s)
- Joakim Ölmestig
- Neurovascular Research Unit, Department of Neurology, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ida R. Marlet
- Neurovascular Research Unit, Department of Neurology, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark
| | - Tina Vilsbøll
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark,Steno Diabetes Center Copenhagen, Copenhagen, Denmark
| | - Jørgen Rungby
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark,Department of Endocrinology, Copenhagen University Hospital – Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Egill Rostrup
- Center for Neuropsychiatric Schizophrenia Research, Copenhagen University Hospital – Mental Health Center Glostrup, Copenhagen, Denmark
| | - Kate L. Lambertsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark,Department of Neurology, Odense University Hospital, Odense, Denmark,BRIDGE – Brain Research-Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Christina Kruuse
- Neurovascular Research Unit, Department of Neurology, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark,*Correspondence: Christina Kruuse,
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32
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Trabucco Aurilio M, Maiorino MI, Mennini FS, Scappaticcio L, Longo M, Nardone C, Coppeta L, Gazzillo S, Migliorini R, Bellastella G, Giugliano D, Esposito K. Applications for social security benefits related to diabetes in the working age in Italy between 2009 and 2019: a nationwide retrospective cohort study. BMJ Open 2022; 12:e057825. [PMID: 35613811 PMCID: PMC9174764 DOI: 10.1136/bmjopen-2021-057825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVES The aim of this study is to estimate the average number of claims for social security benefits from workers with diabetes-related disability. DESIGN Nationwide retrospective cohort study. SETTING The database of the Italian Social Security Institute (INPS) was used to analyse the trends and the breakdown of all claims for social security benefit with diabetes as primary diagnosis from 2009 to 2019. PARTICIPANTS We selected all the applications with the 250.xx International Classification of Diseases, Ninth Revision-CM diagnosis code from 2009 to 2019. PRIMARY AND SECONDARY OUTCOME MEASURES The ratio between accepted or rejected claims for both ordinary incapacity benefit (OIB) and disability pension (DP) and total submitted claims over a 10-year period was computed. RESULTS From 2009 to 2019, 40 800 applications for social security benefits were filed with diabetes as the principal diagnosis, with an annual increase of 30% per year. Throughout the study decade, there was a higher rate of rejected (67.2%) than accepted (32.8%) applications. Among the accepted requests, most of them (30.7%) were recognised as OIB and the remaining 2.1% were recognised as DP. When related to the total number of claims presented per year, there was a 8.8% decrease of rejected applications, associated with a 20.6% increase of overall acceptance rate. In terms of time trends, the overall rise of submitted requests from 2009 to 2019 resulted in an increase in both rejected (+18%) and accepted (+61% for OIB, +11% for DP) applications. The higher rate of accepted requests was for workers aged 51-60 years, with 52% of admitted applications. CONCLUSIONS Between 2009 and 2019, the number of applications for social security benefits due to diabetes in Italy increased significantly, and so did the number of applications approved, mainly represented by the OIBs.
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Affiliation(s)
- Marco Trabucco Aurilio
- Office of Medical Forensic Coordination, Italian National Social Security Institute (INPS), Rome, Italy
- Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
| | - Maria Ida Maiorino
- Department of Advanced Medical and Surgical Sciences, Division of Endocrinology and Metabolic Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Francesco Saverio Mennini
- CEIS-Economic Evaluation and HTA (EEHTA), Faculty of Economics, University of Rome Tor Vergata, Rome, Italy
- Department of Accounting and Finance, Kingston University, Kingston, UK
| | - Lorenzo Scappaticcio
- Department of Advanced Medical and Surgical Sciences, Division of Endocrinology and Metabolic Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Miriam Longo
- Department of Advanced Medical and Surgical Sciences, Division of Endocrinology and Metabolic Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Claudia Nardone
- CEIS-Economic Evaluation and HTA (EEHTA), Faculty of Economics, University of Rome Tor Vergata, Rome, Italy
| | - Luca Coppeta
- Department of Occupational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Simone Gazzillo
- CEIS-Economic Evaluation and HTA (EEHTA), Faculty of Economics, University of Rome Tor Vergata, Rome, Italy
| | - Raffaele Migliorini
- Office of Medical Forensic Coordination, Italian National Social Security Institute (INPS), Rome, Italy
| | - Giuseppe Bellastella
- Department of Advanced Medical and Surgical Sciences, Division of Endocrinology and Metabolic Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Dario Giugliano
- Department of Advanced Medical and Surgical Sciences, Division of Endocrinology and Metabolic Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Katherine Esposito
- Department of Advanced Medical and Surgical Sciences, Division of Endocrinology and Metabolic Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
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33
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Strain WD, Frenkel O, James MA, Leiter LA, Rasmussen S, Rothwell PM, Sejersten Ripa M, Truelsen TC, Husain M. Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6. Stroke 2022; 53:2749-2757. [PMID: 35582947 PMCID: PMC9389936 DOI: 10.1161/strokeaha.121.037775] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
GLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.
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Affiliation(s)
- W David Strain
- University of Exeter Medical School, St Luke's Campus, United Kingdom (W.D.S., M.A.J.).,Academic Department of Healthcare for Older People, Royal Devon and Exeter NHS Foundation Trust, United Kingdom (W.D.S., M.A.J.)
| | - Ofir Frenkel
- Novo Nordisk A/S, Søborg, Denmark (O.F., S.R., M.S.R.)
| | - Martin A James
- University of Exeter Medical School, St Luke's Campus, United Kingdom (W.D.S., M.A.J.).,Academic Department of Healthcare for Older People, Royal Devon and Exeter NHS Foundation Trust, United Kingdom (W.D.S., M.A.J.)
| | - Lawrence A Leiter
- Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, ON, Canada. (L.A.L.)
| | | | - Peter M Rothwell
- Wolfson Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, United Kingdom (P.M.R.)
| | | | - Thomas C Truelsen
- Department of Neurology, University of Copenhagen, Rigshospitalet, Denmark (T.C.T.)
| | - Mansoor Husain
- Ted Rogers Centre for Heart Research, University of Toronto, ON, Canada. (M.H.)
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34
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Goldenberg RM, Cheng AYY, Fitzpatrick T, Gilbert JD, Verma S, Hopyan JJ. Benefits of GLP-1 (Glucagon-Like Peptide 1) Receptor Agonists for Stroke Reduction in Type 2 Diabetes: A Call to Action for Neurologists. Stroke 2022; 53:1813-1822. [PMID: 35259929 DOI: 10.1161/strokeaha.121.038151] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
People living with diabetes are at higher risk for stroke and have a poorer prognosis following a stroke event than those without diabetes. Data from cardiovascular outcome trials and meta-analyses indicate that GLP-1RAs (glucagon-like peptide 1 receptor agonists) reduce the risk of stroke in individuals with type 2 diabetes. Accordingly, many guidelines now recommend the addition of GLP-1RAs to ongoing antihyperglycemic regimens to lower the risk of stroke in type 2 diabetes. The current work summarizes evidence supporting the use of GLP-1RAs for stroke reduction in people with type 2 diabetes and offers 2 new resources for neurologists who are considering GLP-1RAs for their patients-a list of frequently asked questions with evidence-based answers on safely initiating and managing GLP-1RAs, and a practical decision-making algorithm to assist in using GLP-1RAs as part of a stroke reduction strategy.
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Affiliation(s)
| | - Alice Y Y Cheng
- Trillium Health Partners, St Michael's Hospital, University of Toronto, Canada (A.Y.Y.C.)
| | | | - Jeremy D Gilbert
- Sunnybrook Health Sciences Centre, University of Toronto, Canada (J.D.G.)
| | - Subodh Verma
- St Michael's Hospital, University of Toronto, Canada (S.V.)
| | - Julia J Hopyan
- Sunnybrook Health Sciences Centre, University of Toronto, Canada (J.J.H.)
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35
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Mouhammad ZA, Vohra R, Horwitz A, Thein AS, Rovelt J, Cvenkel B, Williams PA, Azuara-Blanco A, Kolko M. Glucagon-Like Peptide 1 Receptor Agonists – Potential Game Changers in the Treatment of Glaucoma? Front Neurosci 2022; 16:824054. [PMID: 35264926 PMCID: PMC8899005 DOI: 10.3389/fnins.2022.824054] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 01/10/2022] [Indexed: 12/22/2022] Open
Abstract
Glaucoma is a common ocular neurodegenerative disease characterized by the progressive loss of retinal ganglion cells and their axons. It is the most common cause of irreversible blindness. With an increasing number of glaucoma patients and disease progression despite treatment, it is paramount to develop new and effective therapeutics. Emerging new candidates are the receptor agonists of the incretin hormone glucagon-like-peptide-1 (GLP-1), originally used for the treatment of diabetes. GLP-1 receptor (GLP-1R) agonists have shown neuroprotective effects in preclinical and clinical studies on neurodegenerative diseases in both the brain (e.g., Alzheimer’s disease, Parkinson’s disease, stroke and diabetic neuropathy) and the eye (e.g., diabetic retinopathy and AMD). However, there are currently very few studies investigating the protective effects of GLP-1R agonists in the treatment of specifically glaucoma. Based on a literature search on PubMed, the Cochrane Library, and ClinicalTrials.gov, this review aims to summarize current clinical literature on GLP-1 receptor agonists in the treatment of neurodegenerative diseases to elucidate their potential in future anti-glaucomatous treatment strategies.
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Affiliation(s)
- Zaynab Ahmad Mouhammad
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Rupali Vohra
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anna Horwitz
- Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark
| | - Anna-Sophie Thein
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Jens Rovelt
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Barbara Cvenkel
- Department of Ophthalmology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Pete A. Williams
- Division of Eye and Vision, Department of Clinical Neuroscience, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | | | - Miriam Kolko
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
- Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark
- *Correspondence: Miriam Kolko,
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36
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Florentin M, Kostapanos MS, Papazafiropoulou AK. Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment. World J Diabetes 2022; 13:85-96. [PMID: 35211246 PMCID: PMC8855136 DOI: 10.4239/wjd.v13.i2.85] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/29/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
The last few years important changes have occurred in the field of diabetes treatment. The priority in the therapy of patients with diabetes is not glycemic control per se rather an overall management of risk factors, while individualization of glycemic target is suggested. Furthermore, regulatory authorities now require evidence of cardiovascular (CV) safety in order to approve new antidiabetic agents. The most novel drug classes, i.e., sodium-glucose transporter 2 inhibitors (SGLT2-i) and some glucagon-like peptide-1 receptor agonists (GLP-1 RA), have been demonstrated to reduce major adverse CV events and, thus, have a prominent position in the therapeutic algorithm of hyperglycemia. In this context, the role of previously used hypoglycemic agents, including dipeptidyl peptidase 4 (DPP-4) inhibitors, has been modified. DPP-4 inhibitors have a favorable safety profile, do not cause hypoglycemia or weight gain and do not require dose uptitration. Furthermore, they can be administered in patients with chronic kidney disease after dose modification and elderly patients with diabetes. Still, though, they have been undermined to a third line therapeutic choice as they have not been shown to reduce CV events as is the case with SGLT2-i and GLP-1 RA. Overall, DPP-4 inhibitors appear to have a place in the management of patients with diabetes as a safe class of oral glucose lowering agents with great experience in their use.
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Affiliation(s)
- Matilda Florentin
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina 45221, Greece
| | - Michael S Kostapanos
- Lipid Clinic, Department of General Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Athanasia K Papazafiropoulou
- 1st Department of Internal Medicine and Diabetes Center, Tzaneio General Hospital of Piraeus, Athens 18536, Greece
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37
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Abdel-Qadir H, Gunn M, Lega IC, Pang A, Austin PC, Singh SM, Jackevicius CA, Tu K, Dorian P, Lee DS, Ko DT. Association of Diabetes Duration and Glycemic Control With Stroke Rate in Patients With Atrial Fibrillation and Diabetes: A Population-Based Cohort Study. J Am Heart Assoc 2022; 11:e023643. [PMID: 35132863 PMCID: PMC9245806 DOI: 10.1161/jaha.121.023643] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Background There are limited data on the association of diabetes duration and glycemic control with stroke risk in atrial fibrillation (AF). Our objective was to study the association of diabetes duration and glycated hemoglobin (HbA1c) with the rate of stroke in people with diabetes and newly diagnosed AF. Methods and Results This was a population‐based cohort study using linked administrative data sets. We studied 37 209 individuals aged ≥66 years diagnosed with AF in Ontario between April 2009 and March 2019, who had diabetes diagnosed 1 to 16 years beforehand. The primary outcome was hospitalization for stroke at 1 year. Cause‐specific hazard regression was used to model the association of diabetes duration and glycated hemoglobin (HbA1c) with the rate of stroke. Restricted cubic spline analyses showed increasing hazard ratios (HR) for stroke with longer diabetes duration that plateaued after 10 years and increasing HRs for stroke with HbA1c levels >7%. Relative to patients with <5 years diabetes duration, stroke rates were significantly higher for patients with ≥10 years duration (HR, 1.45; 95% CI, 1.16–1.82; P=0.001), while diabetes duration 5 to <10 years was not significantly different. Relative to glycated hemoglobin 6% to <7%, values ≥8% were associated with higher stroke rates (HR, 1.44; 95% CI, 1.12–1.84; P=0.004), while other HbA1c categories were not significantly different. Conclusions Longer diabetes duration and higher glycated hemoglobin were associated with significantly higher stroke rates in patients with AF and diabetes. Models for stroke risk prediction and preventive care in AF may be improved by considering patients’ diabetes characteristics.
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Affiliation(s)
- Husam Abdel-Qadir
- Women's College Hospital Toronto Canada.,University Health Network Toronto Canada.,ICES (Formerly Known as the Institute for Clinical Evaluative Sciences) Toronto Canada.,Institute of Health Policy Management, and Evaluation University of Toronto Canada.,Department of Medicine University of Toronto Canada
| | - Madison Gunn
- Schulich School of Medicine Western University London ON Canada
| | - Iliana C Lega
- Women's College Hospital Toronto Canada.,ICES (Formerly Known as the Institute for Clinical Evaluative Sciences) Toronto Canada.,Department of Medicine University of Toronto Canada
| | - Andrea Pang
- ICES (Formerly Known as the Institute for Clinical Evaluative Sciences) Toronto Canada
| | - Peter C Austin
- ICES (Formerly Known as the Institute for Clinical Evaluative Sciences) Toronto Canada.,Institute of Health Policy Management, and Evaluation University of Toronto Canada
| | - Sheldon M Singh
- Department of Medicine University of Toronto Canada.,Schulich Heart Centre Sunnybrook Health Sciences Centre Toronto Canada
| | - Cynthia A Jackevicius
- University Health Network Toronto Canada.,ICES (Formerly Known as the Institute for Clinical Evaluative Sciences) Toronto Canada.,Institute of Health Policy Management, and Evaluation University of Toronto Canada.,College of Pharmacy Western University of Health Sciences Pomona CA
| | - Karen Tu
- University Health Network Toronto Canada.,Institute of Health Policy Management, and Evaluation University of Toronto Canada.,North York General Hospital Toronto Canada.,Department of Family and Community Medicine University of Toronto Canada
| | - Paul Dorian
- Department of Medicine University of Toronto Canada.,Division of Cardiology Unity Health Toronto Canada
| | - Douglas S Lee
- University Health Network Toronto Canada.,ICES (Formerly Known as the Institute for Clinical Evaluative Sciences) Toronto Canada.,Institute of Health Policy Management, and Evaluation University of Toronto Canada.,Department of Medicine University of Toronto Canada
| | - Dennis T Ko
- ICES (Formerly Known as the Institute for Clinical Evaluative Sciences) Toronto Canada.,Institute of Health Policy Management, and Evaluation University of Toronto Canada.,Department of Medicine University of Toronto Canada.,Schulich Heart Centre Sunnybrook Health Sciences Centre Toronto Canada
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38
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Bradley SA, Spring KJ, Beran RG, Chatzis D, Killingsworth MC, Bhaskar SMM. Role of diabetes in stroke: Recent advances in pathophysiology and clinical management. Diabetes Metab Res Rev 2022; 38:e3495. [PMID: 34530485 DOI: 10.1002/dmrr.3495] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/28/2021] [Accepted: 08/31/2021] [Indexed: 02/05/2023]
Abstract
The increasing prevalence of diabetes and stroke is a major global public health concern. Specifically, acute stroke patients, with pre-existing diabetes, pose a clinical challenge. It is established that diabetes is associated with a worse prognosis after acute stroke and the various biological factors that mediate poor recovery profiles in diabetic patients is unknown. The level of association and impact of diabetes, in the setting of reperfusion therapy, is yet to be determined. This article presents a comprehensive overview of the current knowledge of the role of diabetes in stroke, therapeutic strategies for primary and secondary prevention of cardiovascular disease and/or stroke in diabetes, and various therapeutic considerations that may apply during pre-stroke, acute, sub-acute and post-stroke stages. The early diagnosis of diabetes as a comorbidity for stroke, as well as tailored post-stroke management of diabetes, is pivotal to our efforts to limit the burden. Increasing awareness and involvement of neurologists in the management of diabetes and other cardiovascular risk factors is desirable towards improving stroke prevention and efficacy of reperfusion therapy in acute stroke patients with diabetes.
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Affiliation(s)
- Sian A Bradley
- University of New South Wales (UNSW), South Western Sydney Clinical School, Liverpool, New South Wales, Australia
- Neurovascular Imaging Laboratory, Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
| | - Kevin J Spring
- University of New South Wales (UNSW), South Western Sydney Clinical School, Liverpool, New South Wales, Australia
- NSW Brain Clot Bank, NSW Health Pathology, Sydney, New South Wales, Australia
- Medical Oncology Group, Liverpool Clinical School, Western Sydney University & Ingham Institute of Applied Medical Research, Sydney, New South Wales, Australia
| | - Roy G Beran
- University of New South Wales (UNSW), South Western Sydney Clinical School, Liverpool, New South Wales, Australia
- Department of Neurology and Neurophysiology, Liverpool Hospital and South Western Sydney Local Health District, Sydney, New South Wales, Australia
- Medical School, Griffith University, Southport, Queensland, Australia
- Sechenov Moscow First State University, Moscow, Russia
| | | | - Murray C Killingsworth
- University of New South Wales (UNSW), South Western Sydney Clinical School, Liverpool, New South Wales, Australia
- Neurovascular Imaging Laboratory, Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
- NSW Brain Clot Bank, NSW Health Pathology, Sydney, New South Wales, Australia
- Department of Anatomical Pathology, Correlatively Microscopy Facility, NSW Health Pathctology, Sydney, New South Wales, Australia
| | - Sonu M M Bhaskar
- University of New South Wales (UNSW), South Western Sydney Clinical School, Liverpool, New South Wales, Australia
- Neurovascular Imaging Laboratory, Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
- NSW Brain Clot Bank, NSW Health Pathology, Sydney, New South Wales, Australia
- Department of Neurology and Neurophysiology, Liverpool Hospital and South Western Sydney Local Health District, Sydney, New South Wales, Australia
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39
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Katsiki N, Fonseca V. Stroke prevention in diabetes with glucagon-like peptide-1 receptor agonists: A game-changer? J Diabetes Complications 2021; 35:108075. [PMID: 34656423 DOI: 10.1016/j.jdiacomp.2021.108075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/04/2021] [Indexed: 11/20/2022]
Affiliation(s)
- Niki Katsiki
- First Department of Internal Medicine, Diabetes Center, Division of Endocrinology and Metabolism, AHEPA University Hospital, Thessaloniki, Greece.
| | - Vivian Fonseca
- Section of Endocrinology and Metabolism, Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States of America
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40
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Cui C, Wu Z, Shi Y, Xu Z, Zhao B, Zhou D, Miao X, He C, Xu X. Sex-specific association of BMI change with stroke in middle-aged and older adults with type 2 diabetes. Nutr Metab Cardiovasc Dis 2021; 31:3095-3102. [PMID: 34511289 DOI: 10.1016/j.numecd.2021.07.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/29/2021] [Accepted: 07/13/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND AIMS We aimed to evaluate the association between BMI change and stroke in middle-aged and older adults with type 2 diabetes and identify sex differences. METHODS AND RESULTS The China Health and Retirement Longitudinal Study is an ongoing national population-based cohort study. Participants aged 45 or above with type 2 diabetes were enrolled and followed for stroke incidence. BMI change was defined as BMI at 2013-BMI at 2011. Of 1774 participants (mean [SD] age in 2011, 60.23 [8.88] years), 795 (44.8 %) were men. A total of 112 incident stroke cases were confirmed up to 2018. The incidence rate of stroke was similar between men and women (6.79 % vs 5.92 %, P = 0.516). BMI increase was independently associated with an increased stroke risk (adjusted odds ratio, 1.15; 95 % CI, 1.05-1.31) in men, while this positive association was not significant in women (adjusted odds ratio, 1.12; 95 % CI, 0.98-1.29). In addition, the positive dose-response relationship between BMI increase and stroke was observed only in men. CONCLUSION Among middle-aged and older adults with type 2 diabetes, there is a sex-specific association of BMI change with stroke. An increase in BMI could result in a higher risk of incident stroke in men.
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Affiliation(s)
- Cancan Cui
- China-Japan Union Hospital of Jilin University, Jilin University, China.
| | - Zhiyuan Wu
- School of Public Health, Capital Medical University, China; School of Medical and Health Sciences, Edith Cowan University, Perth, Australia.
| | - Yunke Shi
- School of Public Health, Capital Medical University, China.
| | - Zhonghang Xu
- China-Japan Union Hospital of Jilin University, Jilin University, China.
| | - Bing Zhao
- State Key Laboratory of Supramolecular Structure and Materials, Jilin University, China.
| | - Di Zhou
- School of Public Health, Capital Medical University, China.
| | - Xinlei Miao
- School of Public Health, Capital Medical University, China.
| | - Chengyan He
- China-Japan Union Hospital of Jilin University, Jilin University, China.
| | - Xuesong Xu
- China-Japan Union Hospital of Jilin University, Jilin University, China.
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Maiorino MI, Longo M, Scappaticcio L, Bellastella G, Chiodini P, Esposito K, Giugliano D. Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression. Cardiovasc Diabetol 2021; 20:210. [PMID: 34663316 PMCID: PMC8522255 DOI: 10.1186/s12933-021-01401-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/09/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. METHODS An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. RESULTS The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P < 0.001), with significant heterogeneity between studies (I2 = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta = - 0.298, P = 0.007), with significant heterogeneity (I2 = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta = - 0.531, R2 = 100%), without heterogeneity (I2 = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death. CONCLUSIONS The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R2 = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.
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Affiliation(s)
- Maria Ida Maiorino
- Diabetes Unit, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.
| | - Miriam Longo
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Lorenzo Scappaticcio
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Giuseppe Bellastella
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Paolo Chiodini
- Medical Statistics Unit, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Katherine Esposito
- Diabetes Unit, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Dario Giugliano
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
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Penlioglou T, Stoian AP, Papanas N. Diabetes, Vascular Aging and Stroke: Old Dogs, New Tricks? J Clin Med 2021; 10:jcm10194620. [PMID: 34640636 PMCID: PMC8509285 DOI: 10.3390/jcm10194620] [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: 07/22/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Stroke remains a leading cause of death and disability throughout the world. It is well established that Diabetes Mellitus (DM) is a risk factor for stroke, while other risk factors include dyslipidaemia and hypertension. Given that the global prevalence of diabetes steadily increases, the need for adequate glycaemic control and prevention of DM-related cardiovascular events remains a challenge for the medical community. Therefore, a re-examination of the latest data related to this issue is of particular importance. OBJECTIVE This review aims to summarise the latest data on the relationship between DM and stroke, including epidemiology, risk factors, pathogenesis, prevention and biomarkers. METHODS For this purpose, comprehensive research was performed on the platforms PubMed, Google Scholar and EMBASE with a combination of the following keywords: diabetes mellitus, stroke, macrovascular complications, diabetic stroke, cardiovascular disease. CONCLUSIONS Much progress has been made in stroke in people with DM in terms of prevention and early diagnosis. In the field of prevention, the adaptation of the daily habits and the regulation of co-morbidity of individuals play a particularly important role. Simultaneously, the most significant revolution has been brought by the relatively new treatment options that offer protection to the cardiovascular system. Moreover, many prognostic and diagnostic biomarkers have been identified, paving the way for early and accurate diagnoses. However, to date, there are crucial points that remain controversial and need further clarification.
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Affiliation(s)
- Theano Penlioglou
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, 68132 Alexandroupolis, Greece;
| | - Anca Pantea Stoian
- Diabetes, Nutrition and Metabolic Diseases Department, “Carol Davila” University of Medicine, 020021 Bucharest, Romania;
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, 68132 Alexandroupolis, Greece;
- Correspondence: ; Fax: +30-25513-51723
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43
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Giugliano D, Scappaticcio L, Longo M, Caruso P, Maiorino MI, Bellastella G, Ceriello A, Chiodini P, Esposito K. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs. Cardiovasc Diabetol 2021; 20:189. [PMID: 34526024 PMCID: PMC8442438 DOI: 10.1186/s12933-021-01366-8] [Citation(s) in RCA: 144] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/19/2021] [Indexed: 12/11/2022] Open
Abstract
Background A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). Methods We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease). Results GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79–0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67–0.82, P < 0.001). Conclusions GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.
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Affiliation(s)
- Dario Giugliano
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. .,PHD Program of Translational Medicine, Department Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
| | - Lorenzo Scappaticcio
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.,PHD Program of Translational Medicine, Department Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Miriam Longo
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.,PHD Program of Translational Medicine, Department Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Paola Caruso
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.,PHD Program of Translational Medicine, Department Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Ida Maiorino
- Diabetes Unit, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Bellastella
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Paolo Chiodini
- Medical Statistics Unit, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Katherine Esposito
- PHD Program of Translational Medicine, Department Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.,Diabetes Unit, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
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44
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Lee M, Ovbiagele B, Saver JL. Intensive Medical Management to Prevent Large and Small Artery Atherothrombotic Stroke: Time to Expand the Horizon. JAMA 2021; 326:217-218. [PMID: 34196657 DOI: 10.1001/jama.2021.9917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Meng Lee
- Department of Neurology, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi, Taiwan
| | - Bruce Ovbiagele
- Department of Neurology, University of California, San Francisco, San Francisco
| | - Jeffrey L Saver
- Department of Neurology and Stroke Center, University of California, Los Angeles, Los Angeles
- Associate Editor, JAMA
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45
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Benn M, Emanuelsson F, Tybjærg-Hansen A, Nordestgaard BG. Impact of high glucose levels and glucose lowering on risk of ischaemic stroke: a Mendelian randomisation study and meta-analysis. Diabetologia 2021; 64:1492-1503. [PMID: 33765180 DOI: 10.1007/s00125-021-05436-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 01/26/2021] [Indexed: 10/21/2022]
Abstract
AIMS/HYPOTHESIS It is unclear whether glucose per se has a causal impact on risk of stroke and whether glucose-lowering drugs reduce this risk. This is important for the choice of treatment for individuals at risk. We tested the hypotheses that high plasma glucose has a causal impact on increased risk of ischaemic stroke, and that glucose-lowering drugs reduce this risk. METHODS Using a Mendelian randomisation design, we examined 118,838 individuals from two Copenhagen cohorts, the Copenhagen General Population Study and the Copenhagen City Heart Study, and 440,328 individuals from the MEGASTROKE study. Effects of eight glucose-lowering drugs on risk of stroke were summarised by meta-analyses. RESULTS In genetic, causal analyses, a 1 mmol/l higher plasma glucose had a risk ratio of 1.48 (95% CI 1.04, 2.11) for ischaemic stroke in the Copenhagen studies. The corresponding risk ratio from the MEGASTROKE study combined with the Copenhagen studies was 1.74 (1.31, 2.18). In meta-analyses of glucose-lowering drugs, the risk ratio for stroke was 0.85 (0.77, 0.94) for glucagon-like peptide-1 receptor agonists and 0.82 (0.69, 0.98) for thiazolidinediones, while sulfonylureas, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors, α-glucosidase inhibitors, meglitinides and metformin individually lacked statistical evidence of an effect on stroke risk. CONCLUSIONS/INTERPRETATION Genetically high plasma glucose has a causal impact on increased risk of ischaemic stroke. Treatment with glucose-lowering glucagon-like peptide-1 receptor agonists and thiazolidinediones reduces this risk. These results may guide clinicians in the treatment of individuals at high risk of ischaemic stroke.
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Affiliation(s)
- Marianne Benn
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
- The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
- Faculty of Health and Medical Sciences, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
| | - Frida Emanuelsson
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Anne Tybjærg-Hansen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | - Børge G Nordestgaard
- The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
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46
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Augestad IL, Dekens D, Karampatsi D, Elabi O, Zabala A, Pintana H, Larsson M, Nyström T, Paul G, Darsalia V, Patrone C. Normalisation of glucose metabolism by exendin-4 in the chronic phase after stroke promotes functional recovery in male diabetic mice. Br J Pharmacol 2021; 179:677-694. [PMID: 33973246 PMCID: PMC8820185 DOI: 10.1111/bph.15524] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/30/2021] [Accepted: 04/27/2021] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND AND PURPOSE Glucagon-like peptide-1 (GLP-1) receptor activation decreases stroke risk in people with Type 2 diabetes (T2D), while animal studies have shown the efficacy of this strategy to counteract stroke-induced acute brain damage. However, whether GLP-1 receptor activation also improves recovery in the chronic phase after stroke is unknown. We investigated whether post-acute, chronic administration of the GLP-1 receptor agonist, exendin-4, improves post-stroke recovery and examined possible underlying mechanisms in T2D and non-T2D mice. EXPERIMENTAL APPROACH We induced stroke via transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (8 months of high-fat diet) and age-matched controls. Exendin-4 was administered for 8 weeks from Day 3 post-tMCAO. We assessed functional recovery by weekly upper-limb grip strength tests. Insulin sensitivity and glycaemia were evaluated at 4 and 8 weeks post-tMCAO. Neuronal survival, stroke-induced neurogenesis, neuroinflammation, atrophy of GABAergic parvalbumin+ interneurons, post-stroke vascular remodelling and fibrotic scar formation were investigated by immunohistochemistry. KEY RESULTS Exendin-4 normalised T2D-induced impairment of forepaw grip strength recovery in correlation with normalised glycaemia and insulin sensitivity. Moreover, exendin-4 counteracted T2D-induced atrophy of parvalbumin+ interneurons and decreased microglia activation. Finally, exendin-4 normalised density and pericyte coverage of micro-vessels and restored fibrotic scar formation in T2D mice. In non-T2D mice, the exendin-4-mediated recovery was minor. CONCLUSION AND IMPLICATIONS Chronic GLP-1 receptor activation mediates post-stroke functional recovery in T2D mice by normalising glucose metabolism and improving neuroplasticity and vascular remodelling in the recovery phase. The results warrant clinical trial of GLP-1 receptor agonists for rehabilitation after stroke in T2D.
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Affiliation(s)
- Ingrid Lovise Augestad
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Doortje Dekens
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Dimitra Karampatsi
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Osama Elabi
- Translational Neurology Group, Department of Clinical Sciences, Wallenberg Neuroscience Center, Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
| | - Alexander Zabala
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Hiranya Pintana
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Martin Larsson
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Thomas Nyström
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Gesine Paul
- Translational Neurology Group, Department of Clinical Sciences, Wallenberg Neuroscience Center, Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
| | - Vladimer Darsalia
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Cesare Patrone
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
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47
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Diener HC, Nickenig G. [Secondary stroke prevention after TIA or ischemic stroke]. Herz 2021; 46:293-302. [PMID: 33914089 DOI: 10.1007/s00059-021-05035-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/25/2021] [Indexed: 10/21/2022]
Abstract
Stroke is one of the main causes of mortality and permanent disability. Secondary prevention of stroke recurrence therefore has a high priority. Secondary prevention of ischemic stroke includes optimization of the lifestyle and diet, treatment of risk factors, such as hypertension, diabetes mellitus and hyperlipidemia, prophylaxis of recurrence with antiplatelet treatment in patients with high vascular risk and anticoagulation in atrial fibrillation. In addition, secondary prevention includes carotid surgery or stenting in selected symptomatic patients and closure of a patent foramen ovale after cryptogenic stroke.
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Affiliation(s)
- Hans Christoph Diener
- Institut für Medizinische Informatik, Biometrie und Epidemiologie (IMIBE), Medizinische Fakultät, Universität Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Deutschland.
| | - Georg Nickenig
- Herzzentrum, Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Bonn, Deutschland
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48
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McLean BA, Wong CK, Campbell JE, Hodson DJ, Trapp S, Drucker DJ. Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation. Endocr Rev 2021; 42:101-132. [PMID: 33320179 PMCID: PMC7958144 DOI: 10.1210/endrev/bnaa032] [Citation(s) in RCA: 166] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Indexed: 02/06/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection of the GLP-1R is technically challenging, highly method dependent, and subject to misinterpretation. Here we revisit the actions of GLP-1, scrutinizing key concepts supporting gut vs extra-intestinal GLP-1 synthesis and secretion. We discuss new insights refining cellular localization of GLP-1R expression and integrate recent data to refine our understanding of how and where GLP-1 acts to control inflammation, cardiovascular function, islet hormone secretion, gastric emptying, appetite, and body weight. These findings update our knowledge of cell types and mechanisms linking endogenous vs pharmacological GLP-1 action to activation of the canonical GLP-1R, and the control of metabolic activity in multiple organs.
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Affiliation(s)
- Brent A McLean
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada
| | - Chi Kin Wong
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada
| | - Jonathan E Campbell
- The Department of Medicine, Division of Endocrinology, Department of Pharmacology and Cancer Biology, Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - David J Hodson
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, and Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | - Stefan Trapp
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, UCL, London, UK
| | - Daniel J Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada
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Ferrari F, Moretti A, Villa RF. The treament of hyperglycemia in acute ischemic stroke with incretin-based drugs. Pharmacol Res 2020; 160:105018. [PMID: 32574826 DOI: 10.1016/j.phrs.2020.105018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/21/2020] [Accepted: 06/10/2020] [Indexed: 12/14/2022]
Abstract
Stroke is a major cause of mortality and morbidity worldwide. Considerable experimental and clinical evidence suggests that both diabetes mellitus (DM) and post-stroke hyperglycemia are associated with increased mortality rate and worsened clinical conditions in acute ischemic stroke (AIS) patients. Insulin treatment does not seem to provide convincing benefits for these patients, therefore prompting a change of strategy. The selective agonists of Glucagon-Like Peptide-1 Receptors (GLP-1Ras) and the Inhibitors of Dipeptidyl Peptidase-IV (DPP-IVIs, gliptins) are two newer classes of glucose-lowering drugs used for the treatment of DM. This review examines in detail the rationale for their development and the physicochemical, pharmacokinetic and pharmacodynamic properties and clinical activities. Emphasis will be placed on their neuroprotective effects at cellular and molecular levels in experimental models of acute cerebral ischemia. In perspective, an adequate basis does exist for a novel therapeutic approach to hyperglycemia in AIS patients through the additive treatment with GLP-1Ras plus DPP-IVIs.
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Affiliation(s)
- Federica Ferrari
- Department of Advanced Diagnostic and Therapeutic Technologies, Section of Neuroradiology, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy; Departments of Biology-Biotechnology and Chemistry, Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy
| | - Antonio Moretti
- Departments of Biology-Biotechnology and Chemistry, Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy
| | - Roberto Federico Villa
- Departments of Biology-Biotechnology and Chemistry, Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy.
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50
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Giugliano D, Longo M, Maiorino MI, Bellastella G, Chiodini P, Solerte SB, Esposito K. Efficacy of SGLT-2 inhibitors in older adults with diabetes: Systematic review with meta-analysis of cardiovascular outcome trials. Diabetes Res Clin Pract 2020; 162:108114. [PMID: 32165164 DOI: 10.1016/j.diabres.2020.108114] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/03/2020] [Accepted: 03/05/2020] [Indexed: 12/13/2022]
Abstract
AIMS Sodium-glucose cotransporter-2 inhibitors (gliflozins) and statins are oral drugs that may have beneficial cardiovascular effects in patients with type 2 diabetes, especially in those with known cardiovascular disease. We planned a systematic review and meta-analysis of cardiovascular outcome trials (CVOTs) that evaluated the effect of gliflozins on MACE risk in patients with T2D stratified by age and by statin use. METHODS The electronic search was carried out until 20 January 2020. RCTs were included if they were CVOTs performed in adults with T2D, compared add-on therapy with any gliflozin versus placebo, and had major cardiovascular events (MACE) as primary outcome. We limited the evaluation to MACE in order to minimize the statistical impact of post-hoc analyses. We used a random-effect model to calculate hazard ratio (HR) and 95% CI. RESULTS The hazard ratio for MACE was 0.95 (95% CI, 0.86-1.05) in people <65 years and 0.83 (95% CI, 0.71-0.96) for people ≥65 years, with no subgroup differences (P-value = 0.15), suggesting that the effect was consistent across age categories. The hazard ratio for MACE was 0.87 (95% CI, 0.81-0.94) in people taking a statin and 0.88 (95% CI, 0.77-1.01) for people not taking statin, with no subgroup differences (P-value = 0.90). CONCLUSIONS The results are reassuring, as they confirm that the efficacy profile of gliflozins is unchanged by age, and may further enhance the CV protection offered by statin.
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Affiliation(s)
- Dario Giugliano
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, Università della Campania Luigi Vanvitelli, Naples, Italy.
| | - Miriam Longo
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, Università della Campania Luigi Vanvitelli, Naples, Italy
| | - Maria Ida Maiorino
- Diabetes Unit, Department of Advanced Medical and Surgical Sciences, Università della Campania Luigi Vanvitelli, Naples, Italy
| | - Giuseppe Bellastella
- Division of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, Università della Campania Luigi Vanvitelli, Naples, Italy
| | - Paolo Chiodini
- Medical Statistics Unit, Università della Campania Luigi Vanvitelli, Naples, Italy
| | - Sebastiano Bruno Solerte
- Department of Internal Medicine, Section of Geriatrics and Gerontology, University of Pavia, Azienda di Servizi alla Persona "Istituto Santa Margherita", Pavia, Italy
| | - Katherine Esposito
- Diabetes Unit, Department of Advanced Medical and Surgical Sciences, Università della Campania Luigi Vanvitelli, Naples, Italy
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