The Effect of GLP-1 Agonist, SGLT2 Inhibitor and Their Combination on Endothelial Function, Arterial Stiffness and Left Ventricular Deformation in Patients With Type 2 Diabetes With High Cardiovascular Risk
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 240
- 试验地点
- 1
- 主要终点
- Comparison of Global Longitudinal Strain (GLS) difference among treatment groups.
研究概览
简要总结
A. Four groups of patients with type 2 diabetes mellitus with high or very high cardiovascular risk or heart failure with preserved ejection fraction (HFpEF) will be studied before and at 6 and 12 months of treatment:
- 60 patients treated with a combination of GLP1 analogue and SGLT2 inhibitor ± metformin
- 60 patients treated with GLP-1 agonist as a second step after metformin
- 60 patients treated with SGLT2 inhibitor as a second step after metformin
- 60 patients treated with a combination of insulin and other antidiabetic agents (metformin - DPP4 inhibitors) Individuals will be equal distributed as far as age, gender and body mass index concerned. In addition, patients suffered from kidney disease and retinopathy are excluded.
详细描述
Disordered glucose tolerance in patients with type 2 diabetes mellitus is multifactorial and includes dysfunction not only of β-cells of the pancreas, liver and muscles, but also of the adipose tissue, gastrointestinal tract, kidney, α-cells of the pancreas and the brain. Therefore, it is likely that the use of drugs that act on multiple aspects of the pathophysiology of diabetes will have beneficial effects on glycemic control and outcome of patients.In addition to the many possible causes of glucose deregulation, people with type 2 diabetes have comorbidities such as hypertension, hyperlipidemia and obesity resulting in increased cardiovascular risk. Optimal treatment of hyperglycaemia and cardiovascular risk factors is necessary to reduce adverse events. Although the initial approach is the modification of dietary factors (physical activity, diet, smoking cessation), the progressive nature of type 2 diabetes ultimately leads to the use of multiple therapies. Guidelines for the treatment of patients with type 2 diabetes with high HbA1c are initial double-combined therapy or triple combination if glycemic control is not achieved after 3 months. Although insulin is usually included in such combinations, additional treatment options are required for patients with high HbA1c who also need to lose weight and avoid hypoglycaemia. It is likely that the outcome of patients could be improved by using drugs targeting different aspects of the disease (glycemia, body weight, blood pressure, lipids).
Over the last decade, two classes of antidiabetic drugs have been added to weight loss, improved cardiovascular risk factors and a low risk of hypoglycemia: glucagon-like peptide-1 agonists (GLP-1, glucagon like peptide-1) and inhibitors of the sodium glucose subtype 2 (SGLT2, sodium-glucose co-transporters). Recent studies have shown that these two drugs have cardioprotective effects possibly through different mechanisms of action, while their complementary mechanical, pharmacological and clinical effects make their combination (in addition to metformin) potentially beneficial in type 2 diabetes patients. Specifically, SGLT2 inhibitors manifest their cardioprotective activity by improving hemodynamic parameters, while GLP-1 agonists through antiatherogen / anti-inflammatory mechanisms.
The increased arterial stiffness with the associated increase in the range of reflected pressure waves, determines not only the augmentation of systolic pressure but also the rate of increase which depends on age. Increased levels of pulse pressure (indirect atherosclerotic index) and pulse wave velocity (PWV), a reliable measure of arterial stiffness, predict future cardiovascular events. Endothelial dysfunction is associated with the presence of atherosclerosis and is also considered as an indicator of the early changes preceding it. The role of impaired endothelial function of large arteries seems to be significant in the pathogenesis of cardiovascular disease. Endothelial glycocalyx is a glycoprotein layer that covers the surface of endothelial cells and regulates arterial wall permeability and the interaction of endothelial cells with circulating blood cells. Inflammatory or atherogenic stimuli, such as hyperglycemia, lead to glucocalyx disorder and increased vascular sensitivity to further atherogenic stimuli. The two-dimensional speckle tracking ultrasound allows accurate estimation of left ventricular distortion, which is disordered in diabetics in relation to healthy subjects.
Hypothesis of the proposed study:
Endothelial function, arterial stiffness and left ventricular deformation are improved in patients with type 2 diabetes with high or very high cardiovascular risk or heart failure with preserved ejection fraction (HFpEF) treated with GLP-1 agonist and SGLT2 inhibitor compared to either one or both combination of insulin and other antidiabetic tablets.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 45 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject has type 2 diabetes mellitus
- •Subject has high or very high cardiovascular risk
- •Subject has heart failure with preserved ejection fraction
排除标准
- •Subject has type 1 diabetes mellitus
- •Subject has kidney disease
- •Subject has retinopathy
研究组 & 干预措施
SGLT2i group
60 patients treated with empagliflozin. All subjects will undergo an echocardiographic study in order to estimate GLS, left ventricular twisting-untwisting using speckle tracking imaging and carotid intima-media thickness. PWV, AIx, SBPao and PPao with Arteriograph, Mobilograph and Complior, and perfused boundary region (PBR) of sublingual vessels using Sideview Darkfield Imaging (Microscan, Glucockeck). PBR consists the cell-free space which is formed from the separation of red blood cells from plasma at the surface of the endothelial glycocalyx. Oxidative stress markers, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, thrombomodulin, nitrites and nitrates, N-terminal pro B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, mitochondrial-derived peptide-c (MOTS-c), blood glucose, glycosylated hemoglobin (HbA1c) and a full lipidemic profile will be measured before and at 6 and 12 months of treatment.
Control group
60 patients treated with insulin and metformin.All subjects will undergo an echocardiographic study in order to estimate GLS, left ventricular twisting-untwisting using speckle tracking imaging and carotid intima-media thickness. PWV, AIx, SBPao and PPao with Arteriograph, Mobilograph and Complior, and perfused boundary region (PBR) of subglottic vessels using Sideview Darkfield Imaging (Microscan, Glucockeck). PBR consists the cell-free space which is formed from the separation of red blood cells from plasma at the surface of the endothelial glycocalyx. Oxidative stress markers, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, thrombomodulin, nitrites and nitrates, N-terminal pro B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, mitochondrial-derived peptide-c (MOTS-c), blood glucose, glycosylated hemoglobin (HbA1c) and a full lipidemic profile will be measured before and at 6 and 12 months of treatment.
GLP1 and SGLT2i group
60 patients treated with a combination of liraglutide and empagliflozin. All subjects will undergo an echocardiographic study to estimate GLS, left ventricular twisting-untwisting using speckle tracking imaging and carotid intima-media thickness. PWV, AIx, SBPao and PPao with Arteriograph, Mobilograph and Complior, and perfused boundary region (PBR) of sublingual vessels using Sideview Darkfield Imaging (Microscan, Glycockeck). PBR consists the cell-free space which is formed from the separation of red blood cells from plasma at the surface of the endothelial glycocalyx. Oxidative stress markers, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, thrombomodulin, nitrites and nitrates, N-terminal pro B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, mitochondrial-derived peptide-c (MOTS-c), blood glucose, glycosylated hemoglobin (HbA1c) and lipid profile will be measured before and at 6 and 12 months of treatment.
GLP1 group
60 patients treated with liraglutide. All subjects will undergo an echocardiographic study in order to estimate GLS, left ventricular twisting-untwisting using speckle tracking imaging and carotid intima-media thickness. PWV, AIx, SBPao and PPao with Arteriograph, Mobilograph and Complior, and perfused boundary region (PBR) of sublingual vessels using Sideview Darkfield Imaging (Microscan, Glycockeck). PBR consists the cell-free space which is formed from the separation of red blood cells from plasma at the surface of the endothelial glycocalyx. Oxidative stress markers, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, thrombomodulin, nitrites and nitrates, N-terminal pro B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, mitochondrial-derived peptide-c (MOTS-c), blood glucose, glycosylated hemoglobin (HbA1c) and a full lipidemic profile will be measured before and at 6 and 12 months of treatment.
结局指标
主要结局
Comparison of Global Longitudinal Strain (GLS) difference among treatment groups.
时间窗: 12 months
Comparison of Global Longitudinal Strain (GLS) difference among treatment groups, measured by echocardiographic study
次要结局
- Comparison of arterial stiffness markers difference among treatment groups.(12 months)
- Comparison of wave reflection markers difference among treatment groups(12 months)
- Comparison of central aortic blood pressure differences among treatment groups(12 months)
- Comparison of endothelial glycocalyx thickness difference among treatment groups(12 months)
- Comparison of oxidative stress and endothelial function biomarkers differences among treatment groups(12 months)
- Comparison of cardiac biomarkers differences among treatment groups.(12 months)
- Comparison of left ventricular myocardial function difference between coronary artery disease patients and non-coronary artery disease patients in each study group.(12 months)
- Comparison of arterial stiffness difference between coronary artery disease patients and non-coronary artery disease patients in each study group.(12 months)
- Comparison of endothelial glycocalyx thickness difference between coronary artery disease patients and non-coronary artery disease patients in each study group.(12 months)
- Comparison of oxidative stress and endothelial function biomarkers differences between coronary artery disease patients and non-coronary artery disease patients in each study group.(12 months)
- Comparison of cardiac biomarkers differences between coronary artery disease patients and non-coronary artery disease patients in each study group.(12 months)
- Comparison of liver steatosis level between treatment groups(12 months)
- Comparison of carotid atherosclerotic markers between treatment groups(12 months)
- Comparison of non-fatal cardiovascular events' incidence between the treatment groups(6 years)
- Comparison of cost analysis for the four treatment groups(6 years)
研究者
Ignatios Ikonomidis
Professor of Cardiology
University of Athens