A Randomized, Double-blind, Placebo-controlled Study of the Effect of Mineralocorticoid Receptor Antagonists in Type 2 Diabetes Patients on Myocardial Function, Glucose and Fat Metabolism (The MIRAD-study)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 140
- 试验地点
- 1
- 主要终点
- Liver fat content
研究概览
简要总结
The aim of this study is to investigate the effect of selective blocking of the mineralocorticoid receptor in patients with type 2 diabetes on insulin resistance, lipid metabolism and myocardial function.
详细描述
In this randomized, double-blind, placebo-controlled study we want to investigate the effect of mineralocorticoid receptor antagonists in type 2 diabetes patients on myocardial function, glucose and fat metabolism.
Background The mortality rate in T2 DM is still increased by almost a factor 2 although poly pharmacological therapy of risk factors has been recommended for years. Treatment with MR antagonists in patients with primary hyperaldosteronism and systolic heart failure improves insulin resistance, myocardial function and prognosis. Further, recent evidence has suggested that aldosterone participates in the regulation of glucose and lipid metabolism, as MR expression has been identified in adipocytes and beneficial metabolic effects of selective MR blockade has been demonstrated in several animal models. Notably, there is no available data in humans with T2DM.
A key feature of T2 DM is altered body composition characterized by increased metabolic active visceral adipose tissue (VAT) and increased fat content of the liver, which has been associated with cardiac dysfunction and outcome. Gold standard for measurement of VAT is magnetic resonance imaging (MRI), and proton MRI spectroscopy can quantitatively measure fat content in the liver with high precision. The pathogenesis of myocardial dysfunction in T2DM is linked with insulin resistance (IR) of adipose tissue mediating increased supply of free fatty acids and intra myocardial lipid accumulation. Thus, beneficial effects of lipid metabolism could in theory indirectly improve myocardial function in type 2 diabetics.
Global longitudinal strain (GLS) is a validated method for evaluating regional and global function of the left ventricle, which is a strong predictor of incident HF in patients with myocardial infarction and closely related with plasma NT-proBNP concentrations.
Hypothesis Selective blocking of the MR receptor in patients with T2 DM improves insulin resistance, lipid metabolism and myocardial function.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able to understand the written patient information and to give informed consent
- •Type 2 diabetes mellitus (WHO criteria), diagnosed at least 3 months prior to baseline
- •Blood pressure treatment according to standard guidelines
- •Negative pregnancy test (fertile women)
- •Be willing to change/pause potassium sparing medication
- •Age 18-85 years
- •Patients must have high cardiovascular risk factors, defined as one of the following:
- •NT-proBNP ≥ 70 pg/ml (taken within the last 6 months prior to baseline) Albuminuria ( albumin/creatinine ratio ≥ 30 mg/g Confirmed history of myocardial infarction (≥ 3 months prior to baseline) Or patient discharged from hospital with a documented diagnosis of unstable angina within 24 months prior to baseline Evidence of coronary artery disease by CAG in 1 or more major coronary arteries OR at least one of the following: a positive noninvasive stress test, OR a positive stress echocardiography showing regional systolic wall motion abnormalities, OR a positive scintigraphy test showing stress-induced ischemia History of ischemic or hemorrhagic stroke (≥ 3 months prior to informed consent) Presence of peripheral artery disease (symptomatic or not ) documented by either: previous limb angioplasty, stenting or bypass surgery; or previous limb or foot amputation due to circulatory insufficiency; or angiographic evidence of significant (≥ 50%) peripheral artery stenosis in at least one limb; or evidence from a non-invasive measurement of significant (≥50% or as reported as hemodynamically significant) peripheral artery stenosis in at least one limb; or ankle brachial index of ≤ 0.9
- •Left ventricle hypertrophy:
- •Documented at echocardiography ECG: R-spike in V5/V6 ≥ 25 mm or S-spike in V1 + R-spike in V5/V6 ≥ 35 mm Patients both with and without a cardiovascular risk factor can be randomized to the fat biopsy sub study.
排除标准
- •Allergic to the study medication
- •Systolic HF (LVEF ≤ 40%)
- •Impaired kidney function, eGFR ≤ 40 ml/min
- •Severe liver insufficiency (Child-Pugh class C)
- •Treatment with MR antagonist within 3 months prior to baseline
- •Treatment with both ACE inhibitors and Angiotensin II Receptor blockers.
- •Serum-potassium ≥ 5.0 mmol/l
- •Serum-sodium ≤ 135 mmol/l
- •Myocardial infarction, unstable angina pectoris or bypass graft surgery within 3 months prior to baseline
- •Persistant atrial fibrillation (except for the fat biopsy sub population)
- •ECG showing malign ventricular arrhythmia or prolonged QT-interval (> 500ms)
- •Untreated heart valve disease
- •ICD-unit/pacemaker
- •Pregnancy or desire hereof or breastfeeding
- •Women in the fertile age not using safe contraceptives (spiral, hormonal contraceptives)
- •Cancer unless complete remission ≥ 5 year
- •Alcohol-/drug-abuse
- •Inflammatory bowel disease
- •Other concomitant disease or treatment that according to the investigator's assessment makes the patient unsuitable to participate in the study
- •Simultaneous participation in another clinical study
- •Treatment with CYP3A4-inhibitors (e.g. itraconazol, etoconazol, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodon)
研究组 & 干预措施
Eplerenone
Eplerenone 50 mg tablets. 2-4 tablets once daily for 26 weeks
干预措施: Eplerenone (Drug)
placebo
sugar pill manufactured to mimic Eplerenone 50 mg tablet. 2-4 tablets once daily for 26 weeks.
干预措施: Placebo (Drug)
结局指标
主要结局
Liver fat content
时间窗: 26 weeks
changes in liver fat content by proton MR spectroscopy
次要结局
- 24 Hour blood pressure(26 weeks)
- Global longitudinal strain (GLS)(26 weeks)
- Fat mass distribution(26 weeks)
- Biomarkers of adipocyte function(26 weeks)
- insulin resistance(26 weeks)
- Urinary albumin/creatinine ratio(26 weeks)
- systolic and diastolic function og left ventricule(26 weeks)
- Regional and global fibrosis by cardiac magnetic resonance(26 weeks)
- biomarkers of myocardial stress and fibrosis(26 weeks)
- pulse wave analysis(26 weeks)
- Quality of life(26 weeks)
- Diabetes related changes in quality of life(26 weeks)
- kidney function(26 weeks)
- potassium(26 weeks)
研究者
Marie Louise Johansen
MD, PhD student
Herlev and Gentofte Hospital