Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus (or Pre-diabetes) and Heart Failure (SUGAR-DM-HF)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 105
- 试验地点
- 1
- 主要终点
- Left Ventricular End Systolic Volume Index (LVESVI)
研究概览
简要总结
The investigators hypothesise that empagliflozin 10mg daily will have haemodynamic, cardiac, and renal benefits compared to placebo over 36 weeks in heart failure patients with type 2 diabetes (or pre-diabetes), leading to measurable improvements in clinical measures of cardiac structure and function (LVESVI, and LV strain) as well as renal blood flow.
详细描述
The results of the EMPA-REG OUTCOME trial on CVD outcomes and heart failure hospitalisation suggests that empagliflozin works quickly to lessen CVD mortality and reduce heart failure hospitalisations in patients with diabetes and existing cardiovascular disease. The lack of effect on non-fatal MI and stroke would suggest limited impact on atherothrombotic mechanisms. It is important to understand the mechanisms by which empagliflozin is acting in more detail, in order that the drug can be more widely targeted at patient groups that might benefit most; particularly patients with heart failure and diabetes (or pre-diabetes) (as discussed in the rationale).
The investigators have hypothesised, in a detailed published review, that the benefit derives from the specific effects of sodium-glucose linked transporter-2 (SGLT2) inhibition on renal sodium and glucose handling, leading to both diuresis and improvements in diabetes-related maladaptive renal arteriolar responses. These haemodynamic and renal effects are likely to be beneficial in patients with clinical or subclinical cardiac dysfunction. The net result of these processes is an improvement in cardiac systolic and diastolic function and, thereby, a lower risk of heart failure hospitalisation (HFH) and sudden cardiac death.
The investigators have therefore designed the present trial to perform a comprehensive clinical trial to interrogate in detail the effects of empagliflozin on specific pathways (inclusive of cardiac and renal effects) in patients with type 2 diabetes (or pre-diabetes) and heart failure.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
placebo controlled trial
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent
- •Male or female, aged ≥18 years age
- •Type 2 DM (diet-controlled or on stable treatment) or prediabetes
- •Stable treatment defined as no change in oral therapy agents or doses for diabetes mellitus and (where applicable) <10% change in average total daily insulin dose over last 6 weeks
- •HbA1c ≤97 mmol/mol (11%) (routine available data from medical records, recorded in the last year)
- •Prediabetes defined as HbA1c 39-47 mmol/mol (5.7-6.4%) at the time of screening (specifically for the prediabetes group, HbA1c will be repeated at the time of screening if there are no recent results within the last 3 months, in order to confirm the diagnosis of prediabetes)
- •Heart failure (as defined by the presence of typical signs and symptoms of heart failure with documented reduced ejection fraction (ref SIGN and ESC guidelines))
- •NYHA class II-IV
- •LVEF ≤40%
- •On stable doses of ACEI, ARB or ARNI for 4 weeks prior to randomisation unless contraindicated or not tolerated. They should also be taking a beta-blocker at a stable dose for 4 weeks unless contraindicated or not tolerated
- •Women of childbearing potential (WOCBP) must be currently adhering to, or be willing to use, highly effective birth control methods for study treatment duration including:
- •Combined hormonal contraception (oestrogen and progestogen containing medication) either orally, intravaginally, or transdermally
- •Progesterone only hormonal contraception either orally, injected, or implanted
- •Intrauterine device (IUD)
- •Intrauterine hormone release system (IUS)
- •Bilateral fallopian tube occlusion
- •Vasectomised partner
- •Complete sexual abstinence where this is their preferred and usual lifestyle
- •WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilisation (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal. Post-menopausal is defined as:
- •o Women who have had amenorrhea for ≥12 consecutive months (without another medical cause)
排除标准
- •Type 1 DM
- •History of hospital admission with a diagnosis of diabetic ketoacidosis (DKA)
- •Insulin use within 1 year of diagnosis of diabetes
- •History of acute or chronic pancreatitis
- •eGFR <30 ml/min/1.73m2 (derived using CKD EPI)
- •Persistent/permanent atrial fibrillation/flutter (conditions which significantly impede MRI image interpretability)
- •Acute coronary syndrome, stroke or surgery within 1 month (small type 2 MI in the context of acute HF does not apply)
- •BMI >52 kg/m2
- •Liver disease, defined by serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal (ULN) during screening
- •Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
- •Any condition outside the cardiovascular and renal disease area, such as but not limited to malignancy, with a life expectancy of less than 2 years based on investigator's clinical judgement
- •Active malignancy requiring treatment at the time of visit 1 (with the exception of successfully treated basal cell or treated squamous cell carcinoma, adjuvant hormonal therapy for breast cancer and hormone therapy for prostate cancer)
- •Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. malaria, babesiosis, haemolytic anaemia)
- •Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent
- •Any uncontrolled endocrine disorder except Type 2 DM
- •Alcohol or drug abuse within 3 months of informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance with study procedures or study drug intake
- •Known hypersensitivity to the empagliflozin or excipients
- •Known hypersensitivity to gadolinium
- •Inability to give informed consent
- •SGLT2 inhibitor use (current or previous)
- •Devices or any other contraindication to MRI scans
- •Currently pregnant, planning pregnancy, or currently breastfeeding
- •History of previous lower limb amputation
- •Current participation in another interventional medical study or within the last 90 days
- •Anyone who, in the investigators' opinion, is not suitable to participate in the trial for other reasons
研究组 & 干预措施
Empagliflozin
Empagliflozin 10mg tablets for oral self-administration once daily
干预措施: Empagliflozin 10 MG (Drug)
Placebo Oral Tablet
placebo tablets for oral self-administration once daily
干预措施: Placebo Oral Tablet (Drug)
结局指标
主要结局
Left Ventricular End Systolic Volume Index (LVESVI)
时间窗: 36 weeks
Cardiac structure measured by left ventricular end-systolic volume index measured by cardiac magnetic resonance imaging as mL/m2
left ventricular global longitudinal strain (GLS)
时间窗: 36 weeks
Cardiac structure measured by left ventricular global longitudinal strain measured by cardiac magnetic resonance imaging GLS%
次要结局
- Intensification of diuretic therapy(36 weeks)
- Microvascular perfusion(36 weeks)
- Left atrial volume index (LAVI)(36 weeks)
- Extracellular volume fraction(36 weeks)
- 6 minute walk distance (Exercise Capacity)(36 weeks)
- Biomarker profile - uric acid(36 weeks)
- Left ventricular mass index (LVMI)(36 weeks)
- Left ventricular global function index (LVGFI)(36 weeks)
- Pulmonary congestion(36 weeks)
- Biomarker profile -glycated haemaglobin (HbA1c)(36 weeks)
- Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)(36 weeks)
- Biomarker profile - creatine(36 weeks)
- Biomarker profile - liver function tests (LFTs)(36 weeks)
- Left ventricular end diastolic volume index (LVEDVI)(36 weeks)
- Left ventricular ejection fraction (LVEF)(36 weeks)
- Biomarker profile - estimated glomerular filtration rate (eGFR)(36 weeks)