Empagliflozin as a Modulator of Systemic Vascular Resistance and Cardiac Output in Patients With Type 2 Diabetes
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Mode of action
研究概览
简要总结
SGLT2 inhibitors are a novel class of glucose lowering drugs that act in the kidney by inhibiting SGLT2-mediated glucose reabsorption in the proximal tubule. The resulting increase in urinary glucose excretion leads to a reduction in plasma glucose levels. This is accompanied by reduction of total body weight due to urinary energy loss. In addition, glucose dependent osmotic diuresis contributes to blood pressure lowering effects of SGLT2 inhibition.
Aim of the trial is to assess hemodynamic changes by empagliflozin, identify new empagliflozin dependent metabolic regulators and evaluate empagliflozin dependent effects on cardiac function.
详细描述
Strikingly, empagliflozin was recently found to reduce cardiovascular mortality in addition to heart failure in the EMPA-REG OUTCOME trail. This multi-center, randomized, placebo controlled study enrolled 7020 patients with type 2 diabetes at high cardiovascular risk. Patients were randomized to placebo or one of 2 doses of empagliflozin (10 or 25 mg/d) on the background of state-of-the-art glucose-lowering therapy with good control of associated CV risk factors at trial entry. At the end of the study, empagliflozin led to a slightly lower HbA1c of 0.3 - 0.4 % in comparison to placebo with higher addition of other anti-hyperglycemic medications found in the placebo group. Moreover, empagliflozin compared with placebo led to a significant reduction in blood pressure and body weight, similar to what has been reported in earlier studies. For the primary outcome empagliflozin significantly reduced the risk of cardiovascular death, myocardial infarction and stroke compared with placebo with a hazard ratio of 0.86 (95% CI 0.74-0.99; p=0.038). This reduction was mainly driven by a highly significant 38% reduction in cardiovascular death (HR 0.62; 95% CI 0.49-0.77), with a very early separation of the curves evident as early as 2 months into the trial. There was a non-significant 13% reduction of non-fatal myocardial infarction (p=0.30) and a non-significant 24% increased risk for non-fatal stroke (p=0.16). In addition, in a secondary/exploratory analysis, empagliflozin led to a significant reduction of hospitalization for heart failure with a 35% risk reduction (HR 0.65; 95% CI 0.50-0.85; p<0.002), with separation of the curves evident almost immediately during trial observation, suggesting a very early effect of the SGLT2-inhibitor. Finally, empagliflozin reduced overall mortality by 32% (HR 0.68; 95% CI 0.57-0.82; p<0.0001), a highly significant effect translating into a number-needed-to-treat (NNT) of 39 over 3 years to prevent one death.
These large unexpected, beneficial effects of empagliflozin on all-cause death, CV death and HF hospitalization have raised important questions, as to the mechanism underpinning these favorable CV actions, which cannot be explained by glucose control nor a reduction of atherosclerotic events.
The rapid separation of survival and HF-event curves suggest an instant mode of empagliflozin action - which we here hypothesize to be driven by immediate changes of hemodynamic parameters. This might be followed by more delayed metabolic effects contributing to the beneficial risk profile.
The investigators speculate empagliflozin dependent hemodynamic changes to be responsible for the early and longer term blood pressure lowering effects. This might initially be driven a rapidly occurring empagliflozin dependent natriuresis.
This hypothesis is based on:
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
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Type 2 diabetes
- •Serum levels of HbA1c ≥ 6.5 %, despite treatment with diet and glucose lowering agents, which should include metformin (unless intolerance or contraindication to metformin exists)
- •Age ≥ 18 years
- •Participants of child-bearing age should use adequate contraception
- •Written informed consent prior to study participation
排除标准
- •Type 1 diabetes
- •Systolic blood pressure ≥ 160 mmHg, diastolic blood pressure ≥ 90 mmHg
- •Age ≥ 75 years
- •Pregnancy or lactating females
- •Urinary tract infections or significant formation of residual urine in medical history
- •Renal impairment (GFR < 30 ml/min/1.73 m2)
- •Liver disease (serum levels of AST, ALT or AP more than three times the upper limit of normal)
- •Uncontrolled thyroid disease
- •Endocrinopathies like Graves' disease, acromegaly, Cushing's disease
- •Hypertensive retinopathy or encephalopathy
- •Acute coronary syndrome, stroke or transient ischemic attack in last 6 weeks prior to randomization
- •The subject is mentally or legally incapacitated
- •The subject received an investigational drug within 30 days prior to inclusion into this study
- •Patients with newly diagnosed diabetes, who have not been subjected to diet and glucose lowering drug treatment.
- •Patients with particular risk for ketoacidosis (alcohol abuse, pancreatitis, pancreatic insulin deficiency from any cause, caloric restriction etc.) or ketoacidosis in the past
- •Frequent hypoglycaemic events (in the opinion of the investigator)
- •Patients in whom study participation is not deemed appropriate under consideration of clinical wellbeing by the principal investigator
- •Intolerance to Empagliflozin and excipients in Empagliflozin or rather placebo
- •Hypotension in the past (systolic blood pressure < 90 mmHg) in patients receiving treatment with blood lowering drugs
- •Signs of exsiccosis
- •Previous treatment with Empagliflozin in the past
- •Critically ill patients (in the opinion of the investigator)
研究组 & 干预措施
Placebo
Patients of the placebo arm will receive placebo tablets qd for a period of 3 months.
干预措施: Placebo (Other)
Empagliofizin
Patients will receive empagliflozin 10 mg qd for a period of 3 months.
干预措施: Empagliflozin (Drug)
结局指标
主要结局
Mode of action
时间窗: 3 months
cardiac output (l/min)
次要结局
- Hemodynamics(3 months)
- Energie expenditure(3 months)
- Cardio cascular(3 months)
- Urine(3 months)
- Body weight(3 months)
- Cardio vascular(3 months)
- Metabolism(3 months)
- Blood(3 months)