Phase 4, Randomized, Placebo-controlled, Cross-over Trial to Assess the Effect of 4-week Ertugliflozin (SGLT-2 Inhibitor) Therapy on Renal Oxygenation by BOLD-MRI and Renal Oxygen Consumption by PET Using ¹¹C-acetate in T2DM Without Kidney Disease and Healthy Controls.
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Renal oxygenation measured by BOLD-MRI (R2*)
研究概览
简要总结
Current study will render insight in to the role of renal hypoxia in the diabetic kidney and is able to associate its finding with measurements of renal perfusion and glomerular filtration rate. Moreover, this research will focus on the effects of sodium-glucose cotransporter 2 inhibition on renal tissue oxygenation and oxygen consumption as well as a change in intrarenal hemodynamics and perfusion, and a shift of fuel metabolites. Elucidation the mechanisms underlying the effects of SGLT2 inhibition will advance our knowledge and contribute to their optimal clinical utilization in the treatment of chronic kidney disease in diabetes and possibly beyond.
详细描述
Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) are a relatively new class of drugs in the treatment of diabetes and improve glycemic control by blocking SGLT-2 in the proximal tubule, the main transporter of coupled sodium-glucose reabsorption Three large cardiovascular outcome trials (EMPA-REG, CANVAS, DECLARE- TIMI 58) showed SGLT-2 inhibition to have a renoprotective effect, including on renal outcomes. Moreover, the recently publicized CREDENCE trial concluded early after the planned interim analyses showed a striking renoprotective effect of SGLT-2 inhibition in patients with T2DM and CKD. The mechanisms underlying their beneficial effects remain to be elucidated, as the small SGLT-2 induced reduction in glucose level (0.5% HbA1c), bodyweight (about 3%), systolic blood pressure (about 4 mmHg), or uric acid (about 6%) are insufficient to fully account for the effect.
The pathological mechanisms underlying DKD involve complex interactions between metabolic and haemodynamic factors which are not fully understood. However, accumulating evidence of foremost animal studies indicates that a chronic state of renal tissue hypoxia is the final common pathway in the development and progression of diabetic kidney disease. Therefore several hypothesis have been proposed on the alleviation of chronic tissue hypoxia following SGLT-2 inhibition: (1) A decrease in workload by a decrease in GFR. (2) A shift in renal fuel energetics by increasing ketone body oxidation, which renders high ATP/oxygen consumption ratio's compared to glucose or free fatty acids. (3) An improvement of cardiac function and systemic hemodynamics to lead to an increase in renal perfusion, and (4) an increase in erythropoietin (EPO) levels to stimulate oxygen delivery.
Current study will examine the above hypothesis by researching renal oxygenation by BOLD-MRI, oxygen consumption by PET-CT, and hemodynamic kinetics by the Iohexol clearance method/contrast-enhance ultrasound/arterial spin labeling. Blood sampling will allow for the measurement of EPO and ketone bodies, as well as a resting energy expenditure will elucidate a shift in use of energy substrate metabolism. The research will be performed in T2DM without overt kidney disease (n=20) before and after a 4 week treatment with SGLT-2 inhibition (ertugliflozin), and will be compared the obtained results from healthy controls (n=20).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Ertugliflozin 15mg once daily
Once daily treatment with oral ertugliflozin (steglatro) 15mg for 4 consecutive weeks.
干预措施: Ertugliflozin 15 mg (Drug)
Placebo
Once daily treatment with a placebo pill for 4 consecutive weeks.
干预措施: Ertugliflozin 15 mg (Drug)
结局指标
主要结局
Renal oxygenation measured by BOLD-MRI (R2*)
时间窗: After 4 week treatment with ertugliflozin 15mg QD versus placebo
Renal (separated as cortical and medullar) oxygenation measured by BOLD-MRI (R2\*)
次要结局
- Renal oxygen consumption by PET/CT-scan using 11C-Acetate(After 4 week treatment with active drug intervention versus placebo)
- Renal hemodynamics(After 4 week treatment with active drug intervention versus placebo)
- Chronic 24-hour sodium and glucose excretion(After 4 week treatment with active drug intervention versus placebo)
- Changes in plasma energy substrate: ketone bodies(After 4 week treatment with active drug intervention versus placebo)
- Cortical blood flow(After 4 week treatment with active drug intervention versus placebo)
- Acute 24-hour sodium and glucose excretion(After 2 days of treatment with active drug intervention versus placebo)
- Renal efficiency(After 4 week treatment with active drug intervention versus placebo)
- Renal arterial blood flow(After 4 week treatment with active drug intervention versus placebo)
- Renal tubular function: Urine Osmolality(After 4 week treatment with active drug intervention versus placebo)
- Energy expenditure(After 4 week treatment with active drug intervention versus placebo)
- Beta-cell function(After 4 week treatment with active drug intervention versus placebo)
- Total insulin extraction(After 4 week treatment with active drug intervention versus placebo)
- Renal tubular function: sodium transport(After 4 week treatment with active drug intervention versus placebo)
- Changes in plasma energy substrate: free fatty acids(After 4 week treatment with active drug intervention versus placebo)
- Changes in plasma energy substrate:triglycerides(After 4 week treatment with active drug intervention versus placebo)
- Renal tubular function: Urinary pH(After 4 week treatment with active drug intervention versus placebo)
- Renal damage markers(After 4 week treatment with active drug intervention versus placebo)
- Changes in plasma energy substrate: glucose(After 4 week treatment with active drug intervention versus placebo)
- Insulin sensitivity(After 4 week treatment with active drug intervention versus placebo)
- Changes in erythropoietin (EPO) levels(After 4 week treatment with active drug intervention versus placebo)
- Peripheral insulin extraction(After 4 week treatment with active drug intervention versus placebo)
研究者
D van Raalte
Dr. D.H. van Raalte
Amsterdam UMC, location VUmc