Renal Oxygenation, Oxygen Consumption and Hemodynamic Kinetics in Type 2 DIabetes: an Ertugliflozin Study.
- Conditions
- ErtugliflozinType 2 Diabetes MellitusRenoprotectionDiabetic Kidney DiseaseRenal HypoxiaDiabetic NephropathySGLT2 Inhibitor
- Interventions
- Registration Number
- NCT04027530
- Lead Sponsor
- Amsterdam UMC, location VUmc
- Brief Summary
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.
- Detailed Description
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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 40
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Ertugliflozin 15mg once daily Ertugliflozin 15 mg Once daily treatment with oral ertugliflozin (steglatro) 15mg for 4 consecutive weeks. Placebo Ertugliflozin 15 mg Once daily treatment with a placebo pill for 4 consecutive weeks.
- Primary Outcome Measures
Name Time Method Renal oxygenation measured by BOLD-MRI (R2*) After 4 week treatment with ertugliflozin 15mg QD versus placebo Renal (separated as cortical and medullar) oxygenation measured by BOLD-MRI (R2\*)
- Secondary Outcome Measures
Name Time Method Renal oxygen consumption by PET/CT-scan using 11C-Acetate After 4 week treatment with active drug intervention versus placebo Renal oxygen consumption will be measured by PET/CT-scan using 11C-Acetate and compartment model parameter k2
Renal hemodynamics After 4 week treatment with active drug intervention versus placebo GFR and ERPF
Chronic 24-hour sodium and glucose excretion After 4 week treatment with active drug intervention versus placebo 24-hour sodium and glucose excretion after 4 weeks
Changes in plasma energy substrate: ketone bodies After 4 week treatment with active drug intervention versus placebo Changes in plasma energy substrate: ketone bodies
Cortical blood flow After 4 week treatment with active drug intervention versus placebo measured by contrast-enhanced ultrasound
Acute 24-hour sodium and glucose excretion After 2 days of treatment with active drug intervention versus placebo 24-hour sodium and glucose excretion after 2 days
* Urine osmolality
* Urinary pHRenal efficiency After 4 week treatment with active drug intervention versus placebo Measured as sodium reabsorption divided by oxygen consumption
Renal arterial blood flow After 4 week treatment with active drug intervention versus placebo measured by arterial spin labelling
Renal tubular function: Urine Osmolality After 4 week treatment with active drug intervention versus placebo Urine osmolality
Energy expenditure After 4 week treatment with active drug intervention versus placebo By resting energy expenditure
Beta-cell function After 4 week treatment with active drug intervention versus placebo Beta-cell function will be derived from HOMA-B modelling during an oral glucose tolerance test (OGTT).
Total insulin extraction After 4 week treatment with active drug intervention versus placebo Arterial-venous difference before and following an OGTT
Renal tubular function: sodium transport After 4 week treatment with active drug intervention versus placebo Iohexol corrected sodium excretion
Changes in plasma energy substrate: free fatty acids After 4 week treatment with active drug intervention versus placebo Changes in plasma energy substrate: free fatty acids
Changes in plasma energy substrate:triglycerides After 4 week treatment with active drug intervention versus placebo Changes in plasma energy substrate:triglycerides
Renal tubular function: Urinary pH After 4 week treatment with active drug intervention versus placebo Urinary pH
Renal damage markers After 4 week treatment with active drug intervention versus placebo Renal damage markers will include: urinary albumin excretion in 24-hour urine samples and other markers depending on relevant (emerging) metabolic and humoral biomarkers of renal damage, conditional to available budget.
Changes in plasma energy substrate: glucose After 4 week treatment with active drug intervention versus placebo Changes in plasma energy substrate: glucose
Insulin sensitivity After 4 week treatment with active drug intervention versus placebo OGIS and Matsuda Index during an oral glucose tolerance test (OGTT)
Changes in erythropoietin (EPO) levels After 4 week treatment with active drug intervention versus placebo Changes in erythropoietin (EPO) levels
Peripheral insulin extraction After 4 week treatment with active drug intervention versus placebo Arterial-venous difference before and following an OGTT
Trial Locations
- Locations (1)
VU University Medical Center
🇳🇱Amsterdam, Netherlands
VU University Medical Center🇳🇱Amsterdam, Netherlands