Renal Oxygenation, Oxygen Consumption and Hemodynamic Kinetics in Type 2 DIabetes: an Ertugliflozin Study.

Study Overview
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Brief Summary
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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
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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).

Official Title
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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.

Conditions
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Type 2 Diabetes Mellitus, Diabetic Kidney Disease, Diabetic Nephropathy, Renal Hypoxia, Renoprotection, SGLT2 Inhibitor, Ertugliflozin

Intervention / Treatment
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* Drug: Ertugliflozin 15 mg


Participation Criteria
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Eligibility Criteria
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Group 1: T2DM patients Inclusion criteria Provision of signed and dated, written informed consent prior to any study specific procedures. Caucasian*; female or male aged ≥18 years and <80 years. Females must be post-menopausal (defined as no menses >1 year and follicle stimulating hormone (FSH) >31 U/L)*. Type 2 diabetes mellitus since at least 3 years with HbA1c ≥ 6.5% (≥57mmol/mol) and <10% (<94mmol/mol) An appropriate stable dose of metformin and/or sulfonylurea as glucose-lowering therapy for the last 12 weeks Maximum tolerated antihypertensive dose of an ARB for at least 6 weeks prior to randomization. eGFR 60-90 ml/min/1.73m² BMI 25-35 kg/m² * In order to increase homogeneity Exclusion criteria Involvement in the planning and/or conduction of another study Participation in another clinical study with an investigational product during the last 3 months Diagnosis of type 1 diabetes mellitus CKD defined as eGFR<60 ml/min/1.73m² or albuminuria (defined as an UACR > 2.5 mg/mol). Cardiovascular disease event in the last 6 months prior to enrollment as assessed by the investigator, including: myocardial infarction, cardiac surgery or revascularization (CABG/PTCA), unstable angina, heart failure, transient ischemic attack (TIA) or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia. Current/chronic use of the following medication: insulin, thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors, oral glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), immune suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs), diuretics, and monoamine oxidase inhibitors. Current urinary tract infection or active nephritis History of ketoacidosis History of allergy/hypersensitivity to any of the test agents. Group 2: Age-matched and eGFR-matched non-diabetic controls Inclusion criteria Provision of signed and dated, written informed consent prior to any study specific procedures. Caucasian*; female or male aged ≥18 years and <80 years. Females must be post-menopausal (defined as no menses >1 year and follicle stimulating hormone (FSH) >31 U/L)*. Normal glucose tolerance at screening as confirmed by OGTT Maximum tolerated antihypertensive dose of an ARB for at least 6 weeks prior to randomization in case of hypertension. BMI 25-35 kg/m2 eGFR 60-90ml/min * In order to increase homogeneity Exclusion criteria Involvement in the planning and/or conduction of another study Participation in another clinical study with an investigational product during the last 3 months CKD defined as eGFR<60ml/min or macro-albuminuria or proteinuria Cardiovascular disease event in the last 6 months prior to enrollment, as assessed by the investigator, including: myocardial infarction, cardiac surgery or revascularization (CABG/PTCA), unstable angina, heart failure, transient ischemic attack (TIA) or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia. Use of medication that may interfere with study endpoints non-steroidal anti-inflammatory drugs (NSAIDs), immune suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs), diuretics, and monoamine oxidase inhibitors. Current urinary tract infection and active nephritis Any other condition that prevents participation as judged by investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ertugliflozin 15mg once daily<br>Once daily treatment with oral ertugliflozin (steglatro) 15mg for 4 consecutive weeks. | Drug: Ertugliflozin 15 mg<br>* Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks<br>* Other names: Steglatro;|
| Placebo Comparator: Placebo<br>Once daily treatment with a placebo pill for 4 consecutive weeks. | Drug: Ertugliflozin 15 mg<br>* Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks<br>* Other names: Steglatro;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal oxygenation measured by BOLD-MRI (R2*) | Renal (separated as cortical and medullar) oxygenation measured by BOLD-MRI (R2*) | After 4 week treatment with ertugliflozin 15mg QD versus placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal oxygen consumption by PET/CT-scan using 11C-Acetate | Renal oxygen consumption will be measured by PET/CT-scan using 11C-Acetate and compartment model parameter k2 | After 4 week treatment with active drug intervention versus placebo | 
| Renal hemodynamics | GFR and ERPF | After 4 week treatment with active drug intervention versus placebo | 
| Renal efficiency | Measured as sodium reabsorption divided by oxygen consumption | After 4 week treatment with active drug intervention versus placebo | 
| Cortical blood flow | measured by contrast-enhanced ultrasound | After 4 week treatment with active drug intervention versus placebo | 
| Renal arterial blood flow | measured by arterial spin labelling | After 4 week treatment with active drug intervention versus placebo | 
| Acute 24-hour sodium and glucose excretion | 24-hour sodium and glucose excretion after 2 days Urine osmolality Urinary pH | After 2 days of treatment with active drug intervention versus placebo | 
| Chronic 24-hour sodium and glucose excretion | 24-hour sodium and glucose excretion after 4 weeks | After 4 week treatment with active drug intervention versus placebo | 
| Renal tubular function: Urinary pH | Urinary pH | After 4 week treatment with active drug intervention versus placebo | 
| Renal tubular function: Urine Osmolality | Urine osmolality | After 4 week treatment with active drug intervention versus placebo | 
| Renal tubular function: sodium transport | Iohexol corrected sodium excretion | After 4 week treatment with active drug intervention versus placebo | 
| Renal damage markers | 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. | After 4 week treatment with active drug intervention versus placebo | 
| Changes in plasma energy substrate: glucose | Changes in plasma energy substrate: glucose | After 4 week treatment with active drug intervention versus placebo | 
| Changes in plasma energy substrate: free fatty acids | Changes in plasma energy substrate: free fatty acids | After 4 week treatment with active drug intervention versus placebo | 
| Changes in plasma energy substrate: ketone bodies | Changes in plasma energy substrate: ketone bodies | After 4 week treatment with active drug intervention versus placebo | 
| Changes in plasma energy substrate:triglycerides | Changes in plasma energy substrate:triglycerides | After 4 week treatment with active drug intervention versus placebo | 
| Energy expenditure | By resting energy expenditure | After 4 week treatment with active drug intervention versus placebo | 
| Changes in erythropoietin (EPO) levels | Changes in erythropoietin (EPO) levels | After 4 week treatment with active drug intervention versus placebo | 
| Insulin sensitivity | OGIS and Matsuda Index during an oral glucose tolerance test (OGTT) | After 4 week treatment with active drug intervention versus placebo | 
| Beta-cell function | Beta-cell function will be derived from HOMA-B modelling during an oral glucose tolerance test (OGTT). | After 4 week treatment with active drug intervention versus placebo | 
| Peripheral insulin extraction | Arterial-venous difference before and following an OGTT | After 4 week treatment with active drug intervention versus placebo | 
| Total insulin extraction | Arterial-venous difference before and following an OGTT | After 4 week treatment with active drug intervention versus placebo |