Acute Effects of SGLT2 Inhibition on Renal Oxygenation and Autonomic Function in Type 1 Diabetes

Study Overview
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Brief Summary
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Background: Inhibiting the sodium-glucose cotransporter-2 (SGLT2) has been observed to reduce risk of cardiovascular events and kidney failure in type 2 diabetes. The exact mechanisms of the beneficial effects of SGLT2 inhibition (SGLT2i) are still unknown. Kidney hypoxia has been demonstrated in diabetic kidney disease and SGLT2i is thought to relieve hypoxia in the kidneys. Mitochondrial dysfunction and autonomic dysfunction might also contribute to kidney hypoxia. Objective: The primary aim of the study is to assess the acute effects of SGLT2 inhibition on parameters reflecting oxygenation and oxygen consumption of the human kidney in persons with type 1 diabetes. Exploratory aims are to investigate acute changes in oxygen availability and oxygen access to the kidneys after SGLT2i. This include measures of peripheral blood oxygenation, mitochondrial function and autonomic function. Methods: Acute intervention study with oral dapagliflozin given in two doses each of 50 mg or matching placebo as intervention. Kidney oxygenation and perfusion parameters will be assessed by blood-oxygen-dependant level magnetic resonance imaging. Mitochondrial function will be assessed by extracellular flux analysis on lymphocytes. Autonomic function will be assessed by measuring baroreflex sensitivity. Design: Randomized, double blinded, placebo-controlled, cross-over intervention study. Study population: Fifteen healthy controls are recruited by advertisement and 15 patients with type 1 diabetes recruited from Steno Diabetes Center Copenhagen. Endpoints: Primary end-point: Renal cortical and medullary oxygenation (T2*). Exploratory end-points: Renal cortical and medullary perfusion, renal artery flow, renal oxygen consumption, peripheral capillary oxygen saturation (SpO2), arterial oxygen partial pressure (PaO2), arterial oxygen saturation (SaO2), lymphocyte mitochondrial function, baroreflex sensitivity. Timeframe: Inclusion of patients from January 2020. Last patient last visit January 2021. Data analysis completed spring 2021, presentation autumn 2021 and publications Winter 2021.

Official Title
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Acute Effects of Sodium-glucose Cotransporter-2 Inhibition on Renal Oxygenation and Autonomic Function in Type 1 Diabetes

Conditions
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Nephropathy, Hypoxia, Mitochondrial Alteration, Type 1 Diabetes, Autonomic Neuropathy, Diabetic

Intervention / Treatment
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* Drug: Forxiga


Participation Criteria
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Eligibility Criteria
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Inclusion criteria healthy controls: Written informed consent must be provided before participation Male or female patients > 18 years of age Capable of lying in a MR-scanner for two hours Inclusion criteria persons with type 1 diabetes: Written informed consent must be provided before participation Male or female patients >18 years of age with a diagnosis of type 1 diabetes (WHO criteria) Urinary albumin creatinine ratio (UACR) ≥30 mg/g in 2 out of 3 consecutive samples (albuminuria) prior to randomization assessed from electronic laboratory database. Capable of lying in a MR-scanner for two hours Exclusion criteria for all: Non-diabetic kidney disease as indicated by medical history and/or laboratory findings Renal failure (eGFR<15 ml/min/1.73m2), dialysis or kidney transplantation Treatment with beta-blocking medication Uncontrolled arrhythmia, 2. or 3. degree AV-block or sick sinus syndrome - assessed from a standard 12-lead electrocardiogram Pregnancy or breastfeeding (urine HCG is performed on all fertile women) Systolic blood pressure < 90 or > 200 mmHg Patients who, in the judgement of the investigator, is incapable of participating Exclusion criteria for MRI Claustrophobia Known heart disease Known lung disease Have had surgery the past six weeks Have foreign bodies of metal in the body (e.g. pacemaker, metal plates, metal screws) Exclusion criteria for arterial blood gas sampling (only patients with type 1 diabetes) Absent pulse Raynauds syndrome Buergers Disease (thromboangiitis obliterans) Inadequate or interrupted circulation Anticoagulation treatment Coagulopathies (hypo or hyper coagulable states) Arterial atherosclerosis Insufficient collateral perfusion Partial or full thickness burns over the cannulation site Synthetic arterial or vascular grafts or infection at the proposed site of cannulation Patients with type 1 diabetes will have the possibility to participate in the study without getting arterial blood gas sampling.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized, double blinded, placebo-controlled, cross-over intervention study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dapagliflozin<br>Patients in the active arm will be treated with dapagliflozin 50 mg once on site for visit 2 and once at home on the evening before visit 3. Forxiga®, dapagliflozin 10 mg film-coated tablet. For further information please refer to: https://www.ema.europa.eu/en/documents/product-information/forxiga-epar-product-information_en.pdf. | Drug: Forxiga<br>* Forxiga®, dapagliflozin 10 mg film-coated tablet. For further information please refer to: https://www.ema.europa.eu/en/documents/product-information/forxiga-epar-product-information_en.pdf. Common side effects include hypoglycemia, hypotension, elevated hematocrite, dyslipidemia, back pain, dizziness, skin rash, urinary tract infection, vulvovaginitis and dehydration. Very rare incidents of ketoacidosis have been observed. Side effects have only been observed after use in longer periods and not in single-dose usage, as planned in the present study. A dose of 50 mg has been chosen to achieve optimal efficacy. Once-per-day doses of dapagliflozin for 12 weeks of 2.5 mg, 5 mg, 10 mg, 20 mg and 50 mg have been demonstrated to be relatively safe across the mentioned doses (20) and no apparent risk is expected from instituting two single-doses of 50 mg dapagliflozin.<br>* Other names: dapagliflozin;|
| Placebo Comparator: Placebo<br>Patients in the placebo arm will be treated with placebo once on site for visit 2 and once at home on the evening before visit 3. Placebo drug: The composition equals the composition of Forxiga® - just with the active ingredient omitted. Active drug and placebo are similar in appearance and smell. | Drug: Forxiga<br>* Forxiga®, dapagliflozin 10 mg film-coated tablet. For further information please refer to: https://www.ema.europa.eu/en/documents/product-information/forxiga-epar-product-information_en.pdf. Common side effects include hypoglycemia, hypotension, elevated hematocrite, dyslipidemia, back pain, dizziness, skin rash, urinary tract infection, vulvovaginitis and dehydration. Very rare incidents of ketoacidosis have been observed. Side effects have only been observed after use in longer periods and not in single-dose usage, as planned in the present study. A dose of 50 mg has been chosen to achieve optimal efficacy. Once-per-day doses of dapagliflozin for 12 weeks of 2.5 mg, 5 mg, 10 mg, 20 mg and 50 mg have been demonstrated to be relatively safe across the mentioned doses (20) and no apparent risk is expected from instituting two single-doses of 50 mg dapagliflozin.<br>* Other names: dapagliflozin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Renal oxygenation | Blood Oxygen Level Dependent (BOLD) Magnetic Resonance Imaging (MRI) assessing the transverse relaxation time of atomic nuclei in the tissue (T2*) in miliseconds (ms). | From baseline to +3 hours from intervention | 
| Change in Renal oxygenation | BOLD MRI assessing the transverse relaxation time of atomic nuclei in the tissue (T2*) in miliseconds (ms). | From baseline to +6 hours from intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in renal cortical and medullary perfusion | Renal tissue perfusion can be measured noninvasively with MRI using arterial spin labelling (ASL). It is measured in mL/g/min. | From baseline to +3 hours from intervention | 
| Change in renal cortical and medullary perfusion | Renal tissue perfusion can be measured with MRI using arterial spin labelling (ASL). It is measured in mL/g/min. | From baseline to +6 hours from intervention | 
| Change in renal artery flow | Renal artery flow can be measured by using phase contrast (PC) MRI. It is measured in mL/min. | From baseline to +3 hours from intervention | 
| Change in renal artery flow | Renal artery flow can be measured by using phase contrast (PC) MRI. It is measured in mL/min. | From baseline to +6 hours from intervention | 
| Change in renal oxygen consumption | Renal oxygen consumption can be measured using Q-flow combined with BOLD MRI. It is measured in pmol/min/microgram protein. | From baseline to +3 hours from intervention | 
| Change in renal oxygen consumption | Renal oxygen consumption can be measured using Q-flow combined with BOLD MRI. pmol/min/microgram protein | From baseline to +6 hours from intervention | 
| Change in peripheral capillary oxygen saturation (SpO2) | Pulse oximetry on index finger of the right hand. Estimates blood oxygen saturation from capillary blood. Measured in %. | From baseline to +3 hours from intervention | 
| Change in peripheral capillary oxygen saturation (SpO2) | Pulse oximetry on index finger of the right hand. Estimates blood oxygen saturation from capillary blood. Measured in %. | From baseline to +6 hours from intervention | 
| Change in blood oxygen partial pressure (PaO2) | Blood gas analysis on arterial blood. Measured in kPa. | From baseline to +3 hours from intervention | 
| Change in blood oxygen partial pressure (PaO2) | Blood gas analysis on arterial blood. Measured in kPa. | From baseline to +6 hours from intervention | 
| Change in arterial blood oxygen saturation | Blood gas analysis on arterial blood. Measured in %. | From baseline to +3 hours from intervention | 
| Change in arterial blood oxygen saturation | Blood gas analysis on arterial blood. Measured in %. | From baseline to +6 hours from intervention | 
| Change in Peripheral Blood Monocyte mitochondrial function | Seahorse X96 analyzer. Analyzes the oxygen consumption rate (OCR), measured in pMoles/min. | From baseline to +12 hours from intervention | 
| Change in levels of circulating inflammatory markers | Commercially available panel from the company Olink. Includes 92 biomarkers. Information on the panel can be found here: https://www.olink.com/products/inflammation/#. | From baseline to +12 hours from intervention | 
| Change in baroreflex sensitivity | Calculated from continous blood pressure and the distance between the R-waves in a continuous ecg. Baroreflex sensitivity describes how much heart-rate changes when blood pressure changes. Assessment of baroreflex sensitivity is done in a measurement of 5 minutes. The unit is ms/mmHg. | From baseline to +12 hours from intervention |