Steno Diabetes Center Copenhagen
Gentofte Municipality, 2820, Denmark
NCT Number: NCT04193566
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.
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Notify Me18 year and older
All sexes
Interventional
Phase 4
Gentofte Municipality, 2820, Denmark
Healthy volunteers accepted: Yes
Only the study team can determine whether someone qualifies for participation.
Inclusion criteria
healthy controls:
Inclusion criteria
persons with type 1 diabetes:
Exclusion criteria
for all:
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.
Other names: dapagliflozin
Time frame: From baseline to +3 hours from intervention
Blood Oxygen Level Dependent (BOLD) Magnetic Resonance Imaging (MRI) assessing the transverse relaxation time of atomic nuclei in the tissue (T2*) in miliseconds (ms).
Time frame: From baseline to +6 hours from intervention
BOLD MRI assessing the transverse relaxation time of atomic nuclei in the tissue (T2*) in miliseconds (ms).
Time frame: From baseline to +3 hours from intervention
Renal tissue perfusion can be measured noninvasively with MRI using arterial spin labelling (ASL). It is measured in mL/g/min.
Time frame: From baseline to +6 hours from intervention
Renal tissue perfusion can be measured with MRI using arterial spin labelling (ASL). It is measured in mL/g/min.
Time frame: From baseline to +3 hours from intervention
Renal artery flow can be measured by using phase contrast (PC) MRI. It is measured in mL/min.
Time frame: From baseline to +6 hours from intervention
Renal artery flow can be measured by using phase contrast (PC) MRI. It is measured in mL/min.
Time frame: From baseline to +3 hours from intervention
Renal oxygen consumption can be measured using Q-flow combined with BOLD MRI. It is measured in pmol/min/microgram protein.
Time frame: From baseline to +6 hours from intervention
Renal oxygen consumption can be measured using Q-flow combined with BOLD MRI. pmol/min/microgram protein
Time frame: From baseline to +3 hours from intervention
Pulse oximetry on index finger of the right hand. Estimates blood oxygen saturation from capillary blood. Measured in %.
Time frame: From baseline to +6 hours from intervention
Pulse oximetry on index finger of the right hand. Estimates blood oxygen saturation from capillary blood. Measured in %.
Time frame: From baseline to +3 hours from intervention
Blood gas analysis on arterial blood. Measured in kPa.
Time frame: From baseline to +6 hours from intervention
Blood gas analysis on arterial blood. Measured in kPa.
Time frame: From baseline to +3 hours from intervention
Blood gas analysis on arterial blood. Measured in %.
Time frame: From baseline to +6 hours from intervention
Blood gas analysis on arterial blood. Measured in %.
Time frame: From baseline to +12 hours from intervention
Seahorse X96 analyzer. Analyzes the oxygen consumption rate (OCR), measured in pMoles/min.
Time frame: From baseline to +12 hours from intervention
Commercially available panel from the company Olink. Includes 92 biomarkers. Information on the panel can be found here: https://www.olink.com/products/inflammation/#.
Time frame: From baseline to +12 hours from intervention
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.
Steno Diabetes Center Copenhagen
Other
Acute Effects of Sodium-glucose Cotransporter-2 Inhibition on Renal Oxygenation and Autonomic Function in Type 1 Diabetes
Acronym: Astronaut
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