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

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

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.

Study Overview

• Status: Completed
• Conditions: Hypoxia; Type 1 Diabetes; Nephropathy; Autonomic Neuropathy, Diabetic; Mitochondrial Alteration
• Intervention / Treatment: Drug: Forxiga

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Gentofte, Denmark, 2820
    • Steno Diabetes Center Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dapagliflozin; 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; 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
Placebo Comparator: Placebo; 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; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: Novo Nordisk A/S; Glostrup University Hospital, Copenhagen

Publications and helpful links

General Publications

• Laursen JC, Sondergaard-Heinrich N, de Melo JML, Haddock B, Rasmussen IKB, Safavimanesh F, Hansen CS, Storling J, Larsson HBW, Groop PH, Frimodt-Moller M, Andersen UB, Rossing P. Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial. EClinicalMedicine. 2021 Jun 28;37:100895. doi: 10.1016/j.eclinm.2021.100895. eCollection 2021 Jul.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2020
• Primary Completion (Actual): September 1, 2020
• Study Completion (Actual): January 1, 2021

Study Registration Dates

• First Submitted: December 3, 2019
• First Submitted That Met QC Criteria: December 6, 2019
• First Posted (Actual): December 10, 2019

Study Record Updates

• Last Update Posted (Actual): February 3, 2021
• Last Update Submitted That Met QC Criteria: January 29, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Complications; Neuromuscular Diseases; Peripheral Nervous System Diseases; Signs and Symptoms, Respiratory; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoxia; Diabetic Neuropathies; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: H-19052662; 2019-004557-92 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No