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

Phase 4

Completed

• Conditions: Nephropathy; Hypoxia; Type 1 Diabetes; Autonomic Neuropathy, Diabetic; Mitochondrial Alteration
• Interventions: Drug: Forxiga

• Registration Number: NCT04193566
• Lead Sponsor: Steno Diabetes Center Copenhagen

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-12-03
• Study First Submitted QC: 2019-12-06
• Study First Posted: 2019-12-10
• Study Start: 2020-02-01
• Primary Completion: 2020-09-01
• Status Verified: 2021-01
• Study Completion: 2021-01-01
• Last Update Submitted: 2021-01-29
• Last Update Posted: 2021-02-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Dapagliflozin	Forxiga	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.
Placebo	Forxiga	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.

Primary Outcome Measures

Name	Time	Method
Change in Renal oxygenation	From baseline to +6 hours from intervention	BOLD MRI assessing the transverse relaxation time of atomic nuclei in the tissue (T2\*) in miliseconds (ms).

Secondary Outcome Measures

Name	Time	Method
Change in levels of circulating inflammatory markers	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/#.
Change in renal oxygen consumption	From baseline to +6 hours from intervention	Renal oxygen consumption can be measured using Q-flow combined with BOLD MRI. pmol/min/microgram protein
Change in renal cortical and medullary perfusion	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.
Change in renal artery flow	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.
Change in Peripheral Blood Monocyte mitochondrial function	From baseline to +12 hours from intervention	Seahorse X96 analyzer. Analyzes the oxygen consumption rate (OCR), measured in pMoles/min.
Change in baroreflex sensitivity	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.
Change in blood oxygen partial pressure (PaO2)	From baseline to +6 hours from intervention	Blood gas analysis on arterial blood. Measured in kPa.
Change in arterial blood oxygen saturation	From baseline to +6 hours from intervention	Blood gas analysis on arterial blood. Measured in %.
Change in peripheral capillary oxygen saturation (SpO2)	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 %.

Trial Locations

Locations (1)

Steno Diabetes Center Copenhagen; 🇩🇰 Gentofte, Denmark