Clinical trial NCT04193566: Acute Effects of SGLT2 Inhibition on Renal Oxygenation and Autonomic Function in Type 1 Diabetes
Official title: Acute Effects of Sodium-glucose Cotransporter-2 Inhibition on Renal Oxygenation and Autonomic Function in Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Nephropathy
Hypoxia
Mitochondrial Alteration
Type 1 Diabetes
Autonomic Neuropathy, Diabetic
Lead sponsor: Steno Diabetes Center Copenhagen
Sponsor class: OTHER
Collaborators: name: Glostrup University Hospital, Copenhagen
name: Novo Nordisk A/S
First posted: 2019-12-10
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized, double blinded, placebo-controlled, cross-over intervention study
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change in Renal oxygenation
timeFrame: From baseline to +3 hours from intervention
measure: Change in Renal oxygenation
timeFrame: From baseline to +6 hours from intervention
Secondary outcomes:
measure: Change in renal cortical and medullary perfusion
timeFrame: From baseline to +3 hours from intervention
measure: Change in renal cortical and medullary perfusion
timeFrame: From baseline to +6 hours from intervention
measure: Change in renal artery flow
timeFrame: From baseline to +3 hours from intervention
measure: Change in renal artery flow
timeFrame: From baseline to +6 hours from intervention
measure: Change in renal oxygen consumption
timeFrame: From baseline to +3 hours from intervention
measure: Change in renal oxygen consumption
timeFrame: From baseline to +6 hours from intervention
measure: Change in peripheral capillary oxygen saturation (SpO2)
timeFrame: From baseline to +3 hours from intervention
measure: Change in peripheral capillary oxygen saturation (SpO2)
timeFrame: From baseline to +6 hours from intervention
measure: Change in blood oxygen partial pressure (PaO2)
timeFrame: From baseline to +3 hours from intervention
measure: Change in blood oxygen partial pressure (PaO2)
timeFrame: From baseline to +6 hours from intervention
measure: Change in arterial blood oxygen saturation
timeFrame: From baseline to +3 hours from intervention
measure: Change in arterial blood oxygen saturation
timeFrame: From baseline to +6 hours from intervention
measure: Change in Peripheral Blood Monocyte mitochondrial function
timeFrame: From baseline to +12 hours from intervention
measure: Change in levels of circulating inflammatory markers
timeFrame: From baseline to +12 hours from intervention
measure: Change in baroreflex sensitivity
timeFrame: From baseline to +12 hours from intervention
Other outcomes:
Locations:
city: Gentofte
country: Denmark
facility: Steno Diabetes Center Copenhagen
Study officials:
References:
citation: 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.