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

NCT04193566 | Completed Phase 4 DMC

• 2 other identifiers: H-190526622019-004557-92
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (15)

• Change in renal cortical and medullary perfusion

  From baseline to +3 hours from intervention

• Change in renal cortical and medullary perfusion

  From baseline to +6 hours from intervention

• Change in renal artery flow

  From baseline to +3 hours from intervention

• Change in renal artery flow

  From baseline to +6 hours from intervention

• Change in renal oxygen consumption

  From baseline to +3 hours from intervention

Study Arms (2)

Dapagliflozin

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Forxiga DRUG

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.

Also known as: dapagliflozin

Dapagliflozin; Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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)
• Absent pulse
• Raynauds syndrome
• Buergers Disease (thromboangiitis obliterans)

Sponsors & Collaborators

• Steno Diabetes Center Copenhagen: lead
• Glostrup University Hospital, Copenhagen: collaborator
• Novo Nordisk A/S: collaborator

Study Sites (1)

Steno Diabetes Center Copenhagen

Gentofte Municipality, 2820, Denmark

Location

Related Publications (1)

• 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.

  PMID: 34386735 DERIVED

MeSH Terms

Conditions

Kidney Diseases; Hypoxia; Diabetes Mellitus, Type 1; Diabetic Neuropathies

Interventions

dapagliflozin

Condition Hierarchy (Ancestors)

Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Diabetes Complications

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Group allocation is concealed to patients as well as investigators. 60 sequentially numbered, opaque, sealed envelopes will be produced by Glostrup Apotek. All persons involved in the conduct of the study are blinded to the randomization code. Randomization codes and envelopes are stored securely at the study site available only for the unblinded site staff in charge of randomizing subjects and dispensing study products to subjects. Sealed codes are marked according to randomization code and distributed according to a pre-distributed order. Should unblinding of a study participant be necessary because of an emergency, a dedicated person at Steno Diabetes Center Copenhagen, not involved in the study, will perform the procedure. Alternatively, the Principal investigator will be able to perform unblinding
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, double blinded, placebo-controlled, cross-over intervention study

Study Record Dates

• First Submitted: December 3, 2019
• First Posted: December 10, 2019
• Study Start: February 1, 2020
• Primary Completion: September 1, 2020
• Study Completion: January 1, 2021
• Last Updated: February 3, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)