Renal Oxygenation, Oxygen Consumption and Hemodynamic Kinetics in Type 2 DIabetes: an Ertugliflozin Study.

Type 2 Diabetes Mellitus Clinical Trial

— ROCKIES  

Official title:

Phase 4, Randomized, Placebo-controlled, Cross-over Trial to Assess the Effect of 4-week Ertugliflozin (SGLT-2 Inhibitor) Therapy on Renal Oxygenation by BOLD-MRI and Renal Oxygen Consumption by PET Using ¹¹C-acetate in T2DM Without Kidney Disease and Healthy Controls.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04027530
• Other study ID #: DC2019 ROCKIES 1
• Status: Completed
• Phase: Phase 4
• Start date: December 10, 2020
• Est. completion date: January 9, 2023

Study information

• Verified date: April 2023
• Source: Amsterdam UMC, location VUmc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Current study will render insight in to the role of renal hypoxia in the diabetic kidney and is able to associate its finding with measurements of renal perfusion and glomerular filtration rate. Moreover, this research will focus on the effects of sodium-glucose cotransporter 2 inhibition on renal tissue oxygenation and oxygen consumption as well as a change in intrarenal hemodynamics and perfusion, and a shift of fuel metabolites. Elucidation the mechanisms underlying the effects of SGLT2 inhibition will advance our knowledge and contribute to their optimal clinical utilization in the treatment of chronic kidney disease in diabetes and possibly beyond.

Description:

Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) are a relatively new class of drugs in the treatment of diabetes and improve glycemic control by blocking SGLT-2 in the proximal tubule, the main transporter of coupled sodium-glucose reabsorption Three large cardiovascular outcome trials (EMPA-REG, CANVAS, DECLARE- TIMI 58) showed SGLT-2 inhibition to have a renoprotective effect, including on renal outcomes. Moreover, the recently publicized CREDENCE trial concluded early after the planned interim analyses showed a striking renoprotective effect of SGLT-2 inhibition in patients with T2DM and CKD. The mechanisms underlying their beneficial effects remain to be elucidated, as the small SGLT-2 induced reduction in glucose level (0.5% HbA1c), bodyweight (about 3%), systolic blood pressure (about 4 mmHg), or uric acid (about 6%) are insufficient to fully account for the effect.

The pathological mechanisms underlying DKD involve complex interactions between metabolic and haemodynamic factors which are not fully understood. However, accumulating evidence of foremost animal studies indicates that a chronic state of renal tissue hypoxia is the final common pathway in the development and progression of diabetic kidney disease. Therefore several hypothesis have been proposed on the alleviation of chronic tissue hypoxia following SGLT-2 inhibition: (1) A decrease in workload by a decrease in GFR. (2) A shift in renal fuel energetics by increasing ketone body oxidation, which renders high ATP/oxygen consumption ratio's compared to glucose or free fatty acids. (3) An improvement of cardiac function and systemic hemodynamics to lead to an increase in renal perfusion, and (4) an increase in erythropoietin (EPO) levels to stimulate oxygen delivery.

Current study will examine the above hypothesis by researching renal oxygenation by BOLD-MRI, oxygen consumption by PET-CT, and hemodynamic kinetics by the Iohexol clearance method/contrast-enhance ultrasound/arterial spin labeling. Blood sampling will allow for the measurement of EPO and ketone bodies, as well as a resting energy expenditure will elucidate a shift in use of energy substrate metabolism. The research will be performed in T2DM without overt kidney disease (n=20) before and after a 4 week treatment with SGLT-2 inhibition (ertugliflozin), and will be compared the obtained results from healthy controls (n=20).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: January 9, 2023
• Est. primary completion date: January 9, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Group 1: T2DM patients

Inclusion criteria

• Provision of signed and dated, written informed consent prior to any study specific procedures.

• Caucasian*; female or male aged =18 years and <80 years. Females must be post-menopausal (defined as no menses >1 year and follicle stimulating hormone (FSH) >31 U/L)*.

• Type 2 diabetes mellitus since at least 3 years with HbA1c = 6.5% (=57mmol/mol) and <10% (<94mmol/mol)

• An appropriate stable dose of metformin and/or sulfonylurea as glucose-lowering therapy for the last 12 weeks

• Maximum tolerated antihypertensive dose of an ARB for at least 6 weeks prior to randomization.

• eGFR 60-90 ml/min/1.73m²

• BMI 25-35 kg/m² * In order to increase homogeneity

Exclusion criteria

• Involvement in the planning and/or conduction of another study

• Participation in another clinical study with an investigational product during the last 3 months

• Diagnosis of type 1 diabetes mellitus

• CKD defined as eGFR<60 ml/min/1.73m² or albuminuria (defined as an UACR > 2.5 mg/mol).

• Cardiovascular disease event in the last 6 months prior to enrollment as assessed by the investigator, including: myocardial infarction, cardiac surgery or revascularization (CABG/PTCA), unstable angina, heart failure, transient ischemic attack (TIA) or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia.

• Current/chronic use of the following medication: insulin, thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors, oral glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), immune suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs), diuretics, and monoamine oxidase inhibitors.

• Current urinary tract infection or active nephritis

• History of ketoacidosis

• History of allergy/hypersensitivity to any of the test agents.

Group 2: Age-matched and eGFR-matched non-diabetic controls Inclusion criteria

• Provision of signed and dated, written informed consent prior to any study specific procedures.

• Caucasian*; female or male aged =18 years and <80 years. Females must be post-menopausal (defined as no menses >1 year and follicle stimulating hormone (FSH) >31 U/L)*.

• Normal glucose tolerance at screening as confirmed by OGTT

• Maximum tolerated antihypertensive dose of an ARB for at least 6 weeks prior to randomization in case of hypertension.

• BMI 25-35 kg/m2

• eGFR 60-90ml/min * In order to increase homogeneity

Exclusion criteria

• Involvement in the planning and/or conduction of another study

• Participation in another clinical study with an investigational product during the last 3 months

• CKD defined as eGFR<60ml/min or macro-albuminuria or proteinuria

• Cardiovascular disease event in the last 6 months prior to enrollment, as assessed by the investigator, including: myocardial infarction, cardiac surgery or revascularization (CABG/PTCA), unstable angina, heart failure, transient ischemic attack (TIA) or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia.

• Use of medication that may interfere with study endpoints non-steroidal anti-inflammatory drugs (NSAIDs), immune suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs), diuretics, and monoamine oxidase inhibitors.

• Current urinary tract infection and active nephritis

• Any other condition that prevents participation as judged by investigator.

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Diabetic Kidney Disease
• Diabetic Nephropathies
• Diabetic Nephropathy
• Ertugliflozin
• Hypoxia
• Kidney Diseases
• Renal Hypoxia
• Renoprotection
• SGLT2 Inhibitor
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Ertugliflozin 15 mg
Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks

Locations

Country	Name	City	State
Netherlands	VU University Medical Center	Amsterdam

Sponsors (1)

Lead Sponsor	Collaborator
Amsterdam UMC, location VUmc

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Renal oxygenation measured by BOLD-MRI (R2*)	Renal (separated as cortical and medullar) oxygenation measured by BOLD-MRI (R2*)	After 4 week treatment with ertugliflozin 15mg QD versus placebo
Secondary	Renal oxygen consumption by PET/CT-scan using 11C-Acetate	Renal oxygen consumption will be measured by PET/CT-scan using 11C-Acetate and compartment model parameter k2	After 4 week treatment with active drug intervention versus placebo
Secondary	Renal hemodynamics	GFR and ERPF	After 4 week treatment with active drug intervention versus placebo
Secondary	Renal efficiency	Measured as sodium reabsorption divided by oxygen consumption	After 4 week treatment with active drug intervention versus placebo
Secondary	Cortical blood flow	measured by contrast-enhanced ultrasound	After 4 week treatment with active drug intervention versus placebo
Secondary	Renal arterial blood flow	measured by arterial spin labelling	After 4 week treatment with active drug intervention versus placebo
Secondary	Acute 24-hour sodium and glucose excretion	24-hour sodium and glucose excretion after 2 days; Urine osmolality; Urinary pH	After 2 days of treatment with active drug intervention versus placebo
Secondary	Chronic 24-hour sodium and glucose excretion	24-hour sodium and glucose excretion after 4 weeks	After 4 week treatment with active drug intervention versus placebo
Secondary	Renal tubular function: Urinary pH	Urinary pH	After 4 week treatment with active drug intervention versus placebo
Secondary	Renal tubular function: Urine Osmolality	Urine osmolality	After 4 week treatment with active drug intervention versus placebo
Secondary	Renal tubular function: sodium transport	Iohexol corrected sodium excretion	After 4 week treatment with active drug intervention versus placebo
Secondary	Renal damage markers	Renal damage markers will include: urinary albumin excretion in 24-hour urine samples and other markers depending on relevant (emerging) metabolic and humoral biomarkers of renal damage, conditional to available budget.	After 4 week treatment with active drug intervention versus placebo
Secondary	Changes in plasma energy substrate: glucose	Changes in plasma energy substrate: glucose	After 4 week treatment with active drug intervention versus placebo
Secondary	Changes in plasma energy substrate: free fatty acids	Changes in plasma energy substrate: free fatty acids	After 4 week treatment with active drug intervention versus placebo
Secondary	Changes in plasma energy substrate: ketone bodies	Changes in plasma energy substrate: ketone bodies	After 4 week treatment with active drug intervention versus placebo
Secondary	Changes in plasma energy substrate:triglycerides	Changes in plasma energy substrate:triglycerides	After 4 week treatment with active drug intervention versus placebo
Secondary	Energy expenditure	By resting energy expenditure	After 4 week treatment with active drug intervention versus placebo
Secondary	Changes in erythropoietin (EPO) levels	Changes in erythropoietin (EPO) levels	After 4 week treatment with active drug intervention versus placebo
Secondary	Insulin sensitivity	OGIS and Matsuda Index during an oral glucose tolerance test (OGTT)	After 4 week treatment with active drug intervention versus placebo
Secondary	Beta-cell function	Beta-cell function will be derived from HOMA-B modelling during an oral glucose tolerance test (OGTT).	After 4 week treatment with active drug intervention versus placebo
Secondary	Peripheral insulin extraction	Arterial-venous difference before and following an OGTT	After 4 week treatment with active drug intervention versus placebo
Secondary	Total insulin extraction	Arterial-venous difference before and following an OGTT	After 4 week treatment with active drug intervention versus placebo