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

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.

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus; Diabetic Nephropathy; Diabetic Kidney Disease; Renal Hypoxia; Renoprotection; SGLT2 Inhibitor; Ertugliflozin
• Intervention / Treatment: Drug: Ertugliflozin 15 mg

Detailed 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).

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Anne Hesp, Msc.; Phone Number: +31-20-4444260; Email: a.c.hesp@amsterdamumc.nl
• Study Contact Backup: Name: Daniel van Raalte, Dr.; Phone Number: +31-20-4440534; Email: d.vanraalte@amsterdamumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ertugliflozin 15mg once daily; Once daily treatment with oral ertugliflozin (steglatro) 15mg for 4 consecutive weeks.	Drug: Ertugliflozin 15 mg; Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks; Other Names: Steglatro
Placebo Comparator: Placebo; Once daily treatment with a placebo pill for 4 consecutive weeks.	Drug: Ertugliflozin 15 mg; Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks; Other Names: Steglatro

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Renal hemodynamics	GFR and ERPF	After 4 week treatment with active drug intervention versus placebo
Renal efficiency	Measured as sodium reabsorption divided by oxygen consumption	After 4 week treatment with active drug intervention versus placebo
Cortical blood flow	measured by contrast-enhanced ultrasound	After 4 week treatment with active drug intervention versus placebo
Renal arterial blood flow	measured by arterial spin labelling	After 4 week treatment with active drug intervention versus placebo
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
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
Renal tubular function: Urinary pH	Urinary pH	After 4 week treatment with active drug intervention versus placebo
Renal tubular function: Urine Osmolality	Urine osmolality	After 4 week treatment with active drug intervention versus placebo
Renal tubular function: sodium transport	Iohexol corrected sodium excretion	After 4 week treatment with active drug intervention versus placebo
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
Changes in plasma energy substrate: glucose	Changes in plasma energy substrate: glucose	After 4 week treatment with active drug intervention versus placebo
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
Changes in plasma energy substrate: ketone bodies	Changes in plasma energy substrate: ketone bodies	After 4 week treatment with active drug intervention versus placebo
Changes in plasma energy substrate:triglycerides	Changes in plasma energy substrate:triglycerides	After 4 week treatment with active drug intervention versus placebo
Energy expenditure	By resting energy expenditure	After 4 week treatment with active drug intervention versus placebo
Changes in erythropoietin (EPO) levels	Changes in erythropoietin (EPO) levels	After 4 week treatment with active drug intervention versus placebo
Insulin sensitivity	OGIS and Matsuda Index during an oral glucose tolerance test (OGTT)	After 4 week treatment with active drug intervention versus placebo
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
Peripheral insulin extraction	Arterial-venous difference before and following an OGTT	After 4 week treatment with active drug intervention versus placebo
Total insulin extraction	Arterial-venous difference before and following an OGTT	After 4 week treatment with active drug intervention versus placebo

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2020
• Primary Completion (Actual): January 9, 2023
• Study Completion (Actual): January 9, 2023

Study Registration Dates

• First Submitted: July 9, 2019
• First Submitted That Met QC Criteria: July 16, 2019
• First Posted (Actual): July 22, 2019

Study Record Updates

• Last Update Posted (Actual): May 1, 2023
• Last Update Submitted That Met QC Criteria: April 28, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Signs and Symptoms, Respiratory; Diabetes Mellitus, Type 2; Kidney Diseases; Diabetic Nephropathies; Hypoxia; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Ertugliflozin
• Other Study ID Numbers: DC2019 ROCKIES 1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No