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

NCT ID: NCT04027530

Last Updated: 2023-05-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-12-10
• Study Completion Date: 2023-01-09

Brief 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.

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).

Conditions

Type 2 Diabetes Mellitus; Diabetic Kidney Disease; Diabetic Nephropathy; Renal Hypoxia; Renoprotection; SGLT2 Inhibitor; Ertugliflozin

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Ertugliflozin 15mg once daily

Once daily treatment with oral ertugliflozin (steglatro) 15mg for 4 consecutive weeks.

Group Type: EXPERIMENTAL

Ertugliflozin 15 mg

Intervention Type: DRUG

Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks

Placebo

Once daily treatment with a placebo pill for 4 consecutive weeks.

Group Type: PLACEBO_COMPARATOR

Ertugliflozin 15 mg

Intervention Type: DRUG

Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks

Interventions

Ertugliflozin 15 mg

Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks

Intervention Type: DRUG

Other Intervention Names

Steglatro

Eligibility Criteria

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

• 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
• 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.

• 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Amsterdam UMC, location VUmc

OTHER

Sponsor Role: lead

Responsible Party

D van Raalte

Dr. D.H. van Raalte

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

VU University Medical Center

Amsterdam, , Netherlands

Countries

Netherlands

Other Identifiers

DC2019 ROCKIES 1

Identifier Type: -

Identifier Source: org_study_id