Kidney Fat in Type 2 Diabetes and the Effects of Ezetimibe (DiaKidZ)

Kidney Fat in Type 2 Diabetes & Diabetic Kidney Disease and the Effects of Ezetimibe: A Cross-Sectional Study and Randomized, Placebo-Controlled Trial

In this study, we seek to explore the importance of fat accumulation in the kidneys in relation to diabetic kidney disease (DKD). To do this, we conduct an intervention trial in individuals with type 2 diabetes (T2D) and DKD where we investigate whether the inhibition of intestinal cholesterol absorption with ezetimibe affects albuminuria (a strong risk factor for diabetic complications) and kidney fat accumulation. At the same time and to confirm that kidney fat accumulation is, in fact, abnormal in T2D and DKD, we conduct a cross-sectional study in which we compare kidney fat accumulation in participants at baseline from the intervention trial with a group of individuals with T2D and no DKD and a group of healthy individuals.

Study Overview

• Status: Active, not recruiting
• Conditions: Diabetes Mellitus, Type 2; Diabetic Kidney Disease
• Intervention / Treatment: Drug: Placebo; Drug: Ezetimibe 10mg

Detailed Description

Objective:

1. To compare cross-sectionally the fractions of kidney lipid between controls, individuals with type 2 diabetes and no diabetic kidney disease and individuals with type 2 diabetes and non-severe diabetic kidney disease.
2. To assess by intervention trial whether ezetimibe reduces albuminuria and kidney parenchymal triglyceride fraction in individuals with type 2 diabetes and non-severe diabetic kidney disease.

Design:

1. Cross-sectional study on 30 controls, 30 individuals with type 2 diabetes and no diabetic kidney disease and 60 individuals with type 2 diabetes and non-severe diabetic kidney disease.

2. Single-center, randomized, double-blinded, placebo-controlled and parallel intervention trial in 60 individuals with type 2 diabetes and non-severe diabetic kidney disease Comparative treatment regime: Ezetimibe 10mg per day versus placebo for 16 weeks

   Primary endpoint in cross-sectional study:

   • Kidney parenchymal triglyceride fraction (estimated by magnetic resonance spectroscopy)

   Primary endpoint in intervention trial:

   • Urinary albumin creatinine ratio

   Secondary endpoint in intervention trial:

   • Kidney parenchymal triglyceride fraction (estimated by magnetic resonance spectroscopy)

   Main eligibility criteria for control group (cross-sectional study alone):

   • Age 40-75 years

   • No diabetes mellitus

   • No kidney disease or urinary albumin creatinine ratio ≥ 30mg/g

   • No contraindication to examination by magnetic resonance

   Main eligibility criteria for group of individuals with type 2 diabetes and no diabetic kidney disease (cross-sectional study alone):

   • Age 40-75 years

   • Type 2 diabetes
   • No kidney disease or urinary albumin creatinine ratio ≥ 30mg/g
   • No contraindication to examination by magnetic resonance

   Main eligibility criteria for group of individuals with type 2 diabetes and non-severe diabetic kidney disease (intervention trial):

   • Age 40-75 years

   • Type 2 diabetes
   • Estimated glomerular filtration rate ≥30ml/min/1,73m2
   • Urinary albumin creatinine ratio ≥ 30mg/g
   • No contraindication to examination by magnetic resonance

   Recruitment

   • Controls are recruited via announcements on relevant websites and, if necessary, in newspapers
   • Individuals with type 2 diabetes are primarily recruited from the ambulatory at Steno Diabetes Center Copenhagen

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Capital Region
    • Gentofte, Capital Region, Denmark, 2820
      • Steno Diabetes Center Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 36 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria for the intervention trial

• Age ≥ 40 and ≤ 75 years
• T2D (World Health Organization criteria)
• eGFR ≥ 30ml/min/1,73m2 at screening
• Persistent UACR ≥ 30mg/g (in more than two out of three valid measurements over a minimum of three months)
• LDL > 1.5mmol/L at screening
• Ability to communicate with the investigator and give informed consent

Exclusion criteria for the intervention trial

• Chronic kidney disease primarily ascribed to other causes than diabetes
• Acute kidney disease within 3 months
• No UACR ≥ 3000mg/g in history
• Current or recent (within 3 months) treatment with ezetimibe
• Initiation or adjustment in dosage within 1 month of an angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), glucagon-like peptide-1 receptor (GLP-1RA) agonists, sodium-glucose cotransporter 2 (SGLT-2) inhibitors or anti-dyslipidemia drug, e.g. a statin
• Any contraindication to MR-examination (e.g. magnetic foreign body that cannot easily be removed from the body prior to the examination, claustrophobia or body size not compatible with the scanner)
• Intolerance to trial drug components
• Any previous major organ transplantation
• Elective major surgery during the trial
• Pregnancy, planned pregnancy or breastfeeding during the trial
• Insufficient contraception during the trial in women of childbearing potential
• Severe alcohol consumption or abuse of recreational drugs
• Moderate to severe liver failure (Child Pugh 7-15)
• Any surgical or medical condition which can be expected to significantly alter the absorption of the trial drug (e.g. major gastrointestinal tract surgery or inflammatory bowel disease)
• Recent (within 30 days or 5-half-lives, whichever is longer) or current participation in another clinical study in which an investigational medicinal product or device has been received
• Any medical condition or history thereof or any deviation from normal laboratory values that, in the opinion of the investigator, clinically contraindicates or hinders the completion of the trial
• Any reason for suspecting a considerable lack of compliance to the trial

Inclusion criteria for the control group (cross-sectional study alone):

• Age ≥ 40 and ≤ 75 years
• eGFR ≥60ml/min/1,73m2 at screening
• Ability to communicate with the investigator and give informed consent

Exclusion criteria for the control group (cross-sectional study alone):

• Any major chronic disease, e.g. diabetes mellitus, chronic kidney disease, ischemic heart disease, chronic obstructive pulmonary disease (this criterium does not include conditions that may be considered risk factors for chronic diseases, e.g. essential hypertension, primary hypercholesterolemia)
• Acute kidney disease within 3 months
• History of persistent UACR ≥ 30mg/g (in more than two out of three valid measurements over a minimum of three months including those at screening) or a previous diagnosis of micro- or macroalbuminuria
• Current or recent (within 3 months) treatment with ezetimibe
• Any contraindication to an MR-examination (e.g. magnetic foreign body that cannot easily be removed from the body prior to the examination or claustrophobia)
• Any previous major organ transplantation
• Elective major surgery during the study
• Pregnancy, planned pregnancy or breastfeeding during the study
• Severe alcohol consumption or abuse of recreational drugs
• Moderate to severe liver failure (Child Pugh 7-15)
• Recent (within 30 days or 5-half-lives, whichever is longer) or current participation in another clinical study in which an investigational medicinal product or device has been received
• Any medical condition or history thereof or any deviation from normal laboratory values that, in the opinion of the investigator, clinically contraindicates or hinders the completion of the study
• Any reason for suspecting a considerable lack of compliance to the study

Inclusion criteria for the group of participants with T2D and no DKD (cross-sectional study alone):

• Age ≥ 40 and ≤ 75 years
• T2D (World Health Organization criteria)
• eGFR ≥60ml/min/1,73m2 at screening
• Ability to communicate with the Investigator and give informed consent

Exclusion criteria for the group of participants with T2D and no DKD (cross-sectional study alone):

• Any chronic kidney disease
• Acute kidney disease within 3 months
• History of persistent UACR ≥ 30mg/g (in more than two out of three valid measurements over a minimum of three months including those at screening) or a previous diagnosis of micro- or macroalbuminuria
• Current or recent (within 3 months) treatment with ezetimibe
• Any contraindication to an MR-examination (e.g. magnetic foreign body that cannot easily be removed from the body prior to the examination or claustrophobia)
• Any previous major organ transplantation
• Elective major surgery during the study
• Pregnancy, planned pregnancy or breastfeeding during the study
• Severe alcohol consumption or abuse of recreational drugs
• Moderate to severe liver failure (Child Pugh 7-15)
• Recent (within 30 days or 5-half-lives, whichever is longer) or current participation in another clinical study in which an investigational medicinal product or device has been received
• Any medical condition or history thereof or any deviation from normal laboratory values that, in the opinion of the investigator, clinically contraindicates or hinders the completion of the study procedures
• Any reason for suspecting a considerable lack of compliance to the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ezetimibe; One treatment period of 16 weeks with1 capsule of ezetimibe 10mg per day, as add-on to standard care.	Drug: Ezetimibe 10mg; Ezetimibe is a cholesterol absorption inhibitor with marketing approval. The recommended dose as per label is 10mg once a day.
Placebo Comparator: Placebo; One treatment period of 16 weeks with 1 capsule of matching placebo per day, as add-on to standard care.	Drug: Placebo; Matching placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Urinary albumin creatinine ratio (UACR)	Change over 16 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Magnetic resonans estimate of kidney parenchymal triglyceride fraction	Change over 16 weeks of treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine metabolomic profile	Metabolomic profiling of polar and non-polar urinary metabolites	Change over 16 weeks of treatment
Plasma extracellular vesicles	number, number from relevant cell types and for all extracellular vesicles the presence of fatty acid transporter proteins	Change over 16 weeks of treatment
Urine extracellular vesicles	number, number from relevant cell types and for all extracellular vesicles the presence of fatty acid transporter proteins	Change over 16 weeks of treatment

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: Department of Clinical Physiology, Nuclear Medicine and PET at Rigshospitalet Glostrup, Valdemar Hansens Vej 1-23, 2600 Glostrup, Denmark; Aase Handberg, professor, dr.med., Department of Clinical Biochemistry, Aalborg University Hospital; Capital Region's Pharmacy (Region Hovedstadens Apotek), Marielundvej 25, 2730 Herlev, Denmark; Alessia Fornoni, MD PhD, Professor of Medicine, Chief, Katz Family Division of Nephrology and Hypertension

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2020
• Primary Completion (Anticipated): May 1, 2022
• Study Completion (Anticipated): May 1, 2022

Study Registration Dates

• First Submitted: October 2, 2020
• First Submitted That Met QC Criteria: October 9, 2020
• First Posted (Actual): October 19, 2020

Study Record Updates

• Last Update Posted (Actual): January 18, 2022
• Last Update Submitted That Met QC Criteria: January 14, 2022
• Last Verified: January 1, 2022

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; Diabetes Mellitus, Type 2; Kidney Diseases; Diabetic Nephropathies; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Ezetimibe
• Other Study ID Numbers: 16032020; 2020-001155-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No