DiEtary Sodium Intake Effects on Ertugliflozin-induced Changes in GFR, reNal Oxygenation and Systemic Hemodynamics: the DESIGN Study

Sponsor

Amsterdam UMC, location VUmc (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05727579

Collaborator

Merck Sharp & Dohme LLC (Industry), University of Colorado, Denver (Other)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

SGLT2 inhibitors such as ertugliflozin improve blood pressure and kidney outcomes in people living with diabetes through incompletely understood mechanisms, however, not all patients treated with SGLT2 inhibition have improved outcomes. Changes in kidney sodium handling is among the mechanisms by which SGLT2 inhibition may reduce blood pressure and drive beneficial kidney outcomes. This process is heavily dependent on daily sodium intake by patients receiving SGLT2 inhibitor treatment. In this study, the effect of daily sodium intake on SGLT2-inhibitor induced physiological effect is studied, including blood pressure regulation and kidney physiology.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus Diabetic Kidney Disease Hypertension	Other: Salt-Diet and/or Ertugliflozin	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

34 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

While the treatment by ertugliflozin or placebo will be blinded, the sodium interventions are open-label.While the treatment by ertugliflozin or placebo will be blinded, the sodium interventions are open-label.

Masking:

Double (Participant, Investigator)

Primary Purpose:

Basic Science

Official Title:

DiEtary Sodium Intake Effects on Ertugliflozin-induced Changes in GFR, reNal Oxygenation and Systemic Hemodynamics: the DESIGN Study, a Randomized, Placebo-controlled, Cross-over Study With Ertugliflozin in People With Type 2 Diabetes

Anticipated Study Start Date :

Mar 1, 2023

Anticipated Primary Completion Date :

Sep 1, 2024

Anticipated Study Completion Date :

Mar 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Other: low-sodium diet; placebo	Other: Salt-Diet and/or Ertugliflozin The interventions consist of an determined amount of dietary sodium intake in combination with either Ertugliflozin 15mg once daily or placebo
Other: low-sodium diet; ertugliflozin 15 once daily	Other: Salt-Diet and/or Ertugliflozin The interventions consist of an determined amount of dietary sodium intake in combination with either Ertugliflozin 15mg once daily or placebo
Other: high-sodium diet; placebo	Other: Salt-Diet and/or Ertugliflozin The interventions consist of an determined amount of dietary sodium intake in combination with either Ertugliflozin 15mg once daily or placebo
Other: High-sodium diet; ertugliflozin 15 mg once daily	Other: Salt-Diet and/or Ertugliflozin The interventions consist of an determined amount of dietary sodium intake in combination with either Ertugliflozin 15mg once daily or placebo

Outcome Measures

Primary Outcome Measures

To investigate the modifying effect of sodium intake on Ertugliflozin on blood pressure [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on 24-hour blood pressure in overweight/obese adults with type 2 diabetes

Secondary Outcome Measures

To investigate the effect of Ertugliflozin on the hypertensive effects of high dietary sodium intake [24 weeks]
To investigate the efficacy of ertugliflozin 15 mg daily, versus placebo, in overweight/obese adults with type 2 diabetes to reduce the hypertensive effects of a high-sodium diet (250 mmol per day) versus participant's normal diet (170 mmol/per day).

Other Outcome Measures

Glomerular filtration rate (GFR) [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on GFR.
Hematocrit [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on hematocrit.
Blood pressure [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on blood pressure.
Kidney oxygenation [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on kidney oxygenation.
Effective renal plasma flow [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on effective renal plasma flow.
Renal vasculare resistance [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on renal vasculare resistance.
Body anthropometrics [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on body anthropometrics
Fasting plasma glucose [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on fasting plasma glucose
Albumin excretion rate [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on albumin excretion rate
Glucose excretion [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on 24hr urinary glucose excretion
Biomarkers [24 weeks]
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on biomarkers

Eligibility Criteria

Criteria

Ages Eligible for Study:

35 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adults with previously diagnosed T2DM according to American Diabetes Association (ADA) criteria
HbA1c 6.5-10%
Age 35-80 years of age
Overweight or obese with BMI: >25 kg/m2
We will make every effort to enrol participants of all races/ethnicities."
Both sexes (females must be post-menopausal; no menses >1 year; in case of doubt, Follicle-Stimulating Hormone (FSH) will be determined with cut-off defined as >31 U/L)
Ability to provide signed and dated, written informed consent prior to any study procedures
Estimated GFR 60-90 ml/min/1.73m2 by CKD-EPI matching the eGFR range of most participants in VERTIS-CV
Sodium intake at baseline < 200 mmol/day
UACR < 30 mg/mmol
All participants need to be on a stable dose of Diabetes medication, including Metformin, SU, insulin
All participants need to be on a stable dose of RAS inhibition

Exclusion Criteria:

History of unstable or rapidly progressing renal disease

Estimated GFR <60 mL/min/1.73m2 or eGFR > 90 mL/min/1.73m2 determined by CKD-EPI
UACR > 30 mg/mmol
Current/chronic use of the following medication: SGLT2 inhibitors, TZD, GLP-1RA, glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Subjects on diuretics will only be excluded when these drugs cannot be stopped for the duration of the study.
Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, headache or back ache). However, no such drug can be taken within a timeframe of 2 weeks prior to renal testing
History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g. emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.
Current urinary tract infection and active nephritis
Recent (<6 months) history of cardiovascular disease, including:
Acute coronary syndrome
Chronic heart failure (New York Heart Association grade II-IV)
Stroke or transient ischemic neurologic disorder
Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN
History of or actual malignancy (except basal cell carcinoma)
History of or actual severe mental disease
Substance abuse (alcohol: defined as >4 units/day)
Allergy to any of the agents used in the study
Individuals who are investigator site personnel, directly affiliated with the study, or are immediate (spouse, parent, child, or sibling, whether biological or legally adopted) family of investigator site personnel directly affiliated with the study
Inability to understand the study protocol or give informed consent

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Amsterdam UMC, location VUmc
Merck Sharp & Dohme LLC
University of Colorado, Denver

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

D van Raalte, Dr., Amsterdam UMC, location VUmc

ClinicalTrials.gov Identifier:

NCT05727579

Other Study ID Numbers:

DC2022ERTU

First Posted:

Feb 14, 2023

Last Update Posted:

Feb 14, 2023

Last Verified:

Feb 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Additional relevant MeSH terms:

Kidney Diseases

Diabetic Nephropathies

Ertugliflozin

Study Results

No Results Posted as of Feb 14, 2023