Clinical trial NCT05727579: DiEtary Sodium Intake Effects on Ertugliflozin-induced Changes in GFR, reNal Oxygenation and Systemic Hemodynamics: the DESIGN Study
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Diabetes Mellitus
Diabetic Kidney Disease
Hypertension
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
name: University of Colorado, Denver
First posted: 2023-02-14
Enrollment: 34
Sex: ALL
Minimum age (years): 35
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: While the treatment by ertugliflozin or placebo will be blinded, the sodium interventions are open-label.
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: 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

Primary outcomes:
measure: To investigate the modifying effect of sodium intake on Ertugliflozin on blood pressure
timeFrame: 24 weeks
Secondary outcomes:
measure: To investigate the effect of Ertugliflozin on the hypertensive effects of high dietary sodium intake
timeFrame: 24 weeks
Other outcomes:
measure: Glomerular filtration rate (GFR)
timeFrame: 24 weeks
measure: Hematocrit
timeFrame: 24 weeks
measure: Blood pressure
timeFrame: 24 weeks
measure: Kidney oxygenation
timeFrame: 24 weeks
measure: Effective renal plasma flow
timeFrame: 24 weeks
measure: Renal vasculare resistance
timeFrame: 24 weeks
measure: Body anthropometrics
timeFrame: 24 weeks
measure: Fasting plasma glucose
timeFrame: 24 weeks
measure: Albumin excretion rate
timeFrame: 24 weeks
measure: Glucose excretion
timeFrame: 24 weeks
measure: Biomarkers
timeFrame: 24 weeks
Locations:
Study officials:
References: