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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Diabetes Mellitus, Diabetic Kidney Disease, Hypertension

Intervention / Treatment
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* Other: Salt-Diet and/or Ertugliflozin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: While the treatment by ertugliflozin or placebo will be blinded, the sodium interventions are open-label.
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To investigate the modifying effect of sodium intake on Ertugliflozin on blood pressure | 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 | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To investigate the effect of Ertugliflozin on the hypertensive effects of high dietary sodium intake | 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). | 24 weeks |