DAPAgliflozin Sodium Water glucosE EffecTs in Patients at High Cardiovascular Risk

Study Overview
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Brief Summary
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This study aims to elucidate the impact of SGLT2 inhibition on peripheral vascular function, renal function, fluid volume, neurohormonal activation and inflammatory/fibrotic pathways in patients with T2D at high cardiovascular risk and non-T2D patients.

Detailed Description
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In light of EMPA-REG OUTCOME, CANVAS Program and DECLARE trials, we aim to elucidate the impact of SGLT2 inhibition on peripheral vascular function while also exploring the effects of this therapy on renal function, fluid volume, neurohormonal activation and inflammatory/fibrotic pathways in patients with T2D at high cardiovascular risk to best replicate the patient populations in recent cardiovascular outcome trials (CVOT), who are also participating in ongoing CVOTs such as VERTIS (ertugliflozin), as well as non-T2D patients in other ongoing trials examining cardiorenal effects of these therapies. We will test the hypothesis that in a high- risk population, regardless of T2D status, SGLT2 inhibition will improve markers of arterial stiffness (decreases in pulse wave velocity and augmentation index) in the study cohort - a surrogate marker of cardiovascular risk independent of glucose lowering. In addition, dapagliflozin will improve endothelial function (flow-mediated vasodilatation - FMD) and increase natriuresis (fractional excretion of sodium or FENa+), thereby reducing blood pressure, without inducing renal vasoconstriction or activation of the sympathetic nervous system (SNS). Based on extensive experimental literature, we also hypothesize that SGLT2 inhibition will suppress levels of pro-inflammatory/fibrotic mediators (see below) that have been linked with progression of cardiovascular and renal disease. The systematic understanding of the effects of SGLT2 inhibitors in the setting of patients at high cardiovascular risk will enable the design of rational physiology-based strategies to decrease the burden of cardiorenal disease, which could have important clinical and research implications. Data from DAPA-SWEET will also be valuable to better understand the results of trials that include patients using SGLT2 inhibitors as primary prevention strategies, such as in DECLARE TIMI-58.

Official Title
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DAPAgliflozin Sodium Water glucosE EffecTs in Patients at High Cardiovascular Risk

Conditions
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Cardiovascular Risk Factor

Intervention / Treatment
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* Drug: Dapagliflozin 10 MG
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: eGFR ≥30 ml/min/1.73m2 In patients with type 2 diabetes, HbA1c <12.0% Body Mass Index (BMI) 18.5-45.0 kg/m2 Blood pressure < or = 160/100 at screening (sitting) Stable dose of maximally tolerated ACE inhibitor, angiotensin receptor blocker or renin inhibitor for at least 30 days Stable diuretic dose for at least 14 days prior to baseline study Visit High cardiovascular risk: an age of 50 years or more with at least one cardiovascular coexisting condition (coronary heart disease, cerebrovascular disease, peripheral vascular disease, chronic kidney disease of stage 3 or greater, or chronic heart failure of New York Heart Association class II or III) OR an age of 60 years or more with at least one cardiovascular risk factor, as determined by the investigator (microalbuminuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or an ankle-brachial index [the ratio of the systolic blood pressure at the ankle to the systolic blood pressure in the arm] of less than 0.9). Exclusion Criteria: Type 1 Diabetes Iodine intolerance Hypersensitivity or allergy to dapagliflozin Use of an SGLT2 inhibitor within 30 days Leukocyte and/or nitrite positive urinalysis that is untreated Severe hypoglycaemia within 1 month prior to screening Unstable coronary artery disease with acute coronary syndrome, percutaneous intervention or bypass surgery within 3 months Clinically significant valvular disease in the opinion of the investigator Congestive heart failure secondary to an infiltrative cardiomyopathic process (for example amyloid) or pericardial constriction Bariatric surgery or other surgeries that induce chronic malabsorption within 1 year; Anti-obesity drugs or diet regimen and unstable body weight three months prior to screening; Treatment with systemic corticosteroids Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control Participation in another trial with an investigational drug within 30 days of informed consent Alcohol or drug abuse within three months prior to informed consent that would interfere with trial participation or any ongoing clinical condition that would jeopardize subject safety or study compliance based on investigator judgement Liver disease, defined by serum levels of alanine transaminase, aspartate transaminase, or alkaline phosphatase >3 x upper limit of normal as determined during screening Medical history of cancer or treatment for cancer in the last five years prior to screening, aside from uncomplicated basal cell or squamous cell carcinoma; Unstable or rapidly progressive renal disease as per investigator judgement Intolerance or sensitivity to SGLT2 inhibitors

Ages Eligible for Study
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Minimum Age: 50 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized to 10mg PO dapagliflozin daily or matching placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin Treatment Arm<br>Dapagliflozin Tablets Total Dose 10mg daily for 12 weeks | Drug: Dapagliflozin 10 MG<br>* Dapagliflozin Tablets Total Dose 10mg daily for 12 weeks<br>|
| Placebo Comparator: Placebo Arm<br>Placebo Matching Dapagliflozin Tablet for 12 weeks | Drug: Placebo oral tablet<br>* Placebo once daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arterial stiffness | Measured using a Sphygmocor device | Acute (1 week) | 
| Arterial stiffness | Measured using a Sphygmocor device | Chronic (12 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glomerular filtration rate | GFR | Glomerular Filtration Rate (GFR, based on plasma iohexol clearance) will be measured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Flow mediated dilation | FMD | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Nitroglycerin mediated dilation |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Systolic blood pressure |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Diastolic blood pressure |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Heart rate |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Echocardiography | Changes to systolic and diastolic function | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Non-Invasive Cardiac Output Monitoring (Measured using a NICOM device) | Cardiac output and systemic vascular resistance | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Bioimpedence spectroscopy | Measure of extracellular water | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Plasma concentration of natriuretic peptides |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Plasma concentration of the renin-angiotensin aldosterone system (RAAS) hormones |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Nitric oxide |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Fractional excretion of sodium, using lithium clearance as a surrogate for proximal tubular sodium handling |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Urinary concentration of the renin-angiotensin aldosterone system (RAAS) markers |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Urinary adenosine |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| mRNA expression of monocyte chemoattractant protein-1(MCP-1) | Measured in urine and skin biopsy samples | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| mRNA expression of intercellular adhesion molecule-1(ICAM-1) | Measured in urine and skin biopsy samples | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| mRNA expression of plasminogen activator inhibitor-1(PAI-1) | Measured in urine and skin biopsy samples | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| mRNA expression of transforming growth factor-beta (TGF-beta) | Measured in urine and skin biopsy samples | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| mRNA expression of connective tissue growth factor (CTGF) | Measured in urine and skin biopsy samples | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| mRNA expression of interleukins (IL-1beta, IL-6) | Measured in urine and skin biopsy samples | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| mRNA expression of tumour necrosis factor-alpha (TNF-alpha) | Measured in urine and skin biopsy samples | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| mRNA expression of matrix metalloproteinases 2 (MMP2) | Measured in urine and skin biopsy samples | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| mRNA expression of matrix metalloproteinases 9 (MMP9) | Measured in urine and skin biopsy samples | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| mRNA expression of advances glycation end-product (AGE) | Measured in urine and skin biopsy samples | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| mRNA expression of receptor for AGE (RAGE) | Measured in urine and skin biopsy samples | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Urinary thiobarbituric acid reactive substances (TBARS) |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 
| Urinary 8-hydroxydeoxyguanosine (8-OHdG) |  | Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SGLT2 inhibition, Cardiovascular risk, Dapagliflozin