DAPAgliflozin Sodium Water glucosE EffecTs in Patients at High Cardiovascular Risk

  • STATUS
    Recruiting
  • End date
    Dec 23, 2022
  • participants needed
    50
  • sponsor
    University Health Network, Toronto
Updated on 23 January 2021
diabetes
body mass index
hypertension
systolic blood pressure
hba1c
heart disease
ace inhibitor
hemoglobin a1c
type 1 diabetes mellitus

Summary

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.

Description

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.

Details
Condition Cardiovascular Risk Factor
Treatment Placebo Oral Tablet, Dapagliflozin 10 mg
Clinical Study IdentifierNCT04258371
SponsorUniversity Health Network, Toronto
Last Modified on23 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 50 yrs?
Gender: Male or Female
Do you have Cardiovascular Risk Factor?
Do you have any of these conditions: Do you have Cardiovascular Risk Factor??
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
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