DAPAgliflozin Sodium Water glucosE EffecTs in Patients at High Cardiovascular Risk

Cardiovascular Risk Factor Clinical Trial

— DAPA-SWEET  

Official title:

DAPAgliflozin Sodium Water glucosE EffecTs in Patients at High Cardiovascular Risk

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04258371
• Other study ID #: 18-5597
• Status: Recruiting
• Phase: Phase 2
• Start date: February 10, 2020
• Est. completion date: December 2023

Study information

• Verified date: May 2023
• Source: University Health Network, Toronto
• Contact: Vesta Lai, RN
• Phone: 416-340-4800
• Email: vesta.lai[@]uhn.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 2023
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

1. eGFR =30 ml/min/1.73m2

2. In patients with type 2 diabetes, HbA1c <12.0%

3. Body Mass Index (BMI) 18.5-45.0 kg/m2

4. Blood pressure < or = 160/100 at screening (sitting)

5. Stable dose of maximally tolerated ACE inhibitor, angiotensin receptor blocker or renin inhibitor for at least 30 days

6. Stable diuretic dose for at least 14 days prior to baseline study Visit

7. 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:

1. Type 1 Diabetes

2. Iodine intolerance

3. Hypersensitivity or allergy to dapagliflozin

4. Use of an SGLT2 inhibitor within 30 days

5. Leukocyte and/or nitrite positive urinalysis that is untreated

6. Severe hypoglycaemia within 1 month prior to screening

7. Unstable coronary artery disease with acute coronary syndrome, percutaneous intervention or bypass surgery within 3 months

8. Clinically significant valvular disease in the opinion of the investigator

9. Congestive heart failure secondary to an infiltrative cardiomyopathic process (for example amyloid) or pericardial constriction

10. Bariatric surgery or other surgeries that induce chronic malabsorption within 1 year;

11. Anti-obesity drugs or diet regimen and unstable body weight three months prior to screening;

12. Treatment with systemic corticosteroids

13. Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells

14. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control

15. Participation in another trial with an investigational drug within 30 days of informed consent

16. 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

17. Liver disease, defined by serum levels of alanine transaminase, aspartate transaminase, or alkaline phosphatase >3 x upper limit of normal as determined during screening

18. 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;

19. Unstable or rapidly progressive renal disease as per investigator judgement

20. Intolerance or sensitivity to SGLT2 inhibitors

Related Conditions & MeSH terms

• Cardiovascular Risk Factor

Intervention

Drug:
• Dapagliflozin 10 MG
Dapagliflozin Tablets Total Dose 10mg daily for 12 weeks
• Placebo oral tablet
Placebo once daily for 12 weeks

Locations

Country	Name	City	State
Canada	Renal Physiology Laboratory	Toronto

Sponsors (3)

Lead Sponsor	Collaborator
University Health Network, Toronto	MOUNT SINAI HOSPITAL, Sunnybrook Health Sciences Centre

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of hypoglycaemic episodes		Throughout study completion, an average of 12 weeks
Other	Serious adverse events		Throughout study completion, an average of 12 weeks
Other	Drug related adverse events		Throughout study completion, an average of 12 weeks
Primary	Arterial stiffness	Measured using a Sphygmocor device	Acute (1 week)
Primary	Arterial stiffness	Measured using a Sphygmocor device	Chronic (12 weeks)
Secondary	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)
Secondary	Flow mediated dilation	FMD	Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Nitroglycerin mediated dilation		Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Systolic blood pressure		Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Diastolic blood pressure		Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Heart rate		Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Echocardiography	Changes to systolic and diastolic function	Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	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)
Secondary	Bioimpedence spectroscopy	Measure of extracellular water	Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Plasma concentration of natriuretic peptides		Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Plasma concentration of the renin-angiotensin aldosterone system (RAAS) hormones		Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Nitric oxide		Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	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)
Secondary	Urinary concentration of the renin-angiotensin aldosterone system (RAAS) markers		Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Urinary adenosine		Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Urinary thiobarbituric acid reactive substances (TBARS)		Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)
Secondary	Urinary 8-hydroxydeoxyguanosine (8-OHdG)		Outcome will remeasured at 2 time points: acute (1 week) and chronic (12 weeks)