Mechanistic Study of the Systolic Blood Pressure Lowering Effect of Dapagliflozin in Type 2 Diabetes

NCT ID: NCT02372955

Last Updated: 2015-02-26

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

21 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-02-28

Study Completion Date

2016-12-31

Brief Summary

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Dapagliflozin has been shown to lower clinic systolic and diastolic blood pressure in patients with type 2 diabetes mellitus. The exact mechanism(s) by which dapagliflozin lowers clinic SBP is unknown. The primary objective of the study is to determine the effect of dapagliflozin , 10 mg daily, on parameters of arterial stiffness: aPWV, augmentation index (AI), 24-hour blood pressure patterns, SBP, and pulse pressure. Urinary sodium excretion, and Intravascular volume status will be recorded. The study will involve 21 subjects for a duration of 16 weeks.

Detailed Description

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Dapagliflozin has been shown to lower clinic systolic and diastolic blood pressure in patients with type 2 diabetes mellitus. In particular, the reduction in SBP is impressive. The effect on circadian patterns of blood pressure measured by ambulatory blood pressure monitoring has not been established. The exact mechanism(s) by which dapagliflozin lowers clinic SBP is not clear although there has been speculation that it is due to a decrease in intravascular volume secondary to the osmotic diuresis produced by the drug. However, SBP is dependent on both pulse volume and vascular stiffness (impedance to ejection).

Dapagliflozin may have a favorable effect on vascular stiffness by a reduction in blood glucose resulting in decreased proximal arterial collagen cross-linking due to non-enzymatic glycosylation of proteins.

Dapagliflozin may also have a favorable effect on vascular stiffness by increasing urinary sodium excretion. Dapagliflozin is a sodium/glucose co-transporter inhibitor and the effects on sodium excretion are not clear. Increased sodium intake is associated with an increase in vascular stiffness.

An increase in vascular stiffness has been correlated with increased cardiovascular morbidity and mortality. Thus, it is important to know if dapagliflozin has an effect on vascular stiffness.

The current "gold standard" for vascular stiffness is aortic pulse wave velocity (aPWV). Other measures of vascular stiffness include: systolic blood pressure, pulse pressure and augmentation index. Also, measurement of calculated central blood pressure provides information that may not be apparent from measurement of brachial blood pressure.

Measures of intravascular volume status include: body weight, jugular venous pressure, orthostatic changes in blood pressure and heart rate.

It is important to recognize that some oral anti-diabetic drugs, e.g. sulfonylurea's are associated with an increase in systemic arterial blood pressure.

Hypothesis

That treatment of type 2 diabetes mellitus with dapagliflozin will result in a decrease in arterial stiffness

Primary Objectives

The primary objective of the study is to determine the effect of dapagliflozin (Appendix A), 10 mg daily, on parameters of arterial stiffness: aPWV, augmentation index (AI), 24-hour blood pressure patterns, SBP, and pulse pressure.

Key Questions

* What effect will dapagliflozin have on measures of arterial stiffness?
* What effect will dapagliflozin have on central blood pressure?
* Will dapagliflozin lower BP over the 24-hour period and will the pattern of BP change?
* Will dapagliflozin increase sodium excretion for 16 weeks?
* What will be the effect of dapagliflozin on intravascular volume status at 16 weeks?

Secondary Objectives

* Urinary sodium excretion
* Intravascular volume status: jugular venous pressure, body weight, orthostatic change in BP and pulse rate

Treatment

All patients will receive a background treatment with metformin. After randomization (2:1) patients will receive dapagliflozin, 10 mg daily or glimpiride (Appendix B), 4 mg daily. The treatment period will last ;16 weeks.

For high risk subjects, dapagliflozin therapy will begin with 5 mg with up-titration at 2 weeks. High risk subjects are those prone to volume depletion and are identified by signs of hypovolemia, e.g. low venous pressure, and a low arteriasl blood pressure.

Subjects will also be closely monitored for the development of hypoglycemia. This risk will be minimized by not enrolling subjects taking insulin. Subjects will be made aware of the signs of hypotlycemia, e.g. sweating and palpitation, and will be instructed to treat with ingestion of sugar, particularly fructose in orange juice.

Conditions

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Diabetes Mellitus Type 2

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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dapagliflozin 10 mg daily

dapagliflozin, 10 mg daily for 16 weeks

Group Type EXPERIMENTAL

dapagliflozin

Intervention Type DRUG

subjects will be randomly assigned to receive dapagliflozin 10 mg daily

glimpiride

glimpiride 4 mg daily for 16 weeks

Group Type ACTIVE_COMPARATOR

glimpiride

Intervention Type DRUG

subjects will be randomly assigned to receive glimpiride 4 mg daily

Interventions

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dapagliflozin

subjects will be randomly assigned to receive dapagliflozin 10 mg daily

Intervention Type DRUG

glimpiride

subjects will be randomly assigned to receive glimpiride 4 mg daily

Intervention Type DRUG

Other Intervention Names

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Farxiga Amaryl

Eligibility Criteria

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Inclusion Criteria

* Type 2 diabetes mellitus
* Metformin treatment

Exclusion Criteria

* • Type 1 diabetes mellitus

* Hgb A1c \> 9
* Advanced diabetic complications, e.g. diabetic renal disease (eGFR \< 60 cc/min), heavy proteinuria, diabetic retinopathy, autonomic neuropathy
* Pregnancy or unwilling to practice contraception.
* Uncontrolled hypertension (SBP \> 150 mm Hg; DBP \> 100 mm Hg)
* Chronic substance abusers
* Carcinoma of the urinary bladder
* Subjects deemed at risk for dehydration
Minimum Eligible Age

21 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Gulf Regional Research & Educational Services, LLC

OTHER

Sponsor Role lead

Responsible Party

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Thomas Giles

Medical Director

Responsibility Role PRINCIPAL_INVESTIGATOR

Locations

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Gulf Regional Research & Educational Services, LLC

Metairie, Louisiana, United States

Site Status RECRUITING

Countries

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United States

Central Contacts

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Thomas D Giles, MD

Role: CONTACT

504.834.8668

Louise E Roffidal, BSN, MPH

Role: CONTACT

504.220.6275

Facility Contacts

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Thomas D Giles, MD

Role: primary

504-834-8668

Louise E Roffidal, BSN, MPH

Role: backup

504.220.6275

Other Identifiers

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ESR-14-10022/D1690L00020

Identifier Type: -

Identifier Source: org_study_id

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