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

February 20, 2015 updated by: Thomas Giles, Gulf Regional Research & Educational Services, LLC
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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

21

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Louisiana
      • Metairie, Louisiana, United States, 70002
        • Recruiting
        • Gulf Regional Research & Educational Services, LLC
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: dapagliflozin 10 mg daily
dapagliflozin, 10 mg daily for 16 weeks
Drug: dapagliflozin
subjects will be randomly assigned to receive dapagliflozin 10 mg daily
Other Names:
  • Farxiga
Active Comparator: glimpiride
glimpiride 4 mg daily for 16 weeks
Drug: glimpiride
subjects will be randomly assigned to receive glimpiride 4 mg daily
Other Names:
  • Amaryl

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
systolic blood pressure by ambulatory blood pressure monitoring (ABPM)
Time Frame: 16 weeks
16 weeks
arterial stiffness
Time Frame: 16 weeks
arterial stiffness will be assessed by measuring aortic pulse wave velocity (aPWV) and augmentation index
16 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
urinary sodium excretion
Time Frame: 16 weeks
16 weeks
composite intravascular volume status
Time Frame: 16 weeks
jugular venous pressure, body weight, orthostatic change in BP and pulse rate
16 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gulf Regional Research & Educational Services, LLC

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2015

Primary Completion (Anticipated)

February 1, 2016

Study Completion (Anticipated)

December 1, 2016

Study Registration Dates

First Submitted

January 7, 2015

First Submitted That Met QC Criteria

February 20, 2015

First Posted (Estimate)

February 26, 2015

Study Record Updates

Last Update Posted (Estimate)

February 26, 2015

Last Update Submitted That Met QC Criteria

February 20, 2015

Last Verified

February 1, 2015

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ESR-14-10022/D1690L00020

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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