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

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ClinicalTrials.gov Identifier: NCT02372955

Recruitment Status : Unknown

Verified February 2015 by Thomas Giles, Gulf Regional Research & Educational Services, LLC.
Recruitment status was: Recruiting

First Posted : February 26, 2015

Last Update Posted : February 26, 2015

Sponsor:

Information provided by (Responsible Party):

Thomas Giles, Gulf Regional Research & Educational Services, LLC

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus Type 2	Drug: dapagliflozin Drug: glimpiride	Phase 4

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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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	21 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	Mechanistic Study of the Systolic Blood Pressure Lowering Effect of Dapagliflozin in Type 2 Diabetes
Study Start Date :	February 2015
Estimated Primary Completion Date :	February 2016
Estimated Study Completion Date :	December 2016

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Type 2 diabetes

Drug Information available for: Dapagliflozin Dapagliflozin propanediol

U.S. FDA Resources

Arms and Interventions

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 Name: 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 Name: Amaryl

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	21 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02372955

Contacts

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Contact: Thomas D Giles, MD	504.834.8668	tgiles4@cox.net
Contact: Louise E Roffidal, BSN, MPH	504.220.6275	lroffidal.grres@gmail.com

Locations

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United States, Louisiana
Gulf Regional Research & Educational Services, LLC	Recruiting
Metairie, Louisiana, United States, 70002
Contact: Thomas D Giles, MD 504-834-8668 tgiles4@cox.net
Contact: Louise E Roffidal, BSN, MPH 504.220.6275 lroffidal.grres@gmail.com

Sponsors and Collaborators

Gulf Regional Research & Educational Services, LLC

More Information

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Responsible Party:	Thomas Giles, Medical Director, Gulf Regional Research & Educational Services, LLC
ClinicalTrials.gov Identifier:	NCT02372955
Other Study ID Numbers:	ESR-14-10022/D1690L00020
First Posted:	February 26, 2015 Key Record Dates
Last Update Posted:	February 26, 2015
Last Verified:	February 2015

Additional relevant MeSH terms:

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Diabetes Mellitus Diabetes Mellitus, Type 2 Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases	2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol Sodium-Glucose Transporter 2 Inhibitors Molecular Mechanisms of Pharmacological Action Hypoglycemic Agents Physiological Effects of Drugs

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