Mechanistic Study of the Systolic Blood Pressure Lowering Effect of Dapagliflozin in Type 2 Diabetes
| Status: | Recruiting |
|---|---|
| Conditions: | Diabetes |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 21 - Any |
| Updated: | 4/2/2016 |
| Start Date: | February 2015 |
| End Date: | December 2016 |
| Contact: | Thomas D Giles, MD |
| Email: | tgiles4@cox.net |
| Phone: | 504.834.8668 |
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.
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.
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.
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.
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
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