Inhibition of Urinary Angiotensinogen and the Reduction of Blood Pressure by SGLT2 Inhibition in Patients With Type 2 Diabetes
| Status: | Recruiting |
|---|---|
| Conditions: | High Blood Pressure (Hypertension), Diabetes, Diabetes |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Endocrinology |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 9/15/2018 |
| Start Date: | March 2016 |
| End Date: | December 2019 |
| Contact: | Bonnie L Katalenich, MPH |
| Email: | bkatalen@tulane.edu |
| Phone: | 504-988-6200 |
To assess the effect of SGLT-2 inhibitors on blood pressure and urinary angiotensinogen. This
is a cross over study design, where 40 subjects will receive Dapagliflozin for 6 weeks
followed by placebo for 6 weeks, or placebo for 6 weeks followed by Dapagliflozin for 6
weeks. In addition there will be an arm of 10 subjects who will receive sulfonylurea in an
open label as a comparative to the cross over subjects to assess if the effect of
Dapagliflozin may also be in part due to improved glycemic control.
is a cross over study design, where 40 subjects will receive Dapagliflozin for 6 weeks
followed by placebo for 6 weeks, or placebo for 6 weeks followed by Dapagliflozin for 6
weeks. In addition there will be an arm of 10 subjects who will receive sulfonylurea in an
open label as a comparative to the cross over subjects to assess if the effect of
Dapagliflozin may also be in part due to improved glycemic control.
Clinical trials of two SGLT2 inhibitors, canagliflozin and dapagliflozin, have reported drops
in systolic blood pressure of ~5 mmHg. Inappropriate activation of intrarenal
renin-angiotensin system (RAS) is a major contributor to the increased arterial pressure and
tissue injury including diabetic nephropathy. A key factor in the intrarenal RAS activation
is stimulation of intrarenal angiotensinogen (AGT) which is the precursor of angiotensin
peptides. From previous studies, it has been shown that high blood sugars in patients with
type1 and type 2 diabetes mellitus is accompanied by elevated intrarenal AGT and urinary AGT
levels. High glucose results in stimulation of AGT production. The high glucose levels
augments intrarenal AGT levels in diabetes mellitus leading to the development of high blood
pressure and diabetic nephropathy.
The investigators propose to conduct a single-center randomized, double blind, cross over
study of the effect of Dapagliflozin over 6 weeks, followed by placebo over 6 weeks on the
other treatment allocation (those getting placebo first will cross over to Dapagliflozin and
vice versa). Treatment will be stratified according to the underlying presence or absence of
hypertension.
1. Type 2 diabetes with hypertension and on RAAS blocking drugs with stable blood pressure
on therapy; n= 20
2. Type 2 diabetes without hypertension and not on RAAS blocking drugs n=10
If unable to recruit 10 participants without hypertension the investigators will increase the
number with hypertension for a total of 30. Stratification by hypertension status will remain
and is important in understanding the effect of SGLT2 inhibition in patients not on BP
lowering drugs.
In addition a Sulfonylurea (SU) arm will also be included - 10 participants who are on
metformin and other background therapy (with the exclusion of SGLT-2 inhibitor and
sulfonylurea) will be recruited. This will be an open-labeled arm. Participants will assessed
at baseline. Participants will then receive usual care for 6 weeks. At the end of 6 weeks,
participants will then undergo another assessment before being provided SU for 6 weeks. At
the end of 6 weeks, participants will undergo assessment again. The aim is to determine
whether any effects seen with Dapagliflozin are specific to that drug or related simply to
improved glycemic control.
in systolic blood pressure of ~5 mmHg. Inappropriate activation of intrarenal
renin-angiotensin system (RAS) is a major contributor to the increased arterial pressure and
tissue injury including diabetic nephropathy. A key factor in the intrarenal RAS activation
is stimulation of intrarenal angiotensinogen (AGT) which is the precursor of angiotensin
peptides. From previous studies, it has been shown that high blood sugars in patients with
type1 and type 2 diabetes mellitus is accompanied by elevated intrarenal AGT and urinary AGT
levels. High glucose results in stimulation of AGT production. The high glucose levels
augments intrarenal AGT levels in diabetes mellitus leading to the development of high blood
pressure and diabetic nephropathy.
The investigators propose to conduct a single-center randomized, double blind, cross over
study of the effect of Dapagliflozin over 6 weeks, followed by placebo over 6 weeks on the
other treatment allocation (those getting placebo first will cross over to Dapagliflozin and
vice versa). Treatment will be stratified according to the underlying presence or absence of
hypertension.
1. Type 2 diabetes with hypertension and on RAAS blocking drugs with stable blood pressure
on therapy; n= 20
2. Type 2 diabetes without hypertension and not on RAAS blocking drugs n=10
If unable to recruit 10 participants without hypertension the investigators will increase the
number with hypertension for a total of 30. Stratification by hypertension status will remain
and is important in understanding the effect of SGLT2 inhibition in patients not on BP
lowering drugs.
In addition a Sulfonylurea (SU) arm will also be included - 10 participants who are on
metformin and other background therapy (with the exclusion of SGLT-2 inhibitor and
sulfonylurea) will be recruited. This will be an open-labeled arm. Participants will assessed
at baseline. Participants will then receive usual care for 6 weeks. At the end of 6 weeks,
participants will then undergo another assessment before being provided SU for 6 weeks. At
the end of 6 weeks, participants will undergo assessment again. The aim is to determine
whether any effects seen with Dapagliflozin are specific to that drug or related simply to
improved glycemic control.
Inclusion Criteria:
- Type 2 diabetes with hypertension and on RAAS blocking drugs OR
- Type 2 diabetes without hypertension and not on RAAS blocking drugs
- Hemoglobin A1c between 7% and 9% (inclusive)
- Estimated glomerular filtration rate (eGFR) ≥60 ml/min
- Capacity to understand and sign informed consent
Exclusion Criteria:
- Severe hepatic insufficiency and/or significant abnormal liver function defined as AST
and/or ALT >3x ULN
- Total bilirubin >2.0 mg/dL
- Positive serologic evidence of current infectious liver disease, including Hepatitis B
viral antibody IGM, Hepatitis B surface antigen, and Hepatitis C virus antibody
- Estimated glomerular filtration rate (eGFR) <60 ml/min
- Recent cardiovascular events with the last 2 months: acute coronary syndrome (ACS),
hospitalization for unstable angina or acute myocardial infarction, acute stroke or
TIA, or post coronary artery revascularization
- Congestive Heart Failure defined as New York Heart Association (NYHA) class IV,
unstable or acute congestive heart failure
- Pregnant or breastfeeding patients
- Patients who, in the judgement of the investigator, may be at risk for dehydration
- Blood pressure at enrollment: Systolic ≥165 mmHg and/or Diastolic ≥110 mmHg; At
randomization: Systolic ≥160 mmHg and/or Diastolic ≥100 mmHg
- Use of SGLT-2 inhibitor class drugs is an exclusion for all patients. For patients in
the sulfonylurea arm, use of sulfonylurea class drugs is an exclusion.
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