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Inhibition of Urinary Angiotensinogen and the Reduction of Blood Pressure by SGLT2 Inhibition in Patients With Type 2 Diabetes

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ClinicalTrials.gov Identifier: NCT02796170
Recruitment Status : Recruiting
First Posted : June 10, 2016
Last Update Posted : September 13, 2018
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Tina K. Thethi, Tulane University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Hypertension Drug: Dapagliflozin Drug: Sulfonylurea Drug: Placebo Phase 4

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Inhibition of Urinary Angiotensinogen and the Reduction of Blood Pressure by SGLT2 Inhibition in Patients With Type 2 Diabetes
Actual Study Start Date : March 2016
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Dapagliflozin
This arm will undergo either 6 weeks of Dapagloflozin then 6 weeks of placebo, or 6 weeks of placebo then 6 weeks of Dapagloflozin
Drug: Dapagliflozin
5mg pill taken once daily

Drug: Placebo
5mg pill taken once daily- placebo of Dapagliflozin

Sulfonylurea
This arm will be open label, participants will receive usual care for 6 weeks, then be provided a sulfonylurea medication for 6 weeks.
Drug: Sulfonylurea
Subjects may take any of the sulfonlyurea medications, titration will be done per standard of care.




Primary Outcome Measures :
  1. Change in blood pressure from baseline to 6 weeks [ Time Frame: baseline to 6 weeks ]
    Blood pressure will be measured at baseline with a 24 hour ambulatory blood pressure machine, and again after 6 weeks of treatment.


Secondary Outcome Measures :
  1. Change in urinary AGT levels from baseline to 6 weeks [ Time Frame: baseline to 6 weeks ]
    Urinary AGT will be measure through the collection of 24 hour urine at baseline and again after 6 weeks of treatment.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT02796170


Contacts
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Contact: Bonnie L Katalenich, MPH 504-988-6200 bkatalen@tulane.edu
Contact: Tina K Thethi, MD, MPH 504-988-0200 tthethi@tulane.edu

Locations
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United States, Louisiana
Tulane University Recruiting
New Orleans, Louisiana, United States, 70112
Contact: Bonnie L Katalenich, MPH    504-988-6200    bkatalen@tulane.edu   
Sponsors and Collaborators
Tulane University
AstraZeneca

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Responsible Party: Tina K. Thethi, Principal Investigator, Tulane University
ClinicalTrials.gov Identifier: NCT02796170     History of Changes
Other Study ID Numbers: 812701
First Posted: June 10, 2016    Key Record Dates
Last Update Posted: September 13, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Tina K. Thethi, Tulane University:
SGLT-2 inhibitor
urinary angiotensinogen

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
Angiotensinogen
Angiotensin II
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Vasoconstrictor Agents