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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 : Completed
First Posted : June 10, 2016
Last Update Posted : June 2, 2020
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Dragana Lovre, MD, Tulane University School of Medicine

Tracking Information
First Submitted Date  ICMJE April 26, 2016
First Posted Date  ICMJE June 10, 2016
Last Update Posted Date June 2, 2020
Actual Study Start Date  ICMJE March 2016
Actual Primary Completion Date August 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2016)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2016)
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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Inhibition of Urinary Angiotensinogen and the Reduction of Blood Pressure by SGLT2 Inhibition in Patients With Type 2 Diabetes
Official Title  ICMJE Inhibition of Urinary Angiotensinogen and the Reduction of Blood Pressure by SGLT2 Inhibition in Patients With Type 2 Diabetes
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Type 2 Diabetes
  • Hypertension
Intervention  ICMJE
  • Drug: Dapagliflozin
    5mg pill taken once daily
  • Drug: Sulfonylurea
    Subjects may take any of the sulfonlyurea medications, titration will be done per standard of care.
  • Drug: Placebo
    5mg pill taken once daily- placebo of Dapagliflozin
Study Arms  ICMJE
  • 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
    Interventions:
    • Drug: Dapagliflozin
    • Drug: Placebo
  • Sulfonylurea
    This arm will be open label, participants will receive usual care for 6 weeks, then be provided a sulfonylurea medication for 6 weeks.
    Intervention: Drug: Sulfonylurea
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 7, 2020)
12
Original Estimated Enrollment  ICMJE
 (submitted: June 6, 2016)
40
Actual Study Completion Date  ICMJE August 2019
Actual Primary Completion Date August 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02796170
Other Study ID Numbers  ICMJE 812701
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Dragana Lovre, MD, Tulane University School of Medicine
Study Sponsor  ICMJE Tulane University School of Medicine
Collaborators  ICMJE AstraZeneca
Investigators  ICMJE
Principal Investigator: Dragana Lovre, MD Tulane University School of Medicine
PRS Account Tulane University
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP