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

To assess the effect of sodium-glucose cotransporter 2 (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.

Study Overview

• Status: Completed
• Conditions: Hypertension; Type 2 Diabetes
• Intervention / Treatment: Drug: Dapagliflozin; Drug: Placebo

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 renin-angiotensin-aldosterone system (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: Interventional
• Enrollment (Actual): 11
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3x upper limit of normal (ULN)
• Total bilirubin >2.0 mg/dL
• Positive serologic evidence of current infectious liver disease, including Hepatitis B viral antibody immunoglobulin M (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 transient ischemic attack (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Dapagliflozin; Participants underwent 6 weeks of Dapagliflozin or placebo (washout period for 2 weeks) and then crossed over to 6 weeks of placebo or Dapagliflozin.	Drug: Dapagliflozin; 5mg pill taken once daily; Drug: Placebo; 5mg pill taken once daily- placebo of Dapagliflozin
ACTIVE_COMPARATOR: Placebo; Participants underwent 6 weeks of Dapagliflozin or placebo (washout period for 2 weeks) and then crossed over to 6 weeks of placebo or Dapagliflozin.	Drug: Dapagliflozin; 5mg pill taken once daily; Drug: Placebo; 5mg pill taken once daily- placebo of Dapagliflozin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Blood Pressure From Baseline to 6 Weeks Measured by ABPM	Blood pressure was measured at baseline with a 24 hour ambulatory blood pressure machine (ABPM), and again after 6 weeks of treatment.	Baseline to 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Urinary AGT Levels From Baseline to 6 Weeks	Urinary Angiotensinogen (AGT) was measured through the collection of 24 hour urine at baseline and again after 6 weeks of treatment. Angiotensinogen was normalized to creatinine.	Baseline to 6 weeks

Collaborators and Investigators

• Sponsor: Tulane University School of Medicine
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Dragana Lovre, MD, Tulane University School of Medicine

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2016
• Primary Completion (ACTUAL): August 1, 2019
• Study Completion (ACTUAL): August 1, 2020

Study Registration Dates

• First Submitted: April 26, 2016
• First Submitted That Met QC Criteria: June 6, 2016
• First Posted (ESTIMATE): June 10, 2016

Study Record Updates

• Last Update Posted (ACTUAL): November 1, 2022
• Last Update Submitted That Met QC Criteria: October 5, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: SGLT-2 inhibitor; urinary angiotensinogen
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 812701

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO