An Investigation Into The Anti-hypertensive And Potential Anti-inflammatory Actions Of Dapagliflozin

This is a single center, prospective, randomized, placebo -controlled, parallel design and double blind study to evaluate oxidative stress, inflammation and hypertension markers and mediators before and after treatment with dapagliflozin.

Study Overview

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

Detailed Description

Two groups of 26 patients each (total 52 patients) with type 2 diabetes on oral agents will be included in the study. One group will be randomized to dapagliflozin (a dose of 5 mg daily will be titrated to 10 mg daily during the first week) while the other will be placebo. The patients will be treated for 12 weeks. Only half the patients (equal numbers in both groups) will be tested for the secondary endpoints related to postprandial and single dose induced changes. The primary endpoint of the study is to detect a significant difference in the percent change in fasting Nuclear factor-k B (NFκB) activation (DNA binding activity) in mononuclear cells (MNC) before and after dapagliflozin use (0 week vs. 12 weeks) as compared to placebo.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14215
      • ECMC Ambulatory Center, 3rd Floor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 20-80 years inclusive.
• Type 2 diabetes
• BMI ≥30 kg/m2
• Subjects on statins, ACE inhibitors, ARBs, thiazolidinediones and -antioxidants will be allowed as long as they are on stable doses of these -compounds and the dosage in not changed during the course of study. -Patients will be evenly distributed between the 2 groups based on statins, -ARBs, TZDs and ACE inhibitors use.
• HbA1c ≤ 8.0%

Exclusion Criteria:

• Use of GLP-1 agonists or DPP-IV or SGLT-2 inhibitors therapy in the last 3 -months.
• Risk for pancreatitis, i.e., history of gallstones, alcohol abuse, and -hypertriglyceridemia.
• Coronary event or procedure (myocardial infarction, unstable angina, coronary -artery bypass, surgery or coronary angioplasty) in the previous 3 months.
• Hepatic disease: Severe hepatic insufficiency and/or significant abnormal liver -function defined as:
• aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or -alanine aminotransferase (ALT) >3x ULN
• Total bilirubin >2.0 mg/dL (34.2 µmol/L)
• Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C virus antibody
• (liver function tests more than 3 times the upper limit of normal)
• Renal impairment (serum eGFR <60 ml/min)
• Any other life-threatening, non-cardiac disease
• Uncontrolled hypertension (BP > 160/100 mm of Hg)
• Congestive Heart Failure class III or IV.
• Use of an investigational agent or therapeutic regimen within 30 days of study
• Participation in any other concurrent clinical trial
• pregnant or breastfeeding patients
• Volume depleted patients. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Patients will be treated for 12 weeks with placebo once daily	Drug: Placebo
Active Comparator: Dapagliflozin; 10 mg daily for the 12 weeks	Drug: dapagliflozin; SGLT-2 inhibitor for the treatment of type 2 diabetes; Other Names: Farxiga

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in the Percent Change in Fasting Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells Activation (DNA Binding Activity) in Mononuclear Cells Before and After Dapagliflozin Use	nuclear factor kappa-light-chain-enhancer of activated B cells measurement through Transcription factor assay	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Expression of Inflammatory Mediators	p47phox in mononuclear cells through real time polymerase chain reaction	12 Weeks
Changes in Expression of Inflammatory Mediators	Suppressor Of Cytokine Signaling 3 measurement in Mononuclear cells through real time polymerase chain reaction	12 weeks
Changes in Expression of Inflammatory Mediators	Interleukin 1 Beta measurement in mononuclear cells through real time polymerase chain reaction	12 weeks
Changes in Expression of Inflammatory Mediators	c-Jun N-terminal kinase 1 measurement in Mononuclear cells through real time polymerase chain reaction	12 weeks
Changes in Expression of Inflammatory Mediators	Toll-like receptor 4 measurement in mononuclear cells through real time polymerase chain reaction	12 weeks
Changes in Expression of Inflammatory Mediators	Tumor necrosis factor alpha measurement in mononuclear through real time polymerase chain reaction	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Hypertension Mediators	Plasma concentrations measurement of Angiotensinogen through enzyme-linked immunosorbent assay	12 weeks
Change in Hypertension Mediators	Plasma concentration measurement of Angitosensin II through enzyme-linked immunosorbent assay	12 weeks
Change in Hypertension Mediators	Plasma concentration measurement of Renin through enzyme-linked immunosorbent assay	12 weeks
Change in Hypertension Mediators	Plasma concentration measurement of Atrial natriuretic peptide through enzyme linked immunosorbent assay	12 weeks
Change in Hypertension Mediators	Plasma concentration measurement of B-type natriuretic peptide through enzyme linked immunosorbent assay	12 weeks
Change in Hypertension Mediators	Plasma concentration measurement of Cyclic guanosine monophosphate through enzyme linked immunosorbent assay	12 weeks
Change in Hypertension Mediators	Plasma concentration measurment of Cyclic adenosine monophosphate through enzyme linked immunosorbent assay	12 week

Collaborators and Investigators

• Sponsor: University at Buffalo
• Collaborators: Kaleida Health
• Investigators: Principal Investigator: Paresh Dandona, MD, PhD, University at Buffalo

Publications and helpful links

General Publications

• Ghanim H, Abuaysheh S, Hejna J, Green K, Batra M, Makdissi A, Chaudhuri A, Dandona P. Dapagliflozin Suppresses Hepcidin And Increases Erythropoiesis. J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgaa057. doi: 10.1210/clinem/dgaa057.

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Actual): March 1, 2018
• Study Completion (Actual): November 1, 2018

Study Registration Dates

• First Submitted: April 24, 2015
• First Submitted That Met QC Criteria: April 29, 2015
• First Posted (Estimate): May 5, 2015

Study Record Updates

• Last Update Posted (Actual): October 30, 2019
• Last Update Submitted That Met QC Criteria: October 29, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 1972