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Effect of Saxagliptin on EPCs as a Cellular Biomarker for Evaluating Endothelial Dysfunction in Early T2DM Patients

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ClinicalTrials.gov Identifier: NCT02024477
Recruitment Status : Completed
First Posted : December 31, 2013
Results First Posted : January 29, 2019
Last Update Posted : February 15, 2019
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Sabyasachi Sen, George Washington University

Brief Summary:

Type 2 diabetes is a national epidemic. Diabetes has undesirable effects on blood vessels which may contribute to heart disease. Endothelial Progenitor Cells(EPCs) are found in the blood . Research has shown that improving the survival of these special blood cells may decrease the harmful effects of diabetes on blood vessels and reduce or reverse heart disease. Saxagliptin is an FDA(Food and Drug Administration) approved prescription medicine used along with diet and exercise to lower blood sugar in people with Type 2 diabetes. It is in a class of diabetes medication called DPP-4 inhibitors. DPP-4 inhibitors have been shown to increase EPCs in patients with Type 2 diabetes.

Hypothesis: We believe poor viability and function of EPCs in early diabetes ultimately affects the repair and regeneration of the endothelium and that prompt intervention using saxagliptin with another oral hypoglycemic agent, Metformin, may reduce or reverse cardiovascular risk by improving EPC survival and function above and beyond adequate glucose metabolism control.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Drug: Saxagliptin Drug: Placebo Phase 4

Detailed Description:

Type 2 diabetes is a national epidemic 1,2 with significant macro and microvascular complications. Insulin resistance in prediabetes and early and late diabetes are associated with endothelial dysfunction.

A few studies indicate that EPCs can act as a suitable bio-marker for monitoring cardiovascular morbidity. In this proposal we suggest that EPCs or CD34 positive cells can act as a suitable cellular biomarker for estimating and following endothelial dysfunction in early type 2 diabetes patients.

EPCs have been used as a regenerative tool in ischemic myocardium and diabetic wound healing. Endothelial dysfunction with associated inflammation may be a consequence of excess super-oxide presence in a setting of diabetes which is a pro-oxidative stress condition causing EPC dysfunction and senescence. Therefore monitoring EPC number, function and gene expression may serve as a very useful cellular bio-marker for cardiovascular complications in early type 2 diabetes.

Though lifestyle modification has been proposed as a main stay for prevention and treatment of early type 2 diabetes, several new therapies for diabetes have been developed in recent years. Incretins and incretin mimetics appear to hold promise. Oral DPP-4 inhibitors have been shown to increase EPCs in patients with type 2 diabetes reportedly via SDF-1 alpha up-regulation. Interestingly, up-regulation of SDF-1 alpha and vascular endothelial growth factor (VEGF), both chemotactic factors increase mobilization and recruitment of EPCs in the face of acute ischemic injury for repair and regeneration.

Several studies have shown positive effect of incretins (Glucagon like peptide, GLP-1) and incretin receptor agonists (GLP-1 receptor agonists) on cardiovascular risk factors in type 2 diabetes patients and even in patients with chronic heart failure and left ventricular dysfunction who do not have diabetes.

DPP-4 Inhibitors may have cardio-protective effects of their own, as they increase bio-availability of endogenous GLP-1. They improve blood flow and nitric oxide production in endothelium. These are unique properties not demonstrated by other oral diabetes medications. The mechanism underlying these effects may be mediated by increased nitric oxide bioavailability but is not completely known. It is possible that Saxagliptin, a member of DPP-4 inhibitor group of drugs may be able to improve number and function of CD34+ endothelial progenitor cells by up-regulating chemotactic agent SDF1 alpha (DPP-4 degrades SDF-1) and its receptor CXCR47, 20, 21, 30, 31.

Poor viability and function of EPCs in early diabetes may ultimately affect the repair and regeneration of the endothelium and prompt intervention may reduce or reverse cardiovascular risk by improving EPC survival and function above and beyond adequate glucose metabolism control.

Therefore we would like to explore the effect of saxagliptin in addition to lifestyle intervention, on number and function and gene expression of EPC and impact on endothelial dysfunction in type 2 diabetes.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Effect of Saxagliptin (DPP-4 Inhibitor) on Endothelial Progenitor Cells (EPCs) as a Cellular Biomarker for Evaluating Endothelial Dysfunction in Early Type 2 Diabetes Patients
Study Start Date : November 2013
Actual Primary Completion Date : September 2017
Actual Study Completion Date : December 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Saxagliptin

Arm Intervention/treatment
Placebo Comparator: Placebo
Matching placebo 1 pill daily for 12 weeks
Drug: Placebo
1 tablet daily for 12 weeks

Active Comparator: saxagliptin
Saxagliptin 5mg once daily for 12 weeks
Drug: Saxagliptin
5 mg tablet once daily for 12 weeks
Other Name: Onglyza




Primary Outcome Measures :
  1. CD34+ Endothelial Progenitor Cells Number [ Time Frame: Up to 12 weeks post saxagliptin ]
    We will use patient's peripheral blood derived CD34+ cells looking at number of CD34+ Endothelial Progenitor Cell as % of the total Mononuclear cell population. Post saxagliptin will be compared to pre saxagliptin measurement

  2. CD 34+ Cell Function [ Time Frame: Up to 12 weeks post saxagliptin Up to 12 weeks post saxagliptin: Visit 1 at Baseline, Visit 2 at 6 weeks, and Visit 3 at 12 weeks ]
    function of EPC cell as migration of CD34+ cells in response to SDF-1a ( 100 ng/mL). Results are expressed in fluorescence ratio between cells exposed to the chemotactic factor and cells exposed to chemo attractant-free media ( control) followed by lysis in presence of CyQuant GR dye.


Secondary Outcome Measures :
  1. Serum Endothelial Inflammatory Marker hsCRP [ Time Frame: Baseline 6 and 12 weeks post saxagliptin ]
  2. Fasting Lipid Profile LDL/HDL [ Time Frame: Baseline, 6 and 12 weeks post saxagliptin ]
    ratio of LDL over HDL

  3. Glycemic Control [ Time Frame: Baseline, 6 and 12 weeks post saxagliptin ]
    measuring HbA1c levels

  4. Adiposity [ Time Frame: Baseline, 6 and 12 weeks post saxagliptin ]
    measured using a Tanita Body Composition Fat Analyzer scale, measured as percentage body fat

  5. Arterial Stiffness [ Time Frame: Baseline, 6 and 12 weeks post saxagliptin ]
    Arterial stiffness assessed using Vascular Flow and wave measurement equipment, SphygmoCor CP system from ATCOR. Reported as Augmentation Index adjusted for a heart rate of 75. Augmentation index (AIx) is a measure of systemic arterial stiffness derived from the ascending aortic pressure waveform. Lower the value, better correlated outcome as positive augmentation represents stiffer artery.



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Ages Eligible for Study:   40 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Adults aged 40-70 years.
  2. Diagnosis of type 2 diabetes within the previous 8 years using criteria of the American Diabetes Association
  3. Currently treated with no hypoglycemic agents other than a stable dose (>3 months) of metformin (≥1.0 to ≤2 grams daily).
  4. HbA1C between 6 to 9% (both inclusive)
  5. BMI 25 to 39.9 kg/m2 (both inclusive)

Exclusion Criteria:

  1. Contraindications for moderate exercise
  2. Implanted devices (e.g., pacemakers) that may interact with Tanita scale
  3. Previous coronary or cerebrovascular event within 6 months of screening or active or clinically significant coronary and/or peripheral vascular disease.
  4. Low hematocrit <28 Units
  5. Pre-existing liver disease and/or ALT and AST >2.5X's UNL
  6. Kidney disease (serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women,Creatinine Clearance ≤50 mL/min)
  7. History of pancreatitis, or cancer (except basal cell carcinoma)
  8. Statin use started (or dose change) in the last 3 months.
  9. Use of oral or injectable anti-diabetic medication other than Metformin
  10. Use of any form of consistent-long term steroid medication (oral, inhaled injected or nasal) within the last 3 months
  11. Systolic BP> 140 mmHg and diastolic BP> 90 mmHg
  12. Active wounds or recent surgery within 3 months.
  13. Inflammatory disease, or current use of anti-inflammatory drugs
  14. triglycerides >400 mg/dL
  15. untreated hyper/hypothyroidism Additionally, patients who are active smokers, patients who are pregnant, nursing women, and post menopausal women who are on hormone replacement therapy will be excluded.

Patients on low dose oral contraceptives will be allowed to participate as these formulations contain lesser amount of estrogens.


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): NCT02024477


Locations
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United States, District of Columbia
Medical Faculty Associates Inc
Washington, District of Columbia, United States, 20037
Sponsors and Collaborators
George Washington University
AstraZeneca
Investigators
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Principal Investigator: Sabyaschi Sen, PhD, MD George Washington University
  Study Documents (Full-Text)

Documents provided by Sabyasachi Sen, George Washington University:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Sabyasachi Sen, Associate Professor of Medicine, George Washington University
ClinicalTrials.gov Identifier: NCT02024477     History of Changes
Other Study ID Numbers: CV181-305
First Posted: December 31, 2013    Key Record Dates
Results First Posted: January 29, 2019
Last Update Posted: February 15, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no current plan for sharing IPD with other researchers.
Keywords provided by Sabyasachi Sen, George Washington University:
endothelial cells
cellular biomarker
endothelial dysfunction
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Saxagliptin
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents