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

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

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.

Study Overview

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

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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • Medical Faculty Associates Inc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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; 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 Names: Onglyza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD34+ Endothelial Progenitor Cells Number	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	Up to 12 weeks post saxagliptin
CD 34+ Cell Function	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.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Endothelial Inflammatory Marker hsCRP		Baseline 6 and 12 weeks post saxagliptin
Fasting Lipid Profile LDL/HDL	ratio of LDL over HDL	Baseline, 6 and 12 weeks post saxagliptin
Glycemic Control	measuring HbA1c levels	Baseline, 6 and 12 weeks post saxagliptin
Adiposity	measured using a Tanita Body Composition Fat Analyzer scale, measured as percentage body fat	Baseline, 6 and 12 weeks post saxagliptin
Arterial Stiffness	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.	Baseline, 6 and 12 weeks post saxagliptin

Collaborators and Investigators

• Sponsor: George Washington University
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Sabyaschi Sen, PhD, MD, George Washington University

Publications and helpful links

General Publications

• Dore FJ, Domingues CC, Ahmadi N, Kundu N, Kropotova Y, Houston S, Rouphael C, Mammadova A, Witkin L, Khiyami A, Amdur RL, Sen S. The synergistic effects of saxagliptin and metformin on CD34+ endothelial progenitor cells in early type 2 diabetes patients: a randomized clinical trial. Cardiovasc Diabetol. 2018 May 3;17(1):65. doi: 10.1186/s12933-018-0709-9.

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): September 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: December 13, 2013
• First Submitted That Met QC Criteria: December 30, 2013
• First Posted (Estimate): December 31, 2013

Study Record Updates

• Last Update Posted (Actual): February 15, 2019
• Last Update Submitted That Met QC Criteria: January 30, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: endothelial dysfunction; endothelial cells; cellular biomarker
• 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; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Saxagliptin
• Other Study ID Numbers: CV181-305

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no current plan for sharing IPD with other researchers.