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

• Sponsor: George Washington University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02024477
• Collaborator: AstraZeneca (Industry)
• Enrollment: 42
• Location: 1
• Arms: 2
• Duration (Months): 49
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Nov 1, 2013
• Actual Primary Completion Date: Sep 1, 2017
• Actual Study Completion Date: Dec 1, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. CD34+ Endothelial Progenitor Cells Number [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 [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 [Baseline 6 and 12 weeks post saxagliptin]

2. Fasting Lipid Profile LDL/HDL [Baseline, 6 and 12 weeks post saxagliptin]

   ratio of LDL over HDL

3. Glycemic Control [Baseline, 6 and 12 weeks post saxagliptin]

   measuring HbA1c levels

4. Adiposity [Baseline, 6 and 12 weeks post saxagliptin]

   measured using a Tanita Body Composition Fat Analyzer scale, measured as percentage body fat

5. Arterial Stiffness [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical Faculty Associates Inc	Washington	District of Columbia	United States	20037

Sponsors and Collaborators

• George Washington University
• AstraZeneca

Investigators

• Principal Investigator: Sabyaschi Sen, PhD, MD, George Washington University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 21, 2015

More Information

Publications

None provided.

• Responsible Party: Sabyasachi Sen, Associate Professor of Medicine, George Washington University
• ClinicalTrials.gov Identifier: NCT02024477
• Other Study ID Numbers: CV181-305
• First Posted: Dec 31, 2013
• Last Update Posted: Feb 15, 2019
• Last Verified: Jan 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Sabyasachi Sen, Associate Professor of Medicine, George Washington University: endothelial cells; cellular biomarker; endothelial dysfunction
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Saxagliptin

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from clinic of the Principle Investigator and Sub-Investigators involved in the trial. First patient was recruited on 26 Nov 2013, last patient was recruited on 24 May 2016.
Pre-assignment Detail	Screening period lasted 2 weeks. No wash-out or run-in periods were necessary.

Arm/Group Title	Placebo	Saxagliptin
Arm/Group Description	Placebo: 1 tablet daily for 12 weeks	Saxagliptin: 5 mg tablet once daily for 12 weeks
Period Title: Overall Study
STARTED	21	21
COMPLETED	21	21
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Saxagliptin	Total
Arm/Group Description	Placebo: 1 tablet daily for 12 weeks	Saxagliptin: 5 mg tablet once daily for 12 weeks	Total of all reporting groups
Overall Participants	21	21	42
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.4 (8.5)	58.3 (5.7)	57.3 (7.1)
Sex: Female, Male (Count of Participants)
Female	7 33.3%	11 52.4%	18 42.9%
Male	14 66.7%	10 47.6%	24 57.1%
Race/Ethnicity, Customized (Count of Participants)
African American	13 61.9%	15 71.4%	28 66.7%
White	6 28.6%	5 23.8%	11 26.2%
Other	2 9.5%	1 4.8%	3 7.1%
Weight (Kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg]	202.3 (38.7)	202.7 (24.5)	202.5 (31.6)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	31.5 (4.8)	32.3 (4.2)	31.9 (4.5)
Duration of Diabetes Mellitus II (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	3.5 (1.8)	3.7 (2.4)	3.6 (2.1)
HBA1c (mmol/mol) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/mol]	6.6 (0.5)	7.0 (0.8)	6.8 (0.65)
Fasting Glucose (mg/Dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/Dl]	114.8 (25)	127.4 (35.9)	121.1 (30.45)
eGFR (mL/min/1.73) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min/1.73]	93.7 (16.7)	98.9 (14.5)	96.3 (15.6)

Outcome Measures

1. Primary Outcome

Title	CD34+ Endothelial Progenitor Cells Number
Description	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
Time Frame	Up to 12 weeks post saxagliptin

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Saxagliptin
Arm/Group Description	Placebo: 1 tablet daily for 12 weeks	Saxagliptin: 5 mg tablet once daily for 12 weeks
Measure Participants	21	21
Mean (Standard Deviation) [% of Mononuclear Cells]	2.0 (0.3)	2.8 (0.5)

2. Primary Outcome

Title	CD 34+ Cell Function
Description	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.
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Saxagliptin
Arm/Group Description	Placebo: 1 tablet daily for 12 weeks	Saxagliptin: 5 mg tablet once daily for 12 weeks
Measure Participants	21	21
Visit 1 - Week 0	1.2 (0.1)	1.05 (0.06)
Visit 2 - Week 6	1.05 (0.15)	1.55 (0.2)
Visit 3 - Week 12	1.0 (0.06)	1.2 (0.05)

3. Secondary Outcome

Title	Serum Endothelial Inflammatory Marker hsCRP
Time Frame	Baseline 6 and 12 weeks post saxagliptin

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Saxagliptin
Arm/Group Description	Placebo: 1 tablet daily for 12 weeks	Saxagliptin: 5 mg tablet once daily for 12 weeks
Measure Participants	21	21
Visit 1 - Baseline	2.4 (0.6)	2.8 (0.5)
Visit 2 - Week 6	2.9 (0.8)	2.7 (0.4)
Visit 3 - Week 12	2.9 (0.7)	2.4 (0.4)

4. Secondary Outcome

Title	Fasting Lipid Profile LDL/HDL
Description	ratio of LDL over HDL
Time Frame	Baseline, 6 and 12 weeks post saxagliptin

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Saxagliptin
Arm/Group Description	Placebo: 1 tablet daily for 12 weeks	Saxagliptin: 5 mg tablet once daily for 12 weeks
Measure Participants	21	21
Visit 1 - Baseline	2.3 (0.2)	1.8 (0.1)
Visit 2 - Week 6	2.1 (0.2)	1.8 (0.1)
Visit 3 - Week 12	2.1 (0.2)	1.8 (0.2)

5. Secondary Outcome

Title	Glycemic Control
Description	measuring HbA1c levels
Time Frame	Baseline, 6 and 12 weeks post saxagliptin

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Saxagliptin
Arm/Group Description	Placebo: 1 tablet daily for 12 weeks	Saxagliptin: 5 mg tablet once daily for 12 weeks
Measure Participants	21	21
Visit 1 - Baseline	6.6 (0.1)	7.0 (0.2)
Visit 2 - Week 6	6.6 (0.1)	6.8 (0.2)
Visit 3 - Week 12	6.5 (0.1)	6.7 (0.2)

6. Secondary Outcome

Title	Adiposity
Description	measured using a Tanita Body Composition Fat Analyzer scale, measured as percentage body fat
Time Frame	Baseline, 6 and 12 weeks post saxagliptin

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Saxagliptin
Arm/Group Description	Placebo: 1 tablet daily for 12 weeks	Saxagliptin: 5 mg tablet once daily for 12 weeks
Measure Participants	21	21
Visit 1 - Baseline	34 (2)	37 (2)
Visit 2 - Week 6	34 (2)	36.5 (2)
Visit 3 - Week 12	35 (2)	36 (2)

7. Secondary Outcome

Title	Arterial Stiffness
Description	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.
Time Frame	Baseline, 6 and 12 weeks post saxagliptin

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Saxagliptin
Arm/Group Description	Placebo: 1 tablet daily for 12 weeks	Saxagliptin: 5 mg tablet once daily for 12 weeks
Measure Participants	21	21
Visit 1: Baseline	18.4 (2.4)	24.1 (2.1)
Visit 2: Week 6	26 (3.9)	22.5 (2.0)
Visit 3: Week 12	23.3 (2.3)	23.1 (2.1)

Adverse Events

Time Frame	20 weeks
Adverse Event Reporting Description	from the day ICF was signed till 1 month after V3.
Arm/Group Title	Placebo		Saxagliptin
Arm/Group Description	Placebo: 1 tablet daily for 12 weeks		Saxagliptin 5mg once daily for 12 weeks
All Cause Mortality
	Placebo		Saxagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/21 (0%)
Serious Adverse Events
	Placebo		Saxagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)		1/21 (4.8%)
Cardiac disorders
Hypertensive Urgency	1/21 (4.8%)		0/21 (0%)
Chest Pain	0/21 (0%)		1/21 (4.8%)
Other (Not Including Serious) Adverse Events
	Placebo		Saxagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/21 (0%)

Limitations/Caveats

Limitations of our study may include the relatively short duration of 12 week Saxagliptin therapy, which may have been inadequate to see significant changes in certain clinical and cellular parameters.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.