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



Status:Completed
Conditions:Diabetes, Diabetes
Therapuetic Areas:Endocrinology
Healthy:No
Age Range:40 - 70
Updated:2/17/2019
Start Date:November 2013
End Date:December 2017

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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.

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.

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.
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