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

NCT ID: NCT02024477

Last Updated: 2019-02-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-11-30
• Study Completion Date: 2017-12-31

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.

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.

Conditions

Type 2 Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Placebo

Matching placebo 1 pill daily for 12 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

1 tablet daily for 12 weeks

saxagliptin

Saxagliptin 5mg once daily for 12 weeks

Group Type: ACTIVE_COMPARATOR

Saxagliptin

Intervention Type: DRUG

5 mg tablet once daily for 12 weeks

Interventions

Saxagliptin

5 mg tablet once daily for 12 weeks

Intervention Type: DRUG

Placebo

1 tablet daily for 12 weeks

Intervention Type: DRUG

Other Intervention Names

Onglyza

Eligibility 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.

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

George Washington University

OTHER

Sponsor Role: lead

Responsible Party

Sabyasachi Sen

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Sabyaschi Sen, PhD, MD

Role: PRINCIPAL_INVESTIGATOR

George Washington University

Locations

Medical Faculty Associates Inc

Washington D.C., District of Columbia, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 29724198 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

CV181-305

Identifier Type: -

Identifier Source: org_study_id