Type 2 Diabetes
Conditions
Keywords
endothelial cells, cellular biomarker, endothelial dysfunction
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.
Interventions
DRUGSaxagliptin
5 mg tablet once daily for 12 weeks
DRUGPlacebo
1 tablet daily for 12 weeks
Sponsors
AstraZeneca
George Washington University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 70 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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
| Measure | Time frame | Description |
|---|---|---|
| Glycemic Control | Baseline, 6 and 12 weeks post saxagliptin | measuring HbA1c levels |
| Serum Endothelial Inflammatory Marker hsCRP | Baseline 6 and 12 weeks post saxagliptin | — |
| 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. |
| Adiposity | Baseline, 6 and 12 weeks post saxagliptin | measured using a Tanita Body Composition Fat Analyzer scale, measured as percentage body fat |
| Fasting Lipid Profile LDL/HDL | Baseline, 6 and 12 weeks post saxagliptin | ratio of LDL over HDL |
Countries
United States
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 details
Screening period lasted 2 weeks. No wash-out or run-in periods were necessary.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: 1 tablet daily for 12 weeks | 21 |
| Saxagliptin Saxagliptin: 5 mg tablet once daily for 12 weeks | 21 |
| Total | 42 |
Baseline characteristics
| Characteristic | Placebo | Saxagliptin | Total |
|---|---|---|---|
| Age, Continuous | 56.4 years STANDARD_DEVIATION 8.5 | 58.3 years STANDARD_DEVIATION 5.7 | 57.3 years STANDARD_DEVIATION 7.1 |
| BMI | 31.5 kg/m^2 STANDARD_DEVIATION 4.8 | 32.3 kg/m^2 STANDARD_DEVIATION 4.2 | 31.9 kg/m^2 STANDARD_DEVIATION 4.5 |
| Duration of Diabetes Mellitus II | 3.5 Years STANDARD_DEVIATION 1.8 | 3.7 Years STANDARD_DEVIATION 2.4 | 3.6 Years STANDARD_DEVIATION 2.1 |
| eGFR | 93.7 mL/min/1.73 STANDARD_DEVIATION 16.7 | 98.9 mL/min/1.73 STANDARD_DEVIATION 14.5 | 96.3 mL/min/1.73 STANDARD_DEVIATION 15.6 |
| Fasting Glucose | 114.8 mg/Dl STANDARD_DEVIATION 25 | 127.4 mg/Dl STANDARD_DEVIATION 35.9 | 121.1 mg/Dl STANDARD_DEVIATION 30.45 |
| HBA1c | 6.6 mmol/mol STANDARD_DEVIATION 0.5 | 7.0 mmol/mol STANDARD_DEVIATION 0.8 | 6.8 mmol/mol STANDARD_DEVIATION 0.65 |
| Race/Ethnicity, Customized African American | 13 Participants | 15 Participants | 28 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Female | 7 Participants | 11 Participants | 18 Participants |
| Sex: Female, Male Male | 14 Participants | 10 Participants | 24 Participants |
| Weight | 202.3 Kg STANDARD_DEVIATION 38.7 | 202.7 Kg STANDARD_DEVIATION 24.5 | 202.5 Kg STANDARD_DEVIATION 31.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 21 |
| other Total, other adverse events | 0 / 21 | 0 / 21 |
| serious Total, serious adverse events | 1 / 21 | 1 / 21 |
Outcome results
Primary
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.
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | CD 34+ Cell Function | Visit 1 - Week 0 | 1.2 Ratio | Standard Deviation 0.1 |
| Placebo | CD 34+ Cell Function | Visit 2 - Week 6 | 1.05 Ratio | Standard Deviation 0.15 |
| Placebo | CD 34+ Cell Function | Visit 3 - Week 12 | 1.0 Ratio | Standard Deviation 0.06 |
| Saxagliptin | CD 34+ Cell Function | Visit 1 - Week 0 | 1.05 Ratio | Standard Deviation 0.06 |
| Saxagliptin | CD 34+ Cell Function | Visit 2 - Week 6 | 1.55 Ratio | Standard Deviation 0.2 |
| Saxagliptin | CD 34+ Cell Function | Visit 3 - Week 12 | 1.2 Ratio | Standard Deviation 0.05 |
Primary
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
Time frame: Up to 12 weeks post saxagliptin
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | CD34+ Endothelial Progenitor Cells Number | 2.0 % of Mononuclear Cells | Standard Deviation 0.3 |
| Saxagliptin | CD34+ Endothelial Progenitor Cells Number | 2.8 % of Mononuclear Cells | Standard Deviation 0.5 |
Secondary
Adiposity
measured using a Tanita Body Composition Fat Analyzer scale, measured as percentage body fat
Time frame: Baseline, 6 and 12 weeks post saxagliptin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Adiposity | Visit 1 - Baseline | 34 % of Body fat | Standard Deviation 2 |
| Placebo | Adiposity | Visit 2 - Week 6 | 34 % of Body fat | Standard Deviation 2 |
| Placebo | Adiposity | Visit 3 - Week 12 | 35 % of Body fat | Standard Deviation 2 |
| Saxagliptin | Adiposity | Visit 1 - Baseline | 37 % of Body fat | Standard Deviation 2 |
| Saxagliptin | Adiposity | Visit 2 - Week 6 | 36.5 % of Body fat | Standard Deviation 2 |
| Saxagliptin | Adiposity | Visit 3 - Week 12 | 36 % of Body fat | Standard Deviation 2 |
Secondary
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.
Time frame: Baseline, 6 and 12 weeks post saxagliptin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Arterial Stiffness | Visit 1: Baseline | 18.4 Augmentation Index | Standard Deviation 2.4 |
| Placebo | Arterial Stiffness | Visit 2: Week 6 | 26 Augmentation Index | Standard Deviation 3.9 |
| Placebo | Arterial Stiffness | Visit 3: Week 12 | 23.3 Augmentation Index | Standard Deviation 2.3 |
| Saxagliptin | Arterial Stiffness | Visit 1: Baseline | 24.1 Augmentation Index | Standard Deviation 2.1 |
| Saxagliptin | Arterial Stiffness | Visit 2: Week 6 | 22.5 Augmentation Index | Standard Deviation 2 |
| Saxagliptin | Arterial Stiffness | Visit 3: Week 12 | 23.1 Augmentation Index | Standard Deviation 2.1 |
Secondary
Fasting Lipid Profile LDL/HDL
ratio of LDL over HDL
Time frame: Baseline, 6 and 12 weeks post saxagliptin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Fasting Lipid Profile LDL/HDL | Visit 1 - Baseline | 2.3 ratio of LDL over HDL | Standard Deviation 0.2 |
| Placebo | Fasting Lipid Profile LDL/HDL | Visit 2 - Week 6 | 2.1 ratio of LDL over HDL | Standard Deviation 0.2 |
| Placebo | Fasting Lipid Profile LDL/HDL | Visit 3 - Week 12 | 2.1 ratio of LDL over HDL | Standard Deviation 0.2 |
| Saxagliptin | Fasting Lipid Profile LDL/HDL | Visit 1 - Baseline | 1.8 ratio of LDL over HDL | Standard Deviation 0.1 |
| Saxagliptin | Fasting Lipid Profile LDL/HDL | Visit 2 - Week 6 | 1.8 ratio of LDL over HDL | Standard Deviation 0.1 |
| Saxagliptin | Fasting Lipid Profile LDL/HDL | Visit 3 - Week 12 | 1.8 ratio of LDL over HDL | Standard Deviation 0.2 |
Secondary
Glycemic Control
measuring HbA1c levels
Time frame: Baseline, 6 and 12 weeks post saxagliptin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Glycemic Control | Visit 3 - Week 12 | 6.5 % of Glycosylated Hemoglobin | Standard Deviation 0.1 |
| Placebo | Glycemic Control | Visit 1 - Baseline | 6.6 % of Glycosylated Hemoglobin | Standard Deviation 0.1 |
| Placebo | Glycemic Control | Visit 2 - Week 6 | 6.6 % of Glycosylated Hemoglobin | Standard Deviation 0.1 |
| Saxagliptin | Glycemic Control | Visit 2 - Week 6 | 6.8 % of Glycosylated Hemoglobin | Standard Deviation 0.2 |
| Saxagliptin | Glycemic Control | Visit 1 - Baseline | 7.0 % of Glycosylated Hemoglobin | Standard Deviation 0.2 |
| Saxagliptin | Glycemic Control | Visit 3 - Week 12 | 6.7 % of Glycosylated Hemoglobin | Standard Deviation 0.2 |
Secondary
Serum Endothelial Inflammatory Marker hsCRP
Time frame: Baseline 6 and 12 weeks post saxagliptin
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Serum Endothelial Inflammatory Marker hsCRP | Visit 1 - Baseline | 2.4 mg/L | Standard Deviation 0.6 |
| Placebo | Serum Endothelial Inflammatory Marker hsCRP | Visit 2 - Week 6 | 2.9 mg/L | Standard Deviation 0.8 |
| Placebo | Serum Endothelial Inflammatory Marker hsCRP | Visit 3 - Week 12 | 2.9 mg/L | Standard Deviation 0.7 |
| Saxagliptin | Serum Endothelial Inflammatory Marker hsCRP | Visit 3 - Week 12 | 2.4 mg/L | Standard Deviation 0.4 |
| Saxagliptin | Serum Endothelial Inflammatory Marker hsCRP | Visit 1 - Baseline | 2.8 mg/L | Standard Deviation 0.5 |
| Saxagliptin | Serum Endothelial Inflammatory Marker hsCRP | Visit 2 - Week 6 | 2.7 mg/L | Standard Deviation 0.4 |