Type 2 Diabetes
Conditions
Brief summary
This is a single center, prospective, randomized, placebo -controlled, parallel design and double blind study to evaluate oxidative stress, inflammation and hypertension markers and mediators before and after treatment with dapagliflozin.
Detailed description
Two groups of 26 patients each (total 52 patients) with type 2 diabetes on oral agents will be included in the study. One group will be randomized to dapagliflozin (a dose of 5 mg daily will be titrated to 10 mg daily during the first week) while the other will be placebo. The patients will be treated for 12 weeks. Only half the patients (equal numbers in both groups) will be tested for the secondary endpoints related to postprandial and single dose induced changes. The primary endpoint of the study is to detect a significant difference in the percent change in fasting Nuclear factor-k B (NFκB) activation (DNA binding activity) in mononuclear cells (MNC) before and after dapagliflozin use (0 week vs. 12 weeks) as compared to placebo.
Interventions
DRUGdapagliflozin
SGLT-2 inhibitor for the treatment of type 2 diabetes
DRUGPlacebo
Sponsors
Kaleida Health
University at Buffalo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age 20-80 years inclusive. * Type 2 diabetes * BMI ≥30 kg/m2 * Subjects on statins, ACE inhibitors, ARBs, thiazolidinediones and -antioxidants will be allowed as long as they are on stable doses of these -compounds and the dosage in not changed during the course of study. -Patients will be evenly distributed between the 2 groups based on statins, -ARBs, TZDs and ACE inhibitors use. * HbA1c ≤ 8.0%
Exclusion criteria
* Use of GLP-1 agonists or DPP-IV or SGLT-2 inhibitors therapy in the last 3 -months. * Risk for pancreatitis, i.e., history of gallstones, alcohol abuse, and -hypertriglyceridemia. * Coronary event or procedure (myocardial infarction, unstable angina, coronary -artery bypass, surgery or coronary angioplasty) in the previous 3 months. * Hepatic disease: Severe hepatic insufficiency and/or significant abnormal liver -function defined as: * aspartate aminotransferase (AST) \>3x upper limit of normal (ULN) and/or -alanine aminotransferase (ALT) \>3x ULN * Total bilirubin \>2.0 mg/dL (34.2 µmol/L) * Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C virus antibody * (liver function tests more than 3 times the upper limit of normal) * Renal impairment (serum eGFR \<60 ml/min) * Any other life-threatening, non-cardiac disease * Uncontrolled hypertension (BP \> 160/100 mm of Hg) * Congestive Heart Failure class III or IV. * Use of an investigational agent or therapeutic regimen within 30 days of study * Participation in any other concurrent clinical trial * pregnant or breastfeeding patients * Volume depleted patients. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in the Percent Change in Fasting Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells Activation (DNA Binding Activity) in Mononuclear Cells Before and After Dapagliflozin Use | 12 weeks | nuclear factor kappa-light-chain-enhancer of activated B cells measurement through Transcription factor assay |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Expression of Inflammatory Mediators | 12 Weeks | p47phox in mononuclear cells through real time polymerase chain reaction |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Hypertension Mediators | 12 weeks | Plasma concentrations measurement of Angiotensinogen through enzyme-linked immunosorbent assay |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients will be treated for 12 weeks with placebo once daily
Placebo | 26 |
| Dapagliflozin 10 mg daily for the 12 weeks
dapagliflozin: SGLT-2 inhibitor for the treatment of type 2 diabetes | 26 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 |
Baseline characteristics
| Characteristic | Dapagliflozin | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 14 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 38 Participants | 16 Participants |
| Age, Continuous | 61 years STANDARD_DEVIATION 9 | 61 years STANDARD_DEVIATION 9 | 61 years STANDARD_DEVIATION 10 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 16 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 35 Participants | 18 Participants |
| Region of Enrollment United States | 26 participants | 52 participants | 26 participants |
| Sex: Female, Male Female | 11 Participants | 19 Participants | 8 Participants |
| Sex: Female, Male Male | 15 Participants | 33 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 26 |
| other Total, other adverse events | 0 / 26 | 0 / 26 |
| serious Total, serious adverse events | 0 / 26 | 0 / 26 |
Outcome results
Primary
Difference in the Percent Change in Fasting Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells Activation (DNA Binding Activity) in Mononuclear Cells Before and After Dapagliflozin Use
nuclear factor kappa-light-chain-enhancer of activated B cells measurement through Transcription factor assay
Time frame: 12 weeks
Population: Out of the 26 total patients in each group, 4 dropped in the placebo arm and 3 dropped in the Dapagliflozin arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Difference in the Percent Change in Fasting Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells Activation (DNA Binding Activity) in Mononuclear Cells Before and After Dapagliflozin Use | baseline | 0.762 arbitrary unit | Standard Deviation 0.14 |
| Placebo | Difference in the Percent Change in Fasting Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells Activation (DNA Binding Activity) in Mononuclear Cells Before and After Dapagliflozin Use | 6 week | 0.802 arbitrary unit | Standard Deviation 0.12 |
| Placebo | Difference in the Percent Change in Fasting Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells Activation (DNA Binding Activity) in Mononuclear Cells Before and After Dapagliflozin Use | 12 week | 0.776 arbitrary unit | Standard Deviation 0.15 |
| Dapagliflozin | Difference in the Percent Change in Fasting Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells Activation (DNA Binding Activity) in Mononuclear Cells Before and After Dapagliflozin Use | 12 week | 0.815 arbitrary unit | Standard Deviation 0.12 |
| Dapagliflozin | Difference in the Percent Change in Fasting Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells Activation (DNA Binding Activity) in Mononuclear Cells Before and After Dapagliflozin Use | baseline | 0.733 arbitrary unit | Standard Deviation 0.11 |
| Dapagliflozin | Difference in the Percent Change in Fasting Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells Activation (DNA Binding Activity) in Mononuclear Cells Before and After Dapagliflozin Use | 6 week | 0.835 arbitrary unit | Standard Deviation 0.13 |
Secondary
Changes in Expression of Inflammatory Mediators
Interleukin 1 Beta measurement in mononuclear cells through real time polymerase chain reaction
Time frame: 12 weeks
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes in Expression of Inflammatory Mediators | baseline | 0.697 arbitrary unit | Standard Deviation 0.21 |
| Placebo | Changes in Expression of Inflammatory Mediators | 12 week | 0.705 arbitrary unit | Standard Deviation 0.21 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | baseline | 0.756 arbitrary unit | Standard Deviation 0.19 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | 12 week | 0.741 arbitrary unit | Standard Deviation 0.17 |
Secondary
Changes in Expression of Inflammatory Mediators
c-Jun N-terminal kinase 1 measurement in Mononuclear cells through real time polymerase chain reaction
Time frame: 12 weeks
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes in Expression of Inflammatory Mediators | baseline | 0.802 arbitrary unit | Standard Deviation 0.19 |
| Placebo | Changes in Expression of Inflammatory Mediators | 12 week | 0.810 arbitrary unit | Standard Deviation 0.21 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | baseline | 0.856 arbitrary unit | Standard Deviation 0.2 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | 12 week | 0.820 arbitrary unit | Standard Deviation 0.19 |
Secondary
Changes in Expression of Inflammatory Mediators
Suppressor Of Cytokine Signaling 3 measurement in Mononuclear cells through real time polymerase chain reaction
Time frame: 12 weeks
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes in Expression of Inflammatory Mediators | baseline | 0.72 arbitrary unit | Standard Deviation 0.2 |
| Placebo | Changes in Expression of Inflammatory Mediators | 12 week | 0.70 arbitrary unit | Standard Deviation 0.19 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | baseline | 0.60 arbitrary unit | Standard Deviation 0.17 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | 12 week | 0.66 arbitrary unit | Standard Deviation 0.19 |
Secondary
Changes in Expression of Inflammatory Mediators
Tumor necrosis factor alpha measurement in mononuclear through real time polymerase chain reaction
Time frame: 12 weeks
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes in Expression of Inflammatory Mediators | 12 week | 0.776 arbitrary unit | Standard Deviation 0.15 |
| Placebo | Changes in Expression of Inflammatory Mediators | baseline | 0.762 arbitrary unit | Standard Deviation 0.14 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | 12 week | 0.815 arbitrary unit | Standard Deviation 0.12 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | baseline | 0.733 arbitrary unit | Standard Deviation 0.11 |
Secondary
Changes in Expression of Inflammatory Mediators
p47phox in mononuclear cells through real time polymerase chain reaction
Time frame: 12 Weeks
Population: Out of the 26 total patients in each group, 4 dropped in the placebo arm and 3 dropped in the Dapagliflozin arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes in Expression of Inflammatory Mediators | baseline | 100 arbitrary unit | Standard Deviation 0 |
| Placebo | Changes in Expression of Inflammatory Mediators | 12 week | 92 arbitrary unit | Standard Deviation 14 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | baseline | 100 arbitrary unit | Standard Deviation 0 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | 12 week | 104 arbitrary unit | Standard Deviation 12 |
Secondary
Changes in Expression of Inflammatory Mediators
Toll-like receptor 4 measurement in mononuclear cells through real time polymerase chain reaction
Time frame: 12 weeks
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes in Expression of Inflammatory Mediators | baseline | 0.704 arbitrary unit | Standard Deviation 0.15 |
| Placebo | Changes in Expression of Inflammatory Mediators | 12 week | 0.708 arbitrary unit | Standard Deviation 0.17 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | baseline | 0.774 arbitrary unit | Standard Deviation 0.21 |
| Dapagliflozin | Changes in Expression of Inflammatory Mediators | 12 week | 0.731 arbitrary unit | Standard Deviation 0.13 |
Other Pre-specified
Change in Hypertension Mediators
Plasma concentration measurement of Angitosensin II through enzyme-linked immunosorbent assay
Time frame: 12 weeks
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Hypertension Mediators | 12 week | 25.1 pg/mL | Standard Deviation 5.9 |
| Placebo | Change in Hypertension Mediators | baseline | 24.5 pg/mL | Standard Deviation 5.5 |
| Dapagliflozin | Change in Hypertension Mediators | baseline | 29.2 pg/mL | Standard Deviation 6.5 |
| Dapagliflozin | Change in Hypertension Mediators | 12 week | 19.6 pg/mL | Standard Deviation 7 |
Other Pre-specified
Change in Hypertension Mediators
Plasma concentration measurement of Atrial natriuretic peptide through enzyme linked immunosorbent assay
Time frame: 12 weeks
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Hypertension Mediators | baseline | 83 pg/mL | Standard Deviation 12 |
| Placebo | Change in Hypertension Mediators | 12 week | 86 pg/mL | Standard Deviation 18 |
| Dapagliflozin | Change in Hypertension Mediators | baseline | 92 pg/mL | Standard Deviation 8 |
| Dapagliflozin | Change in Hypertension Mediators | 12 week | 125 pg/mL | Standard Deviation 37 |
Other Pre-specified
Change in Hypertension Mediators
Plasma concentration measurement of B-type natriuretic peptide through enzyme linked immunosorbent assay
Time frame: 12 weeks
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Hypertension Mediators | baseline | 59.2 pg/mL | Standard Deviation 12.9 |
| Placebo | Change in Hypertension Mediators | 12 week | 64.3 pg/mL | Standard Deviation 20.1 |
| Dapagliflozin | Change in Hypertension Mediators | baseline | 64.7 pg/mL | Standard Deviation 13.7 |
| Dapagliflozin | Change in Hypertension Mediators | 12 week | 62.9 pg/mL | Standard Deviation 13.8 |
Other Pre-specified
Change in Hypertension Mediators
Plasma concentration measurement of Cyclic guanosine monophosphate through enzyme linked immunosorbent assay
Time frame: 12 weeks
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Hypertension Mediators | baseline | 64 pmol/mL | Standard Deviation 18 |
| Placebo | Change in Hypertension Mediators | 12 week | 73 pmol/mL | Standard Deviation 22 |
| Dapagliflozin | Change in Hypertension Mediators | baseline | 73 pmol/mL | Standard Deviation 11 |
| Dapagliflozin | Change in Hypertension Mediators | 12 week | 89 pmol/mL | Standard Deviation 12 |
Other Pre-specified
Change in Hypertension Mediators
Plasma concentration measurment of Cyclic adenosine monophosphate through enzyme linked immunosorbent assay
Time frame: 12 week
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Hypertension Mediators | baseline | 80 pmol/mL | Standard Deviation 4 |
| Placebo | Change in Hypertension Mediators | 12 week | 77 pmol/mL | Standard Deviation 5 |
| Dapagliflozin | Change in Hypertension Mediators | baseline | 78 pmol/mL | Standard Deviation 5 |
| Dapagliflozin | Change in Hypertension Mediators | 12 week | 80 pmol/mL | Standard Deviation 5 |
Other Pre-specified
Change in Hypertension Mediators
Plasma concentrations measurement of Angiotensinogen through enzyme-linked immunosorbent assay
Time frame: 12 weeks
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Hypertension Mediators | baseline | 7.08 ug/mL | Standard Deviation 0.41 |
| Placebo | Change in Hypertension Mediators | 12 week | 6.98 ug/mL | Standard Deviation 0.38 |
| Dapagliflozin | Change in Hypertension Mediators | baseline | 7.23 ug/mL | Standard Deviation 0.6 |
| Dapagliflozin | Change in Hypertension Mediators | 12 week | 5.88 ug/mL | Standard Deviation 0.64 |
Other Pre-specified
Change in Hypertension Mediators
Plasma concentration measurement of Renin through enzyme-linked immunosorbent assay
Time frame: 12 weeks
Population: Out of the 26 patients in each group, 4 dropped in the placebo arm and 3 dropped in the drug arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Hypertension Mediators | 12 week | 1632 pg/mL | Standard Deviation 543 |
| Placebo | Change in Hypertension Mediators | baseline | 1599 pg/mL | Standard Deviation 492 |
| Dapagliflozin | Change in Hypertension Mediators | baseline | 1630 pg/mL | Standard Deviation 133 |
| Dapagliflozin | Change in Hypertension Mediators | 12 week | 1844 pg/mL | Standard Deviation 145 |