Cardiovascular Diseases, Type2 Diabetes
Conditions
Brief summary
The purpose of this study is to evaluate the effect of dapagliflozin, a FDA approved diabetes medication, on measures of nervous system function of the heart in patients with type 2 diabetes. The investigators will compare the effect of dapagliflozin with an active comparator, glimepiride (a different FDA approved diabetes medication) on measures of heart rate variability and assess whether dapagliflozin has modulating effects on measures of nervous system function of the heart. This is a crossover study design where all participants will receive both study medications equally (12-week intervention periods) in a certain order.
Detailed description
Study rationale: Empagliflozin and dapagliflozin are sodium-glucose transporter-2 (SGLT-2) inhibitors which prevent the reabsorption of glucose via proximal renal tubules, and are the most recently approved class for treating hyperglycemia in type 2 diabetes. Besides effective glucose lowering effects as documented by \ 0.7-1.2% HbA1c reduction, these agents also promote weight loss and reduce blood pressure (BP). Furthermore, recent data from the Empagliflozin Cardiovascular Outcome Trial in type 2 diabetes (EMPA-REG OUTCOME) reported significant reduction in main cardiovascular disease (CVD) outcomes and CVD death in patients with type 2 diabetes (T2D). The exact mechanism of the beneficial effects on cardiovascular outcomes is not yet understood, although their effects on body weight, glucose control and BP reduction were suggested. However, other classes of drugs with similar effects such as GLP-1 receptor agonist, thiazolidinedione did not clearly show the beneficial effects in CVD outcomes. The interesting observation is that improvement in BP with SGLT-2 inhibitors occurred without a compensatory increase in HR and that most benefit was obtained also in patients with some evidence of heart failure. Thus, the investigators postulated the hypothesis that SGLT-2 may also have a modulatory effect on the sympathetic/parasympathetic balance, and this may contribute to the potential benefits on cardiovascular outcomes in patients with diabetes. Study Design: The investigators plan to test this hypothesis in a randomized, double-blind, 2-period crossover clinical trial comparing 12-weeks of glycemic intervention with dapagliflozin versus glimepiride. The investigators include an active comparator with glimepiride which have a similar glucose lowering in patients with T2D, to account for the effects of reductions in blood glucose on measures of CAN, and will evaluate whether changes in measures of CAN are different among patients who are taking glimepiride or dapagliflozin. The two crossover periods will be separated by a 2-week wash-out period. All subjects will be allocated and randomized to each treatment sequence. Participants will receive blindly either dapagliflozin 5 mg or glimepiride 2 mg 1 tablet daily initially for 4 weeks then titrating the dose based on blood glucose levels up to 2 tablets daily for 8 more weeks (total 12 weeks) followed by 2-week washout period and then they will receive the study drugs in reverse order to the first period during second crossover period for 12 weeks. Study population: 45 patients with T2D on background metformin monotherapy who are not meeting ADA recommended glycemic target. Primary outcomes: changes in measures of cardiovascular autonomic neuropathy such as heart rate variability (HRV) as defined by frequency domain measures of HRV: low frequency (LF) power (ms2); high frequency (HF) power (ms2) as measured as LF:HF ratio. Secondary outcomes: (i) changes in measures of HRV as defined by time domain measures of HRV: standard deviation of the normal RR interval (SDNN) (msec) and root mean square of the differences of successive RR intervals (rmsSD) (msec); (ii) changes in cardiovascular autonomic reflex tests (CARTs) as defined by: expiration/inspiration (E/I) ratio, Valsalva ratio, and 30:15 ratio; (iii) changes in measures of systolic and diastolic function will be assessed by using stress echocardiogram and evaluate the following measures: i) LVEF, ii) LV end diastolic volume, iii) LV end systolic volume, iv) LV mass, v) cardiac output.
Interventions
DRUGDapagliflozin
Dapagliflozin is a sodium glucose transporter-2 (SGLT-2) inhibitor, a new class of glucose lowering agent that reduces hyperglycemia in patients with T2D by reducing renal glucose reabsorption.
DRUGGlimepiride
Glimepiride is a sulfonylurea agent that reduces hyperglycemia in patients with T2D by stimulating insulin release from the pancreatic beta cells and reduction of glucose output from the liver.
Sponsors
AstraZeneca
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Masking description
Randomization will be performed by the research Pharmacy. The study coordinator will not be blind to the randomization so that they can adequately discuss the medication with the participant. The study investigator will be blind to the randomization so as to not introduce bias in data qualification.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with type 2 diabetes as defined on background metformin monotherapy who are not meeting ADA standard of care recommended glucose target. 2. Age ≥18 years
Exclusion criteria
1. History of multiple urinary tract infections 2. Patients with mycotic infections especially genital infections. 3. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status. This is listed as
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Measure of Heart Rate Variability Using Dapagliflozin vs Active Comparator Glimepiride. | from first baseline to end of 12 weeks' treatment and from second baseline (following 2 weeks of washout) to end of 12 weeks' treatment | Heart Rate Variability, as shown by the difference of the LF:HF ratio from baseline to 12 weeks per arm (two 12-week periods with a 2-week washout period. The frequency domain measures \[ low-frequency (LF) power (0.04-0.15 Hz), high-frequency (HF) power (0.15-0.4 Hz), and LF:HF ratio\] are obtained by spectral analysis of R-R interval from continuous electrocardiogram recordings to evaluate for sympathetic/parasympathetic (autonomic nervous function) balance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. | 12 weeks on each intervention | Changes in measures of HRV as defined by: Time domain measures of HRV (continuous variables): (i) standard deviation of the normal RR interval (SDNN) (msec) and (ii) root mean square of the differences of successive RR intervals (rmsSD) (msec). Time domain (SDNN and rmsSD) measures of the normal R-R intervals are derived from HRV studies using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.) under paced breathing, reflecting parasympathetic activity. Time domain measures of the normal R-R intervals, basically reflecting parasympathetic activity, include: the difference between the longest and shortestR-R interval, standard deviation of 5-min average of normal R-R intervals (SDANN), root-mean square of the difference of successive R-R intervals (rMSSD). |
| Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | 12 weeks on each intervention | Changes in CARTs as defined by: i) expiration/inspiration (E/I) ratio, ii) Valsalva ratio and iii) 30:15 ratio. Cardiovascular autonomic reflex tests assess the cardiovascular autonomic function using provocative physiological maneuvers under paced breathing \[R-R response to breathing (E:I ratio), to Valsalva maneuver (Valsalva ratio) and to postural changes (30:15 ratio)\] at baseline and at the end of each study drug period using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.). |
| Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function | 12 weeks for each intervention | Changes in B-type Natriuretic Peptide (BNP) with each intervention as a measure of left ventricular function. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Glucose Variability | 2 weeks on each intervention | Measures of glucose variability via the continuous glucose monitoring system Libre Pro |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| First Dapagliflozin Then Glimepiride Participants received open-label dapagliflozin 5 mg daily for 4 weeks and then the dose escalated gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin. Patients then began a 2 week washout period where they did not take any study drugs. After the washout period, participants received open-label glimepiride 2 mg daily for 4 weeks and the dose escalated gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride. | 19 |
| First Glimepiride Then Dapagliflozin Participants received open-label glimepiride 2 mg daily for 4 weeks and the dose escalated gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride. Patients then began a 2 week washout period where they did not take any study drugs. After the washout period, participants took open-label dapagliflozin 5 mg daily for 4 weeks and then the dose escalated gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin. | 26 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Lost to Follow-up | 0 | 2 |
| Second Intervention | Lost to Follow-up | 1 | 0 |
| Washout | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | First Dapagliflozin Then Glimepiride | First Glimepiride Then Dapagliflozin | Total |
|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 9 | 56 years STANDARD_DEVIATION 8 | 57 years STANDARD_DEVIATION 8 |
| LF:HF Ratio Baseline before First Intervention | 1.00 Ratio STANDARD_DEVIATION 1.74 | 0.73 Ratio STANDARD_DEVIATION 1.31 | 0.84 Ratio STANDARD_DEVIATION 1.49 |
| LF:HF Ratio Baseline before Second Intervention | 0.82 Ratio STANDARD_DEVIATION 1.32 | 0.35 Ratio STANDARD_DEVIATION 1.36 | 0.61 Ratio STANDARD_DEVIATION 1.46 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 7 Participants | 12 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 12 Participants | 18 Participants | 30 Participants |
| Sex: Female, Male Female | 7 Participants | 12 Participants | 19 Participants |
| Sex: Female, Male Male | 12 Participants | 14 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 43 | 0 / 45 |
| other Total, other adverse events | 11 / 44 | 14 / 43 | 5 / 45 |
| serious Total, serious adverse events | 1 / 44 | 0 / 43 | 0 / 45 |
Outcome results
Primary
Changes in Measure of Heart Rate Variability Using Dapagliflozin vs Active Comparator Glimepiride.
Heart Rate Variability, as shown by the difference of the LF:HF ratio from baseline to 12 weeks per arm (two 12-week periods with a 2-week washout period. The frequency domain measures \[ low-frequency (LF) power (0.04-0.15 Hz), high-frequency (HF) power (0.15-0.4 Hz), and LF:HF ratio\] are obtained by spectral analysis of R-R interval from continuous electrocardiogram recordings to evaluate for sympathetic/parasympathetic (autonomic nervous function) balance.
Time frame: from first baseline to end of 12 weeks' treatment and from second baseline (following 2 weeks of washout) to end of 12 weeks' treatment
Population: All participants who completed both interventions were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| First Dapagliflozin Then Glimepiride | Changes in Measure of Heart Rate Variability Using Dapagliflozin vs Active Comparator Glimepiride. | value at 26 weeks minus value at 2nd baseline | 0.26 LF:HF ratio | Standard Deviation 1.85 |
| First Dapagliflozin Then Glimepiride | Changes in Measure of Heart Rate Variability Using Dapagliflozin vs Active Comparator Glimepiride. | value at 12 weeks minus value at 1st baseline | -0.18 LF:HF ratio | Standard Deviation 1.51 |
| First Glimepiride Then Dapagliflozin | Changes in Measure of Heart Rate Variability Using Dapagliflozin vs Active Comparator Glimepiride. | value at 26 weeks minus value at 2nd baseline | 0.26 LF:HF ratio | Standard Deviation 1.92 |
| First Glimepiride Then Dapagliflozin | Changes in Measure of Heart Rate Variability Using Dapagliflozin vs Active Comparator Glimepiride. | value at 12 weeks minus value at 1st baseline | -0.34 LF:HF ratio | Standard Deviation 1.54 |
Comparison: This is the adjusted mixed models analysis for both periods, both arms, comparing each treatment's change.p-value: 0.2895% CI: [-0.24, 0.8]Mixed Models Analysis
Secondary
Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function
Changes in B-type Natriuretic Peptide (BNP) with each intervention as a measure of left ventricular function.
Time frame: 12 weeks for each intervention
Population: 1 Glimiperide-first person's BNP measurement for Before treatment was missing. Only those who completed it are included in After treatment. Changes in numbers represent participants from an arm leaving before completing an intervention. Since 2 others who began Glimepiride did not complete it, the 43 shown in Before reduces to 41 After.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| First Dapagliflozin Then Glimepiride | Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function | BNP before treatment | 12.72 pg/ml | Standard Deviation 9.76 |
| First Dapagliflozin Then Glimepiride | Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function | BNP after treatment | 14.76 pg/ml | Standard Deviation 13.41 |
| First Glimepiride Then Dapagliflozin | Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function | BNP before treatment | 16.93 pg/ml | Standard Deviation 13.69 |
| First Glimepiride Then Dapagliflozin | Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function | BNP after treatment | 15.49 pg/ml | Standard Deviation 11.58 |
Comparison: This is the adjusted analysis for both periods, both arms, comparing each treatment's change of BNP.p-value: 0.9295% CI: [-0.23, 0.25]Mixed Models Analysis
Secondary
Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs)
Changes in CARTs as defined by: i) expiration/inspiration (E/I) ratio, ii) Valsalva ratio and iii) 30:15 ratio. Cardiovascular autonomic reflex tests assess the cardiovascular autonomic function using provocative physiological maneuvers under paced breathing \[R-R response to breathing (E:I ratio), to Valsalva maneuver (Valsalva ratio) and to postural changes (30:15 ratio)\] at baseline and at the end of each study drug period using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.).
Time frame: 12 weeks on each intervention
Population: All who started an intervention were included in Before rows if data was present. Only those who completed it are included in After treatment. Changes in numbers represent participants from an arm leaving before completing an intervention. Since 3 people who began Glimepiride did not complete it, the 44 shown in Before reduces to 41 After.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| First Dapagliflozin Then Glimepiride | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | EI ratio after treatment | 1.14 ratio | Standard Deviation 0.11 |
| First Dapagliflozin Then Glimepiride | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | Valsalva ratio after treatment | 1.60 ratio | Standard Deviation 0.66 |
| First Dapagliflozin Then Glimepiride | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | E/I ratio before treatment | 1.13 ratio | Standard Deviation 0.07 |
| First Dapagliflozin Then Glimepiride | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | Valsalva ratio before treatment | 1.50 ratio | Standard Deviation 0.36 |
| First Dapagliflozin Then Glimepiride | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | 30:15 ratio after treatment | 1.14 ratio | Standard Deviation 0.11 |
| First Dapagliflozin Then Glimepiride | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | 30:15 ratio before treatment | 1.17 ratio | Standard Deviation 0.15 |
| First Glimepiride Then Dapagliflozin | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | 30:15 ratio after treatment | 1.14 ratio | Standard Deviation 0.1 |
| First Glimepiride Then Dapagliflozin | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | E/I ratio before treatment | 1.14 ratio | Standard Deviation 0.08 |
| First Glimepiride Then Dapagliflozin | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | EI ratio after treatment | 1.14 ratio | Standard Deviation 0.13 |
| First Glimepiride Then Dapagliflozin | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | Valsalva ratio before treatment | 1.44 ratio | Standard Deviation 0.29 |
| First Glimepiride Then Dapagliflozin | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | Valsalva ratio after treatment | 1.58 ratio | Standard Deviation 0.85 |
| First Glimepiride Then Dapagliflozin | Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) | 30:15 ratio before treatment | 1.14 ratio | Standard Deviation 0.09 |
Comparison: This is the adjusted analysis for both periods, both arms, comparing each treatment's change of EI ratio.p-value: 0.5895% CI: [-0.02, 0.04]Mixed Models Analysis
Comparison: This is the adjusted analysis for both periods, both arms, comparing each treatment's change of Valsalva ratio.p-value: 0.5895% CI: [-0.05, 0.09]Mixed Models Analysis
Comparison: This is the adjusted analysis for both periods, both arms, comparing each treatment's change of 30:15 ratio.p-value: 0.5695% CI: [-0.05, 0.03]Mixed Models Analysis
Secondary
Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride.
Changes in measures of HRV as defined by: Time domain measures of HRV (continuous variables): (i) standard deviation of the normal RR interval (SDNN) (msec) and (ii) root mean square of the differences of successive RR intervals (rmsSD) (msec). Time domain (SDNN and rmsSD) measures of the normal R-R intervals are derived from HRV studies using a physiologic monitor (Nightingale PPM2; Zoe Medical Inc.) under paced breathing, reflecting parasympathetic activity. Time domain measures of the normal R-R intervals, basically reflecting parasympathetic activity, include: the difference between the longest and shortestR-R interval, standard deviation of 5-min average of normal R-R intervals (SDANN), root-mean square of the difference of successive R-R intervals (rMSSD).
Time frame: 12 weeks on each intervention
Population: All who started an intervention were included in analysis for Before treatment. Only those who completed it are included in After treatment. Changes in numbers represent participants from an arm leaving before completing an intervention. Since 3 people who began Glimepiride did not complete it, the 44 shown in Before reduces to 41 After.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| First Dapagliflozin Then Glimepiride | Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. | SDNN before treatment | 40.72 msec | Standard Deviation 16.63 |
| First Dapagliflozin Then Glimepiride | Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. | SDNN after treatment | 37.74 msec | Standard Deviation 16.04 |
| First Dapagliflozin Then Glimepiride | Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. | rmsSD before treatment | 26.91 msec | Standard Deviation 17.81 |
| First Dapagliflozin Then Glimepiride | Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. | rmsSD after treatment | 24.30 msec | Standard Deviation 16.44 |
| First Glimepiride Then Dapagliflozin | Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. | rmsSD after treatment | 24.63 msec | Standard Deviation 17.38 |
| First Glimepiride Then Dapagliflozin | Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. | SDNN before treatment | 39.75 msec | Standard Deviation 16.15 |
| First Glimepiride Then Dapagliflozin | Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. | rmsSD before treatment | 25.14 msec | Standard Deviation 13.06 |
| First Glimepiride Then Dapagliflozin | Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. | SDNN after treatment | 36.46 msec | Standard Deviation 17.68 |
Comparison: This is the adjusted analysis to compare the difference between the values from baseline to 12 weeks between each intervention for SDNN.p-value: 0.9795% CI: [-0.16, 0.15]Mixed Models Analysis
Comparison: This is the adjusted analysis to compare the difference between the values from baseline to 12 weeks between each intervention for rmsSD.p-value: 0.7995% CI: [-0.21, 0.16]Mixed Models Analysis
Other Pre-specified
Glucose Variability
Measures of glucose variability via the continuous glucose monitoring system Libre Pro
Time frame: 2 weeks on each intervention