Trial Outcomes & Findings for Dapagliflozin and Measures of Cardiovascular Autonomic Function in Patients With Type 2 Diabetes (T2D) (NCT NCT02973477)

Last Updated: 2020-10-22

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

45 participants

Primary outcome timeframe

from first baseline to end of 12 weeks' treatment and from second baseline (following 2 weeks of washout) to end of 12 weeks' treatment

Results posted on

2020-10-22

Participant Flow

Participant milestones

Participant milestones
Measure	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.	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.
First Intervention STARTED	19	26
First Intervention COMPLETED	19	24
First Intervention NOT COMPLETED	0	2
Washout STARTED	19	24
Washout COMPLETED	18	24
Washout NOT COMPLETED	1	0
Second Intervention STARTED	18	24
Second Intervention COMPLETED	17	24
Second Intervention NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
First Intervention Lost to Follow-up	0	2
Washout Withdrawal by Subject	1	0
Second Intervention Lost to Follow-up	1	0

Baseline Characteristics

3 participants lost to follow up after baseline data collection.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	First Dapagliflozin Then Glimepiride n=19 Participants 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.	First Glimepiride Then Dapagliflozin n=26 Participants 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.	Total n=45 Participants Total of all reporting groups
Age, Continuous	57 years STANDARD_DEVIATION 9 • n=19 Participants	56 years STANDARD_DEVIATION 8 • n=26 Participants	57 years STANDARD_DEVIATION 8 • n=45 Participants
Sex: Female, Male Female	7 Participants n=19 Participants	12 Participants n=26 Participants	19 Participants n=45 Participants
Sex: Female, Male Male	12 Participants n=19 Participants	14 Participants n=26 Participants	26 Participants n=45 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=19 Participants	0 Participants n=26 Participants	0 Participants n=45 Participants
Race (NIH/OMB) Asian	2 Participants n=19 Participants	0 Participants n=26 Participants	2 Participants n=45 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=19 Participants	0 Participants n=26 Participants	0 Participants n=45 Participants
Race (NIH/OMB) Black or African American	5 Participants n=19 Participants	7 Participants n=26 Participants	12 Participants n=45 Participants
Race (NIH/OMB) White	12 Participants n=19 Participants	18 Participants n=26 Participants	30 Participants n=45 Participants
Race (NIH/OMB) More than one race	0 Participants n=19 Participants	0 Participants n=26 Participants	0 Participants n=45 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=19 Participants	1 Participants n=26 Participants	1 Participants n=45 Participants
LF:HF Ratio Baseline before First Intervention	1.00 Ratio STANDARD_DEVIATION 1.74 • n=19 Participants • 3 participants lost to follow up after baseline data collection.	0.73 Ratio STANDARD_DEVIATION 1.31 • n=26 Participants • 3 participants lost to follow up after baseline data collection.	0.84 Ratio STANDARD_DEVIATION 1.49 • n=45 Participants • 3 participants lost to follow up after baseline data collection.
LF:HF Ratio Baseline before Second Intervention	0.82 Ratio STANDARD_DEVIATION 1.32 • n=18 Participants • 3 participants lost to follow up after baseline data collection.	0.35 Ratio STANDARD_DEVIATION 1.36 • n=24 Participants • 3 participants lost to follow up after baseline data collection.	0.61 Ratio STANDARD_DEVIATION 1.46 • n=42 Participants • 3 participants lost to follow up after baseline data collection.

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	First Dapagliflozin Then Glimepiride n=17 Participants 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. 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.	First Glimepiride Then Dapagliflozin n=24 Participants 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.
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	-0.34 LF:HF ratio Standard Deviation 1.54
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	0.26 LF:HF ratio Standard Deviation 1.92

SECONDARY outcome

Timeframe: 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".

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).

Outcome measures

Outcome measures
Measure	First Dapagliflozin Then Glimepiride n=43 Participants 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. 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.	First Glimepiride Then Dapagliflozin n=44 Participants 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.
Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. SDNN before treatment	40.72 msec Standard Deviation 16.63	39.75 msec Standard Deviation 16.15
Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. SDNN after treatment	37.74 msec Standard Deviation 16.04	36.46 msec Standard Deviation 17.68
Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. rmsSD before treatment	26.91 msec Standard Deviation 17.81	25.14 msec Standard Deviation 13.06
Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride. rmsSD after treatment	24.30 msec Standard Deviation 16.44	24.63 msec Standard Deviation 17.38

SECONDARY outcome

Timeframe: 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".

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.).

Outcome measures

Outcome measures
Measure	First Dapagliflozin Then Glimepiride n=43 Participants 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. 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.	First Glimepiride Then Dapagliflozin n=44 Participants 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.
Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) E/I ratio before treatment	1.13 ratio Standard Deviation 0.07	1.14 ratio Standard Deviation 0.08
Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) EI ratio after treatment	1.14 ratio Standard Deviation 0.11	1.14 ratio Standard Deviation 0.13
Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) Valsalva ratio before treatment	1.50 ratio Standard Deviation 0.36	1.44 ratio Standard Deviation 0.29
Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) Valsalva ratio after treatment	1.60 ratio Standard Deviation 0.66	1.58 ratio Standard Deviation 0.85
Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) 30:15 ratio before treatment	1.17 ratio Standard Deviation 0.15	1.14 ratio Standard Deviation 0.09
Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) 30:15 ratio after treatment	1.14 ratio Standard Deviation 0.11	1.14 ratio Standard Deviation 0.10

SECONDARY outcome

Timeframe: 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".

Changes in B-type Natriuretic Peptide (BNP) with each intervention as a measure of left ventricular function.

Outcome measures

Outcome measures
Measure	First Dapagliflozin Then Glimepiride n=43 Participants 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. 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.	First Glimepiride Then Dapagliflozin n=43 Participants 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.
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	16.93 pg/ml Standard Deviation 13.69
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	15.49 pg/ml Standard Deviation 11.58

OTHER_PRE_SPECIFIED outcome

Timeframe: 2 weeks on each intervention

Measures of glucose variability via the continuous glucose monitoring system Libre Pro

Outcome measures

Outcome data not reported

Adverse Events

Dapagliflozin

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Glimepiride

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Not on Drug

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Dapagliflozin n=44 participants at risk Participants will take open-label dapagliflozin 5 mg daily for 4 weeks and escalate the dose gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin.	Glimepiride n=43 participants at risk Participants will take open-label glimepiride 2 mg daily for 4 weeks and escalate the dose 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.	Not on Drug n=45 participants at risk Participants who were not on study drug, either prior to drug assignment, during washout or after ceasing taking drug prior to categorization as lost to follow up. Since all participants were definitionally present in the prior to drug assignment period, all are included here.
Blood and lymphatic system disorders Pulmonary Embolism	2.3% 1/44 • 26 weeks At each study visit, patients were asked about any change in medical history or status as well as adverse events, effects, or reactions. Patients also called the study team when they experienced issues. Patients were encouraged to inform the study team if any adverse events were experienced, regardless of relatedness.	0.00% 0/43 • 26 weeks At each study visit, patients were asked about any change in medical history or status as well as adverse events, effects, or reactions. Patients also called the study team when they experienced issues. Patients were encouraged to inform the study team if any adverse events were experienced, regardless of relatedness.	0.00% 0/45 • 26 weeks At each study visit, patients were asked about any change in medical history or status as well as adverse events, effects, or reactions. Patients also called the study team when they experienced issues. Patients were encouraged to inform the study team if any adverse events were experienced, regardless of relatedness.

Other adverse events

Additional Information

Lynn Ang

University of Michigan

Phone: 734-232-8058

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place