Dapagliflozin and Measures of Cardiovascular Autonomic Function in Patients With Type 2 Diabetes (T2D)

• Sponsor: University of Michigan (Other)
• Overall Status: Completed
• CT.gov ID: NCT02973477
• Collaborator: AstraZeneca (Industry)
• Enrollment: 45
• Location: 1
• Arms: 2
• Actual Duration (Months): 31.3
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type2 Diabetes; Cardiovascular Diseases	Drug: Dapagliflozin; Drug: Glimepiride	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• 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.
• Primary Purpose: Treatment
• Official Title: Dapagliflozin and Measures of Cardiovascular Autonomic Function in Patients With Type 2 Diabetes (T2D)
• Actual Study Start Date: Jan 12, 2017
• Actual Primary Completion Date: Aug 22, 2019
• Actual Study Completion Date: Aug 22, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A: Dapagliflozin/Glimepiride 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. Patients will then begin a 2 week washout period where they are not taking any study drugs. After the washout period, participants will receive 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.	Drug: Dapagliflozin; 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.; Other Names: Study Drug ; Drug: Glimepiride; 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.; Other Names: Active Comparator
Experimental: Group B: Glimepiride/Dapagliflozin 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. Patients will then begin a 2 week washout period where they are not taking any study drugs. After the washout period, participants will receive 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.	Drug: Dapagliflozin; 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.; Other Names: Study Drug ; Drug: Glimepiride; 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.; Other Names: Active Comparator

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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).

2. 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.).

3. 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 Outcome Measures

1. Glucose Variability [2 weeks on each intervention]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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 exclusion criteria but then it says that they just need careful monitoring. Is it an exclusion or not?

4. Severely hypotensive patients

5. History of unexplained microscopic or gross hematuria, or microscopic hematuria at visit 1, confirmed by a follow-up sample at next scheduled visit.

6. Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions

7. Inability or refusal to comply with protocol

8. Current participation or participation in an experimental drug study in the previous three months

9. History of diabetic ketoacidosis

10. Planned cardiac surgery or angioplasty within 3 months

11. Recent history of acute CV events such as MI, stroke, PAD within 3 months prior to enrollment

12. Patients with severe renal impairment or unstable or rapidly progressing renal disease or end stage renal disease.

13. Clinical conditions that could interfere with the cardiovascular autonomic function and heart rate variability (arrhythmias)

14. Severe hepatic insufficiency and/or significant abnormal liver function (defined as aspartate aminotransferase >3× upper limit of normal (ULN) and/or alanine aminotransferase >3× ULN) or creatinine kinase >3× ULN.

15. History of cancer other than basal cell carcinoma and/or treatment for cancer within the last 5 years

16. Women of child-bearing potential who may be pregnant or lactating.

17. History of pancreas, kidney or liver transplant

18. History of drug or alcohol abuse

19. History of allergy to sulfa drugs

20. Presence of any condition that, in the opinion of the investigator would make it unlikely for the subject to complete the study

21. Congestive heart failure (CHF) defined as New York Heart Association class III and IV

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan	Ann Arbor	Michigan	United States	48104

Sponsors and Collaborators

• University of Michigan
• AstraZeneca

Investigators

• Principal Investigator: Rodica Pop-Busui, M.D. Ph.D, University of Michigan Department of Internal Medicine Division of Metabolism, Endocrinology and Diabetes
• Principal Investigator: Lynn P Ang, M.D, University of Michigan Department of Internal Medicine Division of Metabolism, Endocrinology and Diabetes

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 10, 2017

More Information

Publications

None provided.

• Responsible Party: Rodica Pop-Busui, Professor of Internal Medicine, University of Michigan
• ClinicalTrials.gov Identifier: NCT02973477
• Other Study ID Numbers: HUM00121107
• First Posted: Nov 25, 2016
• Last Update Posted: Oct 22, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dapagliflozin; Glimepiride

Study Results

Participant Flow

Arm/Group Title	First Dapagliflozin Then Glimepiride	First Glimepiride Then Dapagliflozin
Arm/Group Description	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.	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.
Period Title: First Intervention
STARTED	19	26
COMPLETED	19	24
NOT COMPLETED	0	2
Period Title: First Intervention
STARTED	19	24
COMPLETED	18	24
NOT COMPLETED	1	0
Period Title: First Intervention
STARTED	18	24
COMPLETED	17	24
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	First Dapagliflozin Then Glimepiride	First Glimepiride Then Dapagliflozin	Total
Arm/Group Description	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.	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 of all reporting groups
Overall Participants	19	26	45
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57 (9)	56 (8)	57 (8)
Sex: Female, Male (Count of Participants)
Female	7 36.8%	12 46.2%	19 42.2%
Male	12 63.2%	14 53.8%	26 57.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 10.5%	0 0%	2 4.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 26.3%	7 26.9%	12 26.7%
White	12 63.2%	18 69.2%	30 66.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 3.8%	1 2.2%
LF:HF Ratio (Ratio) [Mean (Standard Deviation) ]
Baseline before First Intervention	1.00 (1.74)	0.73 (1.31)	0.84 (1.49)
Baseline before Second Intervention	0.82 (1.32)	0.35 (1.36)	0.61 (1.46)

Outcome Measures

1. Primary Outcome

Title	Changes in Measure of Heart Rate Variability Using Dapagliflozin vs Active Comparator Glimepiride.
Description	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

Outcome Measure Data

Analysis Population Description

All participants who completed both interventions were included in the analysis.

Arm/Group Title	First Dapagliflozin Then Glimepiride	First Glimepiride Then Dapagliflozin
Arm/Group Description	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.	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.
Measure Participants	17	24
value at 12 weeks minus value at 1st baseline	-0.18 (1.51)	-0.34 (1.54)
value at 26 weeks minus value at 2nd baseline	0.26 (1.85)	0.26 (1.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Dapagliflozin Then Glimepiride, First Glimepiride Then Dapagliflozin
	Comments	This is the adjusted mixed models analysis for both periods, both arms, comparing each treatment's change.
	Type of Statistical Test	Other
	Comments	Mixed effects model
Statistical Test of Hypothesis	p-Value	0.28
	Comments	Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Coefficient
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; -0.24 to 0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	The outcome was logged in the model. The outcome was the natural log of that variable and the coefficient and CI are for the relationship with the log of the outcome.

2. Secondary Outcome

Title	Changes in Measures of Heart Rate Variability (HRV) Using Dapagliflozin vs Active Comparator Glimepiride.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Participants Who Received Dapagliflozin Intervention	Participants Who Received Glimepiride Intervention
Arm/Group Description	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, whether before or after washout.	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 whether before or after washout.
Measure Participants	43	44
SDNN before treatment	40.72 (16.63)	39.75 (16.15)
SDNN after treatment	37.74 (16.04)	36.46 (17.68)
rmsSD before treatment	26.91 (17.81)	25.14 (13.06)
rmsSD after treatment	24.30 (16.44)	24.63 (17.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Dapagliflozin Then Glimepiride, First Glimepiride Then Dapagliflozin
	Comments	This is the adjusted analysis to compare the difference between the values from baseline to 12 weeks between each intervention for SDNN.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments	Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Coefficient
	Estimated Value	-0.003
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	The outcome was logged in the model. The outcome was the natural log of that variable and the coefficient and CI are for the relationship with the log of the outcome.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	First Dapagliflozin Then Glimepiride, First Glimepiride Then Dapagliflozin
	Comments	This is the adjusted analysis to compare the difference between the values from baseline to 12 weeks between each intervention for rmsSD.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.79
	Comments	Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Coefficient
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	The outcome was logged in the model. The outcome was the natural log of that variable and the coefficient and CI are for the relationship with the log of the outcome.

3. Secondary Outcome

Title	Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	All Participants Who Received Dapagliflozin	All Participants Who Received Glimiperide
Arm/Group Description	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, whether before or after washout.	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.
Measure Participants	43	44
E/I ratio before treatment	1.13 (0.07)	1.14 (0.08)
EI ratio after treatment	1.14 (0.11)	1.14 (0.13)
Valsalva ratio before treatment	1.50 (0.36)	1.44 (0.29)
Valsalva ratio after treatment	1.60 (0.66)	1.58 (0.85)
30:15 ratio before treatment	1.17 (0.15)	1.14 (0.09)
30:15 ratio after treatment	1.14 (0.11)	1.14 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Dapagliflozin Then Glimepiride, First Glimepiride Then Dapagliflozin
	Comments	This is the adjusted analysis for both periods, both arms, comparing each treatment's change of EI ratio.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments	Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Coefficient
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	First Dapagliflozin Then Glimepiride, First Glimepiride Then Dapagliflozin
	Comments	This is the adjusted analysis for both periods, both arms, comparing each treatment's change of Valsalva ratio.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments	Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome. Coefficient provided for Valsalva ratio.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Coefficient
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	The outcome was logged in the model. The outcome was the natural log of that variable and the coefficient and CI are for the relationship with the log of the outcome.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	First Dapagliflozin Then Glimepiride, First Glimepiride Then Dapagliflozin
	Comments	This is the adjusted analysis for both periods, both arms, comparing each treatment's change of 30:15 ratio.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.56
	Comments	Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome. Coefficient provided for 30:15 ratio.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Coefficient
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function
Description	Changes in B-type Natriuretic Peptide (BNP) with each intervention as a measure of left ventricular function.
Time Frame	12 weeks for each intervention

Outcome Measure Data

Analysis Population Description

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/Group Title	All Participants Who Received Dapagliflozin	All Participants Who Received Glimepiride
Arm/Group Description	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, whether before or after washout.	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.
Measure Participants	43	43
BNP before treatment	12.72 (9.76)	16.93 (13.69)
BNP after treatment	14.76 (13.41)	15.49 (11.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Dapagliflozin Then Glimepiride, First Glimepiride Then Dapagliflozin
	Comments	This is the adjusted analysis for both periods, both arms, comparing each treatment's change of BNP.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.92
	Comments	Adjusted analysis used a linear mixed effects model with unstructured covariance matrix controlled for possible period and sequence (carryover) effects for the outcome.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Coefficient
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Other Pre-specified Outcome

Title	Glucose Variability
Description	Measures of glucose variability via the continuous glucose monitoring system Libre Pro
Time Frame	2 weeks on each intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	26 weeks
Adverse Event Reporting Description	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.
Arm/Group Title	Dapagliflozin		Glimepiride		Not on Drug
Arm/Group Description	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.		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.		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.
All Cause Mortality
	Dapagliflozin		Glimepiride		Not on Drug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/43 (0%)		0/45 (0%)
Serious Adverse Events
	Dapagliflozin		Glimepiride		Not on Drug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Blood and lymphatic system disorders
Pulmonary Embolism	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Other (Not Including Serious) Adverse Events
	Dapagliflozin		Glimepiride		Not on Drug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/44 (25%)		14/43 (32.6%)		5/45 (11.1%)
Cardiac disorders
Atrial Fibrillation	0/44 (0%)		1/43 (2.3%)		0/45 (0%)
Chest Pain	0/44 (0%)		1/43 (2.3%)		0/45 (0%)
Endocrine disorders
Hypoglycemia	1/44 (2.3%)		2/43 (4.7%)		0/45 (0%)
Dizziness, Shakiness, Weakness and Sweaty	0/44 (0%)		1/43 (2.3%)		0/45 (0%)
Gastrointestinal disorders
Nausea, Vomiting and Dizziness	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Abdominal Pain	0/44 (0%)		1/43 (2.3%)		0/45 (0%)
Infections and infestations
Genital Yeast Infection	2/44 (4.5%)		0/43 (0%)		0/45 (0%)
Cold Like Symptoms	2/44 (4.5%)		0/43 (0%)		1/45 (2.2%)
Stomach Virus	0/44 (0%)		1/43 (2.3%)		0/45 (0%)
Bronchitis	0/44 (0%)		1/43 (2.3%)		0/45 (0%)
Urinary Tract Infection	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Strep Throat / Tonsillitis	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Food Poisoning	0/44 (0%)		1/43 (2.3%)		0/45 (0%)
Ear and Sinus Infection	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Injury, poisoning and procedural complications
Torn Left Hamstring	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Cut on Foot	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Abrasion of Left Cornea	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Motor Vehicle Accident	0/44 (0%)		0/43 (0%)		1/45 (2.2%)
Musculoskeletal and connective tissue disorders
Right Leg Pain and Swelling	0/44 (0%)		1/43 (2.3%)		0/45 (0%)
Diagnosis of Osteoporosis	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Left Shoulder Pain	0/44 (0%)		0/43 (0%)		1/45 (2.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma	0/44 (0%)		1/43 (2.3%)		0/45 (0%)
Nervous system disorders
Vasovagal Episode	0/44 (0%)		1/43 (2.3%)		0/45 (0%)
Syncope	0/44 (0%)		1/43 (2.3%)		0/45 (0%)
Pins and Needles Sensation of Lower Extremities	0/44 (0%)		0/43 (0%)		1/45 (2.2%)
Dizziness	0/44 (0%)		0/43 (0%)		1/45 (2.2%)
Psychiatric disorders
Worsening Depression and Mental Fogginess	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Renal and urinary disorders
Urinary Frequency and Discomfort - UTI Ruled Out	0/44 (0%)		2/43 (4.7%)		0/45 (0%)
Skin and subcutaneous tissue disorders
Foot Ulcer	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Surgical and medical procedures
Gull Bladder Removal	1/44 (2.3%)		0/43 (0%)		0/45 (0%)
Cataract Surgery	0/44 (0%)		0/43 (0%)		1/45 (2.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.