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

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ClinicalTrials.gov Identifier: NCT02973477
Recruitment Status : Completed
First Posted : November 25, 2016
Last Update Posted : November 21, 2019
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Rodica Pop-Busui, University of Michigan

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.


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Study Type : Interventional  (Clinical Trial)
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 : January 12, 2017
Actual Primary Completion Date : August 22, 2019
Actual Study Completion Date : August 22, 2019

Resource links provided by the National Library of Medicine


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 Name: 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 Name: 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 Name: 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 Name: Active Comparator




Primary Outcome Measures :
  1. Changes in measures of Heart Rate Variability using dapagliflozin vs active comparator glimepiride. [ Time Frame: 26 Weeks ]
    The difference of the LF:HF ratio from baseline to 12 weeks between the two drugs (two 12-week periods with a 2-week washout period).


Secondary Outcome Measures :
  1. Changes in measures of Heart Rate Variability using dapagliflozin vs active comparator glimepiride. [ Time Frame: 26 weeks ]
    ) 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).

  2. Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs) [ Time Frame: 26 weeks ]
    Changes in CARTs as defined by: i) expiration/inspiration (E/I) ratio, ii) Valsalva ratio and iii) 30:15 ratio.

  3. Changes in BNP with each intervention as a measure LV function. [ Time Frame: 26 Weeks ]
    Changes in BNP with each intervention as a measure LV function.


Other Outcome Measures:
  1. Glucose Variability [ Time Frame: 4 Weeks ]
    Measures of glucose variability via the continuous glucose monitoring system Libre Pro



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02973477


Locations
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United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48104
Sponsors and Collaborators
University of Michigan
AstraZeneca
Investigators
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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

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Responsible Party: Rodica Pop-Busui, Professor of Internal Medicine, University of Michigan
ClinicalTrials.gov Identifier: NCT02973477     History of Changes
Other Study ID Numbers: HUM00121107
First Posted: November 25, 2016    Key Record Dates
Last Update Posted: November 21, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Cardiovascular Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Glimepiride
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Immunosuppressive Agents
Immunologic Factors