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

NCT ID: NCT02973477

Last Updated: 2020-10-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-12
• Study Completion Date: 2019-08-22

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.

Conditions

Type2 Diabetes; Cardiovascular Diseases

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

Dapagliflozin

Intervention Type: DRUG

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.

Glimepiride

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Dapagliflozin

Intervention Type: DRUG

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.

Glimepiride

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Study Drug; Active Comparator

Eligibility 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.

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

University of Michigan

OTHER

Sponsor Role: lead

Responsible Party

Rodica Pop-Busui

Professor of Internal Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Rodica Pop-Busui, M.D. Ph.D

Role: PRINCIPAL_INVESTIGATOR

University of Michigan Department of Internal Medicine Division of Metabolism, Endocrinology and Diabetes

Lynn P Ang, M.D

Role: PRINCIPAL_INVESTIGATOR

University of Michigan Department of Internal Medicine Division of Metabolism, Endocrinology and Diabetes

Locations

University of Michigan

Ann Arbor, Michigan, United States

Countries

United States

References

Ang L, Kidwell KM, Dillon B, Reiss J, Fang F, Leone V, Mizokami-Stout K, Pop-Busui R. Dapagliflozin and measures of cardiovascular autonomic function in patients with type 2 diabetes (T2D). J Diabetes Complications. 2021 Aug;35(8):107949. doi: 10.1016/j.jdiacomp.2021.107949. Epub 2021 May 15.

Reference Type: DERIVED

PMID: 34024686 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

HUM00121107

Identifier Type: -

Identifier Source: org_study_id