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

NCT02973477 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: HUM00121107
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

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.

Conditions

Type2 Diabetes; Cardiovascular Diseases

Outcome Measures

Primary Outcomes (1)

• 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.

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

Secondary Outcomes (3)

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

  12 weeks on each intervention

• Changes in Measures of Cardiac Autonomic Reflex Testing (CARTs)

  12 weeks on each intervention

• Change in B-type Natriuretic Peptide With Each Intervention as a Measure of Left Ventricular Function

  12 weeks for each intervention

Other Outcomes (1)

• Glucose Variability

  2 weeks on each intervention

Study Arms (2)

Group A: Dapagliflozin/Glimepiride

EXPERIMENTAL

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; Drug: Glimepiride

Group B: Glimepiride/Dapagliflozin

EXPERIMENTAL

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; Drug: Glimepiride

Interventions

Dapagliflozin 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.

Also known as: Study Drug

Group A: Dapagliflozin/Glimepiride; Group B: Glimepiride/Dapagliflozin

Glimepiride 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.

Also known as: Active Comparator

Group A: Dapagliflozin/Glimepiride; Group B: Glimepiride/Dapagliflozin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with type 2 diabetes as defined on background metformin monotherapy who are not meeting ADA standard of care recommended glucose target.
• Age ≥18 years

You may not qualify if:

• History of multiple urinary tract infections
• Patients with mycotic infections especially genital infections.
• Severely hypotensive patients
• History of unexplained microscopic or gross hematuria, or microscopic hematuria at visit 1, confirmed by a follow-up sample at next scheduled visit.
• Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions
• Inability or refusal to comply with protocol
• Current participation or participation in an experimental drug study in the previous three months
• History of diabetic ketoacidosis
• Planned cardiac surgery or angioplasty within 3 months
• Recent history of acute CV events such as MI, stroke, PAD within 3 months prior to enrollment
• Patients with severe renal impairment or unstable or rapidly progressing renal disease or end stage renal disease.
• Clinical conditions that could interfere with the cardiovascular autonomic function and heart rate variability (arrhythmias)
• 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.
• History of cancer other than basal cell carcinoma and/or treatment for cancer within the last 5 years
• Women of child-bearing potential who may be pregnant or lactating.

Sponsors & Collaborators

• University of Michigan: lead
• AstraZeneca: collaborator

Study Sites (1)

University of Michigan

Ann Arbor, Michigan, 48104, United States

Location

Related Publications (1)

• 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.

  PMID: 34024686 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases

Interventions

dapagliflozin; Drug Evaluation; glimepiride

Intervention Hierarchy (Ancestors)

Drug Development; Investigative Techniques; Evaluation Studies as Topic

Results Point of Contact

• Title: Lynn Ang
• Organization: University of Michigan

angly@med.umich.edu

734-232-8058

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Internal Medicine

Study Record Dates

• First Submitted: November 16, 2016
• First Posted: November 25, 2016
• Study Start: January 12, 2017
• Primary Completion: August 22, 2019
• Study Completion: August 22, 2019
• Last Updated: October 22, 2020
• Results First Posted: October 22, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)