The Effect of SGLT2 Inhibitors on Heart Rate Variability and BDNF Levels in Patients With Type 2 Diabetes

The Effect of SGLT2 Inhibitors on Heart Rate Variability, Sympathetic and Parasympathetic Activity and a Neuroinflammatory Biomarker, Brain-Derived Neurotrophic Factor Levels in Patients With Type 2 Diabetes

Cardiac autonomic neuropathy (CAN) in diabetic patients is an indicator of autonomic nervous system dysfunction and is an important marker for cardiovascular events. Very promising results have been obtained with SGLT2 inhibitors in both cardiac and renal outcomes. The aim is to examine the effects of SGLT2 inhibitor use on cardiac autonomic neuropathy, heart rate variability, sympathetic and parasympathetic nervous system parameters, and their relationship with BDNF levels, one of the neuroinflammatory markers.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes; Heart Rate Variability
• Intervention / Treatment: Diagnostic test: 24-hour rhythm Holter; Diagnostic test: 36 item Short Form Survey (SF-36)

Detailed Description

Cardiac autonomic neuropathy (CAN) in diabetic patients is an indicator of autonomic nervous system dysfunction and is an important marker for cardiovascular events. Five-year mortality rates of diabetic patients with CAN are significantly higher than those without. Although there are various methods, primarily scintigraphic and pharmacological tests, to evaluate CAN, the practical use of these methods remains limited. In recent years, heart rate recovery (HRR) and heart rate variability (HRV) have been increasingly used as simple, inexpensive, and non-invasive methods to evaluate the status of heart sympathetic and vagus nerve functions. Values obtained as a result of 24-hour rhythm Holter provide the measurement of sympathetic and parasympathetic activity. While a significant relationship was observed between blood glucose levels and HRV in previous studies, no relationship was found between HbA1c levels and HRV.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family with growth factor properties. Studies with SGLT2 inhibitors have shown a decrease in HbA1c values, weight loss, and a decrease in both systolic and diastolic blood pressure. Very promising results have been obtained with SGLT2 inhibitors in both cardiac and renal outcomes. As a result of these data, these medications are recommended as drugs that should be used in the foreground following metformin, especially in diabetic patients with cardiac and renal diseases. In the study of Shimuz et al. in which the effects of empagliflozin and placebo on heart rate variability were compared in patients with acute myocardial infarction, HRV improved significantly with the use of empagliflozin in the early period. A study examining the effects of empagliflozin use on HRV in patients with type 2 diabetes is still ongoing. Apart from these 2 studies, no study was found in the literature.

The aim of this study is to examine the effects of SGLT2 inhibitor use on cardiac autonomic neuropathy, heart rate variability, sympathetic and parasympathetic nervous system parameters, and their relationship with BDNF levels, one of the neuroinflammatory markers.

• Study Type: Observational
• Enrollment (Actual): 64

Contacts and Locations

Study Locations

• Turkey
  • Istanbul, Turkey
    • Istanbul Medeniyet University Goztepe Research and TRaining Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

patients who refer to a diabetes outpatients clinics to an university hospital

Description

Inclusion Criteria:

• giving consent
• being 30 years old or older
• HbA1c concentrations between 6.5% and 8%
• using metformin as a single agent for at least 3 months
• diabetes age <10 years

Exclusion Criteria: existence of one of the listed conditions:

• having uncontrolled hypothyroidism, hyperthyroidism, or other diseases that may affect cognitive functions
• ketoacidosis or coma
• cerebrovascular disease or psychiatric disorder
• mental retardation, psychosis, dementia, brain trauma, epilepsy and other cerebral diseases
• alcohol or other substance abuse
• hearing loss
• Presence of diseases that will affect cognitive function such as chronic inflammatory diseases and respiratory system diseases
• chronic kidney failure (GFR <45)
• sleep apnea syndrome
• malignancy
• using a sulfonylurea or glinide
• using beta blocker or non-dihydropyridine group calcium antagonists
• diabetic autonomous neuropathy
• atrial fibrillation
• an acute coronary event within the last 3 months

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with type 2 diabetes treated with SGLT2 inhibitors; metformin using patients with type 2 diabetes who were recently prescribed an SGLT2 inhibitor	Diagnostic test: 24-hour rhythm Holter; Before starting their newly prescribed medication, the investigators will apply 24-hour rhythm Holter and repeat it at the end of the trial.; Diagnostic test: 36 item Short Form Survey (SF-36); Before starting their newly prescribed medication, the investigators will apply SF-36 survey and repeat it at the end of the trial.; Other Names: SF-36
Patients with type 2 diabetes treated with other oral agents; metformin using patients with type 2 diabetes who were recently prescribed a pre-defined antidiabetic medication other than SGLT2 inhibitors	Diagnostic test: 24-hour rhythm Holter; Before starting their newly prescribed medication, the investigators will apply 24-hour rhythm Holter and repeat it at the end of the trial.; Diagnostic test: 36 item Short Form Survey (SF-36); Before starting their newly prescribed medication, the investigators will apply SF-36 survey and repeat it at the end of the trial.; Other Names: SF-36

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate variability parameters	The investigators will evaluate the effects of SGLT2 inhibitor use on heart rate variability derived from 24-hour rhythm Holter compared with other antidiabetic medications.	Six months
BDNF concentrations	The investigators will observe the effects of SGLT2 inhibitors and other oral antidiabetic agents on BDNF levels in type 2 diabetic patients.	Six months

Collaborators and Investigators

• Sponsor: Goztepe Training and Research Hospital
• Investigators: Principal Investigator: Ayşe N Erbakan, MD, Istanbul Medeniyet University Goztepe Research and TRaining Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Actual): December 21, 2022
• Study Completion (Actual): December 30, 2022

Study Registration Dates

• First Submitted: October 17, 2021
• First Submitted That Met QC Criteria: December 7, 2021
• First Posted (Actual): December 20, 2021

Study Record Updates

• Last Update Posted (Actual): September 5, 2023
• Last Update Submitted That Met QC Criteria: September 1, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: type 2 diabetes; SGLT2 inhibitors; heart rate variability; parasympathetic activity; sympathic activity
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: Heart Rate Variability-BDNF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No