Monitoring of the Sympathetic/Vagal Balance Through Multiparametric Analysis of Heart Rate Variability (HRV) (GLIFO-HRV)

March 20, 2026 updated by: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Monitoring of the Sympathetic/Vagal Balance Through Multiparametric Analysis of Heart Rate Variability (HRV) in Patients With Type 2 Diabetes Mellitus (Type 2 DM), With or Without Heart Failure and/or Chronic Kidney Disease, or Cardiomyopathy, With Heart Failure and/or Cardio-renal Syndrome, All Receiving Optimized Pharmacological Treatment, Including a Sodium-Glucose Co-transporter 2 Inhibitor (SGLT2i).

The autonomic nervous system (ANS) plays a crucial role in cardiovascular regulation by modulating heart rate in response to endogenous and environmental stimuli. Heart rate variability (HRV) analysis has been widely used as a non-invasive tool to assess autonomic function and the balance between sympathetic and parasympathetic activity. Although the physiological interpretation of some HRV parameters remains debated-particularly the low-frequency (LF) spectral component as an index of sympathetic activation-HRV remains an important method for evaluating autonomic cardiovascular control.

Reduced HRV has been associated with adverse outcomes in several pathological conditions and physiologically declines with aging, mainly due to progressive neuronal loss at central and spinal levels. Among conditions characterized by autonomic dysfunction, cardiovascular autonomic neuropathy (CAN) represents a common complication of diabetes mellitus (DM) and metabolic syndrome. CAN, defined as impairment of autonomic control of the cardiovascular system, develops early in the disease course and is associated with increased mortality and a higher risk of cardiovascular and renal complications.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed as glucose-lowering agents, have demonstrated significant cardiovascular and renal protective effects beyond glycemic control. Growing evidence suggests that these drugs exert sympathoinhibitory effects that may be beneficial not only in diabetic patients but also in conditions characterized by sympathetic overactivity. Preclinical and clinical studies have shown that SGLT2i influence autonomic regulation, including sympathetic control of renal function, with reported improvements in 24-hour blood pressure regulation and HRV parameters.

Large randomized trials have further confirmed the cardioprotective effects of SGLT2i therapy. Studies such as EMBODY, EMPEROR-Reduced, and EMPEROR-Preserved have demonstrated improvements in HRV indices and significant reductions in cardiovascular death and hospitalization for heart failure, irrespective of diabetic status.

Despite these findings, the mechanisms underlying these benefits remain incompletely understood. While reduced sympathetic activity has been proposed as a key mechanism, emerging evidence suggests that SGLT2i may also enhance vagal modulation. Therefore, the present study aims to investigate, in a larger population, the effects of SGLT2i therapy on sympathovagal balance using both spectral HRV parameters and additional indices, including the parasympathetic nervous system index (PNSi), sympathetic nervous system index (SNSi), and the Baevsky Stress Index.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Observational

Enrollment (Estimated)

150

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

Outpatient patients with:

  • Type 2 DM, with or without heart failure and/or chronic kidney disease, with a clinical indication to undergo HOLTER ECG monitoring to exclude or quantify concomitant autonomic dysfunction.
  • Patients with Cardiomyopathy, with heart failure or cardiorenal syndrome, with a cardiological indication to undergo HOLTER ECG monitoring to exclude or quantify signs attributable to ischemic heart disease and/or cardiac arrhythmias.

Description

Inclusion Criteria:

  • Age over 18 years;
  • Signed informed consent;
  • in Sinus rhythm;
  • Patients for whom HOLTER ECG monitoring is clinically indicated, to early identify the possible onset or progression of diabetic autonomic neuropathy, or ischemic changes, or potentially arrhythmogenic electrophysiological alterations;
  • On optimized pharmacological treatment according to clinical practice, naïve to SGLT2 inhibitor therapy, prescribed according to the (1A) recommendations of the ESC 2023 guidelines.

Exclusion Criteria:

  • Patients with atrial fibrillation or other arrhythmic burden incompatible with accurate HRV analysis;
  • Pacemaker or ICD carriers;
  • Immunodeficient patients or patients at risk of developing infections.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assessment of the sympathetic/vagal balance at baseline
Time Frame: 24 hours
All outcomes (primary and secondary) will be evaluated at rest, during daily activity and NREM sleep, with short-term (2- and 5-minute) Heart Rate Variability (HRV) analysis from 24-hour Holter recordings, with Kubios Scientific, a gold-standard HRV software tool for research, providing automatic calculation of multiple parameters in the time domain (TD), frequency domain (FD), with non-linear (NL) methods, and automatic time-varying computation of the parasympathetic (PNSi), sympathetic (SNSi), and Baevsky stress (BSTRi) indices, for faster and more comprehensive assessment of cardiac autonomic modulation (the PNS index ranges between -1 and 1 for 68% of the adult population at rest, and similarly scaled SNS index values outside the -1 to 1 range indicate higher or lower than average sympathetic activity) [1]. Tables reporting the laboratory's average age-related normal values for all parameters measured in daily activity and NREM sleep are available [2]. (Ref. moved to Citations)
24 hours
Changes the sympathetic/vagal balance during pharmacological treatment with SGLT2 inhibitors
Time Frame: 24 months

Outcome 2 will be assessed with Kubios, measuring the same HRV parameters and indices from the 24-hour follow-up Holter recordings. Changes of the sympathetic/vagal balance will be individually evaluated in each condition (rest, daily activity, and NREM sleep) and compared with the baseline values.

No score on a scale will be used.
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlation between improvement of heart failure or cardiorenal disease
Time Frame: 24 months
Assessment of the possible correlation between improvement of heart failure or cardiorenal disease
24 months
Evaluation of diabetic cardiovascular autonomic neuropathy
Time Frame: 24 months
As for the primary outcome measures, outcome 3 will be assessed with Kubios, measuring the same HRV parameters and indices from the 24-hour baseline and follow-up Holter recordings. The sympathetic/vagal balance will be individually evaluated in each condition (rest, daily activity, and NREM sleep) and compared with the baseline values at each control to identify which HRV parameters/indices can be more sensitive markers for early identification of the onset (or worsening) of diabetic cardiovascular autonomic neuropathy.
24 months
Detection of improvement or normalization of cardiac autonomic balance
Time Frame: 24 months
Outcome 5 will be assessed with Kubios, measuring the same HRV parameters and indices from the 24-hour baseline and follow-up Holter recordings. The comprehensive assessment of cardiac autonomic modulation will be individually performed in each condition (rest, daily activity, and NREM sleep) by comparing the sensitivity of TD, FD, and NL methods, with that provided by the automatic time-varying computation of the PNSi, SNSi, and BSTRi indices. Any change of the cardiac autonomic modulation toward a prevalence of the parasympathetic tone (either for an increase of vagal modulation, or a decrease of sympathetic modulation, or both), will be considered a positive outcome on cardiac autonomic function [3-5].
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Investigators

  • Principal Investigator: Donatella Brisinda, MD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

March 25, 2026

Primary Completion (Estimated)

March 25, 2031

Study Completion (Estimated)

September 1, 2031

Study Registration Dates

First Submitted

March 10, 2026

First Submitted That Met QC Criteria

March 10, 2026

First Posted (Actual)

March 13, 2026

Study Record Updates

Last Update Posted (Actual)

March 24, 2026

Last Update Submitted That Met QC Criteria

March 20, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 27089

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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