Diabete Type 2GLIFO-HRVNCT07471802
Monitoring of the Sympathetic/Vagal Balance Through Multiparametric Analysis of Heart Rate Variability (HRV)
An observational study of Diabete Type 2 and Heart Failure, run by Fondazione Policlinico Universitario Agostino Gemelli IRCCS at 1 site in Italy.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Diabete Type 2, Heart Failure, Kidney Disease, Chronic
- What is being tested?
- HOLTER ECG monitoring
- How many people
- 150 participants
- Where
- 1 siteItaly
- Study dates
- 20 May 2026to 1 Sep 2031
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
Italy1 site
Fondazione Policlinico Universitario Agostino Gemelli, IRCCS
Roma, 00168
About this study
Official title: 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.
Read more
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.
- Being tested
- HOLTER ECG monitoring
- Medical subject headings
- Diabetes Mellitus, Type 2, Heart Failure, Renal Insufficiency, Chronic, Cardio-Renal Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HOLTER ECG monitoringDiagnostic test
Monitoring of the sympathetic/vagal balance through multiparametric analysis of heart rate variability (HRV) using 24 hours ECG HOLTER
What is being measured
The primary outcome is the main question the study is designed to answer.
Assessment of the sympathetic/vagal balance at baseline
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)
Measured: 24 hours
Changes the sympathetic/vagal balance during pharmacological treatment with SGLT2 inhibitors
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.
Measured: 24 months
Secondary outcomes (3)
Evaluation of diabetic cardiovascular autonomic neuropathy
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.
Measured: 24 months
Correlation between improvement of heart failure or cardiorenal disease
Assessment of the possible correlation between improvement of heart failure or cardiorenal disease
Measured: 24 months
Detection of improvement or normalization of cardiac autonomic balance
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].
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Mar 2026
- Study start20 May 2026
- Primary completion25 Mar 2031 (estimated)
- Study completion1 Sep 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Diabete Type 2Studies of the same condition, open and under way.
- More trials run by Fondazione Policlinico Universitario Agostino Gemelli IRCCSThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Donatella Brisinda, MD, Principal investigator, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07471802
- Sponsor's protocol ID
- 27089
- Acronym
- GLIFO-HRV
- Status last verified
- Apr 2026
- First submitted
- 10 Mar 2026
- Last updated
- 4 Sep 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Tarvainen MP, Niskanen JP, Lipponen JA, Ranta-Aho PO, Karjalainen PA. Kubios HRV--heart rate variability analysis software. Comput Methods Programs Biomed. 2014;113(1):210-20. doi: 10.1016/j.cmpb.2013.07.024. Epub 2013 Aug 6.
PubMed 24054542Brisinda D, Picerni M, Fenici P, and Fenici R, "Rapid assessment of cardiac autonomic modulation and adaptive stress responses: Automatic calculation of time-varying parasympathetic, sympathetic, and Baevsky stress indexes," Brain & Heart., vol. 2, no. 4, p. 3503, 2024, doi: 10.36922/bh.3503.
Balcioglu AS, Celik E, Sahin M, Gocer K, Aksu E, Aykan AC. Dapagliflozin Improves Cardiac Autonomic Function Measures in Type 2 Diabetic Patients with Cardiac Autonomic Neuropathy. Anatol J Cardiol. 2022 Nov;26(11):832-840. doi: 10.5152/AnatolJCardiol.2022.1934.
PubMed 35949125Zhou L, Niu M, Chen W, Hu Q, Chen Y, Geng X, Gu J. Effects of dapagliflozin on heart rate variability, cardiac function, and short-term prognosis in early-onset post-myocardial infarction heart failure. Front Cardiovasc Med. 2025 Jan 6;11:1490316. doi: 10.3389/fcvm.2024.1490316. eCollection 2024.
PubMed 39834729Dimitriadis K, Pitsiori D, Alexiou P, Pyrpyris N, Sakalidis A, Beneki E, Iliakis P, Tatakis F, Theofilis P, Tsioufis P, Konstantinidis D, Aggeli K, Tsioufis K. Modulating Sympathetic Nervous System With the Use of SGLT2 Inhibitors: Where There Is Smoke, There Is Fire? J Cardiovasc Pharmacol. 2025 Jan 1;85(1):12-20. doi: 10.1097/FJC.0000000000001644.
PubMed 39436317
Study at a glance
From the registry record, last updated by the sponsor on 4 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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).
- ClinicalTrials.gov ID
- NCT07471802
- Acronym / sponsor ID
- GLIFO-HRV / 27089
- Study type
- Observational
- Recruitment status
- Active, not recruiting
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Fondazione Policlinico Universitario Agostino Gemelli IRCCSUniversity, hospital or other
- Study start
- 20 May 2026 (actual)
- Primary completion
- 25 Mar 2031 (estimated)
- Study completion
- 1 Sep 2031 (estimated)
- First posted
- 13 Mar 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HOLTER ECG monitoringMonitoring of the sympathetic/vagal balance through multiparametric analysis of heart rate variability (HRV) using 24 hours ECG HOLTER | Diagnostic test | – |
Primary outcome
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)
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.
3 secondary outcomes
Evaluation of diabetic cardiovascular autonomic neuropathy
Time frame: 24 months
Correlation between improvement of heart failure or cardiorenal disease
Time frame: 24 months
Detection of improvement or normalization of cardiac autonomic balance
Time frame: 24 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Sep 2026.
- Background: PubMed 24054542Tarvainen MP, Niskanen JP, Lipponen JA, Ranta-Aho PO, Karjalainen PA. Kubios HRV--heart rate variability analysis software. Comput Methods Programs Biomed. 2014;113(1):210-20. doi: 10.1016/j.cmpb.2013.07.024. Epub 2013 Aug 6.
- BackgroundBrisinda D, Picerni M, Fenici P, and Fenici R, "Rapid assessment of cardiac autonomic modulation and adaptive stress responses: Automatic calculation of time-varying parasympathetic, sympathetic, and Baevsky stress indexes," Brain & Heart., vol. 2, no. 4, p. 3503, 2024, doi: 10.36922/bh.3503.
- Background: PubMed 35949125Balcioglu AS, Celik E, Sahin M, Gocer K, Aksu E, Aykan AC. Dapagliflozin Improves Cardiac Autonomic Function Measures in Type 2 Diabetic Patients with Cardiac Autonomic Neuropathy. Anatol J Cardiol. 2022 Nov;26(11):832-840. doi: 10.5152/AnatolJCardiol.2022.1934.
- Background: PubMed 39834729Zhou L, Niu M, Chen W, Hu Q, Chen Y, Geng X, Gu J. Effects of dapagliflozin on heart rate variability, cardiac function, and short-term prognosis in early-onset post-myocardial infarction heart failure. Front Cardiovasc Med. 2025 Jan 6;11:1490316. doi: 10.3389/fcvm.2024.1490316. eCollection 2024.
- Background: PubMed 39436317Dimitriadis K, Pitsiori D, Alexiou P, Pyrpyris N, Sakalidis A, Beneki E, Iliakis P, Tatakis F, Theofilis P, Tsioufis P, Konstantinidis D, Aggeli K, Tsioufis K. Modulating Sympathetic Nervous System With the Use of SGLT2 Inhibitors: Where There Is Smoke, There Is Fire? J Cardiovasc Pharmacol. 2025 Jan 1;85(1):12-20. doi: 10.1097/FJC.0000000000001644.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Donatella Brisinda, MD principal investigator
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Diabete Type 2 and Heart Failure, run by Fondazione Policlinico Universitario Agostino Gemelli IRCCS at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 4 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Assessment of the sympathetic/vagal balance at baseline (time frame: 24 hours). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07471802, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Sep 2026.