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.

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.

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.