SGLT2-inhibitors Reduce the Cardiac Autonomic Neuropathy Dysfunction and Vaso-vagal Syncope Recurrence in Patients With Type 2 Diabetes Mellitus: the SCAN Study

Vaso vagal syncope recurrence is a relevant clinical problem (1). In fact, despite the vaso vagal syncope event is a transient loss of consciousness with rapid onset, short duration, and spontaneous complete recovery after the event, it may be complicated by physical injury (2). Conversely, the syncope recurrence rate is about 35%, and it causes a physical injury until the 29% (3). In addition, the vaso vagal syncope has a frequency between 15% and 39%, with annual number of episodes about 18.1-39.7 per 1000 patients, and an incidence of 6.2 per 1000 person-years, that grows up after 70 years of age with rate annual 19.5 per thousand individuals after 80 years (3). The patients with type 2 diabetes mellitus (T2DM) represent a percentage about the 30% of all the subjects with syncope (4). About the pathophysiology of syncope a central role is played by autonomic nervous system (5). To date, the autonomic nervous system regulates the hemodynamic stability by maintaining a stable blood pressure and heart rate under normal and abnormal physiologic conditions (5). Consequently, the dysfunction of this complex regulatory system, and of its interaction with sensor systems as baroreceptors, mechanoreceptors, chemoreceptors, may alter the vascular reactivity, leading to the clinical event and to future recurrences (5). Multiple factors affecting the autonomic system balance may trigger and cause a syncope event, as the result of an inappropriate response of the autonomic nervous system, with excessive vagal tone, and sympathetic tone withdrawal (2). In this setting, authors may note the diabetes as a common cause of autonomic system dysfunction (6). Moreover, T2DM may cause a severe form of autonomic system dysfunction affecting the cardiac autonomic regulation, and named as cardiac autonomic neuropathy (CAN), (6). Intriguingly, patients with diabetes experience a parasympathetic denervation, with an early augmentation of sympathetic tone, then leading to impaired heart rate variability, resting tachycardia, exercise intolerance, abnormal blood pressure regulation, and orthostatic hypotension (7). In addition, in T2DM there is a compensatory increase in the cardiac sympathetic tone in response to subclinical peripheral denervation (7). However, the T2DM may be seen as a relevant risk factor and a trigger to alter the autonomic system balance, and to cause vaso vagal syncope. In this context, the SGLT2-I are hypoglycemic drugs that might modulate the systemic and cardiac sympathetic dysfunction. On the other hand, the effects of the SGLT2-I therapy on the diabetic autonomic dysfunction and the vaso vagal syncope recurrence at follow up is not well established. Moreover, the recent studies cannot come to definitive conclusion about the impact of SGLT2-I on the vaso vagal syncope events, and about its future recurrences in patients with type 2 diebetes mellitus (T2DM). Conversely, heart rate variability (HRV) is a simple, reproducible and well-recognized method for evaluating sympatho vagal activity (8, 9). In this setting, the 123I-MIBG is an imaging exam to evaluate the cardiac autonomic dysfunction. Indeed, the 123I is an analogous of norepinephrine, and the entity of its myocardial captation is an index of cardiac innervation.

However, in this study authors evaluated the autonomic dysfunction as alteration in HRV, and 123I-MIBG, and its relevance to cause vaso vagal syncope, and the vaso vagal syncope recurrence in SGLT2-I users vs. Non-SGLT2-I users' patients with T2DM at 12 months of follow up.