Possible Glycemic Effects of Vagus Nerve Stimulation Evaluated by Continuous Glucose Monitoring in People with Diabetes and Autonomic Neuropathy: A Randomized, Sham-Controlled Trial

<b><i>Objective:</i></b> Autonomic neuropathy is associated with dysglycemia that is difficult to control. We investigated if transcutaneous vagus nerve stimulation (tVNS) could improve glycemic levels. <b><i>Methods:</i></b> We randomized 145 individuals with type 1 diabetes (T1D) (<i>n</i> = 70) or type 2 diabetes (T2D) (<i>n</i> = 75) and diabetic autonomic neuropathy (DAN) to self-administered treatment with active cervical tVNS (<i>n</i> = 68) or sham (<i>n</i> = 77) for 1 week (4 daily stimulations) and 8 weeks (2 daily stimulations), separated by a wash-out period of at least 2 weeks. Continuous glucose monitoring (CGM) indices were measured for 104 participants starting 5 days prior to intervention periods, during the 1-week period, and at end of the 8-week period. Primary outcomes were between-group differences in changes in coefficient of variation (CV) and in time in range (TIR 3.9-10 mmol/L). Secondary outcomes were other metrics of CGM and HbA1c. <b><i>Results:</i></b> For the 1-week period, median [interquartile range] changes of CV from baseline to follow-up were -1.1 [-4.3;2.0] % in active and -1.5 [-4.4;2.5] % in sham, with no significance between groups (<i>P</i> = 0.54). For TIR, the corresponding changes were 2.4 [-2.1;7.4] % in active and 5.1 [-2.6;8.8] in sham group (<i>P</i> = 0.84). For the 8-week treatment period, changes in CV and TIR between groups were also nonsignificant. However, in the subgroup analysis, persons with T1D receiving active tVNS for 8 weeks had a significant reduction in CV compared with the T1D group receiving sham stimulation (estimated treatment effect: -11.6 [95% confidence interval -20.2;-2.0] %, <i>P</i> = 0.009). None of the changes in secondary outcomes between treatment groups were significantly different. <b><i>Conclusions:</i></b> Overall, no significant changes were observed in CGM metrics between treatment arms, while individuals with T1D and DAN decreased their CV after 8 weeks of tVNS treatment.