Peter S Staats MD MBA, Alyssa Staats MS

Introduction:

Diabetes mellitus, a chronic and progressive condition, affects more than 422 million people worldwide. In 2021 38.4 million in the United States, or 11.6% of the national population. Diabetes incurs significant healthcare costs, including hospitalizations, medications, and outpatient care, especially related to the pain of Diabetic Peripheral Neuropathy (DPN) and the often associated poor glucose control.^[i] [ii]  The total estimated cost of diagnosed diabetes in the U.S. in 2022 is $412.9 billion, including $306.6 billion in direct medical costs and $106.3 billion in indirect costs attributable to diabetes.^[iii].  Unfortunately, there are also additional and indirect costs contributing to the overall financial burden of diabetes. Complications add significantly to the cost of care, for instance the estimated loss of productivity is 90 billion dollars in the United States alone.   The burden of diabetes is particularly severe among Native American populations, who are 2.3 times more likely to die from diabetes compared to the general American population. Most diabetes cases are type 2, a form of the disease linked to poor diet, aging, and genetic predisposition. Despite advances in pharmacological treatments, current medication strategies have proven inadequate in consistently controlling DPN, insulin secretion nor maintaining optimal glucose levels.

Vagus nerve stimulation (VNS) is known to play a critical role in modulating insulin secretion, a key factor in the management of type 2 diabetes. The vagus nerve, as part of the parasympathetic nervous system, innervates the pancreas and influences the release of insulin by modulating the activity of beta cells within the islets of Langerhans. Stimulation of the vagus nerve has been shown to affect the balance between insulin secretion and glucose metabolism, potentially normalizing elevated blood glucose levels. In preclinical studies, VNS has been demonstrated to decrease insulin secretion in response to glucose, which may help counteract the hyper-insulinemia often seen in type 2 diabetes. This ability to regulate insulin production through neural pathways provides a promising alternative to traditional pharmacological approaches, especially for patients who have not responded adequately to medication.

Auricular peripheral nerve stimulation, which can include a specific form of VNS, targets the auricular branch of the vagus nerve, offering a minimally invasive method to influence insulin secretion and improve glucose control in type 2 diabetes. The auricular branch, which connects to the vagus nerve, can be precisely localized within the tragus making it a convenient, and less invasive option compared to traditional dissection of the cervical sheath. Further, as this branch contains less than  one percent of the overall vagal afferent fibers, and does not directly project into the nucleus tractus solitarii (NTS), as the remainder of the vagal fibers do, it activates the NTS indirectly through the lateral trigeminal islands. In part for this reason it’s suspected that early initial clinical trials with combined Trigeminocervical (TCN) and VNS auricular peripheral nerve stimulators have shown promising results in controlling DPN including improvements in glycemic control in active diabetic patients.^[iv] This effect is thought to be mediated by the vagus nerve’s regulation of insulin release, suggesting that combined TCN and VNS auricular peripheral nerve stimulation could be a valuable tool in the treatment of type 2 diabetes, particularly for those who have not achieved adequate control through lifestyle modifications and medications.

The current combined TCN and VNS auricular neurostimulator stimulates the distal auricular branches of the C2 and C3 nerve roots (specifically the lesser occipital and greater auricular nerves), as well as Cranial Nerves 5 and 10 (namely the auricular temporal branch of the Trigeminal, and the auricular branch of the Vagus). Each of these peripheral and cranial nerves have small, afferent branches that can be precisely accessed activating their associated brainstem and projection pathways. It is presumed that these subsequently activate a vagal reflex to various visceral structures including the pancreas, spleen, intestines and other structures.   In addition to pain scores assessing glucose responsiveness to this novel form of stimulation, this study seeks to contribute to the growing body of evidence supporting combined TCN and VNS auricular peripheral nerve stimulation as a potential treatment for diabetes, offering hope for better management of this widespread and life-threatening condition.

Methods:

This is an observational study exploring the efficacy of minimally invasive combined TCN and VNS auricular peripheral nerve stimulation in managing DPN and glucose levels. Ninety-three patients of Native American descent were prescribed and used this device for 19 days and were subsequently followed for an average of 227 days following treatment.  The device is precisely implanted  in the distal auricular branches of the C2 and C3 nerve roots (specifically the lesser occipital and greater auricular nerves), as well as Cranial Nerves 5 and 10 (auricular temporal branch of the Trigeminal, and the auricular branch of the Vagus) — each of these is localized and confirmed with real-time, closed loop neural impedance drop feedback. All patients were prescribed the device on label for pain related to DPN.   Patients then returned for follow up at 30, 60, and 90 days, and measurements of glucose and pain scores were obtained.   In addition, some patients were queried about medication usage.

Results :

Statistics and statistical analysis

Primary outcome measures in this study were pain scores and glucose level and percentage improvements from baseline  to 30, 60 and 90 days post-treatment. Eight patients were lost to follow-up, so statistical analysis was conducted on the remaining 83 patients in our records.   Average improvement at 30, 60, and 90 days after application of the auricular combined TCN and VNS peripheral nerve stimulator were followed for seven months, or an average of 227 days.  Medication usage over time was recorded in 45 patients. Among this subset, 80% reported discontinuing all medications after receiving VNS.

Table 1: Pain Score Values 

Baseline Pain Score	Time Period	Pain Score	Level Difference	% Difference
7.95	30-day	1.87	-6.16	78%
7.95	60-day	1.36	-6.64	83%
7.95	90-day	1.04	-6.94	87%

Table 1 reports the baseline pain levels and the levels of pain reported and 30, 60, and 90 day follow ups.

Table 2: Pain Improvements & One-Sample, Two-Sided Student’s t-Test Results

Indicator	Mean	Lower Bound	Upper Bound	Standard Error	T-Test Statistic	P Value
Pain Level Improvement, 30 Days	-6.16	-6.56	-5.76	0.20	-30.74	8.949e-47***
Pain Percent (%) Improvement, 30 Days	78%	74%	81%	0.02	40.57	4.838-56***
Pain Level Improvement, 60 Days	-6.64	-7.06	-6.23	0.21	-32.07	3.619e-48***
Pain Percent (%) Improvement, 60 Days	83%	79%	86%	0.02	43.85	1.081e-58***
Pain Level Improvement, 90 Days	-6.94	-7.32	-6.56	0.19	-36.08	4.324e-52***
Pain Percent (% Improvement, 90 Days	87%	85%	90%	0.01	61.09	3.763e-70***

Table 2 describes the level and percent improvements in pain scores at 30, 60, and 90 days. Level improvement reflects the subtracted difference between the baseline pain score and the follow-up pain score, as shown also in the fourth column of Table 1. Mean scores for the difference in levels and the percentage improvements were calculated, and standard one sample, two-sided student’s t-tests were run on each. Results were statistically significantly different from baseline at the 5%, 1%, and 0.1% levels.

Table 3: Blood Glucose Levels

Baseline Blood Glucose Levels		Blood Glucose Level	Level Difference	% Difference
209	30-day	159	-50	19%
209	60-day	147	-63	24%
209	90-day	121	-89	37%

Table 3 reports the baseline blood glucose levels and levels and percentage improvements for 30, 60, and 90 day follow ups.

Table 4: Blood Glucose Improvements & One-Sample, Two-Sided Student’s t-Test Results

Indicator	Mean	Lower Bound	Upper Bound	Standard Error	T-Test Statistic	P Value
Blood Glucose Level Improvement, 30 Days	-50.32	-62.75	-37.88	6.25	-8.05	6.858e-12
Blood Glucose Percent (%) Improvement, 30 Days	19%	13%	25%	3%	6.52	6.156e-09
Blood Glucose Level Improvement, 60 Days	-62.64	-76.63	-48.64	7.03	-8.91	1.606e-13
Blood Glucose Percent (%) Improvement, 60 Days	24%	18%	30%	3%	817%	4.502e-12
Blood Glucose Level Improvement, 90 Days	-88.97	-103.26	-74.69	7.17	-12.41	4.793e-20
Blood Glucose Percent (% Improvement, 90 Days	37%	33%	41%	0.02	17.99	4.092e-29

Table 4 describes one-sample, two-sided student’s t-test results for the level and percent improvement in blood glucose measurements following auricular nerve stimulation.  In terms of both level and percentage improvements, results are statistically significant at the 5%, 1%, and 0.1% levels.  Furthermore, it would be impossible to have a 100% improvement in scores in the statistical analysis, as this would reflect a glucose of zero.  However, by 90 days, the glucose mean was 121 mg/dl, which approximates normal glucose levels.   As such, by 90 days, many patients no longer experienced hyperglycemia.

Conclusion:

Combined TCN and VNS auricular peripheral nerve stimulation is currently cleared by the FDA as a for treatment of diabetic neuropathic pain.  In this study, patients were followed in an open label fashion, with pain scores and glucose levels obtained at baseline, as well as  followed for an average of 227 days.  While the reduction in pain and glucose levels was dramatic, it is a retrospective review of a large data set of pain and glycemic levels.   Statistical t-tests reveal that these profound improvements are not a function of chance.   Further studies controlling for the placebo effect, diet, and exercise are warranted.  Strikingly, although the device was used for an average of only 19 days, pain scores and glucose continued to improve over 90 days.  If larger clinical trials confirm early findings, combined TCN and VNS auricular peripheral nerve stimulation stands to be a transformative therapy for the management of diabetes and diabetic neuropathy pain.  

Notes:

Dr Staats was responsible for drafting the protocol and primary writing of the manuscript. Ms. Staats performed the statistical analysis in R 4.3.1 (using tidy-verse, dplyr, and stats packages) and editing of the manuscript.  Data was obtained from NS100 data registry.

^[i] https://www.who.int/health-topics/diabetes#tab=tab_1

^[ii] https://www.cdc.gov/diabetes/php/data-research/index.html

^[iii] Parker ED, Lin J, Mahoney T, Ume N, Yang G, Gabbay RA, ElSayed NA, Bannuru RR. Economic Costs of Diabetes in the U.S. in 2022. Diabetes Care. 2024 Jan 1;47(1):26-43. doi: 10.2337/dci23-0085. PMID: 37909353.

^[iv] Berthoud, et al., Vagal mechanisms as neuromodulatory targets for the treatment of metabolic disease, Annals of the New York Academy of Sciences, Special Issue: Autonomic Nervous System Regulation and Metabolic Diseases, Vol. 1454, p. 42–55 (2019) doi.org/10.1111/nyas.14182