Vagal Nerve Therapy in the Management of Obesity: A Systematic Review and Meta-Analysis

The most common bariatric procedures for weight loss include laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). They produce substantial and sustainable weight loss and remission of obesity-related comorbidities in the long term [1‒5]; however, they are associated with potential risks of morbidity and alterations of the gastrointestinal anatomy [6]. Vagal nerve therapy has been shown to potentially provide a minimally invasive alternative to standard bariatric surgery to provide weight loss. The vagus nerve has an important role in satiety, metabolism, and autonomic control in upper gastrointestinal function [7]. Targeted therapy of the vagus nerve may lead to an improvement in obesity-related conditions such as diabetes mellitus type 2 with an associated low rate of major complications [8‒10].

The vagal nerve blockade (vBloc) device is inserted by standard laparoscopic surgical techniques without permanent anatomical alterations of the gastrointestinal tract. It was developed based on prior observations of vagotomy as a treatment for obesity by reducing sensations of hunger [11, 12]. The vBloc device, the Maestro Rechargeable System, delivers low energy and high frequency intermittent electrical pulses to the intra-abdominal vagal trunks [13]. The vBloc device has been shown to clinically result in weight loss with good safety outcomes. The ReCharge randomised controlled trial (RCT) demonstrated an estimated mean percentage excess weight loss (%EWL) of 26% (10% total weight loss, TWL) for vBloc and 17% (6%TWL) for sham at 12 months (p < 0.001) [8]. The VBLOC DM2 study also found that intermittent vagal blocking led to significant weight loss with improvements in obesity and glycaemic control after 2 years of treatment with a well-tolerated safety profile [14].

Different methods of vagal nerve therapy can provide weight loss. Burneo et al. [15] found that 62% of patients experienced significant weight loss during vagal nerve stimulation (VNS) treatment for epilepsy. An improvement in weight loss was seen when the output current of the stimulator was increased. Pardo et al. [16] observed a similar finding in patients receiving VNS therapy for treatment-resistant depression. In other studies, however, a significant decrease in weight or body mass index (BMI) was not seen [17, 18]. The percutaneous electrical neurostimulation (PENS) of dermatome T6 (“T6 method”) resulted in significant preoperative weight loss in patients with severe obesity prior to bariatric surgery [19, 20]. This technique produces an artificial somato-autonomic reflex whose efferent pathways end in vagal nerve branches stimulating the gastric wall similarly to the gastric pacemaker.

It is still unclear from the literature whether vagal nerve therapy is effective at improving weight loss, BMI, and remission of associated medical problems. We thus performed a systematic review of the literature and meta-analysis to evaluate and determine the efficacy of the different methods of vagal nerve therapy, including vBloc, VNS, and PENS. This in turn should provide further understanding on the clinical application of vagal nerve therapy in the management of obesity along with the safety profile. The main outcome measures assessed were %EWL and BMI reduction at 12 months and the effect on obesity associated medical problems.

We conducted this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [21] and the Cochrane Handbook for Systematic Reviews of Interventions [22]. The study was registered in the PROSPERO database for systematic reviews in May 2022 (CRD42022331947).

A literature search of MEDLINE (via Ovid), EMBASE (via Ovid), and CINAHL (via EBSCO) was performed. Specific research equations were formulated for each database using the following Medical Subject Headings (MesH) terms: vagus nerve, vagal nerve, cranial nerve, stimulation, neuromodulation, vagal nerve stimulation, vagal nerve block and obesity. We retrieved articles published in the English language from January 2000 to April 2022 that reported weight loss outcomes on the management of vagal nerve therapy in obesity. The reference lists from the selected studies were reviewed to identify any additional relevant studies.

RCTs, non-randomised controlled clinical trials, prospective and retrospective cohort studies were included. Studies had to report at least one outcome of %EWL, the effect on BMI at 12 months, or remission of associated medical problems following vagal nerve therapy. Exclusion criteria were the following: (1) no extractable outcomes on weight loss or BMI following vagal nerve treatment; (2) articles published in a non-English language or in a book; (3) letters to the editor, case reports, or conference abstracts; (4) non-available full-text articles; and (5) animal studies.

Two authors (M.F. and B.D.) conducted the search and identification independently, and a third author (M.G.F.) confirmed that the final selected manuscripts met the inclusion criteria. The two authors independently extracted the following information from the included studies: first author, year of publication, country, patient number, study design, type of vagal nerve therapy, age, gender, initial weight, initial BMI, percentage of patients with diabetes mellitus, assessment on quality of life, inclusion/exclusion criteria, and follow-up duration. The following primary outcomes were recorded: %EWL at 12 months and effect on BMI at 12 months. Changes in HbA1c and fasting glucose, and impact on quality of life following vagal nerve treatment were also recorded where reported.

The weighted mean difference (WMD) was calculated for %EWL and BMI. Standard deviation was calculated using statistical algorithms. The logarithm of DerSimonian-Laird (DL) with 95% confidence intervals (CIs) was used as the primary summary statistic. A p value of <0.05 was deemed to be statistically significant. Meta-analysis of data was conducted using a random-effects model. Inter-study heterogeneity was assessed using the I² value to measure the degree of variation not attributable to chance alone. This was graded as low (I² < 25%), moderate (I² = 25–75%), or high (I² > 75%). The study was performed in line with Cochrane recommendations and PRISMA guidelines and using the statistical software STATA V12.

The quality of the included observational studies was assessed using the Newcastle-Ottawa Scale (NOS) [23]. The NOS judges the selection of the study groups according to three domains: method of patient selection, comparability of the study groups, and number of outcomes reported. The full score was nine stars, and studies that had a score of seven stars or more were considered to be of higher quality. The risk of bias of the RCTs was assessed using the Cochrane Risk of Bias 2.0 tool [24] signalling questions. This tool assesses the potential for bias arising from five domains: bias arising from the randomisation process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome, and bias in the selection of the reported results. Two authors (M.G.F. and M.F.) independently assessed the quality of the study, and any disagreement was resolved by re-examining the relevant paper until consensus was achieved.

A total of 491 published articles were identified from the initial search. An additional four articles were identified through other sources. Sixty articles were removed due to duplication. A total of 435 abstracts were screened, of which 381 were excluded based on title and abstract review. The remaining 54 articles underwent full-text evaluation, and 32 studies were further excluded. Fifteen studies [8‒10, 13, 14, 25‒34] were included in the final qualitative and quantitative analyses, compromising a total of 1,447 patients. The PRISMA diagram of the literature search is demonstrated in Figure 1.

The study characteristics of each individual study included in this systematic review are shown in Table 1. There were nine relevant RCTs [8, 10, 25, 27, 28, 30, 31, 33] out of 15 studies. Six [9, 14, 26, 28, 32, 34] were cohort studies, two [9, 32] of which were prospective. The mean age ranged from 40.3 years to 54.4 years with the mean initial weight and BMI ranging from 63.9 kg to 123.3 kg and 24.7 kg/m² to 43 kg/m², respectively. Eight studies [8‒10, 13, 14, 23, 25, 27] described the use of a vagal nerve blocking device, four studies [28‒31] used a PENS of T6 dermatome, two studies [26, 34] used a VNS device, and one study [33] used transcutaneous auricular vagus nerve stimulation. The follow-up duration ranged from after completing the 3-month intervention period to 24 months. The inclusion and exclusion criteria of each individual study are summarised in online supplementary material Table S1 (for all online suppl. material, see https://doi.org/10.1159/000533358), with the most common reason for inclusion being a patient with a BMI 35–40 kg/m² with at least one obesity-related comorbidity (diabetes mellitus type 2, hypertension, dyslipidaemia, sleep apnoea, or obesity-induced cardiomyopathy) or BMI 40–45 kg/m² irrespective of comorbidities.

Regarding quality assessment of the observational studies, four out of five of the studies were considered to be of higher quality studies [9, 25, 26, 29, 32]. The bias summary for the RCT studies is displayed in Figure 2. Four studies described specific methods of allocation concealment, such as computer generated or envelopes [28, 30, 31, 33]. Four studies used a double-blind protocol [8, 10, 25, 27].

Six studies [8, 10, 25, 27, 30, 31], a total of 1,025 patients, were suitable for quantitative analysis on %EWL at 12 months following vagal nerve therapy as shown in Table 2 and Figure 3. There was an improvement in weight loss following vagal nerve therapy at 12 months (WMD 17.19%; 95% CI: 10.94–23.44, p < 0.001). This was subject to great between-study heterogeneity (I² > 99%).

Four studies [28, 30, 31, 33], a total of 322 patients, were suitable for analysis on the effect of BMI at 12 months following vagal nerve therapy as shown in Table 3 and Figure 4. There was a reduction in BMI (WMD −2.24 kg/m²; 95% CI: −4.07 to −0.42, p = 0.016) at 12 months. This was also subject to great between-study heterogeneity (I² > 98%).

Only three studies [9, 13, 33] reported change in HbA1c following vagal nerve therapy. Apovian et al. [13] reported a significant mean improvement in HbA1c by 0.3% (95% CI: −0.4 to −0.3, p < 0.05) following vBloc in 144 patients at 12 months. Shikora et al. [9] demonstrated a significant decline in HbA1c by 1.0 ± 0.2% (p = 0.02) in 26 patients during a similar time period. However, Huang et al. [33] found no significant difference in the reduction of HbA1c between VNS and sham VNS groups (0.23 mmol/L, p = 0.63). Nevertheless, there was a significant decrease noted in HbA1c between VNS and no treatment control groups (12.79 mmol/L, p = 0.001). Changes in fasting plasma glucose were reported in two studies. Apovian et al. [13] did not find a significant difference in fasting plasma glucose (−2 mg/dL) in all vBloc patients but did find a significant decrease (−15 mg/dL, p < 0.05) in vBloc patients with abnormal baseline values of metabolic risk factors at 12 months. Shikora et al. [9] observed a mean 28 mg/dL (p = 0.0003) decline in fasting plasma glucose with vBloc at 12 months. Quality of life following vBloc therapy was reported in one study only [13], and there was a mean improvement of 20 points (p < 0.05) at 12 and 24 months.

This study provides review and meta-analysis of weight loss and BMI outcomes related to vagal nerve therapy in obesity. Fifteen studies, of which nine were RCTs, with a combined population of 1,447 patients met the inclusion criteria and were included in the final quantitative analysis. Following quality and risk of bias assessment, studies were generally found to be high quality, and four studies used a double-blind randomised protocol.

Our meta-analysis demonstrates that vagal nerve therapy can lead to some improvement in %EWL of 17.19% WMD at 12 months. There was also a reduction in BMI of 2.24 kg/m² WMD at 12 months. We found two studies in the literature that reported longer term mean weight loss data (%EWL or %TWL) at 24 months. Apovian et al. [13] observed a mean %EWL of 21% (8%TWL) in 123 vBloc patients. Vijgen et al. [26] found a mean %TWL of 4.3% in 10 patients with VNS therapy. There were limited results on changes in HbA1C, fasting plasma glucose, and quality of life following vagal nerve therapy in obesity. Overall, there was a mild improvement seen in HbA1c when comparing vagal nerve therapy to no treatment. One study [13] reported on quality of life, and an improvement was found following vBloc.

A randomised, double-blind controlled trial, the EMPOWER study, did not demonstrate any difference in the %EWL in the treated group with vBloc and the control group [10]. There was an improved %EWL with increased duration of device usage supporting a potential beneficial effect of vagal blockade on weight loss. The ReCharge study showed that weight loss among patients with vBloc was largely sustained, whereas the sham group regained nearly half of the weight they had lost through 12 months despite remaining blinded through most of the period between 12 and 18 months [25].

Vagal nerve therapy has been considered as another option in the bariatric management pathway. It results in less weight loss than LSG and LRYGB [13], but vBloc has been shown to have similar weight loss when compared to laparoscopic adjustable gastric band (8 ± 9.5%TWL vs. 6 ± 8.2%TWL, respectively) and modern pharmacotherapy [35]. In several studies, the reduction in weight loss and BMI achieved with vagal nerve therapy has been reported to improve obesity-associated medical problems, for example, diabetes and metabolic syndrome, with fewer risks than conventional bariatric surgery such as gastrointestinal leak, intra-abdominal bleeding, bowel obstruction, stricture, and ulceration [36, 37]. Vagal nerve therapy is well tolerated, and there were no major adverse events stated in the literature [38‒43]. Only mild or moderate events of nausea due to anaesthesia were reported [27].

In this systematic review and meta-analysis, we were unable to assess the cost-effectiveness of vagal nerve therapy as none of the included studies reported on the costs of treatment. However, a study by Yu et al. [43] performed a cost-effective analysis of vagal nerve blocking for severe obesity. The initial cost for the device and installation was thought to be approximately USD 20,000. The estimated incremental cost-effectiveness ratio (ICER) for vagal nerve blocking versus conventional therapy was calculated to be USD 17,000–21,000 per quality-adjusted life year (QALY). This compares to ICERs for LRYGB of USD 7,000 and USD 12,000 per QALY for severe obesity with newly diagnosed and established diabetes, respectively. Laparoscopic adjustable gastric band had ICERs of USD 11,000 and USD 13,000 per QALY for the respective groups [44].

However, further long-term data are required on the role of vagal nerve treatment as a monotherapy before it can be routinely recommended as an option in the bariatric pathway. Weight loss at 24 months as a result of vagal nerve therapy does not appear to be hugely different from that at 12 months based on the limited current evidence. Despite the weight loss seen with vagal nerve therapy, there are less invasive and effective options available, such as dietary modifications and pharmacotherapy agents. The more invasive methods, including LRYGB and LSG, provide more effective and sustainable weight loss than vagal nerve therapy. However, implanting vagal nerve blockers concurrently with LRYGB or LSG would completely eliminate risks of anaesthesia and laparoscopic surgery associated with device implantation alone.

Further studies and trials are required to determine whether vagal nerve therapy can be used as a dual or “additive” therapy with LRYGB or LSG to aid weight loss and whether it serves a purpose in managing weight regain. It has also been proposed that weight loss and metabolic enhancement may be greater in patients with type 1 diabetes mellitus who are undergoing definitive bariatric surgery due to the immediate BRAVE (bile flow changes, restriction of stomach size, anatomic gastrointestinal rearrangement, vagal manipulation, enteric hormonal modulation) effects of surgery. These features, which include vagal nerve treatment, can result in cascade effects on gut microbiome and local metabolism (intestinal gluconeogenesis and adipokine fluxes) enhancing weight loss [45]. Bueter et al. [46] proposed that preservation of vagal nerve fibres may play an important role in inducing and maintaining weight loss following gastric bypass in rats. Elbanna et al. [47] carried out an RCT of 200 patients: group 1 had vagus division, and group 2 underwent vagus preservation during One Anastomosis/Mini Gastric Bypass. The study concluded that preservation of the vagus nerve results in similar weight loss and metabolic outcomes to vagal division. However, vagal preservation led to an improvement of gastrointestinal symptoms based on the Gastrointestinal Quality of Life Index (GIQLI). Vagal nerve devices also allow reversibly targeting of the vagus nerve at various anatomical levels and functions maximising metabolic effects and minimising complications such as delayed gastric emptying. Overall, it would therefore be useful to determine whether this “additive” approach of vagal nerve therapy would be best suited to revision cases, resistant metabolic cases, or even cases where vagal nerve sparing has not been possible, so that a device could overcome any vagal division to ensure the benefits of the BRAVE effects. Further clinical trials are required to determine the long-term benefit of vagal nerve therapy as a dual therapy combined with standard surgical bariatric interventions.

Finally, technological advances including next-generation vagal nerve stimulators capable of accommodating diurnal changes, smart watches, and wearable devices with constant heart rate monitoring may further improve the outcome of vagal nerve therapy in the treatment of obesity and associated medical problems [48, 49].

This study is subject to some limitations that must be addressed. We were only able to discover a small number of RCTs relating to vagal nerve therapy in obesity. There was a significant heterogeneity observed between the included studies in weight loss and BMI outcomes. This is most likely due to patient selection variations, different vagal nerve therapy devices, and modes of testing. The different methods of vagal nerve therapy including vagal nerve block, VNS, and PENS have different mechanisms and techniques for weight loss. Vagal nerve blocking has been suggested to enhance satiety and reduce food intake by stopping ascending and descending neural traffic [8, 9, 27], while the stimulation of vagal trunks increases energy expenditure through brown adipose tissue activity [26]. On the other hand, the proposed mechanisms of PENS is related to inducing gastric distension in the fasting state and inhibits postprandial antral contractions, thereby impairing stomach emptying and leading to early satiety [28, 29].

Furthermore, there were only four studies related to the effect on BMI at 12 months suitable for meta-analysis. There were also insufficient data or studies in order to perform a wider analysis of the effect of vagal nerve therapy on obesity-associated medical problems. Ideally, there is a need to assess and titrate the impact of vagal nerve therapy with outcomes other than weight loss to determine the specific role of vagal nerve therapy in clinical practice in the future. For example, alternative measurements that could be considered include hunger/satiety visual analogue scales or questionnaires, evaluation of nutrient intake, and quality of life [50].

This systematic review and meta-analysis demonstrate that vagal nerve therapy can provide a mild-to-moderate improvement in weight loss over 12 months. It can serve as a potential option in patients with obesity who have failed to respond to dietary changes or medical management. Patients that may also benefit include those who are not willing to proceed with standard bariatric surgery due to the associated potential serious complications, long-term sequelae, and permanent anatomical alterations to the gastrointestinal tract. However, further long-term data are required on the role and cost-effectiveness of vagal nerve treatment before it can be routinely recommended as an option in the bariatric pathway. Additional research is also required to compare vagal nerve therapy with other obesity treatments to assess the long-term durability of weight loss and safety.

We are thankful to Mr. Phillip Barlow, NHS Support Librarian at Chelsea and Westminster Hospital, for assisting in conducting the literature search for this study.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Michael G. Fadel, Matyas Fehervari, Bibek Das, and Payam Soleimani-Nouri. The supervision of the project was provided by Hutan Ashrafian. The first draft of the manuscript was written by Michael G. Fadel. All authors commented on previous versions of the manuscript and read and approved the final version of this manuscript prior to submission.

Michael G. Fadel and Matyas Fehervari contributed equally to the manuscript.

All data generated or analysed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.