This column investigates current research in the surgical and clinical aspects of obesity treatment and educates bariatric care professionals on the most up-to-date information on emerging technologies in the field.
This month: Vagal Blocking Therapy: An Overview of How it Works and Review of Available Literature
by Sagar V. Mehta, MD
St. Luke’s Weight Management Center, St. Luke’s University Health Network, Allentown, Pennsylvania
Bariatric Times. 2015;12(10):14–18.
As obesity and its comorbid conditions continue to plague the international health community, there is a constant need for innovative and effective treatments. The current arena for obesity treatment comprises lifestyle intervention, pharmacotherapy, and bariatric surgery. In early 2015, the United States Food and Drug Administration approved the the Maestro® Rechargeable System (EnteroMedics® Inc., St. Paul, Minnesota), which delivers vagal blocking therapy (vBLOC®) for the treatment of obesity. This article provides an overview of vBloc therapy and its role among current obesity treatments and presents a review of available literature of the newly approved medical device.
The obesity epidemic spares no race, creed, socioeconomic status, or region. With increase in excess weight comes increased risk of cardiovascular disease and the development of certain medical conditions including, but not limited to, type 2 diabetes mellitus (T2DM), hypertension, obstructive sleep apnea (OSA), hypercholesterolemia, and nonalcoholic fatty liver disease. In the United States alone, the numbers are staggering with close to 80 million adults considered obese (body mass index [BMI] ≥ 30kg/m2). In 2008, the estimated annual medical cost of obesity was $147 billion. Additionally, approximately 112,000 deaths per year are associated with obesity in the United States. Research has shown that a modest weight loss of just 5 to 10 percent may improve many comorbid conditions, but larger weight losses had greater benefits. Treatment options have historically centered around lifestyle intervention, bariatric surgery, and pharmacotherapy all with variable success. Since the burden of this disease state is so great, a constant need for innovative intervention exists. The United States Food and Drug Administration (FDA) recently approved a new medical device, and the first of its kind, for the treatment of obesity—the Maestro® Rechargeable System (EnteroMedics® Inc., St. Paul, Minnesota), which delivers vagal blocking therapy (vBLOC®). This article provides an overview of vBloc intermittent vagal blockade therapy, discusses its role among current obesity treatments, and presents a review of available literature of the newly approved medical device.
Lifestyle interventions. Lifestyle intervention for obesity and overweight, which is primarily considered first-line treatment, typically involves dietary, behavioral, and exercise modification. Two of the largest studies that looked at lifestyle intervention and health benefits of modest weight loss include the Diabetes Prevention Program (DPP) and Look AHEAD (Action for Health in Diabetes) trials.7 Both have demonstrated meaningful long-term total body weight loss of greater than five percent with concomitant improvement and/or risk reduction in comorbid conditions.[6,7] The Look AHEAD trial specifically demonstrated that approximately 50 percent of participants were able to achieve and maintain greater than five percent total body weight loss at eight years, while an impressive 27 percent of participants managed to lose greater than 10 percent in the same time period. The National Weight Control Registry, which is the largest prospective investigation of long-term weight loss maintenance, has an average weight loss of 66 pounds maintained over five and a half years. Still, there are skeptics about the true effectiveness of lifestyle changes.
Bariatric surgery. Bariatric surgery is considered the most effective intervention for morbid obesity and improvement in comorbid conditions. Furthermore, it has been shown to decrease all-cause mortality compared to nonsurgical intervention.10 Current surgical options fall into the following catgories: 1) restrictive, where weight loss is thought to be mainly through gastric volume reduction (e.g., gastric banding and sleeve gastrectomy); 2) malabsorptive, which is restricting the amount of food the stomach can hold, causing malabsorption of nutrients (e.g., biliopancreatic diversion with duodenal switch [BPD/DS]); and 3) a combination of restrictive and malabsorptive, where, in addition to gastric volume restriction, there is also some small intestinal manipulation, which is also responsible for weight loss through hormonal influences and reduction in caloric uptake (e.g., gastric bypass).
Excess weight loss (EWL) for gastric banding at three years postoperative has been shown to be about 41 percent, with sleeve gastrectomy at 66 percent, and Roux-en-Y gastric bypass (RYGB) at 62 percent.[12–14] RYGB has also demonstrated higher resolution of comorbid conditions, including T2DM, hypertension, hyperlipidemia, and OSA.[15–18]
Long-term data also exist for both gastric band and RYGB patients. RYGB demonstrates a superior %EWL with almost 60% EWL at seven years postoperative compared to about 50% EWL with gastric banding. At five years postoperative, gastric banding had a failure rate of more than 50 percent, and some research suggests up to one-third of patients have weight regain.
Despite the many advantages of bariatric surgery, it is still the most under-utilized intervention to tackle obesity. Some estimates are that less than one percent of the patients who would benefit from bariatric surgery actually undergo a procedure. Access to services, while markedly improved over the past years, still remains a barrier for many, and while the complication risks have drastically improved and remain low, there is still a stigma that exists, preventing some healthcare providers from recommending surgery no matter the benefit.
While pharmacological agents for the treatment of obesity has been around since the 1950s, it has had several limitations, including lack of demonstration of long-term efficacy, side effects, and poor safety profiles. Several medications have been taken off of market due to unacceptable risk. Currently, pharmacotherapy is indicated in patients with BMIs of 30kg/m2 or greater or 27kg/m2 or greater with an obesity-related comorbid condition in conjunction with lifestyle modification. Since 2012, the FDA has approved three new medications to tackle obesity.[20–22] Mechanisms of actions for these medications vary as do side effect profiles, efficacy, and cost.[20–22]
Medical devices. Currently, the FDA has approved three medical devices for the treatment of obesity. Two of them are versions of the adjustable gastric band (Lap-Band [Apollo Endosurgery, Inc., Austin, Texas] and Realize Band, Ethicon, Cincinnati, Ohio), which are used in the laparoscopic adjustable gastric banding procedure and classified as bariatric surgery. The third device, Maestro Rechargeable System (Enteromedics), was approved in January 2015 and is the first of its kind. The Maestro System contains a laparoscopic surgically implanted medical device that transmits an intermittent electric stimulus to cause a disruption in vagal pathways. It is approved for the treatment of obesity in patients with BMIs between 40 and 45kg/m2 or BMIs between 35 and 39.9kg/m2 with an obesity-related comorbid condition.
Vagal Blocking Therapy for Weight Loss
The vagus nerve is the longest of the cranial nerves, extending from the brainstem to the abdomen by way of multiple organs including the heart, esophagus, and lungs. The vagus forms part of the involuntary nervous system and commands unconscious body procedures, such as keeping the heart rate constant and controlling food digestion. Weight loss following vagal blocking therapy has been observed in patients undergoing bilateral truncal vagotomy for the treatment of refractory peptic ulcer disease.[24,25]
The mechanism of action is thought to be modulated through early satiation associated with decreased gastric accommodation and delayed gastric emptying. These observed effects on weight loss, however, were short lived. Some theories for the temporary weight loss effect may be explained by the total vagal interruption promoting the formation of collateral innervations and up regulation of counterbalancing metabolic or neural pathways including reflex accommodation. Intermittent vagal blockade with the vBloc vagal blocking therapy as opposed to complete interruption may be the key to sustained weight loss results.
Mechanisms. The vBLOC therapy delivery system comprises two electrodes (1 for each vagal trunk), a neuroregulator placed subcutaneously, and an external controller to program the device. The device is implanted laparoscopically by a trained surgeon under general anesthesia using five port sites. This takes roughly 60 to 90 minutes. The electrodes are positioned on the anterior and posterior vagal trunks near the esophagogastric junction (EGJ) without anatomic modification or tissue compression of the alimentary tract, and the neuroregulator is placed in a subcutaneous pocket along the thoracic wall. The neuroregulator is then programmed to deliver a charge at a given frequency (5,000Hz based on animal studies of vagal inhibition on pancreatic exocrine function), amplitude, and cycle length to provide the intermittent vagal blockade.
Literature Review of Vagal Blocking Therapy
The first clinical results trial, conducted by Camilleri et al, was a six-month, open-label study performed at three centers. The researchers sought to evaluate feasibility and safety, and obtain preliminary efficacy data on body weight, electrocardiogram, dietary intake, satiation, and satiety and vagal function in the absence of any dietary, exercise, or behavioral interventions. Recruited patients were 25 to 60 years old with BMIs between 31.5 and 55kg/m2. A total of 31 subjects underwent implantation of the device.
Camilleri et al, concluded that the implantation of the device and intermittent vagal blockade delivery appeared to be safe during follow up. There were three reported adverse events, all of which were infectious in nature (lower respiratory tract infection, insertion site seroma, and Clostridium difficile bacterial infection) that were deemed to be unrelated to the device. There were no clinical significant changes in ECG or serum chemistry analysis and minor changes in heart rate and blood were not found to be significant. No major intraoperative complications were reported, specifically organ perforation or bleeding, nor were there reports of postoperative intraperitoneal infections, electrode migration, or tissue erosion.
During the six-month follow up, researchers observed significant EWLs of 7.5%, 11.6%, and 14.2% at four weeks, 12 weeks, and six months, respectively (P<0.0001); however, 10 percent of patients were able to achieve an EWL of 30%, while 25 percent were able to achieve an EWL of 25%.
The study by Camilleri et al led to multiple sub analyses of the device. In one sub analysis, caloric intake had decreased by greater than 30 percent with earlier satiation and enhanced satiety between meals in the six-month period. No change in macronutrient composition of diet was found. In a second sub analysis conducted to assess vagal function following a sham feeding protocol, plasma pancreatic polypeptide (PP) inhibition was found to be increased after 12 weeks of intermittent vagal blockade. Average EWL was doubled in patients able to achieve a PP response of less than 25 pg/mL compared with PP response greater than 25pg/mL.
In brief, the Camilleri et al study and its subsequent sub studies introduced vBloc intermittent vagal blockade therapy as a promising, safe medical device with some efficacy as a potential treatment for obesity.
Since the initial study by Camilleri et al had several limitations, including small sample size and lack of a control group, two other clinical trials ensued: EMPOWER and RECHARGE.
EMPOWER was a randomized, 12-month, prospective multi-center, double blinded, controlled trial. The primary objective of this study was to demonstrate a significantly greater %EWL in the group treated with vBLOC therapy compared to the untreated group at 12 months (superiority margin of 10%). The secondary objective was to determine if a significantly greater percentage of patients achieved 25% EWL at 12 months compared to the control group. The safety objectives were to estimate the rate of serious adverse events related to the implant procedure, the device, or the vBloc therapy delivered by the device system.
Out of the 503 subjects, 294 met the inclusion criteria and had implantation of the device. Subjects recruited were 18 to 65 years old with BMIs between 40 and 45kg/m2 or 35 and 39.9kg/m2 with an obesity-related comorbid condition. These patients were then blindly randomized into a treatment group (N=192) and a control group (N=102). The treatment group had the external program deliver 5,000Hz at 3 to 8 milliamps in a five minute on/off cycle for as long as the external controller was worn. The control group received 1,000Hz at three milliamps in two bursts of 13 impulses at zero minutes and three minutes, followed by a continuous 40Hz at up to one milliamp for the duration of the five-minute on cycle (for safety and impedance checks). Patients were encouraged to wear the external control from 9 to 16 hours per day. Each patient received 15 individual counseling sessions on weight management.
The EMPOWER study met its safety endpoint but did not meet its comparative primary and secondary efficacy endpoints due to an “unanticipated therapeutic effect” in the control group. The occurrence of this effect in the control group may have been due to the fact that the control group also received electrical stimulation, albeit much less, during impedance and safety checks, which may have been enough to interrupt vagal throughput. Also, the coils in the external controllers worn by the control group may have made contact with the implanted device. Finally, both groups received education on weight loss, which may have also resulted in better outcomes than expected in the control group.
At 12 months, overall %EWL was 17±2% in the treatment group versus 16±2% in the control group, Treatment and control subjects who used the device 12 hours per day or more achieved 30±4% EWL and 22±8 %EWL, respectively. Questionnaire results showed some support for decreased hunger and appetite in the treatment group, as well as improvement in quality of life measures. Subgroup analyses revealed a strong and statistically greater weight loss with increased time of usage of the external controller in both groups as well as statistically significant improvement in systolic and diastolic blood pressures in hypertensive patients.
In another study of vBloc therapy called VBLOC-DM2, Shikora et al conducted a multicenter, open-label trial in individuals with obesity and T2DM to assess improvements in body weight, glycemic control, and blood pressure at 12 months. Subjects enrolled had BMIs between 30 and 40kg/m2 and were 25 to 60 years old with a diagnosis of T2DM.
A total of 28 subjects were enrolled in the study and underwent standard procedure laparoscopic implantation of the device. All subjects received 17 individual weight management counseling sessions. There were no deaths nor operative complications. One serious adverse event was reported for pain at the neuroregulator site as it was placed directly on the ribcage. After relocating the device the pain subsided. At 12 months, mean EWL was 25±4% (P<0.0001) with an average daily duration of therapy delivered at 14±0.1 hours. BMI reduction at 12 months was 3±0.4kg/m2 and weight loss was 8.4± 1.4kg (P<0.0001).
With regards to glycemic control, a mean percent reduction in glycosylated hemoglobin (HgbA1C) of 1±0.2 percent (P<0.02) was observed from a mean level of 7.8±0.2 percent. Fasting plasma glucose also reduced at all time periods from a baseline of 157±7mg/dL. Mean reduction of 28±8mg/dL (P<0.02) was observed at 12 months. Furthermore, additional statistical analyses revealed there was an additive effect of EWL achieved and vBLOC therapy on the reduction in HgbA1C and fasting plasma glucose. Beneficial effects were also seen in systolic, diastolic, and mean arterial pressures. A statistically significant reduction in all of these parameters was observed at many time points throughout the study and were sustained out to 12 months. A statistically significant reduction in baseline waist circumference of 11±2cm (P<0.001) was also observed.
While the results of the VBLOC-DM2 trial are encouraging, there are limitations of the study, including small sample size, lack of long-term results beyond 12 months, lack of control group, and relatively low %EWL compared to other interventions (i.e., bariatric surgery). Continued follow up is currently ongoing and may reveal long-term efficacy for vBloc therapy.
In a randomized, double-blind, sham-controlled, multicenter, prospective clinical trial by Ikramuddin et al (ReCharge trial), investigators evaluated vBloc therapy in 239 subjects who had a BMI of 40 to 45kg/m2 or 35 to 39.9kg/m2 with an obesity-related comorbid condition. This trial was intended to clarify the confounding results from the EMPOWER trial related to both groups receiving some form of vagal blockade. The efficacy objectives were to determine whether vagal blockade was superior in mean %EWL compared to the sham controlled group by a 10-point margin. At least 55 percent of patients in the vBloc group achieved a 20% EWL and 45 percent achieved a 25% EWL. The primary safety objective was to determine whether the rate of serious adverse events related to device, procedure, or therapy in the vagal block group was less than 15 percent.
The randomization occurred in a 2:1 fashion with 162 subjects in the treatment group versus 77 in the sham-controlled group. The active vBloc therapy device was implanted similarly compared to other studies, however, the sham device neuroregulator had charges dissipated into an electronic circuit within the device without leads. Both units required twice weekly external charging from 30 to 90 minutes and had external programmers that allowed the blinded investigators to increase the amplitude in both devices as per protocol. The active group had their neuroregulators programmed to deliver 5000Hz in five-minute on/off cycles for at least 12 hours per day. All participants attended 17 individual education sessions on weight management without a specific prescription for diet or exercise. The follow up schedule varied: weekly for the first four weeks, twice weekly up until Week 12, then monthly from Months 3 to 12. There was a 91-percent completion rate at 12 months in the treatment group and an 86-percent completion rate in the sham controlled group.
The ReCharge trial was similar to the EMPOWER trial in that it did not meet its primary objectives. Overall, the vBloc therapy did not show the desired 10 percent superiority margin with respect to EWL. Mean %EWL in the treatment group was 24.4% versus 15.9% in the sham group, a difference of 8.5% (95% confidence interval [CI], 3.1–13.9). However, there was a statistically greater weight loss in the vBloc group compared to the sham group (P=0.02). In the treatment group, fifty-two percent of patients reached 20% EWL and only 38 percent reached 25% EWL as opposed to the respective 55% and 45% targets. The primary safety objective was met, as the rate of serious adverse events that were related directly to the device, operative procedure, or vagal blockade therapy itself was 3.7 percent (95% CI 1.4%–7.9%, P<0.001), which was much lower than the 15 percent target.
Ikramuddin et al stated that the lack of attaining statistically significant results may be attributed to the unusually strong design to study this obesity treatment device. For instance, clinical trials involving the adjustable gastric band rarely included a 10-percent superiority margin or sham comparator group. Furthermore, several studies have shown a significant placebo effect in surgical sham procedures, including arthroscopic knee surgery, vertebroplasty for back pain, and internal mammary artery ligation for angina. In a review by Birch, the author examined the sham effect in device studies and concluded that it can render study results as inconclusive.
Other Factors to Consider
There are several factors that will likely come into play regarding utilization of vBloc therapy as mainstream treatment. For one, while it does not permanently alter the gastrointestinal anatomy, it is still a surgical procedure for which the patient must undergo general anesthesia and, as per study reports, requires an operative time of 60 to 90 minutes. This is the same time frame it takes to undergo a laparoscopic sleeve gastrectomy or gastric bypass, which are procedures with proven safety and long-term outcomes with regards to %EWL, improvement and/or resolution of comorbid conditions, and weight loss maintenance established beyond five years. In my opinion, the vagal disruption that occurs in RYGB (depending on the approach) and less so in the sleeve gastrectomy procedure is only one component to a multifactorial process for weight loss following bariatric surgery that we have yet to fully understand. While vBloc therapy may have some overlapping features, its physiologic effects on weight loss are far more limited than RYGB and sleeve gastrectomy, procedures which are both well established as effective weight loss tools.
The cost of the vBloc is described as being somewhere between the cost of a gastric band and a gastric bypass procedures, estimated at approximately $15,000. In comparison, some weight loss medications can cost significantly less, depending on insurance coverage and industry-sponsored savings programs. For instance, some older generic sympathomimetics (i.e., phentermine) can cost less than $10 per month, while some newer medications such as liraglutide, an injectable GLP-1 agonist, can cost upwards of $1,000 per month, but insurance or savings programs can apply a substaintal discount of up to $200. Lorcaserin, buproprion/naltrexone, and phentermine/topiramate can cost as much as $200 per month, with coverage and savings potentially bringing the cost down to a more affordable $40 to $70 month. In addition to the cost difference between vBloc and medication, these medications have demonstrated the same 5 to 10 percent weight loss at Year 1 that the vBloc was able to achieve. Since insurance companies have a history of reluctance when it comes to reimbursement for obesity treatment, it will be interesting to see how quickly this new therapy will be embraced.
vBloc intermittent vagal blockade therapy has been proven to be a novel yet safe medical device to treat obesity. Although the main studies did not achieve statistical significance in their primary objectives, the encouraging results of patients achieving close to 25% EWL at 12 months is not something to ignore. Enteromedics 2014 annual report stated that weight loss was maintaining at 23.5% EWL and 21.1% EWL at 18 months and 24 months, respectively.33 Even though vBloc therapy will likely not be the most effective obesity therapy treatment, if it can help patients achieve and maintain at least the 5 to 10 percent total body weight loss that correlates with improved health outcomes, it may prove to be beneficial to patients who are averse to altering their anatomy through bariatric surgery or have contraindications to weight loss medications.
While ongoing studies are needed to assess the long-term effects and clinical outcomes, the vBloc therapy may serve a niche role in the obesity treatment market.
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FUNDING: No funding was provided.
DISCLOSURES: The author reports no conflicts relevant to the content of this article.
AUTHOR AFFILIATION: Dr. Mehta is the Director of Bariatric Medicine at St. Luke’s Weight Management Center, St. Luke’s Health Network, Allentown, Pennsylvania.