Endoscopic Procedures for Weight Loss

Intragastric Balloons (IGB)

The IBG is the most ancient EBT. Drs Lloyd and Mary Garren firstly described an implantable gastric-occupying device in the early 1980s [10]. Since then, several refinements have been made to the device, and there is sound evidence supporting the use of the available IGBs.

Currently, there are three Food and Drug Administration-approved (FDA-approved) balloons: the Orbera (Apollo Endosurgery Inc, Austin, TX, USA), the Obalon (Obalon Therapeutics, Carlsbad, CA, USA), and the Reshape DuoTM. However, Apollo company purchased the latter one in 2018 and removed it from the market.

The Orbera is a liquid-filled 6-month or 12-month indwelling device and is most employed IGB worldwide. It has been marketed for more than 20 years in numerous countries and continents. That consistency allowed production and publication of reliable evidence, including a Brazilian consensus pooling experience from more than 40,000 procedures [11]. Several meta-analyses have already demonstrated the efficacy and safety of Orbera compared to placebo [12] and diet alone [13] in addressing severe obesity [14], obesity-related comorbidities [15], and non-alcoholic steatohepatitis (NASH) [16].

In the treatment of NASH, specifically, an interesting study recently demonstrated that a 6-month Orbera treatment leads to histologic and metabolic improvement. Twenty-one patients were enrolled and received preprocedural and postintervention liver biopsies and magnetic resonance elastography (MRE). Non-alcoholic fatty liver disease score (NAS) improved in 90% of patients. Fibrosis improved in 50% of individuals in MRE and 15% of histologic specimens. Mean serum liver enzymes also decreased significantly. Intriguingly, total body weight loss (TBWL) did not correlate with reductions in NAS and fibrosis [17••]. These data suggest an unknown positive effect of the IGB in NASH physiopathology that warrants further investigation. Finally, such a study led the FDA to grant Breakthrough Device Designation for Orbera IGB to treat NASH. That is particularly interesting as it will expand patients’ access to endoluminal therapy.

Beyond organic improvement, Gadd et al. evaluated the impact of IGB treatment on mental health and quality of life. Pooling 9 different studies via meta-analysis with a total sample of 371 patients, the authors demonstrated a considerable improvement in the postprocedural quality of life. As to mental health, five studies were pooled and showed amelioration of depressive symptoms and anxiety [18•].

Concerning patient selection, Lopez-Nava et al. recently proposed a personalized approach based on preprocedural gastric emptying. Since one of the main mechanisms of action of the IGB is delaying gastric emptying, the authors hypothesized that patients with already delayed gastric emptying at baseline would have excessive adaptation symptoms. Contrariwise, patients with faster emptying would benefit the most from the therapy. The authors employed either baseline scintigraphy or a breath test and stratified the cohort of patients in quartiles. The findings corroborated this rationale: individuals in the lowest quartile had a 6-time higher likelihood ratio for intolerance leading to early removal. That result may help determine which patient is unfit for IGBs. Additionally, individuals with delayed gastric emptying at 3 months lost significantly more weight at 6 and 12 months than patients with unchanged results. This finding confirmed that delayed gastric emptying is a critical weight loss promoter during IGB treatment. Also, it may be used as an early-on predictor of poor outcomes and may indicate the need for adjunct therapy in this subset of patients [19•].

The main drawback of the IGB treatment concerns durability. Even though long-term data are somewhat limited, a few studies reveal an overall trend towards weight regain after the IGB removal [20, 21]. Considering obesity is a chronic relapsing disease, one should not expect it differently as it may also happen after bariatric surgery [8]. Chan et al. recently published a 10-year data from a double-blind RCT. The initial trial compared IGB (Orbera balloon) plus placebo versus pharmacotherapy (sibutramine) plus sham procedure in non-morbidly obese individuals (BMI<35kg/m2) [22]. The authors reported a superior weight loss in the IGB group at 2 years, but no difference at 10 years. The groups only diverged in terms of willingness for further bariatric intervention, which favored the IGB (81% vs. 56%, p<0.01) [23•].

Such data indicate that the benefit of IGBs is transient. Nevertheless, it carries adequate control and improvement of organic and mental comorbidities until the relapse occurs. That usually happens between the second and fifth postprocedural year. Since the therapy is repeatable, combinable, and allows sequential treatment, a personalized step-up approach might mitigate this durability shortcoming. Finally, the IGB does not preclude future bariatric procedures. On the contrary, it seems to stimulate the patient to undergo further intervention if needed. Those characteristics led the American Medical Association to designate a specific Current Procedural Terminology (CPT) code for the IGB in the USA, which will expand the clinical use of this device nationwide.

As to novel devices, the Elipse (Allurion Technologies, Wellesley, MA, USA) is a liquid-filled IGB that foregoes endoscopy for both implantation and removal. After 4 months in place, it deflates and passes naturally through the GI tract. Although it is not Food and Drug Administration-approved (FDA-approved) yet, the Allurion company recently announced the completion of its pivotal study and the premarket approval submission. As to medical data, a recent systematic review pooling more than 2000 patients demonstrated that the Elipse balloon promotes an average of 12% TBWL and 49% excess weight loss (EWL). There are also accompanying reductions in waist circumference and triglyceride levels [24]. This device could be revolutionary as it may reduce costs and substantially increase access to weight loss therapies.

The most common side effects of IGBs are nausea and vomiting, especially during the first 2 weeks—the adaptation period. Nausea occurs in approximately 2 out of 3 patients undergoing treatment, and the majority of those also experience vomiting [25]. A combination of full-dose antiemetics is routinely recommended to avoid early removal. Ondansetron and dimenhydrinate are the central drugs in this context. More recently, the netupitant/palonosetron hydrochloride, a potent combination antiemetic drug commonly used to prevent nausea from chemotherapy, has also been shown efficacious in preventing nausea, vomiting, and gastric pain during the IGB adaptation period [26].

On the other hand, serious adverse events (SAEs) are rare but include gastric and esophageal perforations and small bowel obstruction due to migration. The clinical status at presentation should guide the decision between operative and non-operative management. If diffuse peritonitis or clinical instability is present, emergency surgery is needed. In the absence of those signs, one may attempt the non-operative management combining medications and local endoscopic treatment (closure for perforations, removal of migrated devices) [27].

TransPyloric Shuttle

The TPS (BARONova Inc, San Carlos, CA) has recently been approved by the FDA to treat adults with mild to moderate obesity. The device is composed of two smooth bulbs connected by a flexible silicone tether. After an endoscopic deployment, the large bulb attaches to the pylorus, while the small one hangs in the duodenum’s descending portion. During the antral pump contractions, the TPS intermittently obstructs the gastric outlet, ultimately delaying gastric emptying and enhancing satiation.

An initial trial published in 2014 gathered data from 20 procedures in an open-label non-randomized study. At 3 months, patients experienced a mean %TBWL of 8.9 ± 5.0% and a mean % EWL of 25.1 ± 14.0%. At 6 months, the mean %TBWL and %EWL rose to 14.5 ± 5.8% and 41.0 ± 21.1%, respectively. As to safety, there were two cases of persistent gastric ulcers requiring early removal and additional 8 cases of asymptomatic ulcerations [28]. Such a high incidence of gastric ulcers fostered refinements in the device.

A large multicenter sham-controlled trial investigated the new version of the TPS, and the results led the FDA to approve it for clinical use. Two-hundred and seventy subjects (181 TPS and 89 control) were enrolled. Additional 32 individuals from the control group received TPS in the open-label phase after they were unblinded. At 12 months, the intervention group had higher %TBWL and BMI reduction compared to sham (9.5% [8.2, 10.8] vs. 2.8% [1.1, 4.5], p<0.0001 and 3.5 vs. 1.01, p<0.0001). Nausea, vomiting, dyspepsia, and upper abdominal pain were present in more than 50% of treated subjects but were typically mild in severity. Twenty-one (10.3%) patients had at least one ulcer, and a total of 46 in the TPS group exited the study and had the device retrieved before the 12-month follow-up. Nonetheless, the serious adverse events (SAEs) rate was considerably lower than the overall AE: 2.8%, among which gastric impaction was the most frequent event (1.97%) [29].

The TPS seems effective but still carries unpleasant and persistent symptoms during the treatment. This characteristic probably hampered the worldwide spread since its approval in 2019. Further refinements are warranted to grant this device a central role in the war against obesity.

Endoscopic Sleeve Gastroplasty (ESG)

Abu Dayyeh et al. firstly described the ESG in 2013 [30]. This procedure, also called “the Apollo method,” consists in employing a full-thickness endoscopic suturing device (Apollo Overstitch) to create apposition of the anterior, greater curvature, and posterior wall of the gastric body. The fundus remains intact and acts as a pouch with delayed emptying [31]. Since the first description in 2013, the ESG technique suffered several technical refinements. That includes using the helix to grasp tissue, per protocol CO2 insufflation, increasing the number of bites per suture (from 6 up to 12), and adding reinforcement sutures in between the first suturing line [32]. With the current technique, the ESG has been proven reproducible and safe worldwide [33, 34], not only in academic centers but also in community health units [35]. A Brazilian consensus recently gathered 47 experts and provided practical guidelines to previously unattended technical and clinical issues related to the ESG [36]. Table 1 summarizes the main points of consensus in such a study.

Table 1 Summary of practical recommendations to perform the endoscopic sleeve gastroplasty. Adapted from Galvao MG et al. [33]. BMI body mass index, DVT deep venous thrombosis, CO2 carbon dioxide, ESG endoscopic sleeve gastroplasty, PPI proton pump inhibitor

Interestingly, although some authors recently described improved outcomes employing different suturing patterns [37], other data suggest that weight loss outcomes are unrelated to the suture pattern [38]. Still concerning technical refinements, Itani et al. proposed association with argon plasma coagulation to enhance fibrosis in the plication line, resulting in a superior sleeve-like lumen [39]. Albeit clinical data are lacking, the rationale seems appropriate as adequate endoscopic anatomy correlates with better outcomes during follow-up [40]. Nevertheless, one should expect that the imbricated gastric mucosal will eventually unfold. Pizzicannella et al. demonstrated that only 49% of ESGs were fully intact at a 6-month upper endoscopy [40]. Therefore, family history or individual increased risk of adenocarcinoma should not raise further concerns in the context of an ESG. Despite the mucosal unfolding, experts advocate that a fibrotic process in the gastric wall occurs secondary to the full-thickness stitching that permanently hampers gastric accommodation.

Several systematic reviews assessing the efficacy of the ESG were published in 2020. Due-Petersson et al. [41], de Miranda Neto et al. [42], Singh et al. [43], and Hedjoudje et al. [44], in four different articles, pledged the same: ESG is effective in the short-term and promotes average %TBWL up to 20% at 24 months. Although controlled studies are still lacking, the consistency of their findings indicates that the demonstrated efficacy is reliable.

As to original data, Sharaiha et al. published a recent study showing 5-year outcomes of the ESG to treat obesity. From a series of 216 patients, 38 were eligible for a 5-year follow-up assessment. Among them, 18% were lost to follow-up. The remaining individuals presented a mean %total body weight loss (%TBWL) of 15.9% (95% CI, 11.7–20.5). Sixty-one percent of patients sustained at least 10% TBWL at 5 years. Although it is small-sampled, this study suggests that ESG outcomes are also durable in the long term [45••].

Concerning new indications, another recent study investigated the effect of ESG on obesity in children and adolescents. Alqahtani et al. reported a series of 109 consecutive mildly obese patients aged 10 to 21 years old undergoing ESG. At 12 and 24 months, the mean %TBWL was 16.2% ± 8.3% and 13.7% ± 8.0%, respectively. Fourteen patients (12.8%) required ambulatory visits for analgesia, and one underwent endoscopic removal of the stitches due to refractory abdominal pain. However, there were no emergency admissions, deaths, or significant morbidity. This data suggest that ESG is also effective and safe to treat young individuals suffering from obesity [46].

Another recent article assessed the impact of adjunct pharmacotherapy with liraglutide. This glucagon-like peptide-1 agonist amplifies insulin secretion, delays gastric emptying, and upregulates satiety by a central effect on the hypothalamus [47, 48]. In an international cohort study, Badurdeen et al. employed a propensity score analysis to match 26 patients receiving GLP-1 at month 5 after ESG to 26 individuals declining it. At 12 months (7 months after introducing pharmacotherapy), patients from the GLP-1 group presented superior weight loss and greater reduction in percent body fat [49••]. This study is of paramount importance as it proves synergism between endoscopic and pharmacological approaches. Possibly, the combination of such therapies will become the standard of care soon.

Finally, one of the potential negative implications of the ESG would be increased surgical risk due to peritoneal adhesions and gastric imbrication. Although the need for rescue bariatric surgery after ESG is negligible—around 0.8%—surgical conversion had not been proven safe until recently [50]. Two studies demonstrated that a previous ESG does not pose substantial technical issues to a surgical conversion. That applies to Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) [51, 52].

As to comparative data, interesting articles have already been published, but most are non-controlled and non-matched retrospective cohorts. Non-matched studies frequently present groups with unbalanced baseline characteristics due to the intrinsic selection bias [53,54,55]. Dissimilar demographics handicaps interpretation of outcomes. One such study recently demonstrated that ESG is superior to IGB in weight loss, but baseline data typically differed between groups [56].

Consequently, some authors have employed case-matched designs to mitigate the negative impact of selection bias. In this sense, a case-matched cohort comparing ESG to high-intensity diet plus lifestyle therapy recently showed that the former promotes more significant weight loss within 12 months [57].

As to comparison against surgery, another case-matched study with 137 patients compared the LSG to the ESG. The authors demonstrated that the LSG carries superior weight loss at a 6-month follow-up (23.6% ± 7.6% vs 17.1% ± 6.5%, p<0.01). Conversely, it also poses a higher risk for adverse events (AEs) and new-onset GERD (16.9% vs 5.2%, p<0.05 and 14.5% vs 1.9%, p<0.05, respectively) [58].

Finally, Marincola et al. compared those modalities through a meta-analysis design and confirmed that the surgical approach is superior in weight loss. However, no head-to-head study was included as few cohorts, and no controlled studies comparing those two modalities were available [59]. Moreover, another meta-analysis demonstrated identical results, but the limitations persist as they are related to the literature itself and not to the methodology of the study [60].

Arguably, endoscopic and surgical sleeves fit better to different types of patients, which explains the absence of comparative head-to-head studies. Instead, future controlled trials should focus on assessing the efficacy and safety of those strategies according to the severity of obesity. In overweight and mild obesity, one should compare ESG to non-operative modalities (e.g., IGB, diet, medications). In class II patients, ESG should be tested against LSG. However, current data allows anticipating the inferiority of ESG in terms of weight loss and durability for class III obesity [54, 58]. Considering the evident benefit of bariatric surgery for severe obesity [8] and the high cost added to the complex logistics of conducting an RCT [61], one might not need to test ESG against LSG for class III individuals. In this situation, current non-comparative data already support ESG for patients declining or unfit for surgery [62].

Pose and Pose 2.0 (Distal POSE)

The primary obesity surgery endoluminal (POSE) involves the employment of the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, CA, USA). The IOP is a 4-component device that allows endoscopic control of a full-thickness plication system. It delivers sequential anchors in the stomach to promote gastric imbrication [63].

The initial technique proposed impairing gastric accommodation by shrinking the fundus. Several non-controlled studies demonstrated the efficacy and safety of the POSE procedure [64, 65] and led to the development of a large sham-controlled trial. The ESSENTIAL trial, however, failed to demonstrate the long-term efficacy [66].

This failure was credited to technique and not to the device itself, which prompted modifications in the plication sequence. Instead of focusing on the fundus, the new technique, called distal POSE or POSE 2.0, aims to reduce gastric volume and alter motility. The operator creates two transverse plication rows, one in the distal body and the other in the proximal body. Then, they are connected through two longitudinal rows, one in the anterior and the other in the posterior wall. The transverse rows are the belts, while the longitudinal rows are suspenders [67•]. The final aspect reduces the gastric length and alters the motility of the stomach [68].

Two case series describing the distal POSE have been published to date. Jirapinyo et al. reported results from 10 subjects undergoing this novel procedure. All patients received the distal POSE with an average of 21 ± 4 plications per case and experienced a mean shortening by 11.0 ± 5cm in the gastric body. There were no SAEs. At 6 months, the mean %TBWL was 15.0% ± 7.1%, and 8 patients (80%) presented at least 25% EWL [69]. Lopez-Nava et al. reported outcomes of 46 patients at 1 year. Mean %TBWL was 17.8 ± 9.5%, and BMI reduction was 7 ± 4.3kg/m2. Interestingly, endoscopy at 12 months showed intact sutures and sustained reduction in gastric length compared with baseline (26.9 ± 5.3cm vs. 35.7 ± 3.5cm, p<0.001) [70].

The distal POSE seems promising, but open-label followed by sham-controlled trials are warranted to confirm such high expectations. In the meantime, physiology studies could provide valuable information on how POSE 2.0 promotes weight loss. That information would allow better patient selection and even further refinements in this still-evolving technique.

Aspiration Therapy

The AspireAssistTM is a novel FDA-approved device for the treatment of obesity. The index procedure is similar to a standard percutaneous endoscopic gastrostomy. The gastric portion of the device is a thick multi-fenestrated tube (A-tube) directed to the fundus. The outer part is a button-like implant that attaches to an external portable aspiration machine. After eating, the patient aspirates and disposes of around 30% of the ingested food [71]. Adjunct lifestyle interventions and nutritional counseling are also recommended as in all obesity-directed therapy.

The PATHWAY trial, a large open-label multicenter study, enrolled 171 patients to compare the aspiration therapy (n=111) versus lifestyle counseling (n=60). At 12 months, the mean %EWL and %TBWL were 31.5±26.7% and 12.1±9.6%, respectively, in the intervention group versus 9.8±15.5% and 3.5±6.0% in the control group (p<0.001). Aspiration patients also presented significant reductions in triglycerides, HbA1c, low-density lipoprotein, systolic and diastolic blood pressure, and an increase in high-density cholesterol. The SAEs rate was 3.6% (4/111) and entailed severe abdominal pain, peritonitis, gastric ulcer, and port malfunctioning requiring tube replacement [72]. Among the 111 individuals from the aspiration group, 58 continued in the study for a 4-year evaluation. Interestingly, the patients presented a progressive weight loss throughout follow-up: 14.2%, 15.3%, 16.6%, and 18.7% TBWL at 1, 2, 3, and 4 years, respectively (p<0.01). There were two persistent fistulas (2%) requiring surgical repair after tube removal [73].

The low rate of persistent fistula contradicts data from a post-market European registry study published in 2018. Despite similar weight loss throughout a 4-year follow-up, Nystrom et al. reported four such cases among the 47 removals (8.5%) and suggested that the risk escalates after 2 years post-gastrostomy. Additionally, there were 12 cases of gastric leakages and several other device-related adverse events (stomal irritation/granulation tissue, infection, buried bumper, and tube malrotation) [74].

Such data suggest that the AspireAssistTM is effective in the short term, but unwanted complications arise in the long term. Undoubtedly, aspiration is not a definitive therapy, and information on clinical management after device removal is lacking. Furthermore, the ideal indwelling period remains unknown. Future studies should focus on filling those gaps to minimize adverse events and exploit the therapy to its best.

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