A Level 1 evidence study published in The Lancet offers an endoscopic procedure as new hope for patients suffering from obesity. Regardless of specialty or geography, every physician treats patients suffering from obesity and its associated comorbid conditions, and should stay apprised of the latest innovations intended to impact this growing epidemic. A minimally invasive, non-surgical procedure that is safe, effective, scalable and supported by the highest level, peer-reviewed evidence can be considered in discussions with patients seeking relief from this disease.
The National Institutes of Health (NIH), the World Health Organization (WHO), and the American Medical Association (AMA) recognize obesity as a lifelong, chronic disease. Over 40% of the U.S. adult population suffers from obesity. The Centers for Disease Control and Prevention (CDC) further breaks down the patient population to include non-Hispanic black adults (49.9%) with the highest age-adjusted prevalence of obesity, followed by Hispanic adults (45.6%), non-Hispanic white adults (41.4%) and non-Hispanic Asian adults (16.1%). The CDC identified age prevalence is 39.8% among adults aged 20 to 39 years, 44.3% among adults aged 40 to 59 years, and 41.5% among adults aged 60 and older. These statistics are disturbing and immediately raise both a question and interest as to what new or different options can be made available to manage obesity.
These thoughts are further challenged by an increasing prevalence in the associated comorbid conditions:
- coronary heart disease
- sleep apnea
- gallbladder disease
- nonalcoholic fatty liver disease (NAFLD)
Effective treatment of obesity could save about 2.5 million lives annually from deaths attributable to some of the above comorbidities. Analyses estimate that $173 billion is spent annually to treat obesity-attributable medical problems in the United States, accounting for about 21% of healthcare expenditures.
Prevailing treatment options for patients with obesity have included lifestyle intervention, pharmacotherapy and bariatric surgery. The components of lifestyle intervention include diet, exercise and behavior modification and are considered the cornerstone of any obesity treatment. However, as a stand-alone therapy, even intensive lifestyle intervention is only modestly effective, with an expected percent total body weight loss (%TBWL) < 3%.
The available pharmacological approaches for the treatment of obesity increase weight loss significantly compared with lifestyle therapy alone, but some can be associated with unfavorable side effects and significant cost. However, patient compliance with chronic medication use remains a barrier, as weight loss achieved by pharmacotherapy is rarely maintained upon withdrawal of the medication.
The scientific literature has consistently demonstrated that the magnitude of weight loss is strongly associated with improvement in obesity related comorbidities such as diabetes, blood pressure, hyperlipidemia, obstructive sleep apnea, and fatty liver disease. Clinically significant improvements in obesity-related comorbidities can be expected when %TBWL exceeds 10%.
Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, can achieve significant and durable weight loss that exceeds the 10% TBWL threshold in the majority of patients with good safety profile; however, it is estimated that less than 1% of patients with severe obesity (body mass index [BMI] ≥ 40 kg/m₂) undergo surgical interventions given high costs, patient preference, access to care, and risks associated with surgery.
More importantly, patients with mild to moderate obesity (BMI 30-40 kg/m₂) who do not qualify for bariatric surgery do not have effective management options. According to the global, disability-adjusted life-years and deaths study, patients with mild to moderate obesity are the highest contributors to the burden on disease both in terms of comorbidities and overall mortality.
The Agency for Healthcare Research and Quality [AHRQ]16, the American Society of Bariatric and Metabolic Surgery [ASMBS]17, and American Society of Gastrointestinal Endoscopy [ASGE]18 recognize that a significant management gap exists for patients with mild to moderate obesity (BMI between 30-40 kg/m₂) and have defined safety and efficacy thresholds for endoscopic weight-loss interventions.
The endoscopic sleeve gastroplasty (ESG) is an endoscopic, minimally invasive weight-loss procedure reliant on a full-thickness endoscopic suturing device manufactured by Apollo Endosurgery to reduce the stomach volume by 80% through the creation of a restrictive endoscopic sleeve (figure 1). This is accomplished by a series of endolumenally placed full-thickness sutures through the gastric wall, extending from the antrum to the gastroesophageal junction.
Digestive Disease Week represents the largest international meeting in gastroenterology. During the May 2022 conference, the results of the randomized controlled MERIT trial were presented. The trial included adults within a 30–40 BMI range drawn from both academic and community practices. The groups had either moderate-intensity lifestyle modification alone, or moderate-intensity lifestyle modification with ESG. The lifestyle-modification-only group crossed over to ESG at one year if weight loss did not meet the weight-loss thresholds.
The thresholds for the study, defined by a 2011 joint GI and surgical society consensus statement, included:
1) mean excess weight loss (EWL) of more than 25% in the ESG arm at 52 weeks with a 15% EWL difference compared to lifestyle modification
2) Device or procedure-related serious adverse event rate of <5%
Post-procedure, the ESG group patients were followed up for two years and the crossover ESG patients for one year. Two hundred and nine patients were randomized, 85 to ESG and 124 to lifestyle modification, with 72 patients eventually crossing over.
ESG resulted in 44.7% more %EWL compared to moderate-intensity lifestyle intervention alone (p<0.001) at 52 weeks, representing a 12.6% difference in percentage of total body weight loss (%TBWL) between the two groups. At 104 weeks, the ESG cohort maintained 91% of the weight lost at week 52, averaging 12.4±8.4% TBWL. The crossover cohort achieved an additional 44.1± 27% EWL compared to the weight loss achieved after 52 weeks of LS alone (p<0.001).
In addition to the weight loss, ESG resulted in significant improvement in Type 2 DM, hypertension, and metabolic syndrome compared to the lifestyle-only group. HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) significantly improved at 52 weeks in the ESG cohort (p=0.002) vs. worsened in the lifestyle cohort.
Among the 25 patients with HbA1c ≥ 6.5% at baseline who underwent ESG, the mean HbA1c improvement at 52 weeks was 1.65% (p=0.004). Interestingly ESG did not worsen gastroesophageal reflux disease on standardized questionnaires and resulted in significant improvement in quality of life, eating behaviors, and depression. In the ESG cohort, no mortality was reported, and the rate of SAE was 2% (3/149) with none requiring surgical interventions or blood transfusion.
The completed MERIT trial demonstrated that the ESG procedure provides a reliable, safe pathway to weight loss and improvement in comorbidities. The trial outcomes established credibility of the ESG procedure. This credibility was recognized by the FDA in their decision to grant de novo status to the Apollo ESG device. Credibility for the ESG procedure was further demonstrated by publication of the trial outcomes in the Lancet.
MERIT Lancet Publication Analysis
As mentioned above, a joint task force convened by the ASGE and the ASMBS defined safety of efficacy threshold that endoscopic bariatric therapies (EBT), such as ESG, need to meet before societies recommend their widespread adoption. These thresholds are as follows: EBTs intended as a primary obesity intervention in patients with mild to moderate obesity should achieve a mean minimum threshold of 25% excess weight loss (%EWL) measured at 12 months (calculated based on an ideal BMI of 25mg/kg²).
In addition to the absolute threshold of weight loss, the mean %EWL difference between the procedure and control should be a minimum of 15% EWL and be statistically significant. Finally, the risk associated with EBT should equate to a 5% incidence of serious adverse events or less. Based on this task force statement, an endoscopic intervention that meets these established thresholds should be considered appropriate to incorporate into widespread clinical practice, presuming that the appropriate training and credentialing in that EBT has been achieved.
The MERIT trial as formally reported in the Lancet resulted in 49.2% excess body weight loss at 12 months in the treated group, compared to 3.2% in the lifestyle modification group. The responder group experienced a 16.3% average total body weight loss. These outcomes satisfied the task force recommendations.
Durability of weight loss from the ESG procedure has been of common interest to all. The weight-loss trajectory of the crossover ESG group improved substantially, with participants achieving a mean 44·1% EWL at 52 weeks from crossover. The mean EWL of all participants who underwent the ESG procedure (both primary ESG and crossovers) at week 52 post-procedure was a healthy 46·7%.
The MERIT study very importantly further addressed weight loss durability by providing post-procedure follow-up out to 104 weeks. Participants in the primary ESG group maintained 83% of the reached EWL at 104 weeks with 41% EWL and 11.4% total body weight loss. Weight-loss durability was well demonstrated.
Mechanical durability of the gastric reduction also has been of interest to many. At 52 weeks, all participants in the primary ESG group were evaluated for suture-reinforcement candidacy. Nine patients met the protocol-specific criteria to qualify for the reinforcement, having not met the primary endpoint (reached 25% or less of EWL).
An additional five participants underwent a reinforcement procedure at the discretion of the treating investigator. This small number of study participants with findings at one year requiring suture reinforcement speaks to the mechanical durability of the procedure.
The MERIT study stands out as the only RCT for ESG. It effectively demonstrated durable value for weight loss and, as importantly, for improvement in comorbidities, especially for those patients with 30–35 BMI who are trapped in their inability to qualify for traditional bariatric surgery. Hemoglobin A1c has become a meaningful predictor for diabetes and cardiovascular disease. In patients with HbA1c ≥6.5% at baseline (n=25) who underwent ESG, the mean HbA1c improvement at 52 weeks was 1.65% (p=0.004). This change from baseline tells an important story for diabetics who can avoid the need for insulin and for reducing risk from cardiovascular disease.
Looking deeper into comorbidity outcomes within the Lancet publication, more encouraging details emerge, details which are of interest to potential payers in the insurance industry. Fasting glucose improved in the ESG group compared with LS patients. For those with diabetes, HbA1c significantly improved in the ESG group compared with standard-of-care medical diabetes care and lifestyle modification alone. Diabetes improved clinically in 92.3% of ESG patients, compared with only 14.8% in LS patients with standard medical diabetes care.
None of the ESG patients experienced clinical worsening in diabetes, while almost half of LS patients (44.4%) experienced clinical worsening in diabetes at the end of follow-up on standard medical diabetes care. A similar significant clinical improvement was noted in terms of hypertension status, in 60% of ESG patients, compared with 39.6% in the LS group. The ESG patients experienced HDL increase, TG decrease, and improvement in waist-to-hip ratio (WHR) compared with LS patients. Metabolic syndrome significantly improved in 83.3% of ESG patients, compared with only 34.5% in the LS group. ESG led to significantly improved liver-related chemistries given the risks for fatty liver disease in the obese.
Several standardized questionnaires were employed. Changes in quality of life were assessed using the IWQOL-lite and SF-36. Changes in depression were assessed using PHQ-9 questionnaire. Improvement/reduction of hunger and desire to eat were evaluated using validated self-reported ratings of appetite based on a 100-mm, visual-analogue scale. Improvement in eating behaviors were evaluated using the Three Factor Eating Questionnaire. Quality of life, eating behaviors, depression improvement, and patient satisfaction were all superior in the ESG group compared to the LS group. On a different note, sleeve gastrectomy is known to cause or worsen gastroesophageal reflux.
In contrast to these patients, gastroesophageal reflux disease symptoms did not worsen in the ESG recipients compared to the LS group as measured by monthly administration of a validated questionnaire. Removing the risk for GERD is a notable strength to the ESG procedure. These outcomes assign a holistic overall benefit to ESG.
The ESG procedure places itself squarely in the gap between lifestyle modification, drug therapy and bariatric surgery as a viable, safe, weight-loss therapy for the obese patient. Despite more modest weight loss compared to bariatric surgery, the impact on comorbidities demonstrated not only in the MERIT trial but also in preceding publications, can be seen as equaling surgery but with less risk and the added benefit of organ preservation in patients with mild to moderate obesity.
ESG is a scalable procedure that can improve the global health of our population. The procedure can be selected to specifically target a comorbidity to achieve both short- and long-term improvement. Finally, the procedure lends itself well to combination therapy with weight-loss drugs. Combination therapy may be able to improve all weight-loss and metabolic outcomes and will likely be an important management paradigm in the future.
Physicians treating patients suffering from obesity and related comorbidities should become aware of ESG as an effective treatment option. The outpatient setting for the procedure, the relative safety of the procedure over traditional weight-loss surgery, and the potential for successful future re-tightening, can encourage a patient to take the next step to control their disease with a minimally invasive, organ-sparing, and repeatable intervention.
Barham Abu Dayyeh, M.D., M.P.H. FASGE FAGA, is professor of medicine, director of advanced endoscopy, director of metabolic and bariatric endoscopy, associate research chair for innovation, and consultant in gastroenterology and advanced therapeutic endoscopy at the Mayo Clinic in Rochester, MN. He is also the chair of the Bariatric and Metabolic Endoscopy Committee of the International Federation for the Surgery of Obesity and Metabolic Disorders, and co-chair of the bariatric committee of the American Foregut Society. His research focuses on development of minimally invasive endoscopic solutions for gastrointestinal diseases, obesity and metabolic disease.
Dayyeh has multiple patents and is the founder of a ventures-funded start-up company focusing on the endoscopic treatment of diabetes and metabolic disease. He has published more than 260 peer-reviewed articles, reviews and book chapters in the field. His work has been highly cited with more than 7,500 citations.
Potential competing interests: Boston Scientific (consultant), BFKW (consultant), USGI (consultant, grant/research support), Endogenex (consultant), Endo-TAGSS (consultant), Metamodix (consultant), Olympus (speaker), Medtronic (speaker, grant/ research support), Johnson & Johnson (speaker), EndoGastric Slutions (speaker and research support), Apollo Endosurgery (research support and consultant), Cairn Diagnostics (grant/research support), Aspire (grant/research support), and Spatz (research support and consultant).
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