Effect and Safety of Intragastric Balloon (IGB) for Obesity Treatment R3 박남영 / Pf. 김지원

Introduction Endoscopic bariatric metabolic therapy (EBMT) Endoscopy use for the treatment of obesity or glucose intolerance Decreasement in calorie intake More Wt. Loss compared with lifestyle modification ± medication No RCT of EBMT compared with bariatric surgery Less wt. Loss Fewer complications  EBMT could be an attractive treatment for patinets who do not qualify for or do not want bariatric surgery. Endoscopic bariatric metabolic therapy란 obesity나 glucose intolerance의 치료에 flexible endoscopy를 사용하는 것으로 device나 procedure에 따라 그 기전은 다르지만 궁극적으로 calorie intake을 감소시켜 그 효과를 유도합니다. 여러 연구에서 Lifestyle modification 단독 혹은 체중감소를 위한 medication과 병합했을 때보다도 더 효과적인 체중감소를 유도하는 것으로 알려져 있습니다. 아직 bariatric surgery와의 RCT는 없지만, 개별 연구들을 비교했을 때 체중감소의 정도는 적지만 그 합병증의 빈도나 정도도 적은 것으로 보입니다. 또한 모든 환자들이 수술적 접근이 가능한 것은 아니며, 수술을 원치 않는 경우도 많이 있기 때문에 EBMT는 고도 비만과 그에 따른 합병증이 있는 환자들에게 유용한 접근법이 될 것입니다.

Introduction Gatic EBMT도 여러가지 기법이 제시되고 있으며 크게 네가지로 분류할 수 있습니다. Intragastric balloon Transpyloric Shuttle Aspiration therapy Gastric remodeling procedure (Plication and suturing) Shelby Sullivan, et al. Gastroenterology, 2017; 152:1791-1801

Introduction Intragastric Balloons (IGB) Occupy space in the stomach Delay gastric emptying Gastric hormone Significant Wt. Loss after balloon removal ReShape, Orbera, Obalon Spatz, Elipse, Hydrogel Beads Medication은 중단하면 다시 기존 체중으로 돌아옴.

Introduction 12 deaths in patients with liquid-filled IGB systems, worldwide 7 deaths in US 4 with Orbera IGB, 3 with ReShape Balloon deflation, gastrointestinal obstruction, ulceration, gastric/esophageal perforation FDA에서는 2015년부터 IGB system과 관련한 합병증을 조사하고 있으며, 올해 6월에 update된 내용을 확인하면... 7명의 사망, 기타 아래 합병증의 가능성에 주의하는 것을 권고

Eric J. Vargas, et al. Clin Gastroenterol Hepatol 2018;16:1073-1080 따라서 IGB의 효과/안정성에 대한 추가적인 연구가 필요하였습니다. Eric J. Vargas, et al. Clin Gastroenterol Hepatol 2018;16:1073-1080

Methods Investigator-initiated, multicenter study 8 US centers Wt. Loss Weight-related comorbidities Technical aspects of insertion and removal Detailed assessment of all potential adverse events 8 US centers 3 academic 5 private Gastroenterologists : surgeons = 4:4 이 연구는 Orbera balloon에 대해 진행한, multicenter Study 입니다. 참여한 center에서 OIB에 대한 FDA 승인 이후부터 OIB를 삽입한 환자들의 체중 감소 정도와 이와 관련된 comorbidity, insertion/removal procedure의 특이점, adverse events를 조사하여 분석하였습니다.

Methods Inclusion Criteria Age: 18-65 YO BMI: over 30 kg/m2 Received OIB

Methods Primary outcome Secondary outcome Percentage of TBWL at 3,6,9 months (%TBWL) Secondary outcome Absolute Wt. loss at 3,6,9 months Proportion of patients achieving 5, 10% TBWL at 6, 9 months SBP, DBP Total cholesterol, TG, LDL, HDL, FBS, HbA1c Resolution of HTN/DM/DL at 6 months Early balloon removal, peri-procedural complications, dehydration episodes, balloon migration, balloon deflation/hyperinflation, pancreatitis, etc.

Methods Statistics %TBWL, BP, laboratory markers Paired t-test To identify predictors of success and early balloon removal Multivariable linear and logistic regression

Results Basic characteristics Demographics N = 321 Sex Male 20% Female 80% Age, y, means ± SD 48.1 ± 11.9 Weight, kg, means ± SD 108.3 ± 28.8 BMI, kg/m2, means ± SD 37.6 6.9 Hypertension 29% Dyslipidemia 19% Type 2 diabetes 15% Impaired fasting glucose level 4% Nonalcoholic steatohepatitis Depression 16%

Results Balloon Insertion

Results After Balloon Insertion: 0 to 6 months Mean total number of f/u visits: 4.7 ± 3.7

Results Predictors of OIB Intolerance and Early Removal

Results Balloon Removal 54%가 G/A, 나머지는 MAC 마취 모두 EGD로 removal 가능 (수술적 제거 필요없었음) Mean time for removal: 12.5±5.8 mins 제거시 위에 음식이 남아있는 경우: 28% 한명은 antibiotics가 필요했음 Esophagitis 7% (Grade A 50%, B 25%, C 25%) Small clean base ulcer: 1 pt. Superficial esophageal tear: 1pt. Admission: 3% (n = 11)

Results After Balloon Removal: 6 to 12 Months Mean number of f/u visits: 0.4±1.25 6% (n =19): anti-obesity med. f/u visit at 9 mo: 47 pts.

Results Weight Loss, Comorbidity Improvement

Results Weight Loss, Comorbidity Improvement 41 patients (45% of HTN patients): HTN med off 25 patients (50% of DM patients): DM med stop/decrease

Results Predictor of Weight loss

Discussion Value of this study Careful endoscopic exam is mandatory Accommodative symptoms is common Close patient f/u and screening Anxiety / depression Hx Aprepitant (Emend) was only mildly beneficial Predictors of good response to OIB Wt. loss at 3mo Number of f/u visits with a multidisciplinary team Predictors of intolerance to OIB SSRI/SNRI use

Discussion Potential risks issued by the FDA previously Acute pancreatitis Spontaneous balloon hyperinflation Death  None of these complications were reported in this study cohort.  Incidence rate of death is not greater than bariatric surgery. : 4 deaths (0.08%) in 2015. : below 0.01% after FDA approval > 0.1% ~ 0.5% in metabolic surgery.

A Courcoulas, et al. International J of Obesity 2017;41:427-433

Methods Study design Inclusion Criteria Exclusion Criteria Multicenter, prospective, randomized, open-label, comparative, pivotal study Inclusion Criteria 18-65 YO BMI 30-40 kg/m2 ≥2mo obesity history with failure of conservative Wt. loss attempts Exclusion Criteria Foregut or GI surgery Hx GI obstruction, adhesive peritonitis Hx Significant hiatal hernia Esophageal or GI motility disorder, patulous pyloric channel Sx of delayed gastric emptying Hx of IBD Current H. pylori infection

Methods Run-in subjects Up to 5 subjects Before placing IGB in study subjects Included in the safety reporting IGB group: IGB insertion & Lifestyle modification Control group: Lifestyle modification Lifestyle modification: low calorie (1000-1500 kcal/d), food/exercise diary, encouragement to exercise, emphasis on behavioral change

Methods Coprimary effectiveness endpoints Secondary outcomes Mean of %EWL at 9mo Percentage of IGB subjects with significantly greater Wt. Loss than control group at 9mo ≥ 15% EWL Secondary outcomes Changes comorbid conditions HTN, T2DM, DL QoL (including depression) QoL: SF-36, IWQOL-Lite Depression: Beck Depression Inventory II

Methods Statistics Sample size was calculated using corrected χ2 test IGB : control = 160 : 160 Mean of %EWL: Wilcoxon’s sign-rank test Percentage of greater Wt. Loss subjects: exact binomial test Responder rates, comorbidity rates difference: χ2 test

Results 2008.6.20-2011.6.8 까지 enroll 함. 448명 중, 131명은 screening에서 fail 하였고 22%는 HP infection 때문이었음. 317명이 randomized 되었고, 44명은 run in group으로 배정됨. IGB 군에는 137명, control 군에는 136명이 배정되었음. (따라서 목표인원만큼 enroll은 되었으나 최종적으로는 목표인원에 미치지 못한 정도로 연구됨. Run in group을 포함하여 IGB insertion 한 160명의 환자에서 30명은 Aes로 early removal 하였음.

Results

Results %TBWL 6mo: -3.3% vs. 10.2% 9mo: -3.4% vs. -9.1%

Results Weight Loss Measure Group Month 6 Month 9 Month 12 Responder rate n (%) Risk Difference 5% TBWL IGB 99 (79.2) 47.7% (37.0%, 58.4%) <0.001 90 (72.0) 38.9% (27.6%, 50.2%) 75 (60.0) 30.0% (18.4%, 41.7%) Control 41 (31.5) 43 (33.1) 39 (30.0) 7% TBWL 87 (69.6) 47.3% (36.5%, 58.1%) 73 (58.4) 32.3% (20.1%, 43.7%) 54 (43.2) 17.8% (6.4%, 29.3%) 0.003 29 (22.3) 34 (26.2) 33 (25.4) 10% TBWL 58 (46.4) 34.9% (24.5%, 45.2%) 51 (40.8) 27.0% (16.5%, 37.4%) 40 (32.0) 15.9% (5.5%, 26.2%) 15 (11.5) 18 (13.9) 21 (16.2)

Results % total body weight loss at 3 months was predictive of weight loss at 12 months (β=1.23, Po0.001).

Results Comorbid Condition/ Laboratory Measures Treatment Group   Baseline Month 9 P-value1 Type 2 DM n (%) IGB 9 (7.2) 5 (4.0) 0.44 Control 8 (6.1) 3 (2.3) Fasting Glucose Mean (SD) 97.1 (20.35) 95.6 (18.86) 0.73 97.7 (24.92) 97.0 (15.71) Hypertension 33 (26.4) 14 (11.2) 0.33 37 (28.5) 20 (15.4) SBP 125.6 (15.12) 122.4 (14.17) 0.59 126.1 (13.41) 122.0 (11.55) DBP 80.3 (10.59) 78.5 (10.71) 0.97 79.7 (8.82) 77.9 (10.39) Dyslipidemia 49 (39.2) 29 (23.2) 0.64 39 (30.0) 27 (20.8) Total Cholesterol 191.7 (38.91) 192.9 (40.24) 0.82 195.2 (33.67) 195.6 (32.31) HDL 52.1 (12.25) 53.9 (13.11) 0.08 53.8 (12.34) 54.1 (13.63) LDL 112.9 (33.94) 115.3 (34.45) 0.60 116.5 (28.55) 117.3 (27.16)

Results IWQOL Timepoint IGB Control Mean Score Effect Size P-value   Mean Score Effect Size P-value Baseline 68.4 NA 68.5 Month 6 80.7 0.66 73.2 0.27 <0.001 Month 9 82.5 0.75 75.3 0.39 Month 12 83.0 0.78 76.6 0.47 0.001 BDI 7.7 8.4 4.9 0.35 7.4 0.13 0.02 4.6 6.9 0.19 0.05 6.5 0.24

Results

Results: AEs and med for side effects AEs and medications for side effects Serious 16 IGB subjects (10%) Device intolerance (8) Dehydration (2) Gastric outlet obstruction (1) Gastric perforation with sepsis (1) Aspiration pneumonia (1) Severe abdominal cramping (1) Laryngospasm during placement (1) Procedure related-esophageal mucosal injuries (2)

Results

Results Eructation: belching GI AE 로 인해 91.9% 환자에서 antiemetics, anxiolytics 등을 복용하였음.

Results

Discussion IGB system is more effective than lifestyle modification alone Body weight IGB related AEs were GI side effects 91.9% subjects were needed medication to Sx control 16% subjects had the device removed early No difference was seen in improvement of comorbidities in this study HTN, T2DM, DL, depression IGB system is related in QoL improvement

Conclusion Effect on Wt. loss Effect on comorbidities Side effects Produce more Wt. Loss compared with lifestyle therapy Persistent Wt. Loss after balloon removal Effect on comorbidities HTN, T2DM, DL QoL Side effects Mainly GI AEs, accommodative Early removal d/t serious AEs: could be related to depression Serious AEs resolved without sequelae Predictors of good response Wt. Loss at 3mo Number of f/u visits

Critical appraisal (1) Strengths Limitations Real-world investigation in multiple centers Predictors of good response and early removal Limitations f/u loss rate gets higer after balloon removal Long term effects of OIB is still unclear Only 6mo f/u after balloon removal Small sample size to investigate procedure related complications

Critical appraisal (2)

Critical appraisal (2) No data for comorbidities at month 9  Could OIB contribute to survival gain?

Thank you for your attention