Review article: Pharmacologic management of obesity - updates on approved medications, indications and risks.

BACKGROUND: Obesity has reached epidemic proportions, with >40% of the US population affected. Although traditionally managed by lifestyle modification, and less frequently by bariatric therapies, there are significant pharmacological advancements. AIMS: To conduct a narrative review of the neurohormonal and physiological understanding of weight gain and obesity, and the development, clinical testing, indications, expected clinical outcomes, and associated risks of current FDA-approved and upcoming anti-obesity medications (AOMs). METHODS: We conducted a comprehensive review in PubMed for articles on pathophysiology and complications of obesity, including terms 'neurohormonal', 'obesity', 'incretin', and 'weight loss'. Next, we searched for clinical trial data of all FDA-approved AOMs, including both the generic and trade names of orlistat, phentermine/topiramate, bupropion/naltrexone, liraglutide, and semaglutide. Additional searches were conducted for tirzepatide and retatrutide - medications expecting regulatory approval. Searches included combinations of terms related to mechanism of action, indications, side effects, risks, and future directions. RESULTS: We reviewed the pathophysiology of obesity, including specific role of incretins and glucagon. Clinical data supporting the use of various FDA-approved medications for weight loss are presented, including placebo-controlled or, when available, head-to-head trials. Beneficial metabolic effects, including impact on liver disease, adverse effects and risks of medications are discussed, including altered gastrointestinal motility and risk for periprocedural aspiration. CONCLUSION: AOMs have established efficacy and effectiveness for weight loss even beyond 52 weeks. Further pharmacological options, such as dual and triple incretins, are probable forthcoming additions to clinical practice for combating obesity and its metabolic consequences such as metabolic dysfunction-associated steatotic liver disease.

Optimal measurement of gastric emptying of solids in gastroparesis or functional dyspepsia: evidence to establish standard test.

OBJECTIVE: Symptoms in gastroparesis (Gp) and functional dyspepsia (FD) overlap; using egg protein substitute to measure gastric emptying of solids (GES), ~40% of patients are reclassified from Gp to FD, and vice versa. Our aim was to assess inter-individual and intra-individual coefficients of variation (COV) in GES in symptomatic patients with Gp or FD with documented slow or normal GES, respectively. DESIGN: Scintigraphic GES (T1/2 and GE% at 2 and 4 hours) using a 320 kcal real egg meal (30% fat) was tested in the following: single measurements in 20 patients with diabetes mellitus (10 each type 1 and type 2); repeat GES to estimate COVintra measured: 3 days apart in 9 Gp, 4 weeks apart in 21 Gp and 18 with FD with normal GE assigned to placebo and in 70 patients at 94.3 weeks (median) apart. RESULTS: COVinter for GE% at 4 hours and GE T1/2 were respectively 14.2% and 23.5% in FD and 27.5% and 33% in Gp; COVintra for GE% at 4 hours and GE T1/2 up to 4 weeks apart were 23.4% and 37.9% in FD and 20.1% and 33% in Gp. GE% at 2 hours showed less consistent results. However, >85% retained original diagnosis as normal or delayed. From clinical GES to baseline research for Gp group, repeat GES (after treatment) showed the COVintra for GE% at 4 hours was 37.3% at median 94.3 weeks, with 26/70 changed diagnoses. CONCLUSION: The 320 kcal (30% fat) GES scintigraphic test provides consistent diagnosis in >85% and should be the standard test for suspected gastric emptying disorders.

Pharmacogenetic interactions of medications administered for weight loss in adults: a systematic review and meta-analysis.

Aim: To analyze roles of single nucleotide variants (SNVs) on weight loss with US FDA-approved medications. Materials & methods: We searched the literature up until November 2022. Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were followed. Results: 14 studies were included in qualitative analysis and seven in meta-analysis. SNVs in CNR1, GLP-1R, MC4R, TCF7L2, CTRB1/2, ADIPOQ, SORCS1 and ANKK1 were evaluated relative to weight loss with glucagon-like peptide-1 agonists (13 studies) or naltrexone-bupropion (one study). CNR1 gene (rs1049353), GLP-1R gene (rs6923761, rs10305420), TCF7L2 gene (rs7903146) were associated with weight loss in at least one study involving glucagon-like peptide-1 agonist(s). The meta-analysis did not identify any consistent effect of SNVs. Conclusion: Pharmacogenetic interactions for exenatide, liraglutide, naltrexone-bupropion and weight loss were identified, but the directionality was inconsistent.

Acute pancreatitis as an adverse effect of COVID-19 vaccination.

While vaccination against COVID-19 has significantly improved the morbidity and mortality of the disease, with the increase in the administration of COVID-19 vaccines, it is more likely to observe their rare side effects in the clinical settings. Herein, we report a case of an 82-year-old man with history of coronary artery disease, prostate cancer in remission, gastroesophageal reflux disease, and hypothyroidism, who presented with acute pancreatitis few hours after receiving the third dose of Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine, without other identified etiology. His symptoms were mild and he was discharged in a stable condition after improvement in his condition with supportive care.

Fasting pyloric diameter and distensibility by functional endoluminal imaging probe in unsedated healthy volunteers.

BACKGROUND: Recent studies with functional endoluminal imaging probe (EndoFLIP® ) measure physiologic characteristics of the pylorus. EndoFLIP® has the potential to select optimal candidates for gastric peroral endoscopic myotomy (G-POEM). Normative values of the pylorus using EndoFLIP® have not been established. METHODS: Twenty-four healthy volunteers (20-56 years old; 15 females) underwent unsedated, transoral EndoFLIP® measurements of the pylorus after 8 h of fasting. Measurements of diameter (DM), balloon pressure, and distensibility index (DI) of the pylorus were obtained twice over 5 min at 40, 50, and 60 ml balloon distensions. KEY RESULTS: Pyloric DM at 40, 50, and 60 ml balloon distensions were 13.0 ± 2.5, 14.3 ± 1.8, and 17.2 ± 2.0 mm, respectively. DM with 60 ml distension was notably higher than with 40 and 50 ml distensions. Pyloric DI at 40, 50, and 60 ml distensions were 10.9 ± 4.8, 11.3 ± 5.8, and 11.1 ± 4.3 mm2 /mm Hg, respectively (p = 0.86). Linear regression and Bland-Altman plots showed similar distribution of the DM and DI during the second minute compared with the full 5-min measurements at 50 ml distension, as well as between two sequential measurements using 50 ml distension. With 50 ml balloon distension, intraindividual coefficients of variation (COVintra ) for DM and DI were 13.8% and 29.6%, respectively, and interindividual COV (COVinter ) were 12.6% and 51.3%, respectively. Similar reproducibility was obtained with 40 ml balloon distension. CONCLUSIONS AND INFERENCES: Unsedated EndoFLIP® can be used to characterize human fasting pyloric diameter and distensibility, with best performance observed with 40 ml and 50 ml distensions and data collection during the second minute. Normative values reported serve as reference values for future studies.

Gastric per-oral endoscopic myotomy (G-POEM) for refractory gastroparesis: results from an international prospective trial.

OBJECTIVE: Although gastric per-oral endoscopic myotomy (G-POEM) is considered a promising technique for the management of refractory gastroparesis, high-quality evidence is limited. We prospectively investigated the efficacy and safety of G-POEM in unselected patients with refractory gastroparesis. DESIGN: In five tertiary centres, patients with symptomatic gastroparesis refractory to standard medical therapy and confirmed by impaired gastric emptying were included. The primary endpoint was clinical success, defined as at least one score decrease in Gastroparesis Cardinal Symptom Index (GCSI) with ≥25% decrease in two subscales, at 12 months. GCSI Score and subscales, adverse events (AEs) and 36-Item Short Form questionnaire of quality of life were evaluated at baseline and 1, 3, 6 and 12 months after G-POEM. Gastric emptying study was performed before and 3 months after the procedure. RESULTS: Of 80 enrolled patients, 75 patients (94%) completed 12-month follow-up. Clinical success at 12 months was 56% (95% CI, 44.8 to 66.7). GCSI Score (including subscales) improved moderately after G-POEM (p<0.05). In a regression model, a baseline GCSI Score >2.6 (OR=3.23, p=0.04) and baseline gastric retention >20% at 4 hours (OR=3.65, p=0.03) were independent predictors of clinical success at 12 months, as was early response to G-POEM at 1 month after therapy (OR 8.75, p<0.001). Mild procedure-related AEs occurred in 5 (6%) patients. CONCLUSION: G-POEM is a safe procedure, but showed only modest overall effectiveness in the treatment of refractory gastroparesis. Further studies are required to identify the best candidates for G-POEM; unselective use of this procedure should be discouraged. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry NCT02732821.

Association of Glucagon-like Peptide 1 Analogs and Agonists Administered for Obesity with Weight Loss and Adverse Events: A Systematic Review and Network Meta-analysis.

BACKGROUND: Comparative effectiveness of 7 glucagon-like peptide 1 (GLP-1) agents on weight loss (WL) in obesity remains unknown. METHODS: We performed a systematic review, network meta-analysis (NMA) utilizing the following data sources: MEDLINE, EMBASE, Scopus, Cochrane Central and clinical trial registries, from inception to March 2, 2021. The prespecified criteria for study inclusion were randomized clinical trials (RCTs) of ≥12 weeks' duration. The data appraisal and extraction were performed by two investigators independently, using the published reports. The main outcomes and statistical methods were weight loss over placebo (WLOP) and adverse events (AEs) among GLP-1 agents using random-effects NMA (frequentist approach); relative ranking using surface under the cumulative ranking (SUCRA) method and certainty of evidence using grading of recommendations, assessment, development and evaluations (GRADE). FINDINGS: 64 RCTs (from 2004 to 2021) included 27018 patients (median of age, 55.1 years old; 57.4% women; baseline weight 94.8kg and BMI 33.0kg/m2; trial duration 26 weeks). Direct meta-analysis showed significant WLOP with: -1.44kg (95% CI, -2.14 to -0.74) with dulaglutide ≥1.5 mg; -1.82kg (-2.42 to -1.23) with exenatide immediate release (IR); -2.20kg (-4.31 to -0.08) with exenatide extended release (ER); -3.20kg (-6.53 to 0.15) with efpeglenatide; -2.72kg (-3.35 to -2.09) with liraglutide ≤1.8mg; -4.49kg (-5.26 to -3.72) with liraglutide >1.8mg; -0.62kg (-1.22 to -0.02) with lixisenatide; -4.33kg (-5.71 to -3.00) with semaglutide SQ <2.4mg; -9.88kg (-13.17 to -6.59) with semaglutide SQ 2.4mg; -2.73kg (-4.81 to -0.65) with semaglutide oral; and -1.71kg (-2.64 to -0.78) with taspoglutide. Highest WLOP were with semaglutide SQ 2.4mg and <2.4mg, and liraglutide >1.8mg (SUCRAs 100, 86.1, 82.8 respectively). Highest SUCRAs for discontinuation due to AEs were with taspoglutide and liraglutide >1.8mg. Risk of bias was high or unclear for random sequence generation (29.7%), allocation concealment (26.6%), and incomplete outcome data (26.6%). Heterogeneity (I2 >50%) in WL and AEs reflected magnitude, not direction of effect.

Corrigendum to "Pain Relieving Effect of Intraoperative Chemical Splanchnicectomy of Celiac Ganglions in Patients with Resectable Pancreatic or Gastric Masses: A Randomized Clinical Trial".

[This corrects the article DOI: 10.1155/2020/2675940.].

Clinical impact of routine esophagram after peroral endoscopic myotomy.

BACKGROUND AND AIMS: It is unclear whether the common practice of postoperative day (POD) 1 esophagram impacts clinical care or reliably identifies significant adverse events (AEs) related to peroral endoscopic myotomy (POEM). Therefore, we aimed to correlate the most clinically relevant esophagram findings with postoperative outcomes after POEM. METHODS: Patients were retrospectively reviewed and included if they underwent POEM at 1 of the 3 study institutions between 2014 and 2018. Patient outcomes were assessed in relation to relevant POD 1 esophagram findings such as esophageal dissection or leak. RESULTS: One hundred seventy post-POEM contrast esophagrams (139 fluoroscopy-based vs 31 CT-based) performed on POD 1 were included. Most esophagrams (n = 98) contained abnormal findings but only 5 showed esophageal leak or dissection. Confirmed postoperative AEs of leak or dissection occurred in 4 patients. In 2 patients, POD 1 esophagram appropriately identified the leak or dissection, but in the other 2 patients the initial esophagram was negative, and the AEs were not recognized before clinical deterioration. One patient had a false-positive leak and dissection noted on esophagram leading to an unremarkable endoscopy. CONCLUSIONS: Despite the low AE rate after POEM, follow-up esophagram on POD 1 frequently shows expected, unremarkable postprocedural findings and occasionally fails to diagnose serious AEs. This results in pitfalls in accuracy regarding agreement between esophagram versus clinical and endoscopic findings. Relying exclusively on esophagram for post-POEM clinical decision-making can lead to unnecessary additional testing or missed AEs.

Outcomes of anterior versus posterior peroral endoscopic myotomy 2 years post-procedure: prospective follow-up results from a randomized clinical trial.

BACKGROUND: Peroral endoscopic myotomy (POEM) is considered a primary treatment modality for achalasia. It can be performed using either the anterior or posterior approach. A previous randomized clinical trial (RCT) showed that the posterior approach was noninferior to the anterior approach at 1 year post-POEM in terms of clinical success, rate of adverse event, and risk of gastroesophageal reflux disease (GERD). The aim of this post-RCT study was to compare outcomes at ≥ 2 years post-POEM. METHODS: Patients who previously completed the 1-year follow-up were contacted and their Eckardt, dysphagia, and GERD questionnaire (GERDQ) scores and frequency of proton pump inhibitor use were recorded. Clinical success was defined as an Eckardt score < 3. RESULTS: 150 patients were initially randomized and 138 completed the 1-year follow-up. Of the 138, 111 (anterior group 54, posterior group 57) also completed ≥ 2 years of follow-up, with an overall clinical success decrease from 89 % to 82 %. At ≥ 2 years post-POEM, clinical success was achieved in 46/54 (85 %) and 45/57 (79 %) in the anterior and posterior groups, respectively (P = 0.43). A similar decrease in clinical success was noted in both groups at ≥ 2 years (anterior: 90 % to 85 %; posterior 89 % to 79 %; P = 0.47). GERDQ score was 6 (interquartile range 6 - 8; P = 0.08) in both treatment groups. CONCLUSIONS: The anterior and posterior POEM techniques remained equally effective at 2 years and decreases in efficacy were similar between the two approaches over time. GERD outcomes were also similar in both groups during medium-term follow-up.

Full-thickness resection device (FTRD) for treatment of upper gastrointestinal tract lesions: the first international experience.

Background and study aims The Full-Thickness Resection Device (FTRD) provides a novel treatment option for lesions not amenable to conventional endoscopic resection techniques. There are limited data on the efficacy and safety of FTRD for resection of upper gastrointestinal tract (GIT) lesions. Patients and methods This was an international multicenter retrospective study, including patients who had an endoscopic resection of an upper GIT lesion using the FTRD between January 2017 and February 2019. Results Fifty-six patients from 13 centers were included. The most common lesions were mesenchymal neoplasms (n = 23, 41 %), adenomas (n = 7, 13 %), and hamartomas (n = 6, 11 %). Eighty-four percent of lesions were located in the stomach, and 14 % in the duodenum. The average size of lesions was 14 mm (range 3 to 33 mm). Deployment of the FTRD was technically successful in 93 % of patients (n = 52) leading to complete and partial resection in 43 (77 %) and 9 (16 %) patients, respectively. Overall, the FTRD led to negative histological margins (R0 resection) in 38 (68 %) of patients. A total of 12 (21 %) mild or moderate adverse events (AEs) were reported. Follow-up endoscopy was performed in 31 patients (55 %), on average 88 days after the procedure (IQR 68-138 days). Of these, 30 patients (97 %) did not have any residual or recurrent lesion on endoscopic examination and biopsy, with residual adenoma in one patient (3 %). Conclusions Our results suggest a high technical success rate and an acceptable histologically complete resection rate, with a low risk of AEs and early recurrence for FTRD resection of upper GIT lesions.

Esophageal peroral endoscopic myotomy (POEM) for treatment of esophagogastric junction outflow obstruction: results from the first prospective trial.

Background and study aims Esophagogastric junction outflow obstruction (EGJOO) is a rare esophageal dysmotility disease that is characterized by elevated integrated relaxation pressuse (IRP) with evidence of preserved peristalsis. The role of peroral endoscopic myotomy (POEM) in management of EGJOO is currently unknown. Patients and methods This is a prospective trial conducted in a single US tertiary care center from June 2015 to June 2019. Symptomatic patients, diagnosed with EGJOO on both HRM and endoluminal functional lumen imaging probe (EndoFLIP), who were eligible for POEM were recruited. Primary outcome was clinical success, defined as Eckardt score (ES) ≤ 3, at 6 months post-POEM. Other outcomes included dysphagia score, quality of life as measured by 36-item Short Form health survey scales (SF-36), post-POEM HRM, EndoFLIP, and pH measurements, and adverse events. Results A total of 15 patients (51.8 yr. 9 F) with EGJOO underwent POEM. Pre-POEM mean IRP on HRM and Distensibility index (DI) on EndoFLIP were 24.3 ±â€Š2.2 mmHg and 1.1 ±â€Š0.6 mm 2 /mmHg, respectively. Clinical success was achieved in 93 % at 6 months post-POEM. There was significant decrease in IRP (-17.6 mmHg) post-POEM. There was significant improvement at 6 months in two of the SF-36 subscales. Ten patients underwent post-POEM pH testing, seven of whom had abnormal DeMeester score. Seven patients underwent EGD evaluation revealing esophagitis in five (2 Los Angeles grade A and 3 grade B). Conclusions POEM offers a high clinical success rate for patients with EGJOO confirmed by impedance planimetry.

Management of adverse events of EUS-directed transgastric ERCP procedure.

BACKGROUND AND AIMS: Accessing the pancreatobiliary region in patients with a history of Roux-en-Y gastric bypass (RYGB) can be challenging. Traditionally, techniques such as percutaneous biliary drainage, enteroscopy-assisted ERCP, and laparoscopy-assisted ERCP have been used. However, each technique has its limitations. EUS-directed transgastric ERCP (EDGE) using a lumen-apposing metal stent (LAMS) has emerged as a novel endoscopic technique for ERCP in patients who have undergone RYGB. The aim of this case series was to highlight LAMS-related shortcomings and adverse events during the periprocedural period. METHODS: This was a retrospective review of 4 patients with RYGB anatomy who underwent EDGE for the management of pancreaticobiliary disease and experienced LAMS-related adverse events. Techniques for managing and avoiding these events are discussed. RESULTS: Four patients underwent EDGE with both technical and clinical success. Slight LAMS migration with partial mucosal overgrowth was encountered in 1 case and was managed by LAMS removal. A large, bleeding, distal marginal ulcer after the EDGE procedure was encountered in the second case and was managed with proton pump inhibitor and removal of the LAMS, with fistula treatment with argon plasma coagulation used to enhance closure. The third case was complicated by moderate intraprocedural bleeding after LAMS dilation, which was managed by applying balloon tamponade and placing a through-the-scope esophageal stent across the LAMS. Last, preferential food passage to the excluded stomach was noted in the fourth case and resulted in symptomatic distention. The symptomatic distention was managed by another de novo jejunogastrostomy using a LAMS for drainage. CONCLUSIONS: Despite its feasibility and acceptable safety profile, the use of LAMSs during EDGE could be associated with several procedure-specific adverse events, which can be avoided or managed endoscopically with no further consequence.

Unilateral versus bilateral endoscopic stenting in patients with unresectable malignant hilar obstruction: a systematic review and meta-analysis.

Background and study aims Endoscopic stent placement is used for palliative management of unresectable malignant hilar obstruction, which could be achieved by either unilateral or bilateral stent insertion. Materials and methods A literature search was performed to identify studies that reported outcomes of metallic biliary stent placement in patients with malignant hilar obstruction. Weighted pooled rates (WPR) along with 95 % confidence intervals (95 %CI) were calculated to determine and compare outcomes including technical and functional success, early and late adverse events, post procedure cholangitis, and stent occlusion between two groups. Results A total of 21 studies with 1292 patients were included. WPR of technical success was significantly higher in the unilateral group (97 %, 95 %CI: 93 -98 %) vs. bilateral group (89 %, 95 %CI: 84 -92 %) ( P  = 0.0.003). WPR for functional success in the unilateral and bilateral groups were 96 % (95 %CI: 91 -98 %) and 94 % (95 %CI: 91 -97 %), respectively ( P  = 0.48). The rate of early and late complications was comparable between the two groups. Conclusion In patients with unresectable malignant hilar obstruction, unilateral and bilateral metallic stenting techniques are comparable in terms of efficacy and safety.

Role of endoscopic functional luminal imaging probe in predicting the outcome of gastric peroral endoscopic pyloromyotomy (with video).

BACKGROUND AND AIMS: Endoluminal functional luminal imaging probe (EndoFLIP) is an imaging tool that measures the physiologic characteristics of GI sphincters. In this study, we used EndoFLIP to evaluate the association between the pyloric physiologic measurements and the clinical outcomes of gastric peroral endoscopic myotomy (G-POEM) in patients with refractory gastroparesis. METHODS: Thirty-seven patients from 5 centers who underwent G-POEM for management of refractory gastroparesis and had EndoFLIP measurements were evaluated. Cross-sectional area (CSA), balloon pressure, and the distensibility index (DI) of the pylorus were evaluated by EndoFLIP at 40 mL and 50 mL balloon fills before and after G-POEM. One-year clinical success and change in gastric emptying study 3 months after the G-POEM procedure were compared with the EndoFLIP measurements. RESULTS: Clinical success was achieved in 26 (70%) patients. Post-G-POEM CSA and DI were significantly higher in the clinical success group with both 40-mL volume distension (CSA: 89.9 ± 64.8 vs 172.5 ± 71.9 mm2, P =.003; DI: 5.8 ± 4.4 vs 8.8 ± 6.1 mm2/mm Hg, P =.043) and 50-mL volume distention (CSA: 140.1 ± 89.9 vs 237.5 ± 80.3 mm2, P =.003; DI: 5.6 ± 3.3 vs 9.9 ± 6.6 mm2/mm Hg, P =.049). CSA using 40-mL volume distention with an area under the curve of 0.83 yielded a specificity of 91% and a sensitivity of 71% at a cutoff point of 154 mm2. CONCLUSIONS: Post-G-POEM CSA of the pylorus is associated with clinical success and improvement in a gastric emptying scan after G-POEM. EndoFLIP measurements of the pylorus have the potential to be used as a tool to predict the clinical outcome of G-POEM.

Endoscopic ultrasound-guided drainage of pancreatic walled-off necrosis using 20-mm versus 15-mm lumen-apposing metal stents: an international, multicenter, case-matched study.

BACKGROUNDS: Endoscopic ultrasound (EUS)-guided placement of lumen-apposing metal stents (LAMSs) has gained popularity for the treatment of pancreatic walled-off necrosis (WON). We compared the 20-mm and 15-mm LAMSs for the treatment of symptomatic WON in terms of clinical success and adverse events. METHODS: We conducted a retrospective, case-matched study of 306 adults at 22 tertiary centers from 04/2014 to 10/2018. A total of 102 patients with symptomatic WON who underwent drainage with 20-mm LAMS (cases) and 204 patients who underwent drainage with 15-mm LAMS (controls) were matched by age, sex, and drainage approach. Conditional logistic regression analysis was performed to compare clinical success (resolution of WON on follow-up imaging without reintervention) and adverse events (according to American Society for Gastrointestinal Endoscopy criteria). RESULTS: Clinical success was achieved in 92.2 % of patients with 20-mm LAMS and 91.7 % of patients with 15-mm LAMS (odds ratio 0.92; P = 0.91). Patients with 20-mm LAMS underwent fewer direct endoscopic necrosectomy (DEN) sessions (mean 1.3 vs. 2.1; P < 0.001), despite having larger WON collections (transverse axis 118.2 vs. 101.9 mm, P = 0.003; anteroposterior axis 95.9 vs. 80.1 mm, P = 0.01). There was no difference in overall adverse events (21.6 % vs. 15.2 %; P = 0.72) and bleeding events (4.9 % vs. 3.4 %; P = 0.54) between the 20-mm and 15-mm LAMS groups, respectively. CONCLUSIONS: The 20-mm LAMS showed comparable clinical success and safety profile to the 15-mm LAMS, with the need for fewer DEN sessions for WON resolution.