Society: AGA

Background: Transoral outlet reduction endoscopy (TORe) has been shown to be effective in managing weight regain after Roux-en-Y gastric bypass (RYGB), as has the glucagon-like peptide-1 agonist, liraglutide. However, the effect of adjunctive liraglutide after TORe has yet to be assessed. Herein, we evaluate the efficacy of liraglutide treatment when initiated immediately post-TORe or one year post-TORe using a crossover study design.

Methods: This was a retrospective study of prospectively collected data from a double-blinded randomized controlled trial. Participants underwent TORe at three outpatient clinics in São Paulo, Brazil, between December 2018 and December 2022. Two participant cohorts were established. Participants in the placebo-first cohort, “group A,” underwent the TORe procedure and received subcutaneous saline solution. Those in the liraglutide-first cohort, “group B,” initiated subcutaneous liraglutide immediately after the revisional TORe procedure. The average liraglutide dose was 1.8 mg. Participants were dosed weekly for 12 months, at which point crossover occurred. Each participant received placebo and liraglutide for equal duration over the 24-month treatment phase. All participants had their diet and exercise regimens prescribed by the same multidisciplinary team. TORe technique and post-procedure follow-up were identical at all sites. Primary outcomes were percent total body weight loss (%TBWL) 12 and 24 months after treatment initiation. The secondary outcome was change in hepatic steatosis using the Brunt score.

Results: This study included 58 participants in group A and 51 participants in group B. There was no significant difference in mean baseline BMI. Participants in group A had significantly lower %TBWL than those in group B at 6, 9, and 12 months (p<0.001 at each timepoint). After crossover, no significant difference in %TBWL was observed between groups at 15 and 18 months. Group B continued to show greater %TBWL than group A at 21 and 24 months, despite previously discontinuing liraglutide (p<0.001 for both timepoints). Those in group A, who received placebo first, had significantly higher steatosis scores at 12 months compared with those in group B (p<0.05). This between-group difference in steatosis score was eliminated by 24 months.

Conclusions: Immediate post-procedure administration of liraglutide may be superior to placebo in reversing weight regain and in improving hepatic steatosis for patients undergoing revisional TORe. Our study is the first to demonstrate that the timing of post-TORe liraglutide initiation may improve therapeutic benefit of the procedure. Further inquiry is necessary to elucidate the physiologic basis of this observed effect.

Introduction: Obesity is a chronic disease associated with an increased risk of type 2 diabetes mellitus (T2DM). Semaglutide, a GLP-1 receptor agonist, demonstrated substantial obesity and diabetes improvement in randomized clinical trials and real-world settings. The weight loss outcome with semaglutide in patients with diabetes is inferior to patients without diabetes. The individualized metabolic severity score (IMS) classifies patients with T2DM by diabetes severity. It considers number of T2DM medications, use of insulin, duration (years) and control of T2DM (HbA1c), to predict T2DM remission after bariatric surgery. Little is known about the T2DM factors affecting the weight loss outcomes with semaglutide. We aim to use the IMS score to evaluate the effect of semaglutide on weight loss outcomes in patients with obesity and T2DM.
Methods: This is a multi-site retrospective study of patients with T2DM and overweight/obesity (body-mass index [BMI]≥ 27 kg/m²) taking semaglutide for weight loss. We excluded patients with a history of bariatric surgery, taking multiple AOMs, or those with active malignancy or pregnancy. We collected demographic data, weight loss outcomes at 3, 6, 9, and 12 months, and IMS parameters to calculate the IMS score. The primary end point was determining total body weight loss percentage (TBWL%) based on IMS severity (mild, moderate, severe) at semaglutide start date. Our secondary outcomes included comparing weight loss in patients with and without insulin intake and with and without microvascular complications (i.e., retinopathy, nephropathy, and neuropathy); and change in fasting glucose and HbA1c between semaglutide start date and 1 year follow-up. The primary end point was analyzed using ANOVA. Categorical data were analyzed using the Bowker’s test and continuous data using matched pair t-test. Data are presented as mean ± standard deviation (SD).
Results: We included 78 patients (64% female, age (SD) 53 (13) years, BMI 42 (9) kg/m²) in the analysis (Table 1). In our cohort, 17% of patients had mild, 46% had moderate, and 31% had severe IMS score. Patients with moderate and severe IMS scores had lower TBWL% compared to mild score at 3, 6, 9, and 12 months (p<0.001 at all time periods) (Figure 1A). Patients with insulin use and patients with microvascular complications had lower TBWL% compared to patients without insulin use (Figure 1B) or microvascular complications, respectively (Figure 1C). HbA1c and fasting glucose significantly improved by 1.1 (n= 54; p<0.001) and 44 mg/dL (n=41; p=0.001), respectively.
Conclusion: In our study, patients with moderate and severe IMS scores had inferior weight loss outcomes compared to those with mild score when treated with semaglutide for weight loss. Early treatment of patients with T2DM may be crucial to achieve adequate weight loss and improvement in glucose hemostasis.

Table 1: Baseline demographic, individualized metabolic severity score, and clinical outcomes of semaglutide.<br /> Abbreviations: BMI, body mass index; HbA1c, Hemoglobin A1c<br /> Data are presented as mean and standard deviation for continuous variables, and as frequency and percentage for categorical variables.

Table 1: Baseline demographic, individualized metabolic severity score, and clinical outcomes of semaglutide.
Abbreviations: BMI, body mass index; HbA1c, Hemoglobin A1c
Data are presented as mean and standard deviation for continuous variables, and as frequency and percentage for categorical variables.

<b>Figure 1:</b> Total body weight loss percentage (TBWL%) based on IMS score (A), insulin use (B), and microvascular complications (C).

Figure 1: Total body weight loss percentage (TBWL%) based on IMS score (A), insulin use (B), and microvascular complications (C).

Background: Endoscopic sleeve gastroplasty (ESG) and anti-obesity medications (AOMs) are effective weight loss therapies. While the efficacy of ESG and AOMs has been established, the effect of combination therapy, optimal AOMs and timing for combination are unknown.

Aims: 1) To assess and compare the efficacy of combination therapy of ESG and AOM to that of monotherapy and sequential therapy. 2) To compare the efficacy of combination therapy of ESG plus glucagon-like peptide-1 receptor agonist (GLP-1RA) to that of ESG plus other AOMs.

Methods: This is a single-center retrospective study of patients who underwent ESG for the treatment of obesity. Patients were categorized into 3 groups: 1) monotherapy – ESG via a suturing or plication technique without any AOMs added, 2) combination therapy – an AOM prescribed within 6 months prior to or after ESG and 3) sequential therapy – an AOM prescribed greater than 6 months prior to or after ESG. Patients who did not tolerate an AOM and stopped the medication within 3 months were excluded. Outcomes included percent total weight loss (%TWL) at 12 months, success rate (≥10% TWL at 12 months) and serious adverse event (SAE) rate.

Results: 224 patients were included. Of these, 77 (34%), 69 (31%) and 78 (35%) underwent monotherapy, combination therapy and sequential therapy, respectively. Of the 69 patients who underwent combination therapy, 21 (30%) were prescribed a regimen that included GLP-1RA. Of the 78 patients who underwent sequential therapy, 63 (81%) were prescribed an AOM first (>6 months prior to ESG), while 15 (19%) underwent ESG first (>6 months followed by an AOM). Baseline characteristics are shown in Table 1.

At 12 months, patients in the ESG + GLP-1RA combination therapy group experienced the greatest amount of weight loss (23.7 ± 4.6% TWL) compared to the monotherapy and sequential therapy groups. Patients who were started on an AOM first followed by ESG greater than 6 months later experienced the least amount of weight loss (12.0 ± 7.7%TWL) compared to the monotherapy and combination therapy groups (Figure 1). Additionally, all patients (100%) in the ESG + GLP-1RA combination therapy group experienced ≥10% TWL at 12 months, while 56% of the AOM followed by ESG sequential therapy reached this threshold (p=0.02). The ESG-related SAE rates were similar among the three groups (2.6%, 1.4% and 1.3% in the monotherapy, combination therapy and sequential therapy, respectively, p=0.80). The AOM-related SAE rate was 1.3% in the sequential therapy, while no patients in the combination therapy group experienced AOM-related SAEs (0%) (p=0.99) (Table 1).

Conclusion: Combination of ESG with GLP-1RA is superior to ESG alone. The optimal time to add an AOM is within 6 months of ESG. Being on an AOM for greater than 6 months prior to ESG appeared to be a predictor of poor response following the procedure.

<b>Table 1</b>. Baseline characteristics with procedural and anti-obesity medication (AOM) details of the endoscopic sleeve gastroplasty (ESG) monotherapy, ESG + AOM combination therapy and ESG + AOM sequential therapy groups.

Table 1. Baseline characteristics with procedural and anti-obesity medication (AOM) details of the endoscopic sleeve gastroplasty (ESG) monotherapy, ESG + AOM combination therapy and ESG + AOM sequential therapy groups.

<b>Figure 1</b>. Percent total weight loss (%TWL) and proportion of patients who experienced at least 10% TWL at 12 months following endoscopic sleeve gastroplasty (ESG) monotherapy, ESG + anti-obesity medication (AOM) combination therapy and ESG + AOM sequential therapy.

Figure 1. Percent total weight loss (%TWL) and proportion of patients who experienced at least 10% TWL at 12 months following endoscopic sleeve gastroplasty (ESG) monotherapy, ESG + anti-obesity medication (AOM) combination therapy and ESG + AOM sequential therapy.

Background: The response to obesity interventions is highly variable. Previous studies have investigated the factors associated with response to GLP-1 analogues (PMID: 35894080, PMID: 36193713), suggesting that key components of appetite regulation may contribute to GLP-1 response. The goal of this study was to create a machine-learning (ML) model for appetite using the full phenotype tests (FPTs) and to generate a simpler, DNA-only, surrogate using polygenic risk score (PRS) for appetite that may also predict best responders to GLP-1 analogues in patients with obesity.

Methods: We included two independent cohorts of patients with obesity who completed the following validated tests at baseline: a) satiation, studied by ad libitum buffet meal (kcal consumed to maximal fullness), and b) gastric emptying of solids studied by scintigraphy. A fasting blood sample was collected for satiety (PYY, GLP1) hormones (ELISA), metabolomics (Mass Spectometry), and DNA (SNP Array). In the first cohort of a total of 799 patients (BMI: 38.5 ± 4.38 kg/m²), we developed a multivariate logistic regression ML-driven model for appetite using the FPTs with all baseline data collected. The linear predictor was calculated with the model's parameter estimates to fit y=a+bx. We collected SNP variant information from 497 of the 799 patients (BMI: 36.15 ± 4.45 kg/m^2,) and performed logistic regression between the variants using LASSO through the PLINK 2.0 tool. Then we added the created contribution factors to develop a PRSs for an expert-guided set of 22 genes. We validated our FPT and PRS in an independent cohort of 141 patients (BMI: 39.09 ± 7.40 kg/m²). Finally, we tested the performance of the FPT (n=60) and PRS (n=40) models in predicting response to treatment with liraglutide (LIRA) 3mg SQ /day from a randomized, placebo-controlled trial of16 weeks. We defined response as >5% total body weight loss (TBWL%). Analysis was done using Student’s t-test to compare among the predicted groups.

Results: In the training cohort the FPT and PRS models had an AUC>0.80. In the independent validation cohort, the FPT had an AUC=0.84 (Fig 1A) and the PRS had an AUC=0.70 (Fig 1B). When used to predict response, the FPT had an AUC=0.70 and the PRS an AUC=0.69. In patients treated with liraglutide, the TBWL% in groups predicted as responder vs. non-responder using FPT was -7.6+3.4 vs. -3.6+3.3; p<0.001 (Fig 1C) and using the PRS was -8.0+4.4 vs. -5.6+3.3; p=0.056 (Fig 1D). There was no difference among the predicted groups in patients who received placebo.

Conclusion: The ML-driven, full phenotype biomarker and its PRS surrogate for appetite can predict response to treatment with a GLP-1 analogue. The findings support a novel approach for precision medicine for obesity. The PRS model might be a simpler test to deploy in the clinical practice.

<b>Figure 1.</b> A) Validation of ML-driven full phenotype tests (FPTs) biomarker for appetite. B) Validation of ML-driven polygenic risk score (PRS) model for appetite. In patients treated with Liraglutide (3mg), total body weight loss in groups predicted as responder vs. non-responder C) using FPT biomarker and D) using PRS model for appetite.

Figure 1. A) Validation of ML-driven full phenotype tests (FPTs) biomarker for appetite. B) Validation of ML-driven polygenic risk score (PRS) model for appetite. In patients treated with Liraglutide (3mg), total body weight loss in groups predicted as responder vs. non-responder C) using FPT biomarker and D) using PRS model for appetite.

Timothy O'Connor

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