Acosta, Andrés

Abstract Disclosure: S. Fansa: None. W. Ghusn: None. B. Nicolalde: None. D. Anazco: None. E. Tama: None. A. Acosta: None. M.D. Hurtado: None. Introduction: The increasing prevalences of obesity and type 2 diabetes (T2D), the “twin epidemics”, have led to the development of drugs targeting both diseases simultaneously. Liraglutide and semaglutide, GLP-1 receptor agonists used for T2DM, are also FDA-approved for weight loss. Tirzepatide, a novel dual GIP/GLP-1 receptor agonist approved for T2D, has shown promising weight loss outcomes in clinical trials. To date, no study has assessed weight loss outcomes of tirzepatide in a real-world setting. Our aim is to assess its efficacy and safety in patients with overweight or obesity. Methods: This is a retrospective cohort study of adults with overweight or obesity taking weekly subcutaneous tirzepatide for T2D or off-label for weight loss. We excluded patients taking tirzepatide for less than one month, prior bariatric procedure, use of any anti-obesity medications, and active malignancy or pregnancy. The primary outcome was total body weight loss percentage (TBWL%) at 3 months. Secondary outcomes included TBWL% at 1 and 2 months; TBWL% difference by T2D status (with and without) and by sex at 3 months; proportion of patients achieving ≥5%, ≥10%, and ≥15% of TBWL% at 3 months; predictors of TBWL% at 3 months; and reported side effects during follow up. We used paired t-test to assess TBWL% compared to baseline, non-paired t-test to compare TBWL% by T2D status and sex, and univariate analyses to estimate the contribution of other variables to TBWL%. Results are presented as mean ± standard deviation. Results: We included 175 participants (81% female, age 49.8±12.2, 91% white, BMI 38.8±7.3 kg/m2). One third of patients had T2D (n=59, 34%). Most patients were on 5mg (39%) or 7.5mg (22%) of tirzepatide weekly. TBWL% at 1, 2, and 3 months was 3.6±2.5% (n=87), 5.8±3.5% (n=100), and 8.4± 4.3% (n=60), respectively (p <0.0001 compared to baseline at all timepoints). Patients with T2D lost less weight at 3 months compared to patients without T2D: 6.9±4.0% vs. 9.1±4.4% (p= 0.03). At 3 months, TBWL% was greater in females, 9.2±4.3% vs. 5.0±2.5% for males, p<0.0001. Greater baseline weight was associated with greater TBWL% (R=0.32, p<0.0001). At 3 months, 60 patients had documented weights with 81.6% achieving ≥ 5%, 30% achieving ≥10%, and 10% achieving ≥15% TBWL. Forty participants (23%) reported side effects. The most frequent were nausea/vomiting (n=27, 15%), constipation (n=6, 3%), and abdominal pain (n=5, 3%). Eight patients (5%) had to either decrease dosage or discontinue the drug due to side effects. Conclusion: In this retrospective cohort study, tirzepatide led to substantial weight loss at 3 months. Patients with T2DM lost less weight than patients without. Further real-world studies with longer follow-up duration and higher tirzepatide doses are needed to establish the long-term efficacy, safety, and tolerability of this drug in this setting. Presentation: Friday, June 16, 2023

Objective Endoscopic sleeve gastroplasty (ESG) has gained global adoption but our understanding of its mechanism(s) of action and durability of efficacy is limited. We sought to determine changes in gastric emptying (GE), gastric motility (GM), hormones and eating behaviours after ESG. Design A priori-designed single-centre substudy of a large US randomised clinical trial, adults with obesity were randomised to ESG or lifestyle interventions (LS) alone. We measured GE, hormones and weight loss and assessed eating behaviours. In a subset of ESG patients, we assessed GM. The primary outcome was the change in T1/2 (min) at 3 months, and secondary outcomes were changes in weight, GE, GM, hormones and eating behaviours. We used t-test analyses and regression to determine the association between GE and weight loss. Results 36 (ESG=18; LS=18) participated in this substudy. Baseline characteristics were similar between the two groups. At 3 months, T1/2 was delayed in the ESG group (n=17) compared with the LS group (n=17) (152.3±47.3 vs 89.1±27.9; p<0.001). At 12 months, T1/2 remained delayed in the ESG group (n=16) vs control group (n=14) (137±37.4 vs 90.1±23.4; p<0.001). Greater delays in GE at 3 months were associated with greater weight loss. GM was preserved and fasting ghrelin, glucagon-like peptide 1 and polypeptide YY significantly increased 18 months after ESG. Conclusion ESG promotes weight loss through several key mechanistic pathways involving GE and hormones while preserving GM. These findings further support clinical adoption of this technique for the management of obesity. Trial registration number NCT03406975.

Abstract Aim To identify patient factors, including gastrointestinal functions, that are predictive or associated with weight loss in response to once‐daily 3 mg liraglutide administered subcutaneously (SQ) or placebo in obesity. Methods One hundred and thirty‐six obese adults (87% female) were randomized in a placebo‐controlled, 16‐week trial of liraglutide, escalated to 3 mg administered SQ daily. Gastrointestinal functions were measured at baseline and 16 weeks: gastric emptying of solids (GET 1/2 ); fasting and postprandial gastric volumes; kcal ingested during ad libitum buffet meal and the nutrient drink test. GET 1/2 was also measured at 5 weeks. A multiple variable regression model examined variables associated with weight loss of more than 4 kg at 16 weeks. A parsimonious model using backward selection identified the final model. Results Weight loss of more than 4 kg at 16 weeks occurred in 71% of liraglutide‐ and 16% of placebo‐treated patients. In all participants combined, parameters univariately associated with a weight loss of more than 4 kg were GET 1/2 at 5 and 16 weeks, weight loss at 5 weeks and kcal intake during the buffet meal at 16 weeks. The final parsimonious model (area under the receiver operator characteristics [AUROC] curve = 0.832) identified that factors associated with more than 4‐kg weight loss were GET 1/2 at 5 weeks (OR = 2.505; 95% CI: 1.57‐3.997) per 50 minutes and kcal intake during ad libitum meal at 16 weeks (OR = 0.721; 95% CI: 0.602‐0.864) per 100 kcal. Among only the 60 liraglutide‐treated subjects, kcal intake at 16 weeks was associated with 4‐kg weight loss (AUROC = 0.757). Conclusions Slower GET 1/2 and weight loss at 5 weeks predicted a weight loss of more than 4 kg at 16 weeks in all participants. Among liraglutide‐treated adults, weight loss of more than 4 kg was associated with ad libitum meal kcal intake at 16 weeks.

ImportanceNo retrospective cohort study has assessed the effectiveness of semaglutide at doses used in randomized clinical trials to treat obesity (ie, 1.7 and 2.4 mg).ObjectiveTo study weight loss outcomes associated with semaglutide treatment at doses used in randomized clinical trials for patients with overweight or obesity.Design, Setting, and ParticipantsThis cohort study, conducted at a referral center for weight management, retrospectively collected data on the use of semaglutide for adults with overweight or obesity between January 1, 2021, and March 15, 2022, with a follow-up of up to 6 months. A total of 408 patients with a body mass index (BMI) of 27 or more were prescribed weekly semaglutide subcutaneous injections for 3 months or more. Patients with a history of bariatric procedures, taking other antiobesity medications, and with an active malignant neoplasm were excluded.ExposuresWeekly 1.7-mg or 2.4-mg semaglutide subcutaneous injections for 3 to 6 months.Main Outcomes and MeasuresThe primary end point was the percentage of weight loss. Secondary end points were the proportion of patients achieving weight loss of 5% or more, 10% or more, 15% or more, and 20% or more after 3 and 6 months and the percentage of weight loss for patients with or without type 2 diabetes after 3 and 6 months.ResultsThe study included 175 patients (132 women [75.4%]; mean [SD] age, 49.3 [12.5] years; mean [SD] BMI, 41.3 [9.1]) in the analysis at 3 months and 102 patients at 6 months. The mean (SD) weight loss after 3 months was 6.7 (4.4) kg, equivalent to a mean (SD) weight loss of 5.9% (3.7%) (P &lt; .001), and the mean (SD) weight loss after 6 months was 12.3 (6.6) kg, equivalent to a mean (SD) weight loss of 10.9% (5.8%) (P &lt; .001 from baseline). Of the 102 patients who were followed up at 6 months, 89 (87.3%) achieved weight loss of 5% or more, 56 (54.9%) achieved weight loss of 10% or more, 24 (23.5%) achieved weight loss of 15% or more, and 8 (7.8%) achieved weight loss of 20% or more. Patients with type 2 diabetes had a lower mean (SD) percentage weight loss at 3 and 6 months compared with those without type 2 diabetes: 3.9% (3.1%) vs 6.3% (3.7%) at 3 months (P = .001) and 7.2% (6.3%) vs 11.8% (5.3%) at 6 months (P = .005).Conclusions and RelevanceThe results of this cohort study suggest that weekly 1.7-mg and 2.4-mg doses of semaglutide were associated with weight loss similar to that seen in randomized clinical trials. Studies with longer periods of follow-up are needed to evaluate prolonged weight loss outcomes.

Abstract Objective This study aimed to determine the effects of a long‐acting glucagon‐like peptide‐1 (GLP‐1) receptor agonist, liraglutide, and placebo subcutaneously over 16 weeks on weight and gastric functions and to evaluate associations of single‐nucleotide polymorphisms in GLP1R (rs6923761) and TCF7L2 (rs7903146) with effects of liraglutide. Methods The study conducted a randomized, parallel‐group, placebo‐controlled, 16‐week trial of liraglutide, escalated to 3 mg subcutaneously daily in 136 otherwise healthy adults with obesity. Weight, gastric emptying of solids (GES), gastric volumes, satiation, and body composition measured at baseline and after treatment were compared in two treatment groups using analysis of covariance. Results Liraglutide ( n = 59) and placebo ( n = 65) groups completed treatment. Relative to placebo, liraglutide increased weight loss at 5 and 16 weeks (both p < 0.05), slowed time to half GES (T 1/2 ) at 5 and 16 weeks (both p < 0.001), and increased fasting gastric volume ( p = 0.01) and satiation ( p < 0.01) at 16 weeks. GES T 1/2 was positively correlated with weight loss on liraglutide (both p < 0.001). After 16 weeks of liraglutide, GLP1R rs6923761 (AG/AA vs. GG) was associated with reduced percent body fat ( p = 0.062), and TCF7L2 rs7903146 (CC vs. CT/TT) was associated with lower body weight ( p = 0.015). Conclusions Liraglutide, 3 mg, induces weight loss with delay in GES T 1/2 and reduces calorie intake. Slowing GES and variations in GLP1R and TCF7L2 are associated with liraglutide effects in obesity.

Abstract Background: Endoscopic bariatric therapies can help address widening management gaps in obesity. Their ability to facilitate weight loss is largely tied to influences on appetite through perturbations of gastric emptying and accommodation. As these tools gain traction in obesity therapy, their physiologic underpinnings require exploration, which may enhance efficacy, tolerance, and patient-tailored care. Methods: We prospectively assessed consecutive subjects with fluid-filled intragastric balloons (IGBs) (n = 18) placed between October 2016 and June 2017 or underwent endoscopic sleeve gastroplasty (ESG) (n = 23) from March 2018 to June 2018. Patients underwent physiologic appraisal at 3 months with 13C-spirulina-based gastric emptying breath test to determine time to half emptying (T50), as well as maximum tolerated volume (MTV) of a standard nutrient drink test. Changes in T50 and MTV at 3 months were compared with percent total body weight loss (%TBWL) at 3 and 6 months using best-fit linear regression. Results: The change in T50 at 3 months correlated with %TBWL at 3 months for IGB (P = 0.01) and ESG (P = 0.01) but with greater impact on %TBWL in IGB compared to ESG (R 2 = 0.42 vs. 0.26). Change in T50 at 3 months was predictive of weight loss at 6 months for IGB (P = 0.01) but not ESG (P = 0.11). ESG was associated with greater decrease in MTV compared to IGB (340.25 ± 297.97 mL vs. 183.00 ± 217.13 mL, P = 0.08), indicting an enhanced effect on satiation through decreased gastric accommodation. Changes in MTV at 3 months did not correlate with %TBWL for either IGB (P = 0.26) or ESG (P = 0.49) but trended toward significance for predicting %TBWL at 6 months for ESG (P = 0.06) but not IGB (P = 0.19). Conclusion: IGB and ESG both induce weight loss but likely through distinct gastric motor function phenotypes, and gastric emptying may predict future weight loss in patients with IGB.

We show how switching from a regular diet to an HCHF increases cholesterol absorption in patients with normal weight and obesity. The decrease in cholesterol absorption from an HCHF to an LCLF, on the other hand, was only seen in normal-weight controls, underlining the importance of body weight in this regulation. In addition, changes in caloric and fat content had an immediate and direct effect on hepatic bile acid production.

Food intake regulation in humans is a complex process controlled by the dynamic interaction of homeostatic and hedonic systems. Homeostatic regulation is controlled by appetitive signals from the gut, adipose tissue, and the vagus nerve, while conscious and unconscious reward processes orchestrate hedonic regulation. On the one hand, sight, smell, taste, and texture perception deliver potent food-related feedback to the central nervous system (CNS) and influence brain areas related to food reward. On the other hand, macronutrient composition stimulates the release of appetite signals from the gut, which are translated in the CNS into unconscious reward processes. This multi-level regulation process of food intake shapes and regulates human ingestive behavior. Identifying the interface between hormones, neurotransmitters, and brain areas is critical to advance our understanding of conditions like obesity and develop better therapeutical interventions. Neuroimaging studies allow us to take a glance into the central nervous system (CNS) while these processes take place. This review focuses on the available neuroimaging evidence to describe this interaction between the homeostatic and hedonic components in human food intake regulation.