Effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease: Clinical implications.

In this editorial, we comment on the article by Chen et al recently published in 2024. We focus the debate on whether reducing the upper limit of normal of alanine aminotransferase (ALT) would effectively identify cases of fibrosis in metabolic-dysfunction associated fatty liver disease (MAFLD). This is important given the increasing prevalence of MAFLD and obesity globally. Currently, a suitable screening test to identify patients in the general population does not exist and most patients are screened after the finding of an abnormal ALT. The authors of this paper challenge the idea of what a normal ALT is and whether that threshold should be lowered, particularly as their study found that 83.12% of their study population with a diagnosis of MAFLD had a normal ALT. The main advantages of screening would be to identify patients and provide intervention early, the mainstay of this being changing modifiable risk factors and monitoring for liver fibrosis. However, there is not enough suitable therapeutic options available as of yet although this is likely to change in the coming years with more targets for therapy being discovered. Semaglutide is one example of this which has demonstrated benefit with an acceptable side effect profile for those patients with MAFLD and obesity, although studies have not yet shown a significant improvement in fibrosis regression. It would also require a huge amount of resource if a reduced ALT level alone was used as criteria; it is more likely that current scoring systems such as fibrosis-4 may be amended to represent this additional risk. Currently, there is not a good argument to recommend widespread screening with a reduced ALT level as this is unlikely to be cost-effective. This is compounded by the fact that there is a significant heterogeneity in what is considered a normal ALT between laboratories. Although studies previously have suggested a more pragmatic approach in screening those over the age of 60, this is likely to change with the increasing incidence of obesity within the younger age groups. The main message from this study is that those who have hypercholesterolemia and high body metabolic index should have these risk factors modified to maintain a lower level of ALT to reduce the risk of progression to fibrosis and cirrhosis.

The cost-effectiveness of semaglutide in reducing cardiovascular risk among people with overweight and obesity and existing cardiovascular disease, but without diabetes.

BACKGROUND AND AIMS: The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial demonstrated significant reductions in cardiovascular outcomes in people with cardiovascular disease (CVD) and overweight or obesity (but without diabetes). However, the cost of the medication has raised concerns about its financial viability and accessibility within healthcare systems. This study explored whether use of semaglutide for the secondary prevention of CVD in overweight or obesity is cost-effective from the Australian healthcare perspective. METHODS: A Markov model was developed based on the SELECT trial to model the clinical outcomes and costs of a hypothetical population treated with semaglutide versus placebo, in addition to standard care, and followed up over 20 years. With each annual cycle, subjects were at risk of having non-fatal CVD events or dying. Model inputs were derived from SELECT and published literature. Costs were obtained from Australian sources. All outcomes were discounted by 5% annually. The main outcome of interest was the incremental cost-effectiveness ratio (ICER) in terms of cost per year of life saved (YoLS) and cost per quality-adjusted life year (QALY) gained. RESULTS: With an annual estimated cost of semaglutide of A${\$}$4175, the model resulted in ICERs of A${\$}$99 853 (US${\$}$143 504; £40 873) per YoLS and A${\$}$96 055 (US${\$}$138 046; £39 318) per QALY gained. CONCLUSIONS: Assuming a willingness-to-pay threshold of A${\$}$50 000, semaglutide is not considered cost-effective at the current price. A price of ≤ A${\$}$2000 per year or more targeted use in high-risk patients would be needed for it to be considered cost-effective in the Australian setting.

Problematic Pharmacokinetics: A Case of Recurrent Pancreatitis Post Discontinuation of a Glucagon-Like Peptide 1 Receptor Agonists.

Glucagon-like peptide 1 receptor agonists (GLP-1RA) are guideline recommended agents for the treatment of type 2 diabetes mellitus (T2DM) and select agents (liraglutide and semaglutide) are FDA approved as anti-obesity pharmacotherapy options. These drugs act on the incretin hormone system within the body to revive insulin excretion, delay gastric emptying, and inhibit the production of glucagon from pancreatic alpha cells. Acute pancreatitis is a serious condition that may have a fatal outcome. It has been shown, and is now part of the prescribing information label, that GLP-1RA agents can cause changes in the pancreas that may ultimately lead to pancreatitis. We describe the case of a 53-year-old female patient with uncontrolled type II diabetes mellitus, who experienced multiple episodes of pancreatitis, from what we suspect was due to repeated exposure to the GLP-1 RA agent, semaglutide. After discontinuation of semaglutide, our patient experienced another episode of pancreatitis roughly 15-week later; which we believe may be due to the patient experiencing the effects of a smoldering pancreas brought on by repeated injury and prolonged circulation of semaglutide post-discontinuation.

Forecasting Trial Milestones: A Predictive Analysis for Early Termination of the SOUL Study.

INTRODUCTION: Semaglutide, a glucagon-like peptide 1 receptor agonist (GLP1RA), is available in both parenteral and oral preparations. Studies of injectable preparations have convincingly demonstrated its beneficial effect on major adverse cardiac events (MACE). This predictive analysis was undertaken to forecast early termination of the SOUL trial (oral semaglutide) as well as the primary events. METHODS: SOUL is a multicenter, double-blind, placebo-controlled randomized controlled trial (RCT) evaluating the reduction in MACE associated with oral semaglutide versus placebo in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. A sample of 9642 participants will be followed for 5 years and 5 months. A random-effects model meta-analysis, pooling hazard ratios from previous RCTs, was conducted using R software to inform the predictive model. The background CV event rates from the placebo arms of previous RCTs with semaglutide were matched with the pre-adjudicated assumptions of the SOUL trial to create the predictive model. The truncated trial duration, MACE, and its individual components in the intervention and placebo arms were estimated. The predicted difference between the two groups was estimated using the chi-squared test. RESULTS: A pooled analysis of 10,013 patients revealed a significant reduction in the number of MACEs associated with semaglutide (HR 0.79, 95% CI 0.69-0.91). Predictive analysis indicated that 1225 events would be achieved by 3.78 years, suggesting premature termination. CONCLUSION: The mathematical model based on the meta-analysis predicts that the SOUL study on oral semaglutide will be terminated early, with oral semaglutide showing benefits in terms of MACE compared to placebo. If the SOUL study corroborates the findings of this model, it may not only form the basis for the calculation of power but also define the duration of such studies, reducing costs and easing the process of designing cardiovascular outcome trials (CVOTs). PROTOCOL REGISTRATION: INPLASY202460061.

Real-world safety profile of once-weekly semaglutide in people with type 2 diabetes: Analysis of pooled data from the SemaglUtide Real-world Evidence (SURE) programme.

AIM: To investigate, through post hoc analysis of nine studies from the SemaglUtide Real-world Evidence (SURE) programme, the safety of once-weekly (OW) semaglutide in adults with type 2 diabetes (T2D) and in subpopulations in routine clinical practice, complementing findings from the phase 3 randomized clinical trial (RCT) SUSTAIN programme. METHODS: The SURE studies had a duration of ~30 weeks and included adults with diagnosed T2D treated with OW semaglutide. Safety information, including hypoglycaemic events, were collected and analysed for the total study population and for patient subgroups based on baseline patient characteristics, baseline co-medication and prescriber specialty. RESULTS: Of the total 3505 patients, 24.3% reported adverse events (AEs), with most patients reporting non-serious (22.3%) and mild (17.1%) AEs. AEs mainly belonged to the gastrointestinal disorders system organ class (16.3% of patients). In total, 5.1% of patients reported AEs that led to treatment discontinuation, 0.5% reported serious adverse drug reactions and 0.2% had an AE with a fatal outcome, reported as unrelated to treatment. Overall, 1.1% and 0.1% of patients reported level 2 and 3 hypoglycaemic events, respectively. A higher rate of level 2 hypoglycaemia was observed in patients with baseline microvascular complications treated with insulin versus those on insulin without these complications. CONCLUSIONS: Safety data reported in the real-world SURE studies were generally consistent with observations in phase 3 OW semaglutide RCTs. No new safety concerns were identified, highlighting that OW semaglutide is well tolerated by adults with T2D and in subpopulations in routine clinical practice.

Assessing the Renal Outcomes of Semaglutide in Diabetic Kidney Disease: A Systematic Review.

Diabetic kidney disease (DKD) is a prevalent microvascular complication of diabetes, posing a significant health burden. Semaglutide, a glucagon-like peptide-1 receptor agonist, has shown promise in mitigating renal outcomes in DKD. This systematic review aimed to evaluate the renal effects of semaglutide in individuals with DKD. A comprehensive literature search identified six eligible studies, including two case reports and four cohorts, from diverse geographic locations. The primary outcomes assessed were changes in estimated glomerular filtration rate (eGFR) and albuminuria. Secondary outcomes included acute kidney injury (AKI) incidence and other renal biomarkers. The impact of semaglutide on eGFR was variable, with some studies reporting decreases and others showing improvements or no significant changes. Albuminuria, however, was more consistently reduced, particularly in patients with macroalbuminuria. Notably, the case reports described semaglutide-associated AKI, including acute interstitial nephritis, highlighting the need for careful monitoring during therapy. Beyond renal outcomes, semaglutide consistently improved glycemic control and promoted weight loss, with generally manageable gastrointestinal side effects. The findings suggest that semaglutide may effectively reduce albuminuria in DKD, potentially slowing disease progression. However, the risk of AKI and the variable impact on eGFR underscore the need for a personalized approach and vigilant monitoring, particularly in patients with advanced CKD. Future large-scale, long-term randomized controlled trials are warranted to definitively assess the renal benefits and risks of semaglutide in DKD.

Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction-associated steatotic liver disease.

In this editorial, we comment on Yin et al's recently published Letter to the editor. In particular, we focus on the potential use of glucagon-like peptide 1 receptor agonists (GLP-1RAs) alone, but even more so in combination therapy, as one of the most promising therapies in metabolic dysfunction-associated steatotic liver disease (MASLD), the new definition of an old condition, non-alcoholic fatty liver disease, which aims to better define the spectrum of steatotic pathology. It is well known that GLP-1RAs, having shown outstanding performance in fat loss, weight loss, and improvement of insulin resistance, could play a role in protecting the liver from progressive damage. Several clinical trials have shown that, among GLP-1RAs, semaglutide is a safe, well-studied therapeutic choice for MASLD patients; however, most studies demonstrate that, while semaglutide can reduce steatosis, including steatohepatitis histological signs (in terms of inflammatory cell infiltration and hepatocyte ballooning), it does not improve fibrosis. Combinations of therapies with different but complementary mechanisms of action are considered the best way to improve efficiency and slow disease progression due to the complex pathophysiology of the disease. In particular, GLP-1RAs associated with antifibrotic drug therapy, dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA or GLP-1 and glucagon RAs have promoted greater improvement in hepatic steatosis, liver biochemistry, and non-invasive fibrosis tests than monotherapy. Therefore, although to date there are no definitive indications from international drug agencies, there is the hope that soon the therapeutic lines in the most advanced phase of study will be able to provide a therapy for MASLD, one that will certainly include the use of GLP-1RAs as combination therapy.

Therapeutic Effects of Semaglutide on Nonalcoholic Fatty Liver Disease with Type 2 Diabetes Mellitus and Obesity: An Open-Label Controlled Trial.

BACKGROUND: GLP-1 receptor agonists (GLP-1 RAs) have been shown to improve glycemic control and insulin sensitivity and reduce body weight in obese patients with type 2 diabetes mellitus (T2D). This trial sought to evaluate the therapeutic effect of oral and subcutaneous semaglutide in NAFLD and its sequelae in obesity and/or T2D. METHODS: In an open-labelled intervention study, the sample was 180 patients classified into three parallel groups (1:1:1): group I received oral semaglutide, group II patients received injectable semaglutide, and group III received pioglitazone and/or vitamin E. Patients were evaluated at 6 and 12 months. RESULTS: There was a substantial improvement in lipid profile, liver enzymes, and body mass index, especially in group II. As for HDL, only group II showed a consistent increase at both 6 months (51 ± 4.62 mg/dL) and 12 months (50.08 ± 2.45 mg/dL) compared with baseline (45.6 ± 6.37 mg/dL) (p-value < 0.001). Despite the non-significant difference in NAFLD fibrosis score (NFS) (p-value = 0.45 and 0.63), group II had significantly lower scores of the fibrosis-4 score (FIB-4), liver stiffness measurement (LSM), and controlled attenuation parameter (CAP) at 6 and 12 months (p-value < 0.001). Conclusions: Semaglutide improves lipid profile, liver steatosis, and fibrosis parameters and reduces the BMI in T2D and obese patients with NAFLD.

Therapeutic Advances in Obesity: How Real-World Evidence Impacts Affordability Beyond Standard of Care.

Obesity is currently considered a global epidemic, with rising prevalence worldwide and rather pessimistic projections. Based on its close interconnection with various co-morbidities, such as diabetes mellitus and cardiovascular disease, obesity is associated with significant increases in morbidity and mortality, while it also poses a substantial economic burden for national healthcare systems. Apparently, the majority of individuals classified as obese do not achieve adequate weight loss with the adoption of a healthy lifestyle intervention, including dietary modification and physical activity. Fortunately, during the last decade, a significant progress in pharmacotherapy of obesity has been observed, with the introduction of agents that have gained approval from regulatory authorities, namely semaglutide, liraglutide and tirzepatide, due to their impressive results in body weight reduction, alongside their beneficial, pleiotropic effects. The aim of the present review article is to discuss on evidence retrieved from real-world studies regarding the efficacy of those agents in obesity treatment, with emphasis on cost-effectiveness data, towards an effort to tackle efficiently the progression of obesity epidemic.

Safety and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in patients with weight regain or insufficient weight loss after metabolic bariatric surgery: A systematic review and meta-analysis.

INTRODUCTION: Weight regain and insufficient weight loss are major challenges after metabolic bariatric surgery (MBS), affecting patients' comorbidities and quality of life. The current systematic review and meta-analysis aim to assess the efficacy and safety of GLP-1 receptor agonists (GLP-1 RA) in patients with weight regain or insufficient weight loss after MBS. METHODS: A systematic search was conducted across PubMed, Embase, Scopus, and Web of Science databases to find the relevant studies. RESULTS: A total of 19 articles were included. The highest doses of liraglutide and semaglutide were 3 mg per day and 1 mg once weekly, respectively, in the included studies. The mean differences in weight and body mass index after treatment were -7.02 kg or 3.07 kg/m2, -8.65 or -5.22 kg/m2, and -6.99 kg or -3.09 kg/m2 for treatment durations of ≤ 6 months, 6-12 months, and >12 months with liraglutide, respectively. Additionally, weekly semaglutide showed significantly greater weight loss compared to daily liraglutide, with a mean difference of 4.15 kg. Common complications included nausea (19.1%), constipation (8.6%), abdominal pain (3.7%), and vomiting (2.4%). CONCLUSION: Using GLP-1 RA is a safe and effective treatment for weight regain and insufficient weight loss after MBS.

PIONEER REAL Japan: Primary results from a multicenter, prospective, real-world study of oral semaglutide in adults with type 2 diabetes in Japanese clinical practice.

AIMS/INTRODUCTION: PIONEER REAL Japan was a non-interventional prospective study of oral semaglutide in adults with type 2 diabetes in Japanese clinical practice. MATERIALS AND METHODS: Adults naïve to injectable glucose-lowering therapies initiated oral semaglutide in routine clinical practice and were followed for 34-44 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to end of study; the co-primary endpoint was number of adverse events (AEs). Secondary endpoints included change in bodyweight from baseline to end of study. Analyses were also carried out for subgroups aged <75 and ≥75 years. RESULTS: A total of 624 participants initiated oral semaglutide; 578 completed the study. Mean baseline HbA1c and bodyweight were 7.7% and 72.4 kg, respectively. At end of study, estimated change (95% confidence interval [CI]) in HbA1c from baseline was -0.7 percentage points (-0.77, -0.61) overall, -0.8 percentage points (-0.86, -0.67) in the <75 years subgroup and -0.5 percentage points (-0.68, -0.41) in the ≥75 years subgroup (all P < 0.0001). Estimated change (95% CI) in bodyweight was -2.8 (-3.19, -2.50) kg overall, -2.9 (-3.38, -2.49) kg in the <75 years subgroup and - 2.7 (-3.18, -2.14) kg in the ≥75 years subgroup (all P < 0.0001). AEs occurred in 161 (25.8%) participants: 99 of 423 (23.4%) and 62 of 201 (30.8%) participants in the <75 and ≥75 years subgroups, respectively. Gastrointestinal AEs were the AEs most frequently leading to oral semaglutide discontinuation. CONCLUSIONS: In routine clinical practice, HbA1c and bodyweight were significantly reduced from baseline in adults initiating oral semaglutide, including those aged ≥75 years, with no new safety concerns.

Glucagon-Like Peptide-1 Receptor Agonist Use in Pregnancy: A Review.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are peptide analogues that are used to treat type 2 diabetes mellitus (T2DM) and obesity. The first medication in this class, Exenatide, was approved in 2005, and these medications, specifically Semaglutide, have become more popular in recent years due to their pronounced effects on glycemic control, weight reduction, and cardiovascular health. Due to successful weight loss from these medications, many women previously diagnosed with oligomenorrhea and unable to conceive have experienced unplanned pregnancies while taking the medications. However, there is currently little data for clinicians to use in counseling patients in cases of accidental periconceptional exposure. In some studies examining small animals exposed to GLP-1RAs in pregnancy, there has been evidence of adverse outcomes in the offspring, including decreased fetal growth, skeletal and visceral anomalies, and embryonic death. Although there are no prospective studies in humans, case reports, cohort studies, and population-based studies have not shown a pattern of congenital anomalies in infants. A recent large, observational, population-based cohort study examined 938 pregnancies affected by T2DM and compared outcomes from periconceptional exposure to GLP-1RAs and insulin. The authors concluded there was not a significantly increased risk of major congenital malformations in patients taking GLP-1RAs, although there was no information on maternal glycemic control or diabetic fetopathy. As diabetic embryopathy is directly related to the degree of maternal hyperglycemia and not the diagnosis of diabetes itself, it is not possible to make this conclusion without this information. Furthermore, there is little evidence available regarding fetal growth restriction, embryonic or fetal death, or other potential complications. At this time, patients should be counseled there is not enough evidence to predict any adverse effects, or the lack thereof, of periconceptional exposure of GLP-1RAs during pregnancy. We recommend that all patients use contraception to prevent unintended pregnancy while taking GLP-1RAs.

The impact of approved anti-obesity medications on osteoarthritis.

BACKGROUND: Obesity has been established as a significant risk factor for osteoarthritis. Anti-obesity medications (AOMs) have demonstrated efficacy in weight management. However, potential impact on osteoarthritis risk remains uncertain. METHODS: This retrospective cohort study used Kythera data from NOV2022 to JULY2024. Patients with obesity using AOMs were identified through diagnosis and prescription claims for tirzepatide, semaglutide, or liraglutide between 1NOV2023 and 31JAN2024, with a 6-month follow-up to assess OA risk. OA risk, analyzed using Cox regression and propensity score matching, controlled for comorbidities and sociodemographic factors. RESULTS: There were 39,394 patients living with obesity using AOM (23,933 semaglutide 12,854 tirzepatide, 2,607 liraglutide) and 72,405 without AOM use. The adjusted osteoarthritis risk was 27% % lower in AOM users than in non-users (hazard ratio (HR) = 073, 95% CI (0.67-0.79), p < 0.01). Among AOMs, tirzepatide was associated with a significantly lower osteoarthritis (OA) risk compared to semaglutide (HR = 0.57, 95% CI: 0.50-0.65, p < 0.0001). Liraglutide was linked to a significantly higher OA risk vs tirzepatide (HR = 1.63, 95% CI: 1.23-2.15, p = 0.0007). CONCLUSIONS: AOM use was associated with a significantly lower risk of OA and may be an effective obesity management intervention.

Semaglutide Ameliorates Hepatocyte Steatosis in a Cell Co-Culture System by Downregulating the IRE1α-XBP1-C/EBPα Signaling Pathway in Macrophages.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is currently the most common type of chronic liver disease. Semaglutide is a glucose-lowering drug administered for the treatment of type 2 diabetes mellitus (T2DM) and is clinically effective in the treatment of NAFLD. X-box binding protein 1 (XBP1) is related to the pathogenesis of both NAFLD and T2DM. The aim of the present study was to demonstrate whether the underlying mechanism of semaglutide treatment for NAFLD is via downregulation of the inositol-requiring transmembrane kinase/endonuclease-1α (IRE1α)-XBP1-CCAAT/enhancer binding protein α (C/EBPα) signaling pathway in macrophages. METHODS: In the present study, NAFLD cell modeling was induced by oleic acid (0.4 mm) and palmitic acid (0.2 mm). Hepatocytes (AML12) and macrophages (RAW264.7) were co-cultured in 6-well Transwell plates. Semaglutide (60 or 140 nm) was administrated for 24 h, while pioglitazone (2 µm) and toyocamycin (200 nm) were used as a positive control drug and a XBP1 inhibitor, respectively. Autophagy and apoptosis of AML12 cells were detected by transmission electron microscopy and Western blotting (WB). Hepatocyte steatosis was evaluated by adopting total intracellular triglyceride determination, analysis of the relative expression of proteins and genes associated with lipid metabolism and hepatocyte Oil red O staining. Detection of inflammation factors was conducted by ELISA and WB. To explore the underlying mechanism of NAFLD treatment with semaglutide, the relative expression of related proteins and genes were tested. RESULTS: Our study demonstrated that semaglutide treatment improved autophagy and inhibited apoptosis of hepatocytes, while notably ameliorating steatosis of hepatocytes. In addition, inflammation was attenuated in the NAFLD cell co-culture model after semaglutide administration. Semaglutide also significantly reduced the protein and gene expression levels of the IRE1α-XBP1-C/EBPα signaling pathway in macrophages. CONCLUSION: Semaglutide partially ameliorated NAFLD by downregulating the IRE1α-XBP1-C/EBPα signaling pathway in macrophages. These findings may provide a potential theoretical basis for semaglutide therapy for NAFLD.

Weighing your options-intragastric balloon versus semaglutide.

INTRODUCTION: Over half of Americans and up to 78% of US Veteran population meet criteria for obesity. Perioperatively placed intragastric balloon (IGB) can accelerate weight loss goals for safe surgical candidacy, however weight regain is common after removal. Glucagon-like peptide-1-receptor agonists (GLP1RA) may provide a more sustainable weight loss solution after surgery. We hypothesize that weight regain will be less at 1 year after initiation of GLP1RA than IGB placement in Veterans. METHODS: Retrospective review of prospective databases of perioperatively placed intragastric balloon cohort from 1/2019-1/2023 compared to patients who received initiatory GLP1RA from 6/2021-8/2022 at a VA Medical Center(VAMC). All patients were enrolled in the VAMC MOVE! multidisciplinary weight management program for a minimum of 12 weeks. Outcomes measured were patients' weights at 0, 3, 6, and 12 months and weight change for these intervals. Exclusion criteria included history of bariatric surgery and incomplete weight loss data. RESULTS: Two-hundred-twenty-three patients met inclusion criteria; 110 (49%) patients excluded. Mean age was 54 ± 11 years, the majority (78, 69%) were male, and the mean initial BMI was 37 ± 5.9 kg/m2. Seventeen (15%) patients underwent IGB placement and 96 (85%) patients received semaglutide. Weight (kg) change was measured at intervals: 0-3 months:- 11.8(- 17,- 9.5) IGB vs. - 5.1(- 7.4,- 2.3) semaglutide, p < 0.0001; 0-6 months:- 12.7(- 18.4,- 9.9) vs. - 9.4(- 12.6,- 6.1), p = 0.03; 3-6 months:- 0.5(- 2.3,2.3) vs. - 4.3(- 6.8,- 1.6), p < 0.0001; 6-12 months:3(0,7.3) vs. - 1.9(- 4.7,1), p = 0.0006. CONCLUSION: Weight loss occurs more rapidly in the first 6 months after intragastric balloon placement compared to semaglutide (- 12.7 vs. - 9.4 kg, p = 0.03). Despite ongoing attendance in a comprehensive weight loss program, weight regain is common after IGB removal by an average of 3 kg (23.6%) at 1 year. In contrast, patients on GLP1RA (semaglutide) continue to lose weight during this period. Further studies are needed to determine if optimal long-term outcomes may result from combination therapy with intragastric balloon and semaglutide.