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Background: Nicotine use and nicotine use disorder (NUD) are the leading causes of preventable death in the United States. Persons with mental disorders (e.g., bipolar disorder) are differentially susceptible to nicotine use. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are indicated for type 2 diabetes mellitus (T2DM) and obesity and show preliminary evidence of efficacy in addiction-related behaviours. Herein, we synthesize extant preclinical and clinical evidence evaluating the effect of GLP-1RAs on neurobiological systems and behaviours salient to nicotine consumption and cessation. Methods: Online databases (MedLine, Embase, AMED, PsychINFO, JBI EBP Database, PubMed, Web of Science, Google Scholar) were searched from inception to May 21, 2024. Relevant studies were also extracted from the reference lists of the obtained articles. All articles were screened against inclusion and exclusion criteria. Results: Administration of GLP-1RAs reduced nicotine self-administration and nicotine-seeking behaviour in animal models that, in some cases, is sustained beyond exposure to the agent. GLP-1RAs also mitigated post-nicotine cessation weight gain, craving, withdrawal, and hyperphagia. The preceding effects are attributable to modulation of reward-related brain regions (e.g., mesolimbic dopamine system), resulting in nicotine aversion. GLP-1RAs were also efficacious as adjunctive therapies [e.g., in combination with nicotine replacement therapies (NRTs)]. Conclusion: The multi-effect characteristics in NUD paradigms provide a compelling rationale for large, adequately powered, long-term, randomized controlled trials of GLP-1RAs in the treatment and prevention of NUD. The replicated effect on mitigating post-nicotine cessation weight gain is a differentiating feature of GLP-1RAs from extant proven therapies for NUD. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions The study aims to examine the outcome of replacement of prandial insulin with once‐weekly subcutaneous semaglutide in people with type 2 diabetes reasonably controlled on multiple daily insulin injections (MDI).This single‐centre, randomised, open‐label trial enrolled a statistically predetermined sample of 60 adults with HbA1c ≤7.5% (58 mmol/mol) receiving MDI, with a total daily dose (TDD) ≤120 units/day. Participants were assigned 2:1 to subcutaneous semaglutide 1.0 mg plus insulin degludec, or to continue MDI. The primary outcome was percentage of subjects maintaining HbA1c ≤7.5% (58 mmol/mol) at Week 26.At Week 26, 90% of semaglutide and 75% of MDI subjects maintained HbA1c ≤7.5% (≤58 mmol/mol) (p = 0.18). Mean changes (95% CI) in HbA1c, weight and percentage body weight for semaglutide versus MDI, respectively, were −0.5% (−0.7, −0.3) versus 0.0% (−0.3, 0.3; p = 0.009); −8.9 kg (−9.9, −7.8) versus 1.5 kg (−0.1, 3.1; p < 0.001); and −8.6% (−9.6, −7.6) versus 1.4% (0.0, 2.8; p < 0.001). Insulin TDD decreased 56.0% (−62.3, −49.7) with semaglutide and increased 6.7% (−2.5, 16.0) with MDI (p < 0.001). Among semaglutide subjects, 58% reduced insulin TDD > 50%, 97.5% stopped prandial insulin and 45% lost >10% body weight. Participant treatment satisfaction scores trended higher with semaglutide. Hypoglycaemia frequency was similar between groups.In people with type 2 diabetes well controlled (HbA1c ≤7.5% [≤58 mmol/mol]) on MDI ≤120 units/day, replacing multiple daily injections of prandial insulin with once‐weekly subcutaneous semaglutide can maintain and even improve HbA1c, lower body weight and lessen the burden of management. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusion Clinical trial registration number To compare the effects of semaglutide and testosterone replacement therapy (TRT) on semen quality and parameters of functional hypogonadism (FH) in men with type 2 diabetes mellitus and obesity.We designed a randomised open‐label trial in 25 men with type 2 diabetes (aged 50 [46–60] years, BMI 35.9 [32.8–38.7] kg/m2) and FH randomised to semaglutide (SEMA) 1 mg/week or intramuscular testosterone undecanoate (TRT) 1000 mg/10–12 weeks for 24 weeks. Semen analysis and parameters of FH were measured at baseline and after 24 weeks of treatment. Participants completed questionnaires of the International Index of Erectile Function‐15 (IIEF‐15) and the Aging Symptoms in Men (AMS).The quality of baseline sperm parameters of our study cohort was poor, below the 5th percentile of reference values. In the SEMA group, there was a significant increase in morphologically normal sperm from baseline to the end of the study (2% [2; 3.5] vs. 4% [2; 5.5]; p = 0.012), whereas sperm concentration and total number decreased significantly in the TRT group. Compared to TRT, the SEMA group had a significantly higher number of morphologically normal sperm, sperm concentration and total number. Both groups experienced an increase in total testosterone and improvement in the AMS score, whereas the IIEF‐15 score significantly improved only in the TRT group.Semaglutide markedly improved sperm morphology, total testosterone levels and symptoms of hypogonadism. These findings highlight semaglutide's potential as a therapeutic approach for men with obesity‐related FH who desire fertility.NCT06489457, www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

The elimination of side-chain orthogonal protective groups of arginine and histidine is critical to improve solid phase peptide synthesis (SPPS) sustainability through an increase in the peptide atom economy (AE) and decrease in impurities generated during the final cleavage step. The combination of Oxyma Pure and tertbutyl ethyl carbodiimide (TBEC) in the correct ratio allowed the use of side-chain free arginine and histidine in green solvents. Etelcalcetide and vasopressin intermediates as well as critical key fragments of liraglutide and semaglutide were successfully synthetized via SPPS using optimized conditions. In addition, the Oxyma Pure/TBEC protocol in NBP/DMC was successfully applied to a sequence containing side-chain unprotected arginine, histidine, tryptophan and tyrosine. [ABSTRACT FROM AUTHOR]

The use of glucagon-like peptide-1 receptor agonists (GLP-1RA) has experienced rapid growth amidst the obesity epidemic in the United States. While originally developed for glucose control in Type 2 Diabetes Mellitus, the scope of these agents now extends to encompass weight loss and cardiovascular risk reduction. GLP-1RAs have the potential to induce significant weight loss, in combination with lifestyle modifications, among adults who are overweight or obese. Furthermore, these agents demonstrate efficacy in ameliorating hyperglycemia, enhancing insulin sensitivity, regulating blood pressure, improving cardiometabolic parameters, mitigating kidney dysfunction, and potentially reducing the risk of several obesity-related cancers. Drug-related toxicity is primarily gastrointestinal and active management can prevent drug discontinuation. Obesity is associated both with an increased incidence of malignancy but also with decreased survival. More research is needed to evaluate the potential use of GLP-1RA to modify the endocrine function of adipocytes, regulate the chronic inflammatory state associated with obesity, and prospective applications in oncology. These agents can impact patients with gynecologic malignancies both through their direct mechanism of action as well as potential drug toxicity. • The use of GLP-1 receptor agonists (RA) for weight management is expanding rapidly. • GLP-1RAs have diverse and far-reaching impacts and therapeutic indications are expanding rapidly. • Understanding GLP-1RAs and their potential to impact our patients is important for the Gynecologic Oncologist. [ABSTRACT FROM AUTHOR]

Background: Developing anti-obesity interventions targeting appetite or food intake, the primary driver of obesity, remains challenging. Here, we demonstrated that dietary γ-aminobutyric acid (GABA) with GABA-degradation inhibitory drugs could be an anti-obesity intervention possessing strong food intake-suppressive and weight-loss effects. Methods: High-fat (HF)-diet-induced obese mice were divided into six groups receiving either the HF diet or the 2% GABA-HF diet with daily administration of PBS or the GABA-degradation inhibitory drugs, vigabatrin and ethanolamine-O-sulfate (EOS). In 24-h fast-induced refeeding, lean mice with a basal diet were used, and food intake was measured from 0.5 to 24 h after refeeding. Results: Coadministration of the 2% GABA-HF diet with vigabatrin or EOS significantly decreased food intake (−53%, −35%) and body weight (−22%, −16%) within 11 days in obese mice, along with a marked increase in plasma GABA levels. Mice receiving dietary GABA alone or the drugs alone exhibited no such effects. Hypothalamic GABA levels increased in drug-treated mice, regardless of diet. At 0.5 h after refeeding, food intake was similar in all groups. However, at 0.5 h, plasma GABA levels were markedly increased only in mice receiving coadministration of dietary GABA and the drugs, and their food intake was completely inhibited for over 6 h, while mice in other groups gradually increased their food intake. Conclusion: Combining dietary GABA with GABA-degradation inhibitory drugs effectively suppresses food intake and promotes weight loss in obese mice, primarily through increased plasma GABA availability. These findings may advance the development of food intake-controlling strategies for obesity management. [ABSTRACT FROM AUTHOR]

Background: Compared to alternative weight-loss strategies and medications, semaglutide stands out for its convenience and efficacy, resulting in a significant increase in prescriptions and raising public safety concerns. Furthermore, the safety profiles of its oral and subcutaneous formulations require further examination. Objective: Our goal is to investigate the potential safety risks associated with semaglutide by analyzing data from the FAERS database and social media. Additionally, we aim to compare the adverse drug reaction (ADR) signals between the oral and subcutaneous administration routes of semaglutide. Methods: We collected semaglutide-related reports from the FAERS database spanning Q1 2018 to Q2 2023, and patient reviews on WebMD and AskaPatient up to 20 July 2023. Following data extraction and cleansing, we conducted descriptive analyses of demographic characteristics. Subsequently, we calculated adverse drug reaction (ADR) signals using the reporting odds ratio (ROR). Results: We identified 19,289 and 422 semaglutide-related adverse drug events (ADEs) reported in the FAERS database and online patient reviews, respectively. Gastrointestinal disorders emerged as the most commonly reported System Organ Class (SOC) in both datasets. Predominant Preferred Terms (PTs) included nausea, vomiting, and diarrhea. Serious outcomes constituted 3.07% and 2.25% of all cases for oral and subcutaneous semaglutide, respectively. At the SOC level, gastrointestinal disorders accounted for 30.19% of total ADEs in oral semaglutide, slightly surpassing the 27.76% in subcutaneous semaglutide. The median onset for gastrointestinal PTs was 4 days in both oral (Q1: 1, Q3: 32) and subcutaneous (Q1: 1, Q3: 35) formulations. Noteworthy, new serious adverse event (AE) signals were identified, including hemorrhagic diarrhea (ROR: 3.69), hepatic pain (ROR: 4.20), abnormal hormone levels (ROR: 6.51), and pancreatic failure (ROR: 36.34) in subcutaneous semaglutide, and Dupuytren's contracture (ROR: 46.85) in oral semaglutide. Conclusion: Our study delineates the safety profile of semaglutide using data from the FAERS database and social media. And identified novel ADR signals specific to oral and subcutaneous forms of semaglutide. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Adherence and treatment continuation rates of the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) semaglutide for both oral (O‐SEMA) and subcutaneous injection (SEMA‐SC) remain unknown in real‐world clinical practice. This retrospective observational study compared the 12 month adherence and treatment discontinuation of O‐SEMA and once‐weekly SEMA‐SC in patients with type 2 diabetes using a real‐world claims database. SEMA‐SC initiators were 1:1 propensity score‐matched to O‐SEMA initiators. Non‐adherence was defined as <0.8 of the proportion of days covered. SEMA‐SC had a significantly higher odds ratio (OR) for non‐adherence than O‐SEMA (OR: 1.39). The hazard ratio for treatment discontinuation, using O‐SEMA as the reference, was 1.45 for SEMA‐SC, although the discontinuation rate of O‐SEMA was higher during the early stage. O‐SEMA initiators showed significantly higher adherence and greater persistence in therapy than SEMA‐SC initiators at 12 months, which could lead to earlier initiation of GLP‐1RA treatment. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Aim: To analyse data from the All of Us Research Program to evaluate the real‐world application and long‐term effectiveness of semaglutide in treating type 2 diabetes and obesity patients in a large population. Materials and Methods: We identified patients prescribed semaglutide and analysed differences in route of administration and the time on semaglutide. For individuals diagnosed with obesity, we measured changes in body mass index (BMI) and weight from baseline, while measured changes in HbA1c for those patients with type 2 diabetes. We also examined the occurrence of newly diagnosed common adverse events from taking semaglutide. Results: For 3739 semaglutide patients, those on injectable semaglutide (3364 patients) averaged 301.54 days on the medication, with 20.36% having no end date, while those on oral semaglutide (435 patients) averaged 172.48 days, with 24.60% having no end date. We found average decreases of 1.54 kg/m2 in BMI, 4.65 kg in weight and 0.75% in HbA1c for semaglutide users. The decreases were larger in participants taking injectable formulation, probably because of higher starting values. Over time, improvements in these outcomes diminished, but the values remained significantly lower than baseline levels. Approximately only 1.0% of patients reported newly diagnosed common adverse events. Conclusions: Consistent with clinical trial findings, this real‐world data analysis showed that semaglutide was well tolerated and that, for a large population, it effectively reduced BMI, body weight and HbA1c, albeit to smaller magnitudes than observed in clinical trials. These findings provide valuable insights into real‐world experience and the long‐term effectiveness of semaglutide. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the efficacy and safety of oral semaglutide for type 2 diabetes mellitus (T2DM) in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). Materials and Methods: This was a single‐arm, multicentre, prospective study. Among 80 consecutive patients with MASLD and T2DM who newly received oral semaglutide, 70 completed 48‐week oral semaglutide treatment as scheduled and were included in an efficacy analysis. Dose adjustments of oral semaglutide were determined by each physician while monitoring efficacy and adverse events. Results: Significant improvements in body weight, liver enzymes, lipid profile, and glycaemic control were found at 48 weeks compared with baseline values (all p < 0.01). Controlled attenuation parameter values significantly decreased from baseline to 48 weeks (p < 0.01). Changes in alanine aminotransferase concentrations (r = 0.37, p < 0.01) and controlled attenuation parameter values (r = 0.44, p < 0.01) were significantly correlated with changes in body weight. Liver fibrosis markers, such as type IV collagen 7S, Wisteria floribunda agglutinin‐positive Mac‐2‐binding protein, fibrosis‐4 index, and liver stiffness measurement, significantly decreased from baseline to 48 weeks (all p < 0.01). The most common adverse events were Grades 1–2 transient gastrointestinal symptoms, such as nausea (23 patients, 28.8%), dyspepsia (12, 15.0%) and appetite loss (4, 5.0%). Conclusions: Oral semaglutide treatment for T2DM in patients with MASLD leads to an improvement in liver steatosis and injury, surrogate markers of fibrosis, diabetic status, and lipid profile, and reduces body weight. [ABSTRACT FROM AUTHOR]

This article examines the early adoption of semaglutide, a drug used to treat type 2 diabetes, in Scandinavia, with a focus on Denmark. The study analyzes nationwide prescription data from Denmark, Norway, and Sweden to compare the use of semaglutide with other glucose-lowering drugs and to compare the characteristics of semaglutide initiators with initiators of other drugs. The findings reveal that semaglutide is widely used in Scandinavia and that the characteristics of semaglutide initiators differ slightly from initiators of other drugs. The study also identifies differences between early and late initiators of semaglutide, suggesting potential off-label use for weight loss. However, the study acknowledges limitations, such as the lack of data on specific indications for use. [Extracted from the article]

Aim: Efficient primary prevention of diabetic kidney disease (DKD) is currently lacking. The identification of people at high DKD risk and timely intervention are key to preventing DKD. Therefore, a model to classify people according to their risk for developing DKD was developed previously and used in the current analysis to assess the effect of semaglutide versus placebo on primary DKD prevention. Methods: Participants with type 2 diabetes from the randomized, double‐blind, placebo‐controlled SUSTAIN 6 trial without DKD at baseline who received 0.5/1.0 mg semaglutide or placebo were grouped by baseline DKD risk, calculated using a validated model. The main post hoc outcome was the effect of semaglutide versus placebo on the proportion of participants who developed DKD [urinary albumin/creatinine ratio (UACR) ≥30 mg/g and/or estimated glomerular filtration rate <60 mL/min/1.73 m2]. Additional post hoc outcomes included changes in DKD risk score, UACR and estimated glomerular filtration rate over time. Results: Of the total 1139 participants included in the analysis, 28.7% developed DKD; more participants with a high DKD risk (952/1139) developed DKD. Semaglutide significantly reduced the risk of developing DKD in both the total [odds ratio 0.56 (95% confidence interval: 0.42; 0.74; p < 0.0001)], and high DKD risk population [odds ratio 0.51 (95% confidence interval: 0.38; 0.69; p < 0.0001)] and significantly delayed DKD development versus placebo. The beneficial effects of semaglutide were largely driven by UACR changes. The number needed to treat for semaglutide in the high DKD risk population was 7. Conclusions: This post hoc study indicates that semaglutide may have beneficial effects on primary DKD prevention in people with T2D. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of overweight and obesity is increasing in America, contributing to various health risks. Glucagon‐like peptide‐1 (GLP‐1) and gastric inhibitory peptide (GIP) receptor agonists have bloomed in popularity due to their efficacy and United States Food and Drug Administration (FDA) approval for weight loss, igniting popularity on social media. This study focuses on the role of TikTok™ (ByteDance, Haidian, Beijing, China), a popular social media platform, in disseminating understandable and actionable information about the side effects of weight loss medications. Methods: The study analyzed the top 50 TikTok videos for each of the following hashtags: #ozempicsideeffects, #semaglutidesideeffects, #mounjarosideeffects, and #wegovysideeffects. Videos were evaluated based on their understandability and actionability using the Patient Education Materials Assessment Tool (PEMAT) for audio‐visual (AV) products. PEMAT‐AV scores and popularity of videos were compared between hashtags utilizing one‐way analysis of variance (ANOVA). An alpha of 0.05 was used, with Bonferroni correction. Results: A total of 165 videos were reviewed for PEMAT‐AV understandability and actionability scores. The total visibility of the videos reached over 19.4 million views. A majority of the videos were personal experiences (89%), with only 5% being health care education videos. The average understandability and actionability scores for all videos were 43% and 20%, respectfully. The data presented a difference between searched hashtags for both evaluation scores, p‐values of <0.001 and 0.093, respectively. Conclusion: TikTok videos covering weight loss medication side effects have poor understandability and actionability scores. This study highlights the opportunity for more educational videos produced by health care professionals on TikTok, and a potential need for health care organizations and/or colleges of pharmacy to provide education to health care providers on how to create quality content for medication education on social media‐based platforms. Further research is needed to evaluate the credibility of content. [ABSTRACT FROM AUTHOR]

Tobacco use represents the leading preventable risk factor for premature deaths worldwide. A meta-analysis of 74 epidemiological studies, including 3.2 million individuals with type 2 diabetes mellitus (T2DM) from 33 countries, reported a pooled prevalence of smoking of 20.8% among individuals with T2DM. Cigarette smoking further aggravates existing deleterious vascular effects of T2DM. Namely, chronic hyperglycemia and exposure to cigarette smoke cause additive injurious effect on the endothelium, leading to an acceleration of vascular complications seen in persons with T2DM and tobacco use disorders (TUD). In a recent study, Wang and colleagues found that semaglutide use was associated with a significantly lower risk for medical encounters for TUD, when compared to other antidiabetic drug classes; indeed, this effect was strongest compared with insulins and weakest compared with other glucagon-like peptide-1 receptor agonists. Semaglutide was associated with reduced smoking cessation medication prescriptions and counseling. Similar findings were observed irrespective of the presence of obesity. Therefore, semaglutide use might be useful in terms of smoking cessation among individuals with T2DM, thus offering an additional benefit for this constantly growing population. However, those interesting findings should be confirmed through dedicated, large-scale randomized controlled trials. [ABSTRACT FROM AUTHOR]

Introduction: Oral semaglutide provides an alternative to injectable glucagon-like peptide-1 receptor agonists (GLP-1RAs) for treatment of type 2 diabetes (T2D). The PIONEER REAL studies evaluate clinical outcomes of oral semaglutide treatment of T2D in a real-world setting. PIONEER REAL UK focused on adults living with T2D in the UK. Methods: The multi-centre, prospective and non-interventional single-arm study enrolled 333 participants and followed them for 34–44 weeks. Participants were treated as part of routine clinical practice and had not been previously treated with injectable glucose-lowering medication. The primary endpoint was change in glycated haemoglobin (HbA1C) from baseline to end of study (EOS). Secondary endpoints included change in body weight, proportion of participants with HbA1C < 7% (53 mmol/mol) at EOS and proportion of participants with ≥ 1%-point HbA1C reduction and body weight reduction of ≥ 3% or ≥ 5% at EOS. Treatment satisfaction was assessed by Diabetes Treatment Satisfaction Questionnaire (DTSQ) status and change. Results: Of 333 participants, 299 completed the study and 227 were on treatment at EOS. People treated with oral semaglutide experienced significantly reduced HbA1C by an estimated change of – 1.1%-points (95% CI – 1.27 to – 0.96; P < 0.0001) or – 12.2 mmol/mol (CI – 13.87 to – 10.47; P < 0.0001). Estimated change in body weight was – 4.8 kg (CI – 5.47 to – 4.12; P < 0.0001). At EOS, an HbA1C level < 7% (53 mmol/mol) was recorded in 46.3% of participants. A ≥ 1%-point reduction in HbA1C combined with a ≥ 3% reduction in body weight was observed in 36.4% of participants, and 27.1% had a ≥ 1%-point reduction in HbA1C and a ≥ 5% body weight reduction. Treatment satisfaction improved significantly during the study. No new safety concerns or cases of severe hypoglycaemia were reported. Conclusion: People living with T2D in the UK experienced a meaningful decrease in HbA1C and body weight after initiation of oral semaglutide treatment. No new safety issues were observed. Trial Registration: ClinicalTrials.gov: NCT04862923. Graphical plain language summary available for this article. Plain Language Summary: PIONEER REAL UK investigated the use of a tablet form of the medicine semaglutide in people living with type 2 diabetes in the UK. The purpose was to determine how well the tablet works for blood sugar control and weight loss in everyday clinical practice. The study followed 333 participants whose doctors had given them semaglutide tablets. Their blood sugar levels and body weight were measured before and after taking the semaglutide tablet for 34–44 weeks. The participants were also asked to fill out questionnaires about their treatment satisfaction and how it changed when taking the semaglutide tablet. The participants' blood sugar levels dropped a lot, and body weight was lowered by an average of 4.8 kg during the 34–44 weeks of the study. The participants were also more satisfied with their treatment at the end of the study than before taking the semaglutide tablet. Doctors treating the participants found the treatment to be a success in more than two-thirds of participants. The study also found that the semaglutide tablet was not associated with cases of too low blood sugar and was generally well tolerated. In summary, the semaglutide tablet is a good option for people living with type 2 diabetes who need better blood sugar control and would benefit from weight loss. The treatment is generally well tolerated, and people are very satisfied with it. Graphical Plain Language Summary: [ABSTRACT FROM AUTHOR]

BACKGROUND Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied. METHODS We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of >30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reducedcalorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being). RESULTS A total of407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6°/o of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (PcO.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (PcO.OOl). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation. CONCLUSIONS Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. [ABSTRACT FROM AUTHOR]

Background & objectives: Obesity is a common comorbidity in heart failure, yet effective pharmacological options for weight loss in these patients are limited. Semaglutide, a glucagon-like peptide 1 receptor agonist, has shown promise for weight reduction in obese adults. This study aims to evaluate semaglutide's impact on weight loss, functional status, and clinical outcomes in obese patients with heart failure. Methods: A retrospective analysis was conducted on all consecutive obese (BMI > 30 kg/m²) patients with heart failure at the University Hospital Bonn outpatient clinic from July 2019 to July 2022. Propensity score matching paired patients receiving semaglutide as an add-on therapy (SEMA) with those on medical therapy alone (Control). Results: Among 1,942 patients with heart failure screened, 26 matched pairs were identified. At one year, the SEMA group exhibited significant weight loss, with a mean BMI reduction of -2.91 kg/m² (95% CI: -4.27 to -1.55; p < 0.001), while the control group showed a non-significant mean change of -0.41 kg/m² (95% CI: -1.08 to 0.26; p = 0.22). The difference in BMI between the two groups was statistically significant (mean difference: 3.42 kg/m², 95% CI: 1.43 to 5.42; p = 0.001). Improvements by at least one NYHA class were observed in 65% of the SEMA group (p < 0.001) compared to 15% of the control group (p = 0.18). The SEMA group also showed a significant increase in 6-minute walk distance (6MWD), with a mean difference of 75 m between the groups at one year (95% CI: 0.53 to 150.02; p = 0.049). NT-proBNP levels significantly decreased in the SEMA group (p < 0.001) compared to the control group (p = 0.78), with a statistically significant difference in NT-proBNP between the groups (p = 0.048). Both improvements in 6MWD and reductions in NT-proBNP were significantly correlated with BMI percentage reductions. Conclusions: Semaglutide was associated with significant weight reduction in obese patients with heart failure, accompanied by improved NYHA classification and 6-minute walk distance. Larger, multi-center trials and prospective, randomized controlled trials are warranted. These studies should focus on assessing long-term outcomes, optimizing dosage, and exploring the potential cardiovascular benefits beyond weight reduction. [ABSTRACT FROM AUTHOR]

Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure–related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined. This study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program. This was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire—Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD, and levels of CRP in semaglutide- vs placebo-treated patients. Patients were stratified into 3 categories based on baseline CRP levels (<2, ≥2 to <10, and ≥10 mg/L). In total, 1,145 patients were randomized, of which 71% of patients had evidence of inflammation (CRP ≥2 mg/L). At baseline, those with higher levels of inflammation were younger, were more likely to be female, and had higher body mass index, worse health status (KCCQ-CSS), and shorter 6MWD. Semaglutide vs placebo led to reductions in HF-related symptoms and physical limitations as well as body weight, and to improvements in 6MWD and the hierarchical composite endpoint that were consistent across baseline CRP categories (all P interaction nonsignificant). Semaglutide also reduced CRP to a greater extent than placebo regardless of baseline CRP levels (P interaction = 0.32). Change in CRP from baseline to 52 weeks was similar regardless of the magnitude of weight loss (P interaction = 0.91). Inflammation is highly prevalent in obesity-related HFpEF. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight across the categories of baseline CRP. Semaglutide also reduced inflammation, regardless of either baseline CRP or magnitude of weight loss during the trials. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511 ]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM; NCT04916470 ]) [ABSTRACT FROM AUTHOR]

Obesity is a key factor in the development and progression of both heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF). In the STEP-HFpEF Program (comprising the STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes] trials), once-weekly semaglutide 2.4 mg improved HF-related symptoms, physical limitations, and exercise function and reduced body weight in patients with obesity-related HFpEF. Whether the effects of semaglutide in this patient group differ in participants with and without AF (and across various AF types) has not been fully examined. The goals of this study were: 1) to evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF with and without a history of AF; and 2) to determine if the efficacy of semaglutide across all key trial outcomes are influenced by baseline history of AF (and AF types) in the STEP-HFpEF Program. This was a secondary analysis of pooled data from the STEP-HFpEF and STEP-HFpEF DM trials. Patients with heart failure, left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to receive once-weekly semaglutide 2.4 mg or matching placebo for 52 weeks. Dual primary endpoints (change in KCCQ-CSS and percent change in body weight), confirmatory secondary endpoints (change in 6-minute walk distance; hierarchical composite endpoint comprising all-cause death, HF events, thresholds of change in KCCQ-CSS, and 6-minute walk distance; and C-reactive protein [CRP]), and exploratory endpoint (change in N-terminal pro–B-type natriuretic peptide [NT-proBNP]) were examined according to investigator-reported history of AF (yes/no). Responder analyses examined the proportions of patients who experienced a ≥5-, ≥10, ≥15, and ≥20-point improvement in KCCQ-CSS per history of AF. Of the 1,145 participants, 518 (45%) had a history of AF (40% paroxysmal, 24% persistent AF, and 35% permanent AF) and 627 (55%) did not. Participants with (vs without) AF were older, more often male, had higher NT-proBNP levels, included a higher proportion of those with NYHA functional class III symptoms, and used more antithrombotic therapies, beta-blockers, and diuretics. Semaglutide led to larger improvements in KCCQ-CSS (11.5 points [95% CI: 8.3-14.8] vs 4.3 points [95% CI: 1.3-7.2]; P interaction = 0.001) and the hierarchal composite endpoint (win ratio of 2.25 [95% CI: 1.79-2.83] vs 1.30 [95% CI: 1.06-1.59]; P interaction < 0.001) in participants with AF vs without AF, respectively. The proportions of patients receiving semaglutide vs those receiving placebo experiencing ≥5-, ≥10-, ≥15-, and ≥20-point improvement in KCCQ-CSS were also higher in those with (vs without) AF (all P interaction values <0.05). Semaglutide consistently reduced CRP, NT-proBNP, and body weight regardless of AF status (all P interaction values not significant). There were fewer serious adverse events and serious cardiac disorders in participants treated with semaglutide vs placebo irrespective of AF history. In the STEP-HFpEF Program, AF was observed in nearly one-half of patients with obesity-related HFpEF and was associated with several features of more advanced HF. Treatment with semaglutide led to significant improvements in HF-related symptoms, physical limitations, and exercise function, as well as reductions in weight, CRP, and NT-proBNP in people with and without AF and across AF types. The magnitude of semaglutide-mediated improvements in HF-related symptoms and physical limitations was more pronounced in those with AF vs without AF at baseline. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511 ]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM; NCT04916470 ]) [ABSTRACT FROM AUTHOR]

Patients with overweight and obesity are at increased risk of death from multiple causes, including cardiovascular (CV) death, with few therapies proven to reduce the risk. This study sought to assess the effect of semaglutide 2.4 mg on all-cause death, CV death, and non-CV death, including subcategories of death and death from coronavirus disease-2019 (COVID-19). The SELECT (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity) trial randomized 17,604 participants ≥45 years of age with a body mass index ≥27 kg/m2 with established CV disease but without diabetes to once-weekly subcutaneous semaglutide 2.4 mg or placebo; the mean trial duration was 3.3 years. Adjudicated causes of all deaths, COVID-19 cases, and associated deaths were captured prospectively. Of 833 deaths, 485 (58%) were CV deaths, and 348 (42%) were non-CV deaths. Participants assigned to semaglutide vs placebo had lower rates of all-cause death (HR: 0.81; 95% CI: 0.71-0.93), CV death (HR: 0.85; 95% CI: 0.71-1.01), and non-CV death (HR: 0.77; 95% CI: 0.62-0.95). The most common causes of CV death with semaglutide vs placebo were sudden cardiac death (98 vs 109; HR: 0.89; 95% CI: 0.68-1.17) and undetermined death (77 vs 90; HR: 0.85; 95% CI: 0.63-1.15). Infection was the most common cause of non-CV death and occurred at a lower rate in the semaglutide vs the placebo group (62 vs 87; HR: 0.71; 95% CI: 0.51-0.98). Semaglutide did not reduce incident COVID-19; however, among participants who developed COVID-19, fewer participants treated with semaglutide had COVID-19–related serious adverse events (232 vs 277; P = 0.04) or died of COVID-19 (43 vs 65; HR: 0.66; 95% CI: 0.44-0.96). High rates of infectious deaths occurred during the COVID-19 pandemic, with less infectious death in the semaglutide arm, and resulted in fewer participants in the placebo group being at risk for CV death. Compared to placebo, patients treated with semaglutide 2.4 mg had lower rates of all-cause death, driven similarly by CV and non-CV death. The lower rate of non-CV death with semaglutide was predominantly because of fewer infectious deaths. These findings highlight the effect of semaglutide on mortality across a broad population of patients with CV disease and obesity. (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity [SELECT]; NCT03574597) [ABSTRACT FROM AUTHOR]

People with type 2 diabetes (T2D) and chronic kidney disease (CKD) are at high risk for heart failure (HF) and premature death from cardiovascular (CV) causes. The FLOW (Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease), which enrolled participants with T2D and CKD, demonstrated that semaglutide, a glucagon-like peptide-1 receptor agonist, reduced the incidence of the primary composite outcome (persistent ≥50% decline in estimated glomerular filtration rate, persistent estimated glomerular filtration rate <15 mL/min/1.73 m2, kidney replacement therapy, and kidney or CV death) by 24%. This prespecified analysis examined the effects of semaglutide on HF outcomes in this high-risk population. Participants were randomized (1:1) to once-weekly subcutaneous semaglutide 1 mg or placebo. The prespecified main outcome was a composite of HF events (new onset or worsening of HF leading to an unscheduled hospital admission or an urgent visit, with initiation of or intensified diuretic/vasoactive therapy) or CV death. HF data were collected by the investigator. CV death was adjudicated by an independent committee. A total of 3,533 randomized participants were followed for a median of 3.4 years. HF was present at baseline in 342 participants (19.4%) in the semaglutide group and 336 (19.0%) in the placebo group. In the overall trial population, semaglutide increased time to first HF events or CV death (HR: 0.73; 95% CI: 0.62-0.87; P = 0.0005), HF events alone (HR: 0.73; 95% CI: 0.58-0.92; P = 0.0068), and CV death alone (HR: 0.71; 95% CI: 0.56-0.89; P = 0.0036). The risk reduction for the composite HF outcome was similar in those with (HR: 0.73; 95% CI: 0.54-0.98; P = 0.0338) and without (HR: 0.72; 95% CI: 0.58-0.89; P = 0.0028) HF at baseline. The risk of HF outcomes (HF events or CV death) was generally higher in participants categorized as NYHA functional class III and those with the HF reduced ejection fraction subtype, regardless of treatment. Semaglutide substantially reduced the risk of time to first composite outcome of HF events or CV death, as well as HF events and CV death alone, in a high-risk population with T2D and CKD. These effects were consistent regardless of history of HF. (A Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease [FLOW]; NCT03819153) [ABSTRACT FROM AUTHOR]

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) represents a major clinical complication of obesity. Methods: In this study, we used magnetic resonance (MR) methods to determine the effect of obesity treatment with semaglutide, a GLP-1 receptor agonist, on the liver fat content and selected metabolic variables. We investigated whether treatment would affect the acute response of liver fat to glucose and fructose administration and whether it would affect the fatty acid profile of VLDL-triglycerides. Sixteen obese non-diabetic men underwent a 16-week dietary intervention and 16-week treatment with subcutaneous semaglutide in a crossover design without a washout period. The order of the interventions was randomized. Results: After treatment, body weight of the subjects decreased by 5% and liver fat by a third, whereas dietary intervention had no impact on these parameters. The decrease in liver fat with semaglutide did not correlate with changes in body weight and other measures of adiposity and was unrelated to improved insulin sensitivity. Conclusions: The proportion of palmitic and palmitoleic acids in VLDL-triglycerides decreased after treatment, suggesting that the beneficial effects of semaglutide on liver fat are mediated by the suppression of de novo lipogenesis. [ABSTRACT FROM AUTHOR]

Aims Design Setting Participants Measurements Findings Conclusions This study aimed to estimate the strength of association between prescriptions of glucose‐dependent insulinotropic polypeptide (GIP) and/or glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) and the incidence of opioid overdose and alcohol intoxication in patients with opioid use disorder (OUD) and alcohol use disorder (AUD), respectively. This study also aimed to compare the strength of the GIP/GLP‐1 RA and substance use‐outcome association among patients with comorbid type 2 diabetes and obesity.A retrospective cohort study analyzing de‐identified electronic health record data from the Oracle Cerner Real‐World Data.About 136 United States of America health systems, covering over 100 million patients, spanning January 2014 to September 2022.The study included 503 747 patients with a history of OUD and 817 309 patients with a history of AUD, aged 18 years or older.The exposure indicated the presence (one or more) or absence of GIP/GLP‐1 RA prescriptions. The outcomes were the incidence rates of opioid overdose in the OUD cohort and alcohol intoxication in the AUD cohort. Potential confounders included comorbidities and demographic factors.Patients with GIP/GLP‐1 RA prescriptions demonstrated statistically significantly lower rates of opioid overdose [adjusted incidence rate ratio (aIRR) in OUD patients: 0.60; 95% confidence interval (CI) = 0.43–0.83] and alcohol intoxication (aIRR in AUD patients: 0.50; 95% CI = 0.40–0.63) compared to those without such prescriptions. When stratified by comorbid conditions, the rate of incident opioid overdose and alcohol intoxication remained similarly protective for those prescribed GIP/GLP‐1 RA among patients with OUD and AUD.Prescriptions of glucose‐dependent insulinotropic polypeptide and/or glucagon‐like peptide‐1 receptor agonists appear to be associated with lower rates of opioid overdose and alcohol intoxication in patients with opioid use disorder and alcohol use disorder. The protective effects are consistent across various subgroups, including patients with comorbid type 2 diabetes and obesity. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aims Methods Results Conclusion Trial Registration Semaglutide, a glucagon‐like peptide‐1 receptor agonist, has demonstrated potential beneficial effects in metabolic dysfunction‐associated steatohepatitis (MASH).To describe the trial design and baseline characteristics of the ‘Effect of Semaglutide in Subjects with Non‐cirrhotic Non‐alcoholic Steatohepatitis’ (ESSENCE) trial (NCT04822181).ESSENCE is a two‐part, phase 3, randomised, multicentre trial evaluating the effect of subcutaneous semaglutide 2.4 mg in participants with biopsy‐proven MASH and fibrosis stage 2 or 3. The primary objective of Part 1 is to demonstrate that semaglutide improves liver histology compared with placebo. The two primary endpoints are: resolution of steatohepatitis and no worsening of liver fibrosis, and improvement in liver fibrosis and no worsening of steatohepatitis. The Part 2 objective is based on clinical outcomes. The current work reports baseline characteristics of the first 800 randomised participants which includes demographics, laboratory parameters, liver histology, non‐invasive tests and presence of metabolic dysfunction‐associated steatotic liver disease (MASLD) cardiometabolic criteria.Of 800 participants, 250 (31.3%) had fibrosis stage 2 and 550 (68.8%) had fibrosis stage 3. In the overall population, mean (standard deviation [SD]) age was 56 (11.6) years, 57.1% were female, mean (SD) body mass index was 34.6 (7.2) kg/m2, 55.5% had type 2 diabetes and > 99% had at least one MASLD cardiometabolic criterion according to the published definition.The ESSENCE baseline population includes participants with clinically significant fibrosis stages 2 and 3. Although MASLD cardiometabolic criteria were not a requirement for study enrolment, almost all participants (> 99%) had at least one MASLD cardiometabolic criterion.NCT04822181 [ABSTRACT FROM AUTHOR]

Background Results Conclusion Semaglutide, a glucagon‐like peptide‐1 (GLP‐1) receptor agonist, is a widely used drug for the treatment of type 2 diabetes that offers significant cardiovascular benefits.This review systematically examines the proteomic and metabolomic indicators associated with the cardiovascular effects of semaglutide. A comprehensive literature search was conducted to identify relevant studies. The review utilizes advanced analytical technologies such as mass spectrometry and nuclear magnetic resonance (NMR) to investigate the molecular mechanisms underlying the effects of semaglutide on insulin secretion, weight control, anti‐inflammatory activities and lipid metabolism. These “omics” approaches offer critical insights into metabolic changes associated with cardiovascular health. However, challenges remain such as individual variability in expression, the need for comprehensive validation and the integration of these data with clinical parameters. These issues need to be addressed through further research to refine these indicators and increase their clinical utility.Future integration of proteomic and metabolomic data with artificial intelligence (AI) promises to improve prediction and monitoring of cardiovascular outcomes and may enable more accurate and effective management of cardiovascular health in patients with type 2 diabetes. This review highlights the transformative potential of integrating proteomics, metabolomics and AI to advance cardiovascular medicine and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Developing anti-obesity interventions targeting appetite or food intake, the primary driver of obesity, remains challenging. Here, we demonstrated that dietary γ-aminobutyric acid (GABA) with GABA-degradation inhibitory drugs could be an anti-obesity intervention possessing strong food intake-suppressive and weight-loss effects. Methods: High-fat (HF)-diet-induced obese mice were divided into six groups receiving either the HF diet or the 2% GABA-HF diet with daily administration of PBS or the GABA-degradation inhibitory drugs, vigabatrin and ethanolamine-Osulfate (EOS). In 24-h fast-induced refeeding, lean mice with a basal diet were used, and food intake was measured from 0.5 to 24 h after refeeding. Results: Coadministration of the 2% GABA-HF diet with vigabatrin or EOS significantly decreased food intake (-53%, -35%) and body weight (-22%, -16%) within 11 days in obese mice, along with a marked increase in plasma GABA levels. Mice receiving dietary GABA alone or the drugs alone exhibited no such effects. Hypothalamic GABA levels increased in drugtreated mice, regardless of diet. At 0.5 h after refeeding, food intake was similar in all groups. However, at 0.5 h, plasma GABA levels were markedly increased only in mice receiving coadministration of dietary GABA and the drugs, and their food intake was completely inhibited for over 6 h, while mice in other groups gradually increased their food intake. Conclusion: Combining dietary GABA with GABA-degradation inhibitory drugs effectively suppresses food intake and promotes weight loss in obese mice, primarily through increased plasma GABA availability. These findings may advance the development of food intake-controlling strategies for obesity management. [ABSTRACT FROM AUTHOR]

Background and Aims Randomized clinical trials (RCTs) assessing semaglutide reported reductions of systolic blood pressure (SBP) in trial populations with baseline blood pressure in the normotensive range. This study aimed to determine whether this SBP reduction is greater in hypertensive groups. Methods Individual patient data (IPD) from three RCTs examining the effect of semaglutide 2.4 mg on body weight over 68 weeks were included. Trial participants were categorized according to a hypertension diagnosis, treatment or baseline measurement (HTN), baseline SBP > 130 mmHg (HTN130) or >140 mmHg (HTN140), and those with apparent resistant hypertension (RH). The primary analysis compared the in-trial change in SBP in the semaglutide and placebo arms. Alterations of anti-hypertensive medications were quantified by treatment intensity score and compared between arms. These analyses were performed using analysis of covariance. Results Overall, 3136 participants were included. The difference in SBP change between the treatment (n = 2109) and placebo (n = 1027) groups was −4.95 mmHg [95% confidence interval (CI) −5.86 to −4.05] overall. This difference was −4.78 mmHg (95% CI −5.97 to −3.59) for HTN, −4.93 mmHg (95% CI −6.75 to −3.11) for HTN130, −4.09 mmHg (95% CI −7.12 to −1.06) for HTN140, and −3.16 mmHg (95% CI −8.69–2.37) for RH. Reduction in SBP was mediated substantially by weight loss. The anti-hypertensive treatment intensity score decreased for those on semaglutide compared to placebo (−0.51; 95% CI −0.71 to −0.32). Conclusions This IPD analysis of three large RCTs found blood pressure reductions with semaglutide in participants with hypertension that were similar to those seen in all trial participants. This finding may in part be due to concurrent reductions to anti-hypertensive medications. These results suggest that semaglutide is a useful adjunctive treatment for patients with hypertension and obesity. [ABSTRACT FROM AUTHOR]

Introduction: Food addiction (FA) is highly prevalent among people with obesity (PwO) and may constitute a key factor in weight loss failure or weight regain. GLP-1 analogues have been shown to act on the mesolimbic system, which is related to hedonic overeating and substance abuse. We aimed to study the effects of low doses of semaglutide on FA symptomatology and to evaluate whether the presence of FA have a negative impact on weight loss despite treatment with semaglutide. Methods: One hundred and thirteen PwO (45.5 ± 10.2 years) were evaluated anthropometrically baseline and after four months of treatment with semaglutide. PwO were evaluated for the presence of FA by completing The Spanish version of the Yale Food Addiction Scale 2.0 questionnaire (YFAS 2.0). Results: Baseline BMI and fat mass (%) were greater among PwO with FA (35.8 ± 4.5 vs 33 ± 3.9 kg/m2and 44.2 ± 6.5 vs 40.1 ± 7.9%; p =.01). After four months of treatment with semaglutide, the prevalence of FA diminished from 57.5% to 4.2% (p <.001). The percentage of weight loss (6.9 ± 12.7 vs 5.3 ± 4.6%; p =.4) and the proportion of fat mass loss (2 ± 9 vs 1.6 ± 3.1%; p =.7) were comparable between PwO with and without FA. No differences regarding side effects and treatment discontinuations were seen between the two groups Conclusion: Semaglutide is an effective tool for the amelioration of FA symptomatology among PwO. Despite PwO with FA had greater basal BMI and fat mass, semaglutide showed similar results compared to PwO without FA in terms of weight and fat mass loss at short term. [ABSTRACT FROM AUTHOR]

Background: Premature cardiovascular disease is the leading cause of death in people living with type 1 diabetes. Therapies are urgently needed to address cardiovascular risk in this group. Semaglutide, a long‐acting glucagon‐like peptide‐1 receptor agonist, has been shown to reduce cardiovascular events and improve weight and glycaemia in type 2 diabetes. Semaglutide may offer cardioprotective and metabolic benefits in type 1 diabetes. Methods: We will study 60 adults aged 25–70 years with type 1 diabetes of duration at least 2 years, body mass index ≥25 kg/m2, HbA1c ≥7% and at least one cardiovascular risk factor (microalbuminuria, hypertension or anti‐hypertensive treatment, hyperlipidemia or lipid lowering therapy, current smoking). Participants will receive semaglutide up to 1.0 mg weekly or matched placebo for 26 weeks. The primary outcome is carotid femoral pulse wave velocity, a measure of arterial stiffness, as a surrogate marker of cardiovascular risk. Potential mechanisms for metabolic changes will be explored including change in insulin sensitivity determined by hyperinsulinaemic‐euglycaemic clamp; and incretin and pancreatic hormone action measured during mixed meal tolerance test. Conclusion: The REducing cardiometabolic risk with SEmaglutide in Type 1 diabetes study will investigate whether semaglutide, a long acting glucagon‐like peptide receptor agonist, can improve markers of cardiometabolic health in T1D. Underlying mechanisms predicting response, including insulin resistance and incretin hormone status, will also be explored. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim/Introduction: The recent adverse reactions associated with semaglutide have led the Food and Drug Administration (FDA) to issue a "black box warning", and it is necessary to analyze all reports of adverse reactions to improve the safety of its clinical use. Materials and Methods: Statistical analyses and signal mining were performed by obtaining the adverse event reports related to semaglutide in the FAERS database from the first quarter of 2018 to the fourth quarter of 2023. We used disproportionality and Bayesian analysis to examine clinical and demographic attributes, trends reported quarterly, and contrasts between two distinct indications (obesity and type 2 diabetes). Results: We found 10 unexpected adverse signals related to "pancreatic cancer", "intestinal obstruction", "cholecystitis", and "polycystic ovary" and both the two different indications had the same serious adverse reaction events occurring. Conclusions: This study identified many unexpected signals of serious adverse reactions, suggesting the importance of continuous post‐marketing surveillance of semaglutide to understand its potential risks. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine patient characteristics and dose titration patterns of real-world semaglutide (Wegovy) users. RESEARCH DESIGN AND METHODS: We used a population-based cohort study including Danish adults who filled semaglutide prescriptions from 12 December 2022 to 31 December 2023. Outcomes were patient characteristics, prescriber type, and dose titration patterns. RESULTS: We identified 110,748 individuals (median age 49 years; 70% female) filling 773,708 prescriptions for semaglutide. General practitioners initiated treatment in 86%. Common comorbidities included hypertension (30%), dyslipidemia (17%), and arthrosis (17%). Only 13% reached the maximum dose of 2.4 mg by their fifth prescription, while 5.7% stopped after the first prescription. Few users (10%) followed recommended dose increases every 4 weeks. Overall, 25% filled at least one prescription of 2.4 mg, while 33–48% continued with the 1.0-mg dosage from the fourth prescription onward. CONCLUSIONS: Real-world semaglutide users generally resembled trial participants, but few follow the dose titration schemes tested in premarket clinical trials. [ABSTRACT FROM AUTHOR]

A study published in the journal Diabetes, Obesity & Metabolism examined the effects of semaglutide injections on treatment satisfaction and eating behavior in Japanese patients with type 2 diabetes mellitus (T2DM). The study found that semaglutide injections increased treatment satisfaction and improved eating behavior in patients with T2DM, particularly those with obesity. The injections also resulted in decreased body weight and HbA1c levels in both groups. However, adverse events were reported, with loss of appetite being the most frequent. The study suggests that semaglutide injections may be a beneficial treatment option for Japanese patients with T2DM and obesity, but further research is needed to confirm these findings. [Extracted from the article]

Aim: To perform a meta‐analysis comparing real‐world medication adherence to sodium–glucose cotransporter‐2 inhibitors (SGLT2is) versus glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs). Materials and Methods: A systematic search of Medline and Embase was conducted through October 2023. To meet inclusion criteria, articles had to be published in full text form and directly compare medication adherence to SGLT2is versus GLP‐1RAs in adults. Only studies evaluating real‐world data and utilizing the proportion of days covered (PDC) to measure adherence were included. Non‐adherence, defined as the proportion of patients with a PDC <80%, was the primary outcome. A subgroup analysis evaluating results among studies conducted in the United States was performed. Results: We identified eight studies evaluating 205 103 patients for inclusion. The most common country from which the data was derived was the United States (n = 5 studies). Upon meta‐analysis, we observed no difference in non‐adherence (i.e. PDC <80%) to SGLT2is versus GLP‐1RAs (relative risk = 0.86; 95% confidence interval = 0.72–1.02). In the analysis, including only US studies, SGLT2i use was associated with a 23% lower risk of non‐adherence compared with GLP‐1RA use (relative risk = 0.77; 95% confidence interval = 0.72–0.82). Conclusions: In this meta‐analysis of eight studies that included approximately 200 000 patients, there was no difference in adherence to SGLT2is versus GLP‐1RAs. However, SGLT2i use was associated with higher adherence when the analysis was limited to US studies. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effects of once‐daily oral semaglutide 50 mg on energy intake, appetite, control of eating and gastric emptying. Methods: A clinical pharmacology, double‐blind study was conducted in 61 adults with obesity randomized to once‐daily oral semaglutide (dose‐escalated to 50 mg) or placebo for 20 weeks. Energy intake was measured during an ad libitum lunch, and participant‐reported appetite ratings and Control of Eating Questionnaire responses were assessed. Gastric emptying was measured using paracetamol absorption following a standardized breakfast. Results: The relative change from baseline in ad libitum energy intake at week 20 (primary endpoint) was −39.2% points (95% confidence interval −59.0%, −19.4%) with semaglutide compared with placebo. Body weight was reduced by 9.8% with semaglutide and by 1.5% with placebo. Semaglutide reduced hunger, increased fullness and satiety, and was associated with fewer food cravings and better control of eating versus placebo. No statistically significant difference in gastric emptying was observed at week 20. Conclusions: In participants with obesity, once‐daily oral semaglutide 50 mg reduced energy intake, body weight and appetite, and improved control of eating. There was no evidence of delayed gastric emptying at week 20, as measured through paracetamol absorption. [ABSTRACT FROM AUTHOR]

Introdroduction: Obesity and its associated metabolic conditions have become a significant global health problem in recent years, with many people living with obesity fulfilling criteria for pharmacological treatment. The development of the glucagon‐like peptide‐1 receptor agonists for chronic weight management has triggered new interest in the incretins and other hormones as targets for obesity, and investigations into dual and triple co‐agonists. Methods: The objective of this narrative review was to summarize the available data on approved and emerging incretin‐based agents for the treatment of obesity. Results: In clinical trials of currently available agents in people with overweight or obesity, weight loss of between 6% and 21% of baseline body weight has been observed, with between 23% and 94% of participants achieving 10% or higher weight loss, depending on the study and the agent used. Favourable outcomes have also been seen with regard to cardiovascular risk and outcomes, diabetes prevention, metabolic dysfunction‐associated steatotic liver disease/steatohepatitis and prevention of weight regain after metabolic surgery. Limitations associated with these agents include high costs, the potential for weight regain once treatment is stopped, the potential loss of lean body mass and gastrointestinal adverse events; potential issues with respect to gallbladder and biliary diseases require further investigation. Conclusions: Many dual and triple co‐agonists are still in development, and more data are needed to assess the efficacy, safety and tolerability of these emerging therapies versus the established incretin‐based therapies; however, data are promising, and further results are eagerly awaited. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Forty percent of Americans are obese and 20% are overweight. Until recently, notwithstanding great efforts to combat this chronic, worsening epidemic, the only therapy that "worked" was surgery. However, recently, a new class of safe drugs (incretins) have been developed that cause obese patients to lose ∼20 to 25% of their body weight. Herein we recount this revolution and its implications. [ABSTRACT FROM AUTHOR]

Purpose: Patients with hypothalamic pathology often develop hypothalamic obesity, causing severe metabolic alterations resulting in increased morbidity and mortality. Treatments for hypothalamic obesity have not proven very effective, although the glucagon-like peptide-1 receptor agonist semaglutide has been shown to have positive effects. We examined semaglutide's effect on weight loss in a sample of patients with hypothalamic obesity. Methods: Four female patients with hypothalamic obesity resulting from treatment of craniopharyngiomas were treated with semaglutide for six months. Whole Body Dual-energy x-ray absorptiometry scans were performed, and blood samples drawn at baseline and after six months. Semaglutide dosages were increased monthly along with tracking of body weight and eating behavior (Three Factor Eating Questionnaire, TFEQ-R18). Results: BMI was reduced in all cases, with an average of 7.9 BMI (range: 6.7 to 10.1) corresponding to a weight loss of 17.0% (range: 11.3–22.4%) or 20.2 kg (range 16.2 kg to 23.4 kg). We found a comparable reduction in total fat mass (17.2%, p = 0.006) and lean mass (16.0%, p = 0.05), whereas bone mass was unchanged (2.6%, p = 0.12). All cases reported an increase in energy levels, improved mobility and physical activity. Unfavorable eating behaviors were reduced after 1 month of treatment (emotional eating − 41 points, p = 0.02, uncontrolled eating − 23 points, p = 0.11). HbA1c and total cholesterol were significantly reduced (p = 0.014 for both). Conclusion: Semaglutide is a promising and safe treatment option for HO, that improves eating behavior, reduces weight, and improves metabolic markers. [ABSTRACT FROM AUTHOR]

Background/Objectives: Food cravings involve a strong drive to consume palatable foods irrespective of nutritional status. Importantly, cravings contribute substantially to the obesity epidemic. Managing hunger alone is insufficient for weight management as this relates only to homeostatic eating and does not address the complex aetiology of hedonic eating and its crucial role in food cravings. Medical weight management clinics and anti-obesity medication trials do not routinely identify and address food cravings. Methods: We conducted a narrative review of the literature consisting of 115 peer-reviewed articles (original articles and reviews). We included articles focused on food craving pathophysiology, assessment, and management strategies providing contrasts against the current medical model of weight management seen in obesity pharmacotherapy trials as well as the current standard of practise. Results: We outline the neurohormonal and psychological drivers of cravings, which lead to a spectrum of eating behaviours, from comfort food eating to binge eating disorders. We provide an overview of ways of identification and measurement options, including their strengths and weaknesses, and an overview of management strategies and their cravings control efficacy, spanning lifestyle modifications like nutrition and sleep, psychological therapies (i.e., cognitive behavioural therapy [CBT], acceptance-based therapies such as mindfulness) and, last but not least, medications that not only are approved for weight reduction but reduce cravings. Finally, based on these findings, we provide a proposed integrated and iterative model that is able to evolve and adapt to the individual over time in tackling cravings for long-term weight loss maintenance. Conclusions: The findings emphasise the importance of cravings management and provide a synthesis on how cravings can be identified in a medical weight management setting, which can be practically implemented in an integrated iterative model spanning anti-obesity medications that have craving control data to evidence-based lifestyle and psychological interventions. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease that can progress to end-stage conditions with life-threatening complications, but no pharmacologic therapy has been approved. Drug delivery systems such as lipid nanocapsules (LNC) are very versatile platforms that are easy to produce and can induce the secretion of the native glucagon-like peptide 1 (GLP-1) when orally administered. GLP-1 analogs are currently being studied in clinical trials in the context of MASLD. Our nanosystem provides with increased levels of the native GLP-1 and increased plasmatic absorption of the encapsulated GLP-1 analog (semaglutide). Our goal was to use our strategy to demonstrate a better outcome and a greater impact on the metabolic syndrome associated with MASLD and on liver disease progression with our strategy compared with the oral marketed version of semaglutide, Rybelsus®. Therefore, we studied the effect of our nanocarriers on a dietary mouse model of MASLD, the Western diet model, during a daily chronic treatment of 4 weeks. Overall, the results showed a positive impact of semaglutide-loaded lipid nanocapsules towards the normalization of glucose homeostasis and insulin resistance. In the liver, there were no significant changes in lipid accumulation, but an improvement in markers related to inflammation was observed. Overall, our strategy had a positive trend on the metabolic syndrome and at reducing inflammation, mitigating the progression of the disease. Oral administration of the nanosystem was more efficient at preventing the progression of the disease to more severe states when compared to the administration of Rybelsus®, as a suspension. [ABSTRACT FROM AUTHOR]

We herein report a case of food-induced small bowel obstruction (FIBO) while using a glucagon-like peptide 1 receptor agonist (GLP1-RA), trying to lose weight due to distorted body image. The patient was a 30-year-old woman who was not obese (height 158 cm, weight 50 kg). She started taking an oral semaglutide, a GLP1-RA, and it was soon switched to weekly subcutaneous semaglutide because of ineffectiveness. More than 6 months after titrating up to 1.0 mg, she got drunk and chomped on a lot of scallops sandwiched between sheets of kelp, so-called "kobujime" in Japan, and half a day later complained of abdominal pain. Based on a finding of computed tomography at our emergency department, she was suspected of having a bowel obstruction and underwent laparoscopic surgery, which resulted in a diagnosis of small bowel obstruction by kelp. FIBO is rare, but it can become very severe once it happens. Although we cannot prove the direct pathophysiological effects of GLP1-RAs on FIBO in this particular case, GLP1-RAs have been reported to be one of the underlying risks of bowel obstruction based on epidemiological and basic research evidence; still, it is under-recognized. For example, the package inserts in Japan do not mention intestinal obstruction. We hope that the present report will prove helpful in paying attention to GLP1-RAs as a factor in bowel obstruction, including FIBO. [ABSTRACT FROM AUTHOR]

Background The introduction of injectable glucagon-like peptide-1 (GLP-1) receptor agonists such as Ozempic (Novo Nordisk, Plainsboro, NJ) and Wegovy (Novo Nordisk Inc.) has transformed weight loss in plastic surgery patients, often leading to excess skin and soft tissue amenable to body contouring procedures. Objectives The aim of this study was to examine the relationship between injectable GLP-1 receptor agonist use and the growing need for body contouring surgeries, focusing on trunk and extremity procedures. Methods A retrospective analysis of the PearlDiver database (PearlDiver, Inc. Colorado Springs, CO) was conducted, examining prescription data for Ozempic, Wegovy, and liraglutide, and correlating these with body contouring procedures across 30 US states from 2011 to 2022. Multimodal statistics were used to compare surgery rates and assess dosage and time interval patterns among GLP-1 receptor agonist users and nonusers. Results Significant correlations between GLP-1 receptor agonist use (881 Ozempic, 59 Wegovy, and 4655 liraglutide users) and increased body contouring surgeries were found. Ozempic showed weak correlations with brachioplasty (r = 0.23) and panniculectomy (r = 0.21), and Wegovy with breast procedures (r = 0.28), while liraglutide showed consistent correlations across surgeries. Time to surgery varied from 87 days (Wegovy) to 1018 days (liraglutide), with higher surgery rates among users (P <.01) and dose-related differences, especially in Ozempic and Wegovy users. Conclusions This study demonstrates a dose-dependent link between the use of GLP-1 receptor agonists and an increase in subsequent aesthetic body contouring surgeries, highlighting the need for surgeons to adapt to the merging of medicinal body transformation and aesthetic plastic surgery. Level of Evidence: 4 [ABSTRACT FROM AUTHOR]

Background: The pericoronary fat attenuation index (FAI) has emerged as a novel and sensitive biomarker reflecting the degree of coronary artery inflammation. Semaglutide has been demonstrated to exert a cardiovascular protective effect independent of hypoglycemia; however, its impact on coronary artery inflammation remains elusive. This study aimed to investigate the association between semaglutide treatment and coronary artery inflammation based on FAI in patients with type 2 diabetes mellitus (T2DM). Methods: This study enrolled 497 T2DM patients who underwent coronary computed tomography angiography (CCTA) at Hebei General Hospital, of whom 93 treated with semaglutide (Sema+) and 404 did not (Sema-). Clinical data, laboratory indicators, and CCTA parameters were collected and compared between the two groups at baseline. Propensity score matching (PSM) was used to adjust for confounders, and pericoronary FAI was compared. Multivariate linear regression models were used to analyze the association between semaglutide treatment and pericoronary FAI. Results: Before PSM, pericoronary FAI of the LAD and LCX was lower in patients treated with semaglutide than those without semaglutide treatment. The results of the PSM analysis revealed a lower FAI in all three major coronary arteries in the Sema + group compared to the Sema- group. Multivariate linear regression analyses revealed an independent association between semaglutide treatment and reduced FAI in all three major coronary arteries. This association varied across T2DM patients of differing profiles. Conclusion: Semaglutide treatment may be associated with lower coronary artery inflammation in patients with T2DM, which might partially explain its cardiovascular protective mechanism. [ABSTRACT FROM AUTHOR]

Purpose: Patients undergoing axillary lymph node dissection (ALND) for breast cancer face a high risk of lymphedema, further increased by high body mass index (BMI) and insulin resistance. GLP-1 receptor agonists (GLP-1RAs) have the potential to reduce these risk factors, but their role in lymphedema has never been investigated. The purpose of this study was to determine if GLP-RAs can reduce the risk of lymphedema in patients undergoing ALND. Methods: All patients who underwent ALND at a tertiary cancer center between 2010 and 2023 were reviewed. Patients with less than 2 years of follow-up from the time of ALND were excluded. Race, BMI, radiation, chemotherapy history, pre-existing diagnosis of diabetes, lymphedema development after ALND, and the use of GLP-1RAs were analyzed. Multivariate logistic regression analysis was performed to assess if there was a significant reduction in the risk of developing lymphedema after ALND. A sub-group analysis of non-diabetic patients was also performed. Results: 3,830 patients who underwent ALND were included, 76 of which were treated with. GLP-1 RAs. The incidence of lymphedema in the GLP-1 RA cohort was 6.6% (5 patients). Compared to 28.5% (1,071 patients) in the non-GLP-1 RA cohort. On multivariate regression analysis, patients who were treated with GLP-1 RA were 86% less likely to develop lymphedema compared to the non-GLP-1 RA cohort (OR 0.14, 95% CI 0.04-0.32, p < 0.0001). A BMI of 25 kg/m 2 or greater was a statistically significant risk factor for developing lymphedema with an odds ratio of 1.34 (95% CI 1.16-1.56, p < 0.0001). Diabetes was associated with lymphedema development that closely approached statistical significance (OR 1.32, 95% CI 0.97-1.78, p = 0.06). A subgroup analysis solely on non-diabetic patients showed similar results. The odds of developing lymphedema were 84% lower for patients without diabetes treated with GLP1-RAs compared to those who did not receive GLP-1 RAs (OR 0.16, 95% CI 0.05-0.40, p < 0.0001). Conclusion: GLP1-RAs appear to significantly reduce the risk of lymphedema in patientsundergoing ALND. The mechanism of action may be multifactorial and not limited to weight reduction and insulin resistance. Future prospective analysis is warranted to clarify the role of GLP-1RAs in reducing lymphedema risk. [ABSTRACT FROM AUTHOR]

Introduction: Alpha-cell hyperplasia (ACH) is a rare pancreatic endocrine condition. Three types of ACH have been described: functional or nonglucagonoma hyperglucagonemic glucagonoma syndrome, reactive or secondary to defective glucagon signaling, and non-functional. Few cases of ACH with concomitant pancreatic neuroendocrine tumors (pNETs) have been reported and its etiology remains poorly understood. A case report of nonfunctional ACH with glucagon-producing NET is herein presented. Case report: A 72-year-old male was referred to our institution for a 2 cm single pNET incidentally found during imaging for acute cholecystitis. The patient's past medical history included type 2 diabetes (T2D) diagnosed 12 years earlier, for which he was prescribed metformin, dapagliflozin, and semaglutide. The pNET was clinically and biochemically non-functioning, apart from mildly elevated glucagon 217 pg/ml (<209), and 68Ga-SSTR PET/CT positive uptake was only found at the pancreatic tail (SUVmax 11.45). The patient underwent a caudal pancreatectomy and the post-operative 68Ga-SSTR PET/CT was negative. A multifocal well-differentiated NET G1, pT1N0M0R0 (mf) strongly staining for glucagon on a background neuroendocrine alpha-cell hyperplasia with some degree of acinar fibrosis was identified on pathology analysis. Discussion and conclusion: This case reports the incidental finding of a clinically non-functioning pNET in a patient with T2D and elevated glucagon levels, unexpectedly diagnosed as glucagon-producing NET and ACH. A high level of suspicion was required to conduct the glucagon immunostaining, which is not part of the pathology routine for a clinically non-functioning pNET, and was key for the diagnosis that otherwise would have been missed. This case highlights the need to consider the diagnosis of glucagon-producing pNET on an ACH background even in the absence of glucagonoma syndrome. [ABSTRACT FROM AUTHOR]