Semaglutide

Safety of Semaglutide.

The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (PIONEER: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.

Wegovy (semaglutide): a new weight loss drug for chronic weight management.

Obesity is a growing epidemic within the USA. Because weight gain is associated with an increased risk of developing life-threatening comorbidities, such as hypertension or type 2 diabetes, there is great interest in developing non-invasive pharmacotherapeutics to help combat obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of antidiabetic medications that have shown promise in encouraging glycemic control and promoting weight loss in patients with or without type 2 diabetes. This literature review summarizes and discusses the weight loss results from the SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes), PIONEER (Peptide Innovation for Early Diabetes Treatment), and STEP (Semaglutide Treatment Effect in People with Obesity) clinical trial programs. The SUSTAIN and PIONEER clinical trials studied the use of 1.0 mg, once-weekly, subcutaneous and oral semaglutide (a new GLP-1 homolog), respectively, on participants with type 2 diabetes. The STEP trial examined the effects of 2.4 mg, once-weekly, subcutaneous semaglutide on patients with obesity. Trial data and other pertinent articles were obtained via database search through the US National Library of Medicine Clinical Trials and the National Center for Biotechnology Information. All three clinical trials demonstrated that semaglutide (injected or oral) has superior efficacy compared with placebo and other antidiabetic medications in weight reduction, which led to Food and Drug Administration approval of Wegovy (semaglutide) for weight loss.

Semaglutide lowers body weight in rodents via distributed neural pathways.

Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here show that semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus but did not cross the blood-brain barrier; it interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles. Semaglutide induced central c-Fos activation in 10 brain areas, including hindbrain areas directly targeted by semaglutide, and secondary areas without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automated analysis of semaglutide access, c-Fos activity, GLP-1R distribution, and brain connectivity revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. Transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. We suggest semaglutide lowers body weight by direct interaction with diverse GLP-1R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure.

As Ozempic's Popularity Soars, Here's What to Know About Semaglutide and Weight Loss.

Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial.

Semaglutide 2&#xb7;4 mg once weekly has been investigated for weight management in global populations. Differences exist between Asian and non-Asian populations in terms of body composition and definitions of obesity. In the Semaglutide Treatment Effect in People with obesity (STEP) 6 trial, we assessed the effect of semaglutide versus placebo for weight management in adults from east Asia with obesity, with or without type 2 diabetes. This randomised, double-blind, double-dummy, placebo-controlled, phase 3a superiority trial was done at 28 outpatient clinics in Japan and South Korea. Eligible participants were adults (aged &#x2265;18 years in South Korea; &#x2265;20 years in Japan) with a BMI of at least 27&#xb7;0 kg/m2 with two or more weight-related comorbidities or a BMI of 35&#xb7;0 kg/m2 or more with one or more weight-related comorbidity (one comorbidity had to be either hypertension, dyslipidaemia, or, in Japan only, type 2 diabetes) who had at least one self-reported unsuccessful dietary attempt to lose bodyweight. Participants were randomly assigned (4:1:2:1) to once-weekly subcutaneous semaglutide 2&#xb7;4 mg or matching placebo, or semaglutide 1&#xb7;7 mg or matching placebo, plus lifestyle recommendations for 68 weeks. Data for the placebo groups were pooled in statistical analyses. The primary endpoints were percentage change in bodyweight from baseline at week 68 and the proportion of participants who had achieved a reduction of at least 5% of baseline bodyweight at week 68. Change in abdominal visceral fat area was assessed as a supportive secondary endpoint using computed tomography scanning in a subset of participants. Efficacy outcomes were assessed in the full analysis set, which included all randomly assigned participants according to the intention-to-treat principle. Safety was assessed in all participants who received at least one dose of the study drug. This trial was registered with ClinicalTrials.gov, NCT03811574. Between Jan 21, 2019 and June 4, 2019, 437 participants were screened, of whom 401 were randomly assigned to semaglutide 2&#xb7;4 mg (n=199), semaglutide 1&#xb7;7 mg (n=101), or placebo (n=101) and included in the intention-to-treat analysis. Estimated mean change in bodyweight from baseline to week 68 was -13&#xb7;2% (SEM 0&#xb7;5) in the semaglutide 2&#xb7;4 mg group and -9&#xb7;6% (0&#xb7;8) in the semaglutide 1&#xb7;7 mg group versus -2&#xb7;1% (0&#xb7;8) in the placebo group (estimated treatment difference [ETD] -11&#xb7;1 percentage points [95% CI -12&#xb7;9 to -9&#xb7;2] for semaglutide 2&#xb7;4 mg vs placebo; -7&#xb7;5 percentage points [95% CI -9&#xb7;6 to -5&#xb7;4] for semaglutide 1&#xb7;7 mg vs placebo; both p<0&#xb7;0001). At week 68, a larger proportion of participants had achieved a 5% or higher reduction in baseline bodyweight in the semaglutide 2&#xb7;4 mg group (160 [83%] of 193 participants) and semaglutide 1&#xb7;7 mg group (71 [72%] of 98 participants) than in the placebo group (21 [21%] of 100 participants); odds ratio [OR] 21&#xb7;7 [95% CI 11&#xb7;3 to 41&#xb7;9] for semaglutide 2&#xb7;4 mg vs placebo; OR 11&#xb7;1 [95% CI 5&#xb7;5 to 22&#xb7;2] for semaglutide 1&#xb7;7 mg vs placebo; both p<0&#xb7;0001). Abdominal visceral fat area was reduced by 40&#xb7;0% (SEM 2&#xb7;6) among participants in the semaglutide 2&#xb7;4 mg group and 22&#xb7;2% (3&#xb7;7) among participants in the semaglutide 1&#xb7;7 mg group versus 6&#xb7;9% (3&#xb7;8) in the placebo group (ETD -33&#xb7;2% [95% CI -42&#xb7;1 to -24&#xb7;2] for semaglutide 2&#xb7;4 mg vs placebo; -15&#xb7;3% [95% CI -25&#xb7;6 to -4&#xb7;9] for semaglutide 1&#xb7;7 mg vs placebo). 171 (86%) of 199 participants in the semaglutide 2&#xb7;4 mg group, 82 (82%) of 100 participants in the semaglutide 1&#xb7;7 mg group, and 80 (79%) of 101 participants in the placebo group reported adverse events. Gastrointestinal disorders, which were mostly mild to moderate, were reported in 118 (59%) of 199 participants in the semaglutide 2&#xb7;4 mg group, 64 (64%) of 100 participants in the semaglutide 1&#xb7;7 mg group, and 30 (30%) of 101 participants in the placebo group. Adverse events leading to trial product discontinuation occurred in five (3%) of 199 participants in the semaglutide 2&#xb7;4 mg group, three (3%) of 100 participants in the semaglutide 1&#xb7;7 mg group, and one (1%) of 101 participants in the placebo group. Adults from east Asia with obesity, with or without type 2 diabetes, given semaglutide 2&#xb7;4 mg once a week had superior and clinically meaningful reductions in bodyweight, and greater reductions in abdominal visceral fat area compared with placebo, representing a promising treatment option for weight management in this population. Novo Nordisk. For the Korean and Japanese translations of the abstract see Supplementary Materials section.

Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial.

In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). In patients treated with semaglutide, weight loss continued over 65&#x2009;weeks and was sustained for up to 4&#x2009;years. At 208&#x2009;weeks, semaglutide was associated with mean reduction in weight (-10.2%), waist circumference (-7.7&#x2009;cm) and waist-to-height ratio (-6.9%) versus placebo (-1.5%, -1.3&#x2009;cm and -1.0%, respectively; P&#x2009;<&#x2009;0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40 and &#x2265;40&#x2009;kg&#x2009;m-2) there were lower rates (events per 100&#x2009;years of observation) of serious adverse events with semaglutide (43.23, 43.54, 51.07 and 47.06 for semaglutide and 50.48, 49.66, 52.73 and 60.85 for placebo). Semaglutide was associated with increased rates of trial product discontinuation. Discontinuations increased as BMI class decreased. In SELECT, at 208&#x2009;weeks, semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. Weight loss was sustained over 4&#x2009;years. ClinicalTrials.gov identifier: NCT03574597 .

Semaglutide (Ozempic) for weight loss.

Semaglutide: First Global Approval.

Novo Nordisk has developed a subcutaneous formulation of semaglutide (Ozempic&#xae;), a modified human glucagon-like peptide-1 (GLP-1) analogue, for the treatment of type 2 diabetes mellitus. It has been developed using Novo Nordisk's proprietary protein-acylation technology, and is administered using an injection device. Semaglutide lowers blood glucose by stimulating the release of insulin and also lowers body weight. Once-weekly subcutaneous semaglutide has recently been approved in the US, Puerto Rico and Canada, and has received a positive opinion in the EU for the treatment of patients with type 2 diabetes. It will be launched as the Ozempic&#xae; Pen, a pre-filled device. Semaglutide is also under regulatory review in Japan and Switzerland for the treatment of type 2 diabetes. Clinical development for obesity, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease is underway worldwide. This article summarizes the milestones in the development of semaglutide leading to this first approval for type 2 diabetes.

Natural Weight Loss or "Ozempic Face": Demystifying A Social Media Phenomenon.

New patients turning to semaglutide (Ozempic&reg; and Wegovy&reg;), a glucagon-like-peptide 1 (GLP-1) agonist, for weight loss, have captivated social media platforms.&nbsp; Wegovy&reg; carries a United States (US) Food and Drug Administration (FDA) approval for chronic weight management in patients who have a body mass index (BMI) 27 kg/m2 or greater and at least one weight-related condition (eg, hypertension, type 2 diabetes, cholesterol) or in patients with a 30 kg/m2 or greater BMI. Although other semaglutide formulations are not FDA approved for weight loss, the term "Ozempic face" has consumed the media with the medication's rising popularity. This term is a new purported side effect, used to describe the rapid facial weight loss leaving a distorted facial appearance. This challenges the healthcare team to discern whether a new adverse effect is a novel or a natural consequence of rapid weight loss. Dermatologists are well positioned to counsel patients receiving or discontinuing GLP-1 agonists and recommend appropriate countermeasures, as appropriate.&nbsp; J Drugs Dermatol. 2024;23(1):1367-1368. &nbsp; &nbsp;&nbsp; doi:10.36849/JDD.7613.

Clinical Pharmacokinetics of Semaglutide: A Systematic Review.

The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide recommendations for clinical use. The PubMed and Embase databases were searched to screen studies associated with the pharmacokinetics of semaglutide. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (Cmax), time to Cmax, half-life (t1/2), and clearance. The systematic literature search retrieved 17 articles including data on pharmacokinetic profiles after subcutaneously and oral applications of semaglutide, and at least one of the above pharmacokinetic parameter was reported in all included studies. Semaglutide has a predictable pharmacokinetic profile with a long t1/2 that allows for once-weekly subcutaneous administration. The AUC and Cmax of both oral and subcutaneous semaglutide increased with dose. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug-drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. Body weight may affect semaglutide exposure, but further studies are needed to confirm this. This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.

The Ethics of Ozempic and Wegovy.

Semaglutide, sold under the brand names of Ozempic, Rybelsus and Wegovy, is one of the most popular drugs on the market. Manufactured by Novo Nordisk, semaglutide is the newest in a family of glucagon-like peptide-1 receptor agonists used most commonly to treat type II diabetes. To date, the results of semaglutide for the treatment of type II diabetes have been overwhelmingly positive. It is for the drug's effects on appetite suppression and weight loss, however, that have led its surge in popularity, with many hailing semaglutide as the new 'miracle drug for weight loss'. Despite its popularity, both the governmental and popular reception to the drug has largely been mixed. In this paper, we address a range of ethical concerns and argue that while many are legitimate, they do not provide conclusive reason not to prescribe semaglutide for weight loss.

Semaglutide attenuates doxorubicin-induced cardiotoxicity by ameliorating BNIP3-Mediated mitochondrial dysfunction.

Doxorubicin is a powerful chemotherapeutic agent for cancer, whose use is limited due to its potential cardiotoxicity. Semaglutide (SEMA), a novel analog of glucagon-like peptide-1 (GLP-1), has received widespread attention for the treatment of diabetes. However, increasing evidence has highlighted its potential therapeutic benefits on cardiac function. Therefore, the objective of this study was to examine the efficacy of semaglutide in ameliorating doxorubicin-induced cardiotoxicity. Doxorubicin-induced cardiotoxicity is an established model to study cardiac function. Cardiac function was studied by transthoracic echocardiography and invasive hemodynamic monitoring. The results showed that semaglutide significantly ameliorated doxorubicin-induced cardiac dysfunction. RNA sequencing suggested that Bnip3 is the candidate gene that impaired the protective effect of semaglutide in doxorubicin-induced cardiotoxicity. To determine the role of BNIP3 on the effect of semaglutide in doxorubicin-induced cardiotoxicity, BNIP3 with adeno-associated virus serotype 9 (AAV9) expressing cardiac troponin T (cTnT) promoter was injected into tail vein of C57/BL6J mice to overexpress BNIP3, specifically in the heart. Overexpression of BNIP3 prevented the improvement in cardiac function caused by semaglutide. In vitro experiments showed that semaglutide, via PI3K/AKT pathway, reduced BNIP3 expression in the mitochondria, improving mitochondrial function. Semaglutide ameliorates doxorubicin-induced mitochondrial and cardiac dysfunction via PI3K/AKT pathway, by reducing BNIP3 expression in mitochondria. The improvement in mitochondrial function reduces doxorubicin-mediated cardiac injury and improves cardiac function. Therefore, semaglutide is a potential therapy to reduce doxorubicin-induced acute cardiotoxicity.

Implications of Ozempic and Other Semaglutide Medications for Facial Plastic Surgeons.

Obesity is a growing global health concern, leading to various health issues, including diabetes. Semaglutide-based medications, such as Ozempic, Wegovy, and Rybelsus, have emerged as potential treatments. These medications, belonging to the glucagon-like peptide-1 (GLP-1) receptor agonist class, mimic the action of GLP-1, regulating appetite and promoting weight loss. Clinical trials have shown their effectiveness in reducing body weight and improving metabolic parameters. Ozempic, though Food and Drug Administration-approved for diabetes, is also used off-label for weight loss alone. Rapid weight and fat loss with Ozempic can lead to the characteristic "Ozempic face," where facial volume and fat are depleted, resulting in wrinkles and sagging skin. Providers prescribing Ozempic seldom counsel patients about the potential impact on the face. As a result, the plastic surgery community faces a challenge in managing facial changes associated with rapid weight loss. Dermal fillers, skin tightening techniques, and surgical interventions are useful for both restoration of facial volume and to manage excess skin. Discontinuation of Ozempic should be considered prior to general anesthesia due to gastrointestinal side effects including delayed gastric emptying. As the popularity of Ozempic grows, facial plastic surgeons must be aware of both the impact on facial appearance and perioperative considerations.

Use of glucagon-like peptide-1 receptor agonists in eating disorder populations.

Glucagon-like peptide-1 receptor agonists (GLP-1As) are being used as approved or off-label treatments for weight loss. As such, there has been increasing concern about the potential for GLP-1As to impact eating disorder (ED) symptomatology. This article seeks to (1) review the current state of knowledge regarding GLP-1As and ED symptomatology; (2) provide recommendations for future research; and (3) guide ED clinicians in how to discuss GLP-1As in clinical practice. Although evidence is limited, it is possible that GLP-1As could exacerbate, or contribute to the development of, ED pathology and negatively impact ED treatment. Preliminary research on the use of GLP-1As to treat binge eating has been conducted; however, studies have design limitations and additional research is needed. Therefore, at the current time there is not sufficient evidence to support the use of GLP-1s to treat ED symptoms. In summary, more research is required before negative or positive conclusions can be drawn about the impact of GLP-1As on EDs psychopathology. Herein, we provide specific recommendations for future research and a guide to help clinicians navigate discussions with their clients about GLP-1As. A client handout is also provided. PUBLIC SIGNIFICANCE: Despite glucagon-like peptide-1 receptor agonists (GLP-1As; e.g., semaglutide) increasingly being the topic of clinical and public discourse, little is known about their potential impact on ED symptoms. It is possible that GLP-1As could maintain, worsen, or improve ED symptoms. This article reviews the limited literature on GLP-1As and ED symptoms, recommends future research, and provides clinicians with a guide for discussing GLP-1As with ED clients.

Semaglutide therapy for metabolic dysfunction-associated steatohepatitis: November 2025 updates to AASLD Practice Guidance.

This practice recommendation serves as an update to the 2023 AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD), and provides implementable guidance on patient selection for treatment, consideration of comorbidities, and monitoring of treatment safety and efficacy of semaglutide. FDA-indication and Practice Recommendation: The Wegovy formulation, whose main ingredient is semaglutide, received accelerated FDA approval in August 2025 for treating MASH with moderate-to-advanced fibrosis (consistent with stages F2-F3 fibrosis), based on interim results of the phase 3 ESSENCE trial where 72 weeks of 2.4&#xa0;mg/week subcutaneous injection resulted in achievement of both primary histologic endpoints: (1) resolution of MASH without worsening of fibrosis (62.9% vs. 34.3% placebo, p <0.001) and (2) &#x2265;1 stage reduction in liver fibrosis without worsening of MASH (36.8% vs. 22.4% placebo, p <0.001); final approval awaits long-term outcomes. Patient Selection: Candidates should have MASH with stage 2-3 fibrosis, identified using non-invasive tests (NITs) such as VCTE (8-15&#xa0;kPa), MRE (3.1-4.4&#xa0;kPa), or ELF (9.2-10.5), rather than liver biopsy, which is impractical and unnecessary for most patients. In those with VCTE (15-20&#xa0;kPa), MRE (4.4-5&#xa0;kPa), or ELF (10.5-11.3), an individualized decision to treat should be based on exclusion of cirrhosis with another confirmatory NIT, or cross-sectional imaging excluding nodular-appearing liver contour and signs of portal hypertension, or a platelet count of <150,000/mm 3 . While semaglutide is not approved to treat patients with MASH cirrhosis (VCTE >20&#xa0;kPa, MRE>5.0&#xa0;kPa, ELF>11.3, and/or evidence of portal hypertension), those with compensated cirrhosis who are receiving semaglutide for another FDA-approved indication should be monitored carefully. Monitoring and Safety: Semaglutide showed a favorable hepatic safety profile in the ESSENCE trial, with no discontinuations due to liver enzyme elevations. Routine hepatic panels are recommended only as clinically indicated. The most common adverse events were gastrointestinal (nausea, diarrhea, constipation, vomiting), generally mild and transient; patient education and dose titration help improve tolerance. Clinicians should monitor for rare but serious risks, including acute kidney injury (from dehydration), symptomatic gallbladder disease, pancreatitis, thyroid C-cell tumors, retinopathy progression, and lean mass loss. Treatment Response and Concomitant Therapy: Lifestyle modification remains the cornerstone of MASLD/MASH management alongside semaglutide. Combination use of resmetirom with semaglutide 2.4mg/week has not been studied. While no NITs reliably predict histologic response at the individual patient level, reductions from baseline to 72 weeks of treatment suggest significant improvement in MASH resolution (ALT &#x2265;17&#xa0;U/L or &#x2265;20%) and fibrosis improvement (VCTE LSM &#x2265;30%; MRE LSM &#x2265;20%; ELF &#x2265;0.5). Non-response may be suspected if ALT or NITs worsen. The benefit is uncertain if a suboptimal response occurs, and may require an individualized approach and further follow-up.

Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide (Ozempic) Therapy for Diabetes Mellitus and Obesity: A Systematic Literature Review.

The broadening application of glucagon-like peptide (GLP)-1 receptor agonists, specifically semaglutide (Ozempic) for the management of diabetes and obesity brings a critical need to evaluate its safety profile, considering estimates of up to 20 million prescriptions per year in the US until 2035. This systematic review aims to assess the incidence of thyroid cancer and detail the spectrum of adverse events associated with semaglutide, focusing on its implications for patient care. Through a systematic search of PubMed, Scopus, and Embase databases up to December 2023, ten randomized controlled trials (RCTs) involving 14,550 participants, with 7830 receiving semaglutide, were analyzed, with an additional number of 18 studies that were separately discussed because they reported data from the same RCTs. The review focused on thyroid cancer incidence, gastrointestinal symptoms, and other significant adverse events attributed to semaglutide. The incidence of thyroid cancer in semaglutide-treated patients was less than 1%, suggesting no significant risk. Adverse events were predominantly gastrointestinal, including nausea (2.05% to 19.95%) and diarrhea (1.4% to 13%). Nasopharyngitis and vomiting were also notable, with mean prevalences of 8.23% and 5.97%, respectively. Other adverse events included increased lipase levels (mean of 6.5%), headaches (mean prevalence of 7.92%), decreased appetite (reported consistently at 7%), influenza symptoms (mean prevalence of 5.23%), dyspepsia (mean prevalence of 5.18%), and constipation (mean prevalence of 6.91%). Serious adverse events varied from 7% to 25.2%, highlighting the need for vigilant patient monitoring. These findings underscore the gastrointestinal nature of semaglutide's adverse events, which, while prevalent, did not significantly deter from its clinical benefits in the treatment landscape. This systematic review provides a comprehensive assessment of semaglutide's safety profile, with a focus on gastrointestinal adverse events and a low incidence of thyroid cancer. Despite the prevalence of gastrointestinal symptoms, semaglutide remains an efficacious option for managing diabetes and obesity. The detailed characterization of adverse events underscores the importance of monitoring and managing these effects in clinical practice, excluding the hypothesis of carcinogenesis.

GLP-1 agonists: A review for emergency clinicians.

Glucagon-like peptide 1 (GLP-1) based therapies, including GLP-1 agonists, are currently in use for treatment of diabetes and obesity. However, several complications may occur with their use. This narrative review provides a focused evaluation of GLP-1 agonist therapy and associated complications for emergency clinicians. GLP-1 agonists potentiate insulin release and reduce gastric emptying and food intake. These agents have demonstrated significant improvements in glucose control in diabetics and weight loss in obese patients. The two most common agents include subcutaneous semaglutide (Ozempic, approved for type 2 diabetes, and Wegovy, approved for weight loss) and liraglutide (Saxenda, approved for weight loss, and Victoza, approved for type 2 diabetes), though an oral formulation of semaglutide is available (Rybelsus). While these drugs are associated with improved long-term outcomes, there are a variety of associated adverse events. The most common include gastrointestinal (GI) adverse events such as nausea, vomiting, diarrhea, and abdominal pain. Pancreatitis and biliary disease may also occur. Hypersensitivity including injection site reactions have been associated with use, with reports of anaphylaxis and other rashes. Renal adverse events are most commonly associated with severe GI losses. Hypoglycemia may occur when these agents are used with sulfonylureas or insulin. There is also an increased risk of diabetic retinopathy. Due to the current shortage and expense of these medications, many patients have attempted to obtain these medications from non-licensed and unregulated agents, which may be associated with increased risk of serious complications. An understanding of the indications for GLP-1 agonist use and associated adverse events can assist emergency clinicians.

Semaglutide: Double-edged Sword with Risks and Benefits.

Type 2 Diabetes Mellitus therapy has evolved over the years to now include a new class of therapeutics, semaglutide. This article reviews the mechanism of action and formulation of semaglutide therapy, potential benefits, contraindications, adverse effects, and drug interactions. Oral and subcutaneous semaglutide therapies have shown effectiveness in improving glycemic control, weight loss, and reducing cardiovascular risks associated with diabetes mellitus. Semaglutide has also shown potential in being used as a therapeutic strategy in Alzheimer's disease due to its anti-neuroinflammatory effects and being used to treat polycystic ovary syndrome. However, semaglutide therapy is also associated with concerning adverse effects like acute pancreatitis, anesthetic risks like pulmonary aspiration or residual gastric content, acute kidney injury, acute gallbladder injury, nonarteritic anterior ischemic optic neuropathy and diabetic retinopathy. Contraindications of semaglutide include history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, and pregnancy. Drug interactions to consider with semaglutide therapy include those also used in diabetes treatment, like metformin, as well as anti-psychotics, due to anti-psychotics associated weight gain. The findings of this article emphasize the need for a cross-disciplinary approach to understand the molecular mechanisms and clinical implications of semaglutide on patients with complex medical histories and treatment regimens. The potential anesthetic risks of semaglutide therapy warrant careful consideratiion with ethical concerns. Further studies can assess if there is a need to modify pre-operative guidelines to account for patient using semaglutide and how delayed gastric emptying and constitpation will affect surgical outcomes and complications. While semaglutide therapy for diabetes mellitus has been established, there is a need for extensive research on repurposing semaglutide in neurodegenerative disease treatment.

The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission.

Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.

Acute pancreatitis due to different semaglutide regimens: An updated meta-analysis.

Some concerns persist regarding the safety of semaglutide. The objective of this updated meta-analysis is to assess the risk of acute pancreatitis with the use of semaglutide, assessing the results according to the different administration regimens. We performed an updated meta-analysis of randomised, placebo-controlled studies of semaglutide therapy that report acute pancreatitis. This meta-analysis was performed in line with PRISMA guidelines. A global and stratified analysis according to the therapeutic scheme used was performed using the fixed-effects model. Twenty-one eligible trials of semaglutide, including 34,721 patients, were identified and considered eligible for the analyses. Globally, semaglutide therapy was not associated with an increased risk of acute pancreatitis (OR 0.7; 95% CI 0.5-1.2, I2 0%). When we analysed the studies according to the different schemes used, the results were similar (group with oral semaglutide: OR 0.40; 95% CI 0.10-1.60, I2 0%; group with low subcutaneous doses of semaglutide: OR 0.80; 95% CI 0.40-1.90, I2 0%; group with high subcutaneous doses of semaglutide: OR 0.70; 95% CI 0.50-1.20, I2 0%; interaction p-value=0.689). This updated meta-analysis demonstrates that the use of semaglutide is not associated with an increased risk of acute pancreatitis compared to placebo. In the stratified analysis, the results were similar with the different semaglutide regimens analysed.

Real-world persistence and adherence to glucagon-like peptide-1 receptor agonists among obese commercially insured adults without diabetes.

In 2014, the US Food and Drug Administration approved the first glucagon-like peptide-1 (GLP-1) receptor agonist product, liraglutide injection, for obesity treatment. Many GLP-1 obesity treatment clinical trials report significant weight loss and medication adherence at more than 85%. Little is known about the real-world GLP-1 obesity treatment adherence, persistence, and switch rates. To measure GLP-1 therapy persistence, adherence, and switch rates in a real-world cohort of members without diabetes using these drugs for obesity treatment. Integrated pharmacy and medical claims data from 16.5 million average monthly commercially insured membership were used to identify obese members without diabetes newly initiating GLP-1 therapy between January 1, 2021, and December 31, 2021. Members were required to be continuously enrolled 1-year before and after the GLP-1 therapy start date and aged 19 years of age or older. Persistence was measured as no greater than or equal to 60-day gap with allowance for GLP-1 switching. Adherence was measured as the proportion of days covered (PDC) and members with a PDC greater than or equal to 80% were considered adherent. GLP-1 product switching was also assessed descriptively. 4,066 commercially insured obese members without diabetes that newly initiated GLP-1 therapy met all study criteria. The mean age was 46 years, and 81% were female. Overall, GLP-1 persistence was 46.3% at 180 days and 32.3% at 1 year. The highest and lowest persistence rates at 1 year were observed for semaglutide (Ozempic) at 47.1% and liraglutide (Saxenda) 19.2%, respectively. Average PDC during the 1-year assessment was 51.0% with 27.2% adherent to therapy and 11.1% switched GLP-1 drugs. This GLP-1 weight loss treatment real-world analysis, among obese individuals without diabetes, found poor 1-year persistence and adherence and low rates of switching between products. These findings will aid in assessing products cost-effectiveness, understanding obesity care management program needs, forecasting future GLP-1 use and cost trends, and negotiating GLP-1 pharmaceutical manufacturer value-based purchasing agreements.

Semaglutide reduces alcohol intake and relapse-like drinking in male and female rats.

Glucagon-like peptide1 receptor (GLP-1R) agonists have been found to reduce alcohol drinking in rodents and overweight patients with alcohol use disorder (AUD). However, the probability of low semaglutide doses, an agonist with higher potency and affinity for GLP-1R, to attenuate alcohol-related responses in rodents and the underlying neuronal mechanisms is unknown. In the intermittent access model, we examined the ability of semaglutide to decrease alcohol intake and block relapse-like drinking, as well as imaging the binding of fluorescently marked semaglutide to nucleus accumbens (NAc) in both male and female rats. The suppressive effect of semaglutide on alcohol-induced locomotor stimulation and in&#xa0;vivo dopamine release in NAc was tested in male mice. We evaluated effect of semaglutide on the in&#xa0;vivo release of dopamine metabolites (DOPAC and HVA) and gene expression of enzymes metabolising dopamine (MAOA and COMT) in male mice. In male and female rats, acute and repeated semaglutide administration reduced alcohol intake and prevented relapse-like drinking. Moreover, fluorescently labelled semaglutide was detected in NAc of alcohol-drinking male and female rats. Further, semaglutide attenuated the ability of alcohol to cause hyperlocomotion and to elevate dopamine in NAc in male mice. As further shown in male mice, semaglutide enhanced DOPAC and HVA in NAc when alcohol was onboard and increased the gene expression of COMT and MAOA. Altogether, this indicates that semaglutide reduces alcohol drinking behaviours, possibly via a reduction in alcohol-induced reward and NAc dependent mechanisms. As semaglutide also decreased body weight of alcohol-drinking rats of both sexes, upcoming clinical studies should test the plausibility that semaglutide reduces alcohol intake and body weight in overweight AUD patients. Swedish Research Council (2019-01676), LUA/ALF (723941) from the Sahlgrenska University Hospital and the Swedish brain foundation.

Semaglutide-associated hyposalivation: A report of case series.

Obesity and diabetes of different types are considered global health risks with rising prevalence. In addition to low-calorie diet and daily exercise, several treatment options have been introduced to help patient in needs. Semaglutide (Ozempic) is one popular agent, which attracted the attention of both physicians and patients due to its positive outcome in improving glucose control and weight loss. However, no reports on the effect of semaglutide use on the oral cavity and specifically xerostomia are available in the literature. We are reporting 3 cases for patients who were using semaglutide and developed secondary xerostomia. Three female patients with median age of 34 (range 27-46) presented to the oral medicine clinic with chief complaint of xerostomia. All patients were overweight with a mean body mass index of 35.6 (range 35-37) and have been using semaglutide for weight loss for a mean duration of 11.3 weeks (range 6-16). All 3 patients had severe dryness in the mouth with minimal frothy saliva with mean modified Schirmer test of 9&#x2009;mL at 3 minutes (range 8-10&#x2009;mL). Following exclusion of other possible underlying medical problems, the diagnosis of semaglutide-induced hyposalivation was given to all patients. The patients' management varied between discontinuation of the drug, the use of pilocarpine, and conservative symptomatic management. The patients resumed acceptable salivary flow. We are reporting for the first time hyposalivation associated with the use of semaglutide. Further prospective, larger studies are warranted to confirm these findings.

Acute Pancreatitis Caused by Tirzepatide.

Glucagon-like peptide-1 (GLP-1) receptor agonists, including tirzepatide (Mounjaro), are widely used to manage type 2 diabetes mellitus (T2DM) and obesity. While gastrointestinal side effects are common, acute pancreatitis remains a rare but significant complication. Limited evidence exists on the risks associated with switching between GLP-1 agonists, emphasizing the need for clinical awareness. We present a 59-year-old male with T2DM, hyperlipidemia, and hypertension, who was recently transitioned from semaglutide (Ozempic) to tirzepatide (Mounjaro). He presented with acute epigastric pain, nausea, and vomiting two days after initiating tirzepatide. Laboratory findings revealed elevated lipase levels (847 U/L), leukocytosis, and diagnostic imaging confirming acute pancreatitis with other causes ruled out. Supportive care improved symptoms initially, but the clinical course was complicated by fevers prompting repeat imaging, revealing worsening pancreatitis with colonic involvement and pleural effusion. The patient was treated with empiric antibiotics and supportive measures, resulting in resolution of symptoms. Tirzepatide was discontinued, with a follow-up arranged for glycemic management. Acute pancreatitis is a rare but documented adverse effect of GLP-1 agonists, with limited cases reported in the literature. Switching between GLP-1 agonists may increase the risk of adverse effects, especially if appropriate dose titration protocols are not followed. This case highlights the recognition of acute pancreatitis as a potential adverse effect of GLP-1 agonists when initiating or transitioning GLP-1 therapies and following titration protocols to help avoid this complication. GLP-1 agonists, including tirzepatide, offer significant therapeutic benefits for T2DM and obesity but carry risks of rare adverse effects like acute pancreatitis. Greater awareness, careful dose adjustments, and vigilant monitoring are essential to optimizing patient safety. Further research is needed to elucidate the safety profile of switching between GLP-1 agonists to guide clinical practice and improve patient outcomes.

Semaglutide and pregnancy.

Gastrointestinal Permeation Enhancers for the Development of Oral Peptide Pharmaceuticals.

Recently, two oral-administered peptide pharmaceuticals, semaglutide and octreotide, have been developed and are considered as a breakthrough in peptide and protein drug delivery system development. In 2019, the Food and Drug Administration (FDA) approved an oral dosage form of semaglutide developed by Novo Nordisk (Rybelsus&#xae;) for the treatment of type 2 diabetes. Subsequently, the octreotide capsule (Mycapssa&#xae;), developed through Chiasma's Transient Permeation Enhancer (TPE) technology, also received FDA approval in 2020 for the treatment of acromegaly. These two oral peptide products have been a significant success; however, a major obstacle to their oral delivery remains the poor permeability of peptides through the intestinal epithelium. Therefore, gastrointestinal permeation enhancers are of great relevance for the development of subsequent oral peptide products. Sodium salcaprozate (SNAC) and sodium caprylate (C8) have been used as gastrointestinal permeation enhancers for semaglutide and octreotide, respectively. Herein, we briefly review two approved products, Rybelsus&#xae; and Mycapssa&#xae;, and discuss the permeation properties of SNAC and medium chain fatty acids, sodium caprate (C10) and C8, focusing on Eligen technology using SNAC, TPE technology using C8, and gastrointestinal permeation enhancement technology (GIPET) using C10.

Efficacy and safety of once-weekly semaglutide 2&#xb7;0 mg versus 1&#xb7;0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial.

Semaglutide is an effective treatment for type 2 diabetes; however, 20-30% of patients given semaglutide 1&#xb7;0 mg do not reach glycaemic treatment goals. We aimed to investigate the efficacy and safety of once-weekly semaglutide 2&#xb7;0 mg versus 1&#xb7;0 mg in adults with inadequately controlled type 2 diabetes on a stable dose of metformin with or without a sulfonylurea. We did a 40-week, randomised, active-controlled, parallel-group, double-blind, phase 3B trial (SUSTAIN FORTE) at 125 outpatient clinics in ten countries. Participants (&#x2265;18 years) with inadequately controlled type 2 diabetes (HbA1c 8&#xb7;0-10&#xb7;0%) with metformin and with or without sulfonylurea were randomly assigned (1:1) by an interactive web-response system to 2&#xb7;0 mg or 1&#xb7;0 mg once-weekly semaglutide. Participants, site personnel, the clinical study group, and investigators were masked to the randomised treatment. Outcomes included change from baseline at week 40 in HbA1c (primary outcome) and bodyweight (secondary confirmatory outcome), evaluated through trial product estimand (no treatment discontinuation or without rescue medication) and treatment policy estimand (regardless of treatment discontinuation or rescue medication) strategies. This study is registered with ClinicalTrials.gov, NCT03989232; EudraCT, 2018-004529-96; and WHO, U1111-1224-5162. Between June 19 and Nov 28, 2019, of 1515 adults assessed for eligibility, 961 participants (mean age 58&#xb7;0 years [SD 10&#xb7;0]; 398 [41%] women) were included. Participants were randomly assigned to once-weekly semaglutide 2&#xb7;0 mg (n=480 [50%]) or 1&#xb7;0 mg (n=481 [50%]); 462 (96%) patients in the semaglutide 2&#xb7;0 mg group and 471 (98%) in the semaglutide 1&#xb7;0 mg group completed the trial. Mean baseline HbA1c was 8&#xb7;9% (SD 0&#xb7;6; 73&#xb7;3 mmol/mol [SD 6&#xb7;9]) and BMI was 34&#xb7;6 kg/m2 (SD 7&#xb7;0). Mean change in HbA1c from baseline at week 40 was -2&#xb7;2 percentage points with semaglutide 2&#xb7;0 mg and -1&#xb7;9 percentage points with semaglutide 1&#xb7;0 mg (estimated treatment difference [ETD] -0&#xb7;23 percentage points [95% CI -0&#xb7;36 to -0&#xb7;11]; p=0&#xb7;0003; trial product estimand) and -2&#xb7;1 percentage points with semaglutide 2&#xb7;0 mg and -1&#xb7;9 percentage points with semaglutide 1&#xb7;0 mg (ETD -0&#xb7;18 percentage points [-0&#xb7;31 to -0&#xb7;04]; p=0&#xb7;0098; treatment policy estimand). Mean change in bodyweight from baseline at week 40 was -6&#xb7;9 kg with semaglutide 2&#xb7;0 mg and -6&#xb7;0 kg with semaglutide 1&#xb7;0 mg (ETD -0&#xb7;93 kg [95% CI -1&#xb7;68 to -0&#xb7;18]; p=0&#xb7;015; trial product estimand) and -6&#xb7;4 kg with semaglutide 2&#xb7;0 mg and -5&#xb7;6 kg with semaglutide 1&#xb7;0 mg (ETD -0&#xb7;77 kg [-1&#xb7;55 to 0&#xb7;01]; p=0&#xb7;054; treatment policy estimand). Gastrointestinal disorders were the most commonly reported adverse events (163 [34%] in the 2&#xb7;0 mg group and 148 [31%] in the 1&#xb7;0 mg group). Serious adverse events were similar between treatment groups, reported for 21 (4%) participants given semaglutide 2&#xb7;0 mg and 25 (5%) participants given semaglutide 1&#xb7;0 mg. Three deaths were reported during the trial (one in the semaglutide 1&#xb7;0 mg group and two in the semaglutide 2&#xb7;0 mg group). Semaglutide 2&#xb7;0 mg was superior to 1&#xb7;0 mg in reducing HbA1c, with additional bodyweight loss and a similar safety profile. This higher dose provides a treatment intensification option for patients with type 2 diabetes treated with semaglutide in need of additional glycaemic control. Novo Nordisk.

Public Interest in the Off-Label Use of Glucagon-like Peptide 1 Agonists (Ozempic) for Cosmetic Weight Loss: A Google Trends Analysis.

Glucagon-like peptide 1 (GLP-1) agonists are a drug class used for the treatment of diabetes that have recently gained FDA approval for medical management of obesity. The off-label use of Ozempic (Novo Nordisk, Bagsv&#xe6;rd, Denmark), the brand name of the GLP-1 agonist semaglutide, for cosmetic weight loss has been popularized by social media and celebrity influence. The aim of this study was to analyze with Google Trends (Alphabet Inc., Mountain View, CA) the recent search popularity of Ozempic and related GLP-1 agonists. The term "Ozempic" was analyzed with Google Trends. Search popularity was assessed in terms of relative search volume (RSV) over a 5-year period. Changes in RSV were further compared with other GLP-1 agonists, "Wegovy" (Novo NordisK) and "Mounjaro" (Eli Lilly and Company, Indianapolis, IN). Between March 2018 and February 2023, overall RSV in "Ozempic" grew exponentially in the United States. Simple linear regression analysis showed significantly increased RSV over time with an R2 of 0.915 and a regression coefficient of 0.957 (P < .001). When comparing "Ozempic," "Wegovy," and "Mounjaro" since June 2021 (FDA approval of Wegovy), Ozempic remained at the greatest RSV. One-way analysis of variance found statistically significant differences between the 3 search terms at all time points between December 2021 and February 2023 (P < .001). This study demonstrates a significant and growing public interest in Ozempic and related GLP-1 agonists. As the use of GLP-1 agonists for weight loss becomes more prevalent, plastic surgeons, particularly in the aesthetic setting, must be prepared for the downstream implications. Increased awareness, understanding, and further scientific studies led by plastic surgeons will help deliver the safest possible patient outcomes.

Otolaryngologic Side Effects of GLP-1 Receptor Agonists.

With the increasing use of GLP-1 receptor agonist (GLP-1 RA) drugs for weight loss and diabetes management, concerns have been raised regarding their potential side effects. We aim to assess the frequency of otolaryngologic adverse events (AEs). Retrospective analysis of national registry. The Food and Drug Administration's Adverse Event Reporting System (FAERS) database was queried for events related to the GLP-1 RA: exenatide, liraglutide, dulaglutide, semaglutide, and tirzepatide from 1&#x2009;year after their approval until the end of 2023. AEs were collected and sub-stratified according to anatomic site. Reporting odds ratios (ROR) and proportional reporting ratios (PRR) were determined for all AEs. The number of AEs reported from all drugs within this study totaled 9,746. Significant signal ratios were defined as a PRR&#x2265;2 and a lower CI ROR >1. Medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) had the highest signals and were significant in virtually all medications. This was followed by GERD which also had very high signal ratios and was significant in all drugs assessed. Semaglutide also had significant signals in anosmia, dry mouth, dysgeusia, and Bell's palsy. Liraglutide had significance in both signals in dysphonia, dysgeusia, tinnitus, and Bell's palsy. This was followed by exenatide which also included dysgeusia and hearing disability. GLP-1 RA were associated with various otolaryngologic AEs, with significant signals observed for semaglutide and liraglutide. GERD, MTC, and PTC were of significance in all GLP-1 RA in this study. Monitoring these AEs is recommended. 4 Laryngoscope, 135:2291-2298, 2025.

Two-year effect of semaglutide 2.4&#xa0;mg on control of eating in adults with overweight/obesity: STEP 5.

This study evaluated&#xa0;the effect of once-weekly semaglutide 2.4&#xa0;mg on 2-year control of eating. In STEP 5, adults with overweight/obesity were randomized 1:1 to semaglutide 2.4&#xa0;mg or placebo, plus lifestyle modification, for 104&#x2009;weeks. A 19-item Control of Eating Questionnaire was administered at weeks 0, 20, 52, and 104 in a subgroup of participants. P values were not controlled for multiplicity. In participants completing the Control of Eating Questionnaire (semaglutide, n&#xa0;=&#xa0;88; placebo, n&#xa0;=&#xa0;86), mean body weight changes were&#x2009;-14.8% (semaglutide) and&#x2009;-2.4% (placebo). Scores significantly improved with semaglutide versus placebo for Craving Control and Craving for Savory domains at weeks 20, 52, and 104 (p&#x2009;<&#x2009;0.01); for Positive Mood and Craving for Sweet domains at weeks 20 and 52 (p&#x2009;<&#x2009;0.05); and for hunger and fullness at week 20 (p&#x2009;<&#x2009;0.001). Improvements in craving domain scores were positively correlated with reductions in body weight from baseline to week 104 with semaglutide. At 104&#x2009;weeks, scores for desire to eat salty and spicy food, cravings for dairy and starchy foods, difficulty in resisting cravings, and control of eating were significantly reduced with semaglutide versus placebo (all p&#x2009;<&#x2009;0.05). In adults with overweight/obesity, semaglutide 2.4&#xa0;mg improved short- and longer-term control of eating associated with substantial weight loss.

A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes.

Oral semaglutide (Rybelsus&#xae;) is a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) with 94% homology to human GLP-1. It is the first GLP-1RA developed for oral administration, and it comprises a co-formulation of the peptide semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which overcomes the challenges of peptide absorption in the acidic conditions of the stomach. Oral semaglutide is indicated for use as an add-on combination therapy (with other glucose-lowering agents, including insulin) or as a monotherapy (in patients who are intolerant to metformin) for type 2 diabetes when diet and exercise do not provide adequate glycemic control. In an extensive phase III clinical program including patients from across the disease spectrum, treatment with oral semaglutide resulted in effective glycemic control, reductions in body weight, and decreases in systolic blood pressure when used as monotherapy or in combination with other glucose-lowering therapies. Studies showed that oral semaglutide was well tolerated, with a safety profile consistent with the GLP-1RA drug class. The risk of hypoglycemia was low, and the most common adverse events were gastrointestinal, with nausea and diarrhea generally being the most frequently reported manifestations. Cardiovascular (CV) safety was shown to be noninferior to placebo and observations suggest that the CV profile of oral semaglutide is likely to be similar to that of subcutaneous semaglutide. The evolution of the GLP-1RA class to include an oral agent could facilitate the use of these agents earlier in the diabetes treatment cascade owing to wider acceptance from patients and healthcare professionals.

Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy Risk Among Patients With Diabetes.

Recent studies have suggested an association between nonarteritic anterior ischemic optic neuropathy (NAION) with semaglutide usage. However, the limitations of those analyses warrant further investigation, given the frequency of use of these medications in people with and without diabetes. To investigate the association between semaglutide use and the risk of NAION among patients with diabetes. This cohort study used data from the TriNetX database between October 1, 2019, and December 31, 2023, to identify patients with diabetes with no history of NAION who were prescribed semaglutide. The semaglutide cohort was compared with a control group of randomly selected patients with diabetes who were prescribed non-glucagonlike peptide 1 (non-GLP-1) receptor agonist (RA) antidiabetic medications. The data analysis for this study was performed on September 1, 2024. Semaglutide history, identified using diagnostic codes. Cumulative incidence and (HR) hazard ratio of NAION. A total of 3&#x202f;344&#x202f;205 patients with diabetes were included in this study. Regarding the diabetes cohort, a total of 174&#x202f;584 patients with diabetes who received semaglutide (mean [SD] age, 58.3 [12.5] years; 90&#x202f;427 female [51.8%]; 71&#x202f;739 male [41.1%]) and 174&#x202f;584 patients with diabetes who received non-GLP-1 RA medications (mean [SD] age, 58.2 [14.3] years; 90&#x202f;475 female [51.82%]; 71&#x202f;989 male [41.24%]) were recruited. Patients with diabetes taking semaglutide exhibited an absence of NAION risk at the 1-month (HR, 2.99; 95% CI, 0.31-28.75), 3-month (HR, 1.33; 95% CI, 0.30-5.93), 6-month (HR, 1.79; 95% CI, 0.60-5.35), and 1-year (HR, 1.94; 95% CI: 0.93-4.02) time points after the index date. However, those taking semaglutide were found to have an increased risk for NAION at the 2-year (HR, 2.39; 95% CI, 1.37-4.18), 3-year (HR, 2.44; 95% CI, 1.44-4.12), and 4-year (HR, 2.05; 95% CI, 1.26-3.34) time points from the index date. Increased risk for NAION was also noted in patients with diabetes and concomitant hypertension who were taking semaglutide (HR, 2.42; 95% CI, 1.19-4.92). An increased NAION risk was also observed among patients with diabetes who had a history of Ozempic (Novo Nordisk) use or stand-alone Ozempic (Novo Nordisk) prescription history. Results of this cohort study suggest that semaglutide use was associated with an increased risk of NAION in patients with diabetes. However, the study's retrospective design presents limitations, as it can only infer associations rather than establish causality; further studies are needed.

Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species.

Semaglutide is a human glucagon-like peptide-1 analogue in clinical development for the treatment of type 2 diabetes. The absorption, metabolism and excretion of a single 0.5mg/450&#x3bc;Ci [16.7MBq] subcutaneous dose of [3H]-radiolabelled semaglutide was investigated in healthy human subjects and compared with data from nonclinical studies. Radioactivity in blood, plasma, urine and faeces was determined in humans, rats and monkeys; radioactivity in expired air was determined in humans and rats. Metabolites in plasma, urine and faeces were quantified following profiling and radiodetection. The blood-to-plasma ratio and pharmacokinetics of both radiolabelled semaglutide-related material and of semaglutide (in humans only) were assessed. Intact semaglutide was the primary component circulating in plasma for humans and both nonclinical species, accounting for 69-83% of the total amount of semaglutide-related material, and was metabolised prior to excretion. Recovery of excreted radioactivity was 75.1% in humans, 72.1% in rats and 58.2% in monkeys. Urine and faeces were shown to be important routes of excretion, with urine as the primary route in both humans and animals. Semaglutide was metabolised through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain, and metabolism was not confined to specific organs. Intact semaglutide in urine accounted for 3.1% of the administered dose in humans and less than 1% in rats; it was not detected in urine in monkeys. The metabolite profiles of semaglutide in humans appear to be similar to the profiles from the nonclinical species investigated.

Misrepresentation of semaglutide in social media.

In recent years, semaglutide has repeatedly attracted attention in the press and on social media due to its effects in weight management. The social media hype led to off-label use and global supply shortages. Our goal was to identify differences in the presentation of semaglutide on individual social media platforms. Additionally, we aim to investigate the mentioning of various aspects such as adverse drug reactions, drug indications, supply shortages, and costs. Current social media trends regarding semaglutide were also included in the analysis. We collected semaglutide-related posts from the social media platforms Instagram, TikTok, X, Facebook, and YouTube. The posts were then analysed and compared with the adverse drug reactions presented in the STEP trials. Semaglutide was presented by social media users almost exclusively for weight reduction. Misrepresentation of the pharmacological properties of semaglutide with respect to mechanism of action, indication, adverse effects, and drug interactions was very common on social media. The important aspect of treatment costs and supply shortages was barely covered, if at all. Most content creators on Instagram and TikTok were female semaglutide users without medical knowledge. Strikingly, the very common gastrointestinal problems during semaglutide therapy were not even mentioned on Instagram. Some of the posts found under the hashtag "ozempic" advertised products that did not contain semaglutide. Violations of the Medicinal Products Act were also identified. Videos of weight loss results have a high probability of artificial intelligence (AI) modification, which can lead to user deception. Social media often provides misleading information, especially regarding drug indications and adverse drug reactions. YouTube has emerged as the most reputable platform for medical information, whereas Instagram provides the least medical knowledge. Misinformation and AI-modified videos can negatively impact the self-perception of young social media users, leading to unreflected medication use.

Are Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists Central Nervous System (CNS) Penetrant: A Narrative Review.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that modulates glucose metabolism and insulin secretion. Recent translational and clinical research has evaluated the effects of GLP-1 receptor agonists (GLP-1 RAs), a class of drugs that mimic the action of native&#xa0;GLP-1 in the central nervous system (CNS). In addition to the efficacy of GLP-1 for the treatment of diabetes mellitus&#xa0;and obesity, preliminary evidence indicates GLP-1s have neuroprotective, therapeutic, and disease modification effects for select&#xa0;neurodegenerative disorders (e.g. Parkinson's disease, Alzheimer's disease). Among the available GLP-1&#xa0;RAs, relatively few have been shown to be&#xa0;CNS penetrant. This article synthesizes extant literature&#xa0;reporting on CNS penetrants of GLP-1 RAs as proxied by brain imaging studies. Where available, studies that reported on the bioavailability of GLP-1 RAs in the CNS were identified. A comprehensive search of PubMed, Ovid, and Web of Science from database inception to July 2024 was conducted. Inclusion criteria were English language publications with no date restrictions, preclinical and&#xa0;clinical studies with participants aged 18-80 and studies which focused on GLP-1 RAs including: "Semaglutide" or "Ozempic" or "Rybelsus" or "Wegovy" or "Dulaglutide" or "Trulicity" or "Exenatide" or "Byetta" or "Bydureon" or "Liraglutide" or "Lixisenatide" or "Tirzepatide" or "Mounjaro" or "Zepbound" or "Bydureon BCise" or "Adlyxin" or "Victoza" or "Saxenda". We identified 14 studies that were included in this synthesis. Preclinical studies suggest that select GLP-1 RAs cross the blood-brain barrier (BBB) (i.e.&#xa0;liraglutide, semaglutide, and exenatide). Replicated evidence suggests that CNS penetration of GLP-1 RAs can be proxied by reported effects of GLP-1 RAs on brain connectivity in human participants. &#xa0;Preclinical studies indicate that select GLP-1 RAs are CNS penetrant;&#xa0;whether GLP-1 RAs reproducibly engage neural targets hypothesized to subserve dimensions of psychopathology (e.g., general cognitive functions) remains incompletely characterized.

Semaglutide alters gut microbiota and improves NAFLD in db/db mice.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease associated with type 2 diabetes mellitus (T2D). NAFLD can progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and even cancer, all of which have a very poor prognosis. Semaglutide, a novel glucagon-like peptide-1 (GLP-1) receptor agonist, has been recognized as a specific drug for the treatment of diabetes. In this study, we used a gene mutation mouse model (db/db mice) to investigate the potential liver-improving effects of semaglutide. The results showed that semaglutide improved lipid levels and glucose metabolism in db/db mice. HE staining and oil red staining showed alleviation of liver damage and reduction of hepatic lipid deposition after injection of semaglutide. In addition, semaglutide also improved the integrity of gut barrier and altered gut microbiota, especially Alloprevotella, Alistpes, Ligilactobacillus and Lactobacillus. In summary, our findings validate that semaglutide induces modifications in the composition of the gut microbiota and ameliorates NAFLD, positioning it as a promising therapeutic candidate for addressing hepatic steatosis and associated inflammation.

Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial.

Semaglutide is a novel glucagon-like peptide-1 (GLP-1) analogue, suitable for once-weekly subcutaneous administration, in development for treatment of type 2 diabetes. We assessed the efficacy and safety of semaglutide versus the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin, thiazolidinediones, or both. We did a 56-week, phase 3a, randomised, double-blind, double-dummy, active-controlled, parallel-group, multinational, multicentre trial (SUSTAIN 2) at 128 sites in 18 countries. Eligible patients were aged at least 18 years (or at least 20 years in Japan) and diagnosed with type 2 diabetes, with insufficient glycaemic control (HbA1c 7&#xb7;0-10&#xb7;5% [53&#xb7;0-91&#xb7;0 mmol/mol]) despite stable treatment with metformin, thiazolidinediones, or both. We randomly assigned participants (2:2:1:1) using an interactive voice or web response system to 56 weeks of treatment with subcutaneous semaglutide 0&#xb7;5 mg once weekly plus oral sitagliptin placebo once daily, subcutaneous semaglutide 1&#xb7;0 mg once weekly plus oral sitagliptin placebo once daily, oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 0&#xb7;5 mg once weekly, or oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 1&#xb7;0 mg once weekly. The two oral sitagliptin 100 mg groups (with semaglutide placebo 0&#xb7;5 mg and 1&#xb7;0 mg) were pooled for the analyses. The primary endpoint was change in HbA1c from baseline to week 56, assessed in the modified intention-to-treat population (all randomly assigned participants who received at least one dose of study drug); change in bodyweight from baseline to week 56 was the confirmatory secondary endpoint. Safety endpoints included adverse events and hypoglycaemic episodes. This trial is registered with ClinicalTrials.gov, number NCT01930188. Between Dec 2, 2013, and Aug 5, 2015, we randomly assigned 1231 participants; of the 1225 included in the modified intention-to-treat analysis, 409 received semaglutide 0&#xb7;5 mg, 409 received semaglutide 1&#xb7;0 mg, and 407 received sitagliptin 100 mg. Mean baseline HbA1c was 8&#xb7;1% (SD 0&#xb7;93); at week 56, HbA1c was reduced by 1&#xb7;3% in the semaglutide 0&#xb7;5 mg group, 1&#xb7;6% in the semaglutide 1&#xb7;0 mg group, and 0&#xb7;5% with sitagliptin (estimated treatment difference vs sitagliptin -0&#xb7;77% [95% CI -0&#xb7;92 to -0&#xb7;62] with semaglutide 0&#xb7;5 mg and -1&#xb7;06% [-1&#xb7;21 to -0&#xb7;91] with semaglutide 1&#xb7;0 mg; p<0&#xb7;0001 for non-inferiority and for superiority, for both semaglutide doses vs sitagliptin). Mean baseline bodyweight was 89&#xb7;5 kg (SD 20&#xb7;3); at week 56, bodyweight reduced by 4&#xb7;3 kg with semaglutide 0&#xb7;5 mg, 6&#xb7;1 kg with semaglutide 1&#xb7;0 mg, and 1&#xb7;9 kg with sitagliptin (estimated treatment difference vs sitagliptin -2&#xb7;35 kg [95% CI -3&#xb7;06 to -1&#xb7;63] with semaglutide 0&#xb7;5 mg and -4&#xb7;20 kg [-4&#xb7;91 to -3&#xb7;49] with semaglutide 1&#xb7;0 mg; p<0&#xb7;0001 for superiority, for both semaglutide doses vs sitagliptin). The proportion of patients who discontinued treatment because of adverse events was 33 (8%) for semaglutide 0&#xb7;5 mg, 39 (10%) for semaglutide 1&#xb7;0 mg, and 12 (3%) for sitagliptin. The most frequently reported adverse events in both semaglutide groups were gastrointestinal in nature: nausea was reported in 73 (18%) who received semaglutide 0&#xb7;5 mg, 72 (18%) who received semaglutide 1&#xb7;0 mg, and 30 (7%) who received placebo, and diarrhoea was reported in 54 (13%) who received semaglutide 0&#xb7;5 mg, 53 (13%) who received semaglutide 1&#xb7;0 mg, and 29 (7%) who received placebo. Seven (2%) patients in the semaglutide 0&#xb7;5 mg group, two (<1%) in the semaglutide 1&#xb7;0 mg group, and five (1%) in the sitagliptin group had blood-glucose confirmed hypoglycaemia. There were six fatal events (two in the semaglutide 0&#xb7;5 mg group, one in the semaglutide 1&#xb7;0 mg group, and three in the sitagliptin group); none were considered likely to be related to the trial drugs. Once-weekly semaglutide was superior to sitagliptin at improving glycaemic control and reducing bodyweight in participants with type 2 diabetes on metformin, thiazolidinediones, or both, and had a similar safety profile to that of other GLP-1 receptor agonists. Semaglutide seems to be an effective add-on treatment option for this patient population. Novo Nordisk A/S.

FDG PET in a Patient on a GLP-1 Agonist/Insulin Secretagogue.

With the increase in use of GLP-1 receptor agonists such as semaglutide (Ozempic, Wegovy, Rybelsus) in the population, nuclear medicine physicians should be aware of the possibility of nondiagnostic FDG PET scans due to these medications, which work partly by increasing insulin secretion. We demonstrate a case where a patient's use of such a medication presumptively led to muscular and myocardial uptake, complicating scan interpretation considerably. Clinicians should be aware of the presence of these drugs and their potential effect on biodistribution in FDG PET. Further study is needed to best understand the effects of these medications on FDG biodistribution.