Efficacy of Different Doses and Forms of the GLP-1 Receptor Agonist Semaglutide in Weight Reduction Among Non-diabetic Obese or Overweight Populations.

Disorders linked to increased body weight are on the rise and obesity is a global epidemic associated with a rising risk for developing comorbidities, such as hypertension or type 2 diabetes. There is a significant need to develop a multimodal approach targeting obesity within clinical medicine. Pharmacological options to produce weight loss have been a popular research area and the novel glucagon-like Peptide-1 receptor agonists (GLP-1 RA) are highly effective glycemic control agents that have shown a substantial weight loss effect. This systematic review explores the efficacy of semaglutide, a GLP-1 RA agent, in a non-diabetic population, looking at endpoints of changes in weight and waist circumference and the percentage of patients achieving a clinically effective weight loss of at least 5%. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A comprehensive search was undertaken to find applicable papers using three databases, including PubMed, PubMed Central, and Cochrane Library. The included articles were narrowed down from an initial pool of 423 papers using filters, automation tools, inclusion/exclusion criteria, and quality appraisal tools. In this systematic review, we have analyzed 10 high-quality studies published in the last five years, including nine randomized control trials (RCTs) and a retrospective cohort study. The aim was to combine the results of these studies, encompassing 6623 participants, to showcase the effectiveness of GLP-1 RAs in the non-diabetic obese or overweight population. The consolidated data from the literature in this systematic review endorses the use of semaglutide as a highly efficient weight-reducing agent, contributing positive insight to both clinicians and researchers in the field of obesity treatment.

Trends in Glucagon-Like Peptide-1 Receptor Agonist Social Media Posts Using Artificial Intelligence.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have surged in popularity in recent years, with discussions about their on-label and off-label use spilling into the public forum. No study has analyzed online discussions about GLP-1RAs. Objectives: The purpose of this study was to analyze perceptions of GLP-1RAs on social media. Methods: We analyzed GLP-1RA-related posts on Reddit between May 28, 2013, and June 1, 2023. All posts were identified that included generic or brand names of GLP-1RAs. Post volume on Reddit was compared to search interest on Google over time. An artificial intelligence (AI) pipeline consisting of a semi-supervised natural language processing model (Bidirectional Encoder Representations from Transformers [BERT]), a dimensionality reduction technique, and a clustering algorithm was used to cluster posts into related topics. Discussion sentiment was classified using a pretrained BERT model and assessed qualitatively. Results: 14,390 GLP-1RA-related Reddit posts by 8,412 authors were identified. Ninety-four percent of posts were created after 2021, consistent with search interest trend on Google. We used the AI model to categorize posts into 30 topics which were hierarchically grouped by the model based on shared content. Posts were identified among communities for individuals with diabetes and obesity, as well as for diseases without a Food and Drug Administration-approved indication. Most posts had a negative sentiment using the pretrained model, acknowledging the pretrained model is at risk for misclassifying posts. Conclusions: AI can generate insights on perceptions of GLP-1RAs on social media. Common themes included success stories of improving diabetes and obesity management, struggles with insurance coverage, and questions regarding diet, side effects, and medication administration.

Subcutaneous Semaglutide during Breastfeeding: Infant Safety Regarding Drug Transfer into Human Milk.

Postpartum mothers and their healthcare providers often face the challenge of limited data regarding the safety of drug therapies during lactation. Pregnancy can lead to sustained weight gain, and obesity can negatively impact both physical and psychological well-being. The introduction of GLP-1 agonists to augment weight loss has become a topic of interest for many postpartum mothers. Our study aims to investigate the transmission of semaglutide into human milk in the first steps to ensure the safety and health of both lactating mothers and their breastfed infants. Semaglutide quantification was performed using high-resolution liquid chromatography-mass spectrometry. InfantRisk Center Human Milk biorepository released milk samples from eight women collected at 0, 12 and 24 h post-semaglutide administration. Semaglutide was extracted using protein precipitation in methanol, followed by chromatographic separation. Linear calibration curves for the method ranged between 2.5-30 ng/mL, with a limit of detection of 1.7 ng/mL and a limit of quantification of 5.7 ng/mL (LLOQ). Semaglutide was not detected in any of the collected human milk samples. A worst-case scenario of the relative infant dose (RID) was calculated using the LLOQ as the drug concentration in milk when considering semaglutide's bioavailability and long-acting dose profile. The maximum RID projected was 1.26%, far below the standard 10% safety threshold. While questions about long-term infant outcomes, the safety of maternal nutrient intake, and the nutrient content of breast milk remain, our findings suggest that semaglutide concentrations in human milk are unlikely to pose clinical concerns for breastfed infants. These results support healthcare providers in making informed decisions regarding postpartum therapeutic interventions.

The Role of Glucagon-Like Peptide-1 Agonists in the Treatment of Multiple Sclerosis: A Narrative Review.

Multiple sclerosis (MS) is a chronic, progressive autoimmune disease modulated by autoantibodies that inflame and destroy the myelin sheath encasing neuronal axons, impairing proper axonal conduction and function. Glucagon-like peptide-1 (GLP-1) receptor agonists have been demonstrated to exert anti-inflammatory and neuroprotective effects, making these drugs particularly exciting prospects in the treatment of MS. While the exact mechanism remains unclear, GLP-1 receptor agonists may modulate inflammatory responses by targeting GLP-1 receptors present on immune cells such as macrophages, monocytes, and lymphocytes. In animal models, GLP-1 agonists have been shown to significantly delay the onset and severity of experimental autoimmune encephalopathy symptoms, as well as to increase nerve myelination and brain weight. In further experiments using animal models of nerve crush injury, specimens given GLP-1 agonists reported a significant increase in the rate and density of nerve regeneration compared to controls. Thus, GLP-1 agonists show promise as both prophylactic and symptomatic treatment for MS and may provide further utility in the treatment of other autoimmune, inflammatory, and neurodegenerative conditions.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may reduce the risk of developing cancer-related lymphedema following axillary lymph node dissection (ALND).

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.

A cost comparison of GLP-1 receptor agonists and bariatric surgery: what is the break even point?

BACKGROUND: With the prevalence of obesity rising in the US, medical management is of increasing importance. Two popular options for the treatment of obesity are bariatric surgery (e.g. sleeve gastrectomy and Roux-en-Y gastric bypass) and the increasingly popular GLP-1 Receptor Agonists (GLP-1 s). This study examines the initial and long-term costs of GLP-1 s compared to bariatric surgery. STUDY DESIGN: We compared average 2023 national retail prices for GLP-1 s to surgical cost estimates from 2015 adjusted for inflation. We then plotted the cumulative medication cost over time against the flat cost of each surgery, thus calculating "break-even points" (when medication costs equal surgery costs). The findings revealed a crucial insight, for some GLP-1 s like Saxenda and Wegovy, the high cost of ongoing use surpasses the cost of RYGB in less than a year and sleeve gastrectomy within nine months. Even the most affordable option, Byetta, becomes costlier than surgery after around 1.5 years. RESULTS: This highlights the importance of looking beyond the initial financial investment when considering cost-effectiveness. Additionally, while not directly assessed, this study acknowledges that GLP-1 s take time to reach full effectiveness, potentially delaying weight loss while accumulating costs. Concerns also exist about weight regain after discontinuing the medication. CONCLUSION: This study is limited by the real-world variation for individual treatment costs (e.g. insurance), a limited evaluation of long-term costs associated with either treatment modality and their co-morbidities, and the reality of patient preference providing subjective value to either modality. Overall, the study offers insights into the financial trade-offs between GLP-1 s and bariatric surgery.

The effectiveness of 0.5 mg and 1mg of semaglutide in patients with type two diabetes and predictors of response: a retrospective cohort study.

Background: Semaglutide is a glucagon-like peptide-1 receptor agonists (GLP-1-RAs) approved for the treatment of type 2 diabetes mellitus (T2DM) at doses up to 1 mg. The results from randomized control trials and real-world studies revealed that weekly semaglutide was associated with significant improvements in HbA1c and body weight. To our knowledge, no study assessed the effectiveness of using semaglutide for patients with T2DM in the Saudi population. We aim to assess the effectiveness of once weekly SC 0.5 and 1 mg of semaglutide on HbA1c and weight reduction in patients with T2DM in the Saudi population within 12 months of use, evaluate the predictors of response, and compare the effect of the two doses. Method: This is a retrospective cohort study conducted at Security Force Hospital in Riyadh, Saudi Arabia. Using electronic medical records of patients with type two diabetes who received semaglutide 0.5 or 1 mg for a total duration of at least 12 months of use. Results: Within the study period of semaglutide use, HbA1c significantly decreased from baseline by -2.1% (-2.3 to -1.91, 95% CI) (P <0.001). While the mean change in weight was -6.19 kg (-6.66 to -5.72, 95% CI) (P<0.001). Moreover, BMI, FBG, total cholesterol, LDL, and TG all decreased significantly from baseline (p<0.001). When comparing the sub-groups of 0.5 and 1 mg doses, although results were numerically favorable of 1 mg, there were no statistically significant differences in HbA1c % (-2.1 ± 1.8 vs. -2.1 ± 1.9, p-value= 0.934, respectively), and weight (-6.1 ± 5 vs. -6.2 ± 4.4 kg, p-value=0.837, respectively). Significant predictors of HbA1c reduction were the duration of DM, baseline HbA1c, and insulin therapy. While the significant predictor for weight reduction was insulin therapy. Conclusion: This study is document the effectiveness of once-weekly SC semaglutide on glycemic control and weight loss in real-world practice. We recommend a starting goal dose of 0.5 mg and gradual increase of dose based individual patient response. further studies are needed to assess the effectiveness and tolerability of various semagltude doses.

Wernicke Encephalopathy Associated With Semaglutide Use.

A patient presenting to the emergency room with neurological symptoms is more commonly found to have manifestations of stroke, transient ischemic attack, or nervous system injury. Alcoholic Wernicke encephalopathy (WE) is also another common manifestation of neurological dysfunction; however, the prevalence of non-alcoholic WE is relatively uncommon. We discuss a 37-year-old male who presented to the ED with dysphagia, slurred speech, word-finding difficulty, and restricted extraocular movements from non-alcoholic WE in the setting of semaglutide use.

Semaglutide and health risk: Development and validation of a LC-HRMS method for testing semaglutide in whole blood and application to real cases.

The use of semaglutide, also known by its trade name Ozempic®, has been increasing worldwide in recent years due to its benefits in treating type II diabetes. Thanks to its effects on appetite regulation, in many countries it is also used to treat obesity. However, due to its promotion by social media and celebrities as a weight-loss treatment, semaglutide is misused by a non-diabetic and non-obese population and by a young public, which is the main target of these media. Following the alert by the ANSM (Agence nationale de sécurité du médicament) in France and the FDA (Food and Drug Administration) in the United States, which imposed the addition of fatal effects to the list of side effects, the misuse of semaglutide seems to be becoming a public health problem. For this reason, it seems important that a toxicology laboratory has the capacity to test for semaglutide in blood. In this study, the authors have developed and validated a method for the identification and quantification of semaglutide in whole blood using a LC-HRMS. After the addition of the internal standard (bovine insulin), the blood was subjected to protein precipitation using a mix of acetonitrile/methanol (70:30,v:v). The validation procedure demonstrated an acceptable linearity between 2 and 500 ng/mL. LOD and LOQ were 1 and 2 ng/mL, respectively. Intra and inter-day precision were below 20 % at three concentrations. The method was successfully applied to the blood samples of 3 diabetic patients under treatment of semaglutide. The samples tested positive with concentrations ranging from 31 to 70 ng/mL which fall within the limits of therapeutic blood concentrations described in the literature.

Interaction of Semaglutide and Ziprasidone in a Patient With Schizophrenia: A Case Report.

Semaglutide (Ozempic), a GLP-1 receptor agonist effective in weight management, and ziprasidone (Geodon), an antipsychotic with a lower risk of metabolic side effects, are well-established in treating type 2 diabetes and schizophrenia, respectively. However, their interactions and effects on psychiatric symptoms are less understood. In this study, we report a case of a 43-year-old male with schizophrenia and diabetes with exacerbated paranoid delusions upon semaglutide administration for weight loss; symptoms peaked at higher doses and subsided after dose reduction. Concurrently, serum ziprasidone levels were significantly elevated at the dose reduction, suggesting a pharmacokinetic interaction likely due to semaglutide-induced slowed gastric emptying affecting ziprasidone's absorption and metabolism. This study illustrates the need for careful monitoring of psychiatric symptoms and drug levels when these medications are used together. Additionally, further research into their interactions to optimize treatment for patients with coexisting metabolic and psychiatric conditions is warranted.

The effect of GLP-1R agonists on the medical triad of obesity, diabetes, and cancer.

Glucagon-like peptide-1 receptor (GLP-1R) agonists have garnered significant attention for their therapeutic potential in addressing the interconnected health challenges of diabetes, obesity, and cancer. The role of GLP-1R in type 2 diabetes mellitus (T2DM) is highlighted, emphasizing its pivotal contribution to glucose homeostasis, promoting ß-cell proliferation, and facilitating insulin release. GLP-1R agonists have effectively managed obesity by reducing hunger, moderating food intake, and regulating body weight. Beyond diabetes and obesity, GLP-1R agonists exhibit a multifaceted impact on cancer progression across various malignancies. The mechanisms underlying these effects involve the modulation of signaling pathways associated with cell growth, survival, and metabolism. However, the current literature reveals a lack of in vivo studies on specific GLP-1R agonists such as semaglutide, necessitating further research to elucidate its precise mechanisms and effects, particularly in cancer. While other GLP-1R agonists have shown promising outcomes in mitigating cancer progression, the association between some GLP-1R agonists and an increased risk of cancer remains a topic requiring more profound investigation. This calls for more extensive research to unravel the intricate relationships between the GLP-1R agonist and different cancers, providing valuable insights for clinicians and researchers alike.

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.

A meta-analysis of the incidence of acne vulgaris in patients treated with GLP-1 agonists.

Background: With the emerging popularity of GLP-1 receptor agonists, patients are noticing acne vulgaris side effects that are seemingly related to the concurrent treatment with the drug. Due to the correspondence between these drugs' relatively recent emergence in the U.S. market and their high demand, it is important to investigate what is currently known in the literature so that patients can be properly informed. Objective: The aim of this study is to investigate the relationship, or lack thereof, between glucagon like peptide 1 (GLP-1) receptor agonist usage and acne-related side effects in patients. Methods: A web-based analysis of 6 GLP-1 receptor agonists (3 with a once-weekly dosing schedule, and 3 with a once-daily dosing schedule) was conducted on PubMed online database. Boolean criteria were used to narrow the search. Included in the meta-analysis were 45 research articles that fulfilled the search criteria. Results: The results of the search showed that from the following long-acting GLP-1 receptor agonists, dulaglutide, exenatide extended release, and semaglutide (Wegovy), no conclusive acne side effects were reported. In addition, the results also showed that from the following short-acting GLP-1 receptor agonists, liraglutide, lixisenatide, and semaglutide (Rybelsus), no conclusive acne side effects were reported. Limitations: Limitations of this study include a limited amount of literature regarding the relationship between GLP-1 agonists and acne vulgaris. Conclusion: It is unlikely that GLP-1 agonists themselves are directly responsible for the acne that some patients may develop during treatment. Rather, it is more probable that the weight loss yielded by treatment with these drugs may induce intrinsic physiologic and hormonal changes that induce or exacerbate acne vulgaris in such patients.

The Impact of Glucagon-like Peptide 1 Receptor Agonists on Obstructive Sleep Apnoea: A Scoping Review.

BACKGROUND: Obstructive sleep apnoea (OSA) and associated hypopnoea syndromes are chronic conditions of sleep-disordered breathing with significant sequelae if poorly managed, including hypertension, cardiovascular disease, metabolic syndrome and increased mortality. Glucagon-like peptide 1 receptor agonists (GLP-1RA) have recently garnered significant interest as a potential therapeutic, attributed to their durable effects in weight loss and glycaemic control in metabolic syndromes, such as obesity and type 2 diabetes mellitus. This has led to significant investment into companies that produce these medications and divestment from traditional gold standard methods of OSA management such as continuous positive airway pressure machines. Despite these sentiments, the impacts of these medications on OSA outcomes are poorly characterised, with no high-quality evidence at this stage to support this hypothesis. This scoping review therefore aims to address the research question of whether GLP-1RAs lead to a direct improvement in OSA and associated hypopnoea syndromes. METHODS: A scoping review was performed following a computer-assisted search of Medline, Embase and Cochrane Central databases. Papers that evaluated the use of GLP-1RA medications related to sleep-disordered breathing, OSA or other sleep-related apnoeic or hypopnoeic syndromes were included. RESULTS: Literature search and evaluation identified 9 articles that were eligible for inclusion. Of these, 1 was a study protocol, 1 was a case report, 1 was an abstract of a randomised controlled trial (RCT), 1 was a non-randomised clinical trial and the remaining 5 were randomised clinical trials of variable rigour. All studies evaluated the outcomes of GLP-1RAs in patients with diagnosed OSA or symptoms suggestive of this condition. CONCLUSION: This scoping review identified early evidence to suggest that GLP-1RAs may improve OSA as defined by reduction in apnoea-hypopnoea index (AHI). This evidence is however conflicting due to contradicting results demonstrated from other studies. Overall, these medications were tolerated well, with minor gastrointestinal side-effects reported in some cases. Of all included studies, the quality of evidence was low, with short lengths of follow-up to identify durable effects of these medications on OSA outcomes and identify adverse events. More rigorous, RCTs with sufficient length of follow-up are required before consideration of formalising these medications into OSA treatment guidelines, frameworks and policies are warranted.

AGA Rapid Clinical Practice Update on the Management of Patients Taking GLP-1 Receptor Agonists Prior to Endoscopy: Communication.

DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Rapid Clinical Practice Update (CPU) Communication is to review the available evidence and provide expert advice regarding the evolving management of patients taking GLP-1 receptor agonists prior to endoscopy. METHODS: This CPU was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPUC and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. This communication incorporates important and recently published studies in this field, and it reflects the experiences of the authors who are experts in bariatric medicine and/or endoscopy.

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.