Semaglutide

In brief: Rybelsus R2 rebranded as Ozempic.

Real-world outcomes of hybrid obesity care using digital coaching and GLP-1 therapy in a multi-ethnic Asian setting.

Shahmir H Ali, Michelle H Lee, Kyle Xin Quan Tan +4 more

Obesity remains a major health challenge globally and in Asia, driving cardio-metabolic disease risks. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and mobile health (mHealth) coaching each demonstrate weight loss efficacy, but real-world evidence for hybrid models combining these treatments remains limited, especially in multi-ethnic Asian settings.

The "Ozempic® Limb": Understanding the Impact of Semaglutide on Prosthesis Use and Residual Limb Care in Individuals with Lower Limb Amputation - Case Report.

Janelle Bykowski, Garrick Loewen, Brock Loewen +1 more

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are well-known medications commonly prescribed for type 2 diabetes management and pharmacologic management of obesity. While GLP-1 RAs have many positive effects on glycemic control and cardiovascular health, the secondary effect of weight loss can present a challenge in maintaining optimal prosthesis fitting and functionality among individuals with prosthetic limbs. More specifically, weight loss can lead to decreased muscle mass and volume of the residual limb, resulting in loosening of the prosthesis. In turn, individuals often require more frequent prosthetic adjustments to ensure their safety and comfort while using the prosthetic device. Herein, we describe three cases of semaglutide use in patients with prosthetic limbs who subsequently presented with a variety of complications including skin breakdown, disproportionate residual limb volume loss, decreased prosthetic use and increased residual limb pain. Such "Ozempic® limbs" have not yet been reported in the literature. These observations suggest that further research in GLP-1 RA selection is required for persons with amputation, as well as increased patient education regarding the unique complications.

Real-world glycemic control, exploratory cardiorenal indicators, and safety of polyethylene glycol loxenatide versus semaglutide in type 2 diabetes patients: a Chinese two-center retrospective cohort study.

Zelin Yu, Duoyi Fu, Jing Xu +7 more

To compare the real-world efficacy and safety of high dose once-weekly glucagon-like peptide-1 receptor agonists polyethylene glycol loxenatide (PEG-Loxe) and subcutaneous (s.c.) semaglutide in patients with suboptimally controlled type 2 diabetes mellitus (T2DM).

Efficacy and safety of semaglutide injection in comparison with reference semaglutide for chronic weight management in indian adults with obesity: A phase III randomized non-inferiority trial.

Prabhat Kumar Sharma, Sagar Vivek Redkar, Abhishek Madhav Karmalkar +23 more

In India, approximately 33-46% people are obese which is a major risk factor to several non-communicable diseases. Amongst all existing treatment modalities, semaglutide injection is the proven most effective glucagon-like peptide-1 (GLP-1) receptor agonist for obesity, but high costs limit global accessibility. We report the Phase III trial evaluating the efficacy, safety and immunogenicity of a novel formulation of Semaglutide Injection in Indian patients with obesity.

Genetic predictors of GLP1 receptor agonist weight loss and side effects.

Qiaojuan Jane Su, James R Ashenhurst, Wanwan Xu +39 more

The development of glucagon-like peptide 1 (GLP1) receptor agonists, including semaglutide and tirzepatide, has transformed the clinical management of overweight and obesity. However, substantial inter-person variability exists in both weight loss efficacy and the incidence of side effects1. To investigate the genetic basis of this variability, here we conduct a genome-wide association study of self-reported weight loss and treatment-related side effects in 27,885 people following GLP1 receptor agonist therapy. We identify a missense variant in GLP1R that is associated significantly with increased efficacy of GLP1 medications (P = 2.9 × 10-10), with an additional -0.76 kg of weight loss expected per copy of the effect allele. Furthermore, we identify associations linking variation in both GLP1R and GIPR to GLP1 medication-related nausea or vomiting, with the GIPR association being restricted to people using tirzepatide. We incorporate these findings into a broader model of GLP1 medication response, and demonstrate the ability to stratify patients by efficacy and side effect risk. These findings provide direct genetic evidence that variation in the drug target genes contributes to inter-person variability in response and lay the foundation for precision medicine approaches in the treatment of obesity.

Oral semaglutide reduces diabetes-related distress in adults with type 2 diabetes mellitus switching from DPP-4 inhibitors. The DOORS prospective real-world Italian study.

Andrea Giaccari, Francesca Borroni, Marco Dauriz +6 more

To evaluate glycaemic control, weight management, and patient-reported outcomes (PROs) in adults with type 2 diabetes mellitus who transitioned to oral semaglutide (OS) after inadequate glycaemic control on dipeptidyl peptidase-4 inhibitors (DPP-4i).

Updated Global Consensus Recommendations for Risk Stratification, Treatment Initiation, and Response Monitoring in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Zobair M Younossi, Markos Kalligeros, Vincent Wai-Sun Wong +47 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) have increased in prevalence alongside the global epidemics of obesity and type 2 diabetes and now represent one of the leading causes of chronic liver disease. Patients with MASLD and significant fibrosis (≥F2) are at increased risk for adverse outcomes. With advances in noninvasive tests (NITs) and the recent approval of resmetirom and semaglutide for noncirrhotic MASH with F2-F3 fibrosis, we provide updated consensus guidance on standardized risk stratification, treatment initiation, and response monitoring.

Emerging natural products against obesity and metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis: Direct target discovery and mechanistic insights.

Wei Hu, Meng Gu, Huibo Li +5 more

Obesity is a multifactorial metabolic condition characterized by dysregulated lipid accumulation and systemic energy imbalance with escalating global prevalence. This chronic disease drives a spectrum of life-threatening comorbidities, including metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), which now represent a primary cause of liver-related morbidity and transplantation. Both conditions share pathophysiological underpinnings such as insulin resistance, chronic inflammation, and mitochondrial dysfunction, creating a vicious cycle where obesity exacerbates hepatic steatosis and fibrosis. Although US Food and Drug Administration-approved antiobesity agents such as glucagon-like peptide-1 receptor agonists (eg, semaglutide) demonstrate weight loss efficacy, their long-term utility is constrained by gastrointestinal intolerance and variable effects on hepatic outcomes. Similarly, the recent approval of resmetirom for MASH, though groundbreaking, leaves unresolved challenges in durability, accessibility and some adverse effects including gastrointestinal reaction. The intricate molecular crosstalk linking adipose and hepatocyte dysfunction necessitates innovative therapeutics targeting shared pathophysiological pathways or novel molecular targets. Natural products, with inherent structural diversity and multitarget potential, offer a promising avenue for dual intervention in the obesity-MASH continuum. This review systematically evaluates emerging endogenous metabolites and plant-derived compounds, elucidating their directly validated molecular targets and preclinical evidence for metabolic reprogramming against obesity and MASLD/MASH. Furthermore, it synthesizes translational insights from natural product research and clinical trial experiences of related synthetic agonists. By integrating mechanistic discovery with a critical assessment of developmental challenges, this review aims to advance strategic frameworks for the concurrent management of obesity and MASLD/MASH. SIGNIFICANCE STATEMENT: Obesity-driven metabolic dysfunction-associated steatotic liver disease and steatohepatitis are leading causes of liver morbidity with limited treatment options. This review systematically evaluates natural products as multitarget therapeutics for these interconnected conditions. By integrating evidence of their efficacy and target mechanisms with modern discovery approaches, this study emphasizes pathways for clinical translation and aims to stimulate future research into novel, mechanism-based interventions.

Real-World Effectiveness and Safety of Escalating Once-Weekly Semaglutide from 0.5 to 1.0 mg in Type 2 Diabetes.

Genki Sato, Hiroshi Uchino, Kota Takuma +5 more

Real-world data on escalation of once-weekly semaglutide from 0.5 to 1.0 mg remain limited. Therefore, we aimed to evaluate the effectiveness and safety of this dose escalation in routine clinical practice.

Molecular Characterization of the Effect of Glucagon-Like Peptide-1 Receptor Agonist Semaglutide in the Nephrotoxic Serum Nephritis Mouse Model.

Jaime Moreno Martinez, Maria Ougaard, Tanya Grancharova +7 more

CKD is a significant public health issue, affecting approximately half a billion people globally. Key risk factors for CKD include obesity, hypertension, cardiovascular diseases and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are effective treatments for obesity and diabetes. The FLOW trial recently showed that treatment with the GLP-1RA semaglutide significantly reduced the incidence of clinically important kidney outcomes in patients with type 2 diabetes and CKD, likely via beneficial effects on kidney blood flow, inflammation and fibrosis as well as effects mediated by improvement of glycemic control. This study aimed to characterize the effects of semaglutide in the mouse nephrotoxic serum nephritis model, a non-obese and non-diabetic mouse model of CKD.

Preoperative GLP-1 Receptor Agonists and Thromboinflammatory Markers in Patients Undergoing Abdominoplasty: A Prospective Monocentric Study.

Agostino Bruno, Marco Schirosi, Riccardo Foti

Abdominoplasty in patients with obesity carries a heightened risk of venous thromboembolism (VTE) due to a proinflammatory and hypercoagulable baseline. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for weight loss and have demonstrated anti-inflammatory and antithrombotic properties, but their role in aesthetic surgery remains unexplored.

Semaglutide-Induced Weight Loss Is the Main Determinant for the Improvement of Hepatic Biochemistry and Elastographic Repeated Measurements with FibroScan® in Patients with Type 2 Diabetes Mellitus and Metabolic Dysfunction-Associated Steatotic Liver Disease.

Savvoula Savvidou, Elektra Augousti-Varela, Aikaterini Damianakou +2 more

Semaglutide is currently being investigated for its effectiveness in metabolic dysfunction-associated steatotic liver disease (MASLD), irrespective of type 2 diabetes mellitus (T2DM) presence, even though its action on hepatic fibrosis is still debated. The aim of this study was to examine the effect of semaglutide on hepatic parameters in patients with both T2DM and MASLD in real-world clinical practice, and to further assess the significance of weight loss during treatment.

Sex-specific metabolic responses to glucagon receptor agonism and modulation of the FGF21-glucagon axis in female mice.

Christoffer Merrild, Valdemar Brimnes Ingemann Johansen, Christoffer Clemmensen +1 more

Glucagon receptor agonism, particularly when combined with incretin analogues, is currently being explored as a treatment for obesity to improve cardiometabolic health, given glucagon's key role in regulating energy homoeostasis. However, male-biased preclinical studies limit our understanding of sex-specific responses to glucagon receptor activation, especially regarding fibroblast growth factor 21 (FGF21), a major downstream effector of glucagon signalling. To test whether responses to glucagon receptor agonism are sex dependent and modulated by FGF21, we compared a long-acting glucagon analogue (LA-Gcg) with the GLP-1 analogue semaglutide in diet-induced obese male and female mice. We then used female Fgf21 knockout (KO) mice to probe the role of the FGF21-glucagon axis in the response to glucagon receptor agonism. LA-Gcg induced greater weight loss, reduced food intake and more strongly altered hepatic gene expression in males, whereas semaglutide effects were comparable between sexes. LA-Gcg impaired glucose tolerance more severely in females than in males. This impairment was exacerbated in female Fgf21 KO mice, despite similar reductions in body weight between genotypes. Notably, FGF21 deficiency potentiated diet-induced obesity in females but had minimal impact under chow diet, fasting or voluntary exercise. Collectively, these findings reveal that both sex and FGF21 modulate metabolic responses to glucagon-based therapies, emphasizing the importance of including female models in preclinical metabolic research to better predict therapeutic efficacy. KEY POINTS: Biological sex is known to affect metabolism, yet this variable remains largely underexplored in metabolic research. In males, glucagon's metabolic benefits often involve another hormone, FGF21 (fibroblast growth factor 21), but this relationship is largely unstudied in females. A long-acting glucagon (LA-Gcg) treatment caused less weight loss in obese female mice, failing to reduce their food intake, unlike in males. LA-Gcg also worsened glucose tolerance in females. Female mice lacking the Fgf21 gene were more susceptible to diet-induced obesity; although LA-Gcg treatment still reduced their weight and cleared liver fat, the absence of FGF21 worsened the drug-induced glucose intolerance. Our findings highlight sex-specific differences in metabolic responses to glucagon, emphasizing the need to consider sex as a key variable in the development of glucagon-based therapies.

Semaglutide as a potential tool in pre-lung transplant weight loss optimization.

Roshaneh Ali, Holly Keyt, Carolina Solis-Herrera +1 more

Patients with end-stage lung disease go through an extensive screening process prior to transplant. Obesity and uncontrolled type 2 diabetes mellitus (T2DM) are unfavorable risk factors that lead to poor outcomes. We present the case of a 69-year-old man with stage IV chronic obstructive pulmonary disease (COPD) on chronic oxygen, T2DM on insulin, and class II obesity (reference range, body mass index [BMI], 35.0-39.9) who underwent pre-lung transplant evaluation. He had a BMI of 38.05, surpassing the institutional transplant eligibility criteria of BMI <32. The patient was initiated on semaglutide for weight loss. After 6 months, the patient's BMI decreased to 30.5, losing 25 kg and qualifying him for transplant. However, given substantial improvements in respiratory status, the pre-lung transplant committee deferred waitlisting. After 16 months of treatment, the patient lost a total of 35.17 kg, his forced vital capacity improved from 44% to 82%, and he was weaned off oxygen. Chronic hypoxia and corticosteroids make weight management challenging for COPD patients. This case demonstrates the use of semaglutide for rapid weight loss and improved respiratory function in patients with end-stage lung disease, emphasizing its emerging potential in pre-lung transplant optimization.

Effect of Semaglutide on Body Weight, Blood Lipid Profile, and Adipokine Status in Obese Patients.

A V Tyurina, N S Kurochkina, M V Yezhov

Aim        To evaluate the dynamic impact of an 8-month glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy with semaglutide on anthropometric metrics, blood lipid profiles, and adipokine status in obese patients, with and without type 2 diabetes mellitus (T2DM).Material and methods    The study included 65 patients with obesity, 26 of whom had T2DM. All participants were prescribed semaglutide, with dose titration up to 1 mg once weekly over 8 months. Before and after the treatment period, the following variables were assessed: anthropometric data (body weight, body weight index, waist circumference), biochemical parameters (lipid profile, glucose, aspartate aminotransferase, alanine aminotransferase, creatinine), and adipokine concentrations (leptin, adiponectin, resistin) via immunofluorescence assay.Results  Semaglutide therapy was associated with a statistically significant reduction in body weight (p<0.001), body mass index (p<0.001), and waist circumference (p<0.001). Improvements in the lipid profile were observed over time, including decreased concentrations of low-density lipoprotein cholesterol (p=0.001), triglycerides (p<0.001), and total cholesterol (p=0.001), alongside an increase in high-density lipoprotein cholesterol (p<0.01). Therapy significantly impacted adipokine status: a statistically significant increase in anti-atherogenic adiponectin (p<0.001) and a decrease in leptin levels (p<0.001) were recorded, indicating improved adipose tissue metabolic function. However, no significant changes in resistin concentrations were found. Additionally, positive effects on liver and kidney function markers were noted, manifested by reductions in aspartate aminotransferase and alanine aminotransferase activity, as well as creatinine levels. In the subgroup of patients with T2DM, a statistically significant improvement in glycemic control was observed.Conclusion         Semaglutide therapy for 8 months in obese patients yielded a robust cardiometabolic impact, characterized by significant weight reduction, optimized lipid profiles, and improved liver and kidney function markers, alongside a favorable restructuring of adipokine status. These results support the use of GLP-1 RAs not only for glycemic and weight control but also as a multifaceted cardioprotective therapy for obese patients.

Responses to GLP-1RA in White and Black Adults With Obesity: Insights From Generalized Additive Mixed Models of EHR Data.

Jordan H Mallette, Joshua S Speed, Seth T Lirette +2 more

This study examined racial differences in weight loss and clinical response to glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy among adults with obesity using real-world data.

Appetite, Obesity, Metabolism, and Malignancy: Do Incretin-Mimetic Drugs Reduce Cancer Risk?

Andrew G Renehan, Michael N Pollak

Obesity is associated with increased risk of at least 13 adult cancer types and is the second most common cause of cancer (after tobacco) in many populations. Uncertainty about the extent to which intentional weight loss leads to reduced cancer risk represents a gap in knowledge. Evidence from bariatric surgery studies shows that sustained weight reduction of 20% to 30% in individuals with severe obesity is associated with reduced risk of obesity-related cancers over 10 years. However, in terms of population health, this is not a viable cancer prevention strategy. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RA), known to be effective antidiabetes drugs, have been shown in randomized trials to cause substantial weight loss (in the order of 15%) in obese individuals with or without diabetes. This is a rapidly evolving field, which has revolutionized the modern management of obesity. Much clinical experience has been with semaglutide (a GLP-1RA) and tirzepatide (a dual agonist of the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide receptor), but newer drugs in the class are being developed. We review available data that provide a strong rationale for evaluating incretin-mimetic drugs in a cancer prevention trial but show that the feasibility of such a trial is questionable.

The Role of Glucagon-Like Peptide-1 Receptor Agonists in Prompting a Meaningful Improvement in Alcohol Use Disorder.

Alyx Meilinger, Michael A Campbell, Hannah M Reynolds +1 more

Emerging research suggests a potential role for glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in alcohol use disorder (AUD), because GLP-1 receptors are present in the brain regions involved in dopamine signaling and the human reward system. We present the case of a man prescribed GLP-1 RAs for obesity who had concomitant AUD. A 34-year-old man was referred to a family medicine clinic for medication therapy management of obesity. His medical history was notable for bipolar disorder, class 2 obesity, and obstructive sleep apnea (OSA). His Alcohol Use Disorders Identification Test score indicated high-risk alcohol use. Over the course of 10 months using an injectable GLP-1 RA (semaglutide), the patient showed a clinically significant decrease in both body weight and alcohol consumption. Although this patient initially sought care for weight loss goals to improve quality of life and symptoms of OSA, after 10 months of treatment with semaglutide he reported a considerable decrease in alcohol consumption leading to mental, social, and home life improvements. Our aim in presenting this case is to illustrate the potential benefit of GLP-1 RAs for decreasing alcohol consumption levels in a patient with multiple comorbid conditions. The case adds to the growing body of evidence supporting the exploration of GLP-1 RAs for the treatment of AUD. Additionally, it underscores the need to enhance AUD screening efforts within family medicine clinics to identify high-risk persons and provide timely interventions.

Fat, muscle, and anti-obesity medications in cardiovascular disease prevention.

Muhammad Shahzeb Khan, Muhammad Hamza Dawood, Yehuda Handelsman +4 more

The rapid expansion of anti-obesity treatments with glucagon-like peptide-1 receptor agonists has redefined weight management. A consistent component of this weight loss, however, involves not only fat mass but also lean body mass, including skeletal muscle. This raises concerns regarding sarcopenia, frailty, and metabolic resilience that may attenuate long-term cardiovascular risk reduction. Muscle loss with these drugs is multifactorial, related to caloric restriction, anabolic resistance, and hormonal shifts. Emerging agents targeting the myostatin/activin pathway, ligand traps, and selective androgen receptor modulators may increase muscle quality and have synergistic benefit with incretin-based therapies. Resistance training is currently the suggested strategy for preserving skeletal muscle and functional capacity during pharmacologic weight loss, while adjunctive strategies such as optimized protein intake and nutraceuticals may further mitigate muscle catabolism. A paradigm shift is needed in obesity treatment away from total weight loss towards high-quality weight loss that preserves or enhances muscle mass, optimizing body composition and supporting durable cardiovascular risk reduction. Future research should study lean mass preservation as a treatment goal, redefine trial endpoints, and validate emerging combination interventions for optimal body composition. This manuscript reviews the evidence on muscle loss with pharmacologic weight loss therapies, its mechanistic underpinnings, explores emerging agents designed to preserve lean tissue, and outlines strategies to optimize body composition in the context of cardiovascular prevention.