Semaglutide

GLP-1-based incretin therapy is associated with lower incident Alzheimer's disease and cardiorenal events in adults with documented neuropsychiatric, cognitive, or sensory risk.

Karthik Murugadoss, A J Venkatakrishnan, Venky Soundararajan

Alzheimer's disease (AD) develops over years, creating an opportunity for interventions that target modifiable risk factors before the onset of clinical dementia. Here we applied a federated electronic health record (EHR) system encompassing over 29 million de-identified patients toward a target-trial emulation framework involving 153,412 adults aged 50 years or older with at least one documented AD risk factor. New users of glucagon-like peptide-1 (GLP-1)-based incretin therapy were compared with new users of non-GLP-1 antidiabetic medications after a 12-month washout, with 1:1 propensity-score matching on 30 baseline variables and additional exact matching on index year of therapy initiation and 5-year age band. In the primary matched cohort, 28,901 patients per arm, incretin initiation was associated with lower first recorded AD diagnosis (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.29-0.73, q = 0.003), all-cause dementia (HR 0.66 [0.55-0.79], q < 0.001), and all-cause mortality (HR 0.46 [0.37-0.58], q < 0.001), with directionally-lower Mild Cognitive Impairment (HR 0.76 [0.61-0.94], q = 0.135) and Alzheimer's-related medication initiation (HR 0.82 [0.65-1.03], q = 0.217). The AD diagnosis mitigation signal was independently reproduced for semaglutide (HR 0.56; N = 23,675 per arm; q = 0.02), with the directionally consistent tirzepatide point estimate (HR 0.60) not reaching significance. GLP-1 RA initiation was also associated with substantially lower (all q < 0.001) incidence of heart failure (HR 0.50 [0.45-0.55]), cardiomyopathy (HR 0.38 [0.31-0.47]), major adverse cardiovascular events (HR 0.74 [0.67-0.82]), acute kidney injury (HR 0.67 [0.67-0.74]), and chronic kidney disease (HR 0.68 [0.62-0.75]). Negative-control outcomes showed no significant separation (all q > 0.45), including allergic rhinitis (HR 0.96 [0.87-1.07]), hemorrhoids (HR 1.07 [0.95-1.21]), and inguinal hernia (HR 1.39 [0.89-2.18]). Stricter two-code ICD definitions supported lower first recorded AD diagnosis in the incretin arm (HR 0.51 [0.29-0.89], q = 0.018) and lower first recorded all-cause dementia diagnosis (HR 0.68 [0.54-0.85], q = 0.003). In 12-month landmark analyses among semaglutide initiators, ≥5% weight-loss responders had lower 3-year AD cumulative incidence than non-responders after matching (0.07% vs. 0.40%; incidence ratio 5.76; P = .036), although this was not significant in the hazard-ratio model (HR 0.54, P = .39). Sustained-dose stratification showed no comparable gradient (high-dose vs. low-dose 0.30% vs. 0.14%; HR 2.77; P = .38), with ≤12 AD events per group. The weight-loss-specific pattern did not extend to all-cause dementia: weight-loss responders and non-responders had similar 3-year cumulative incidence (1.54% vs. 1.70%; HR 0.87, P = .53). Initiation of GLP-1 receptor agonist therapy in adults with documented AD risk factors was associated with lower recorded incidence of AD, dementia, mortality, and multiple cardiovascular and renal outcomes in this observational target-trial emulation. These findings support the hypothesis that earlier incretin therapy may contribute to AD risk modification through upstream cardiometabolic pathways, while prospective randomized prevention studies will be required to determine causality, underlying biological mechanisms, and optimal treatment timing.

Validation of a Pharmacist-Led Semaglutide Prescribing Algorithm for Type 2 Diabetes and Chronic Kidney Disease: Research Letter.

Maneka Sheffield, Emma Phelan, Natalie Ratajczak +10 more

Diabetes is a leading cause of chronic kidney disease, yet gaps in the use of guideline-directed therapies persist in primary care. In 2025, our group developed and validated community pharmacist-led prescribing algorithms for individuals with an estimated glomerular filtration rate ≥30 mL/min/1.73 m2, targeting angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, sodium-glucose cotransporter-2 inhibitors, and nonsteroidal mineralocorticoid receptor antagonists. To address the evolving therapeutic landscape, we developed and validated a semaglutide-specific algorithm to complement this approach. Algorithm development and validation followed Lynn's method. A two-part questionnaire per algorithm item assessed content and face validity, with nephrology clinicians (nephrologists and kidney pharmacists) and community pharmacists rating items using Likert scales. Content validity was measured using item-level (I-CVI) and scale-level (S-CVI/Ave) indices, while face validity was assessed by level of agreement to five statements per round. The algorithm was iteratively revised between rounds. Ten nephrology clinicians (five per round for three rounds) and 12 community pharmacists (six per round for two rounds) participated. For clinicians, the I-CVI ranged from 0.6 to 1.0, with an overall S-CVI/Ave of 0.89 across three rounds. Among pharmacists, all items met the prespecified content validity threshold for both rounds (I-CVI ≥0.83; P < 0.05). Face validity exceeded the 70% consensus threshold for both validator groups. This study adds a validated semaglutide-specific algorithm to our existing pharmacist-led care model, expanding a suite of algorithms to support uptake of disease-modifying therapies for individuals with type 2 diabetes and chronic kidney disease in primary care. Implementation and evaluation in Nova Scotia community pharmacy clinics are underway.

Efficacy and safety of semaglutide injection in Indian patients with type 2 diabetes mellitus inadequately controlled on metformin: A phase 3, randomized, active-controlled, multicenter, non-inferiority trial (WIN-IND study).

Ambrish C, Anurag Ranjan Kundan Lal Lila, Archit Parikh +31 more

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with a rapidly rising global burden. Present study established the non-inferiority and evaluated the safety of Intas semaglutide (test) compared to Innovator semaglutide (reference) in patients with T2DM inadequately controlled on metformin.

Real-world use of oral semaglutide in adults with type 2 diabetes.

Klaus Roslind, Ulrik Bodholdt, Tina Damgaard +1 more

PIONEER REAL Denmark assessed changes in HbA1c, body weight and treatment satisfaction with once-daily oral semaglutide in adults with type 2 diabetes.

Can Carica papaya Serve as an Adjunct to Semaglutide in Mitigating Diabetes-Induced Testicular Injury Through Modulation of Oxidative Stress, Inflammation, Apoptosis, and the miR-34c/miR-155-SIRT1/FOXO1 Axis? An Experimental and Chem-Bio-Informatics Study.

Mohamed M Zeweil, Asmaa F Khafaga, Marium M Shamaa +7 more

Diabetes mellitus (DM) induces significant endocrine disruption and oxidative stress (OS) within the testes, resulting in impaired spermatogenesis, increased sperm abnormalities, and compromised reproductive function. This study aimed to evaluate the combined protective effects of Semaglutide (SEM) combined with Carica papaya (papaya) juice against type 2 diabetes-induced testicular damage in rats. Forty adult male albino rats were divided into four experimental groups: a control group, a Streptozotocin (STZ)-induced diabetic group, a diabetic group treated with SEM (0.3 mg/kg), and a diabetic group treated with SEM (0.3 mg/kg) in combination with 10% papaya juice, administered for eight weeks. Statistically significant superiority over SEM alone was observed for selected endpoints; the findings primarily support the potential of papaya as a dose-sparing adjunct rather than demonstrating uniformly enhanced efficacy. They significantly improved systemic metabolic parameters, as evidenced by reduced fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) levels and restoration of the lipid profile. Importantly, it also attenuated diabetes-induced testicular injury, as demonstrated by improved reproductive hormone levels, enhanced sperm parameters, restoration of antioxidant defenses, modulation of inflammatory and apoptotic signaling, and marked histopathological recovery of seminiferous tubular architecture. Antioxidant markers revealed a notable reduction in malondialdehyde (MDA) and cytochrome P450 2E1 (CYP2E1), along with significant increases in reduced glutathione, catalase (CAT), and superoxide dismutase (SOD). Furthermore, a marked modulation of key pro-inflammatory and pro-apoptotic mediators was observed, including forkhead box protein O1 (FOXO1), microRNA-155 (miR-155), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B cell subunit 1 (NF-κB1), interleukin-6 (IL-6), caspase-3 (CASP3), and BCL2-Associated X Apoptosis Regulator (Bax), while a significant upregulation of sirtuin-1 (SIRT1), microRNA-34c (miR-34c), and B-cell lymphoma-2 (Bcl-2) was also detected. Histopathological assessments confirmed the restoration of normal testicular architecture in the treated groups. These findings indicate that the combination strategy may have the potential to achieve dose savings while maintaining efficacy comparable to the standard-dose SEM, through the enhancement of the antioxidant defenses, modulation of inflammation, and apoptosis, specifically via the modulation of the miR-34c/miR-155 and SIRT1/FOXO1 signaling.

Once-weekly IcoSema versus once-daily insulin glargine U100 in type 2 diabetes management (COMBINE 4): an open-label, multicentre, treat-to-target, randomised, phase 3b trial.

Linong Ji, Malik Benamar, Viswanathan Mohan +5 more

Stepwise treatment intensification is recommended for managing type 2 diabetes, including insulin initiation when non-insulin glucose-lowering medications are insufficient. Guidelines recommend combining a GLP-1 receptor agonist with basal insulin to improve glycaemic efficacy while reducing weight gain and hypoglycaemia risk. COMBINE 4 evaluated the efficacy and safety of IcoSema, a once-weekly combination therapy of basal insulin icodec and semaglutide (a GLP-1-receptor agonist) versus insulin glargine U100 (glargine U100) in people with type 2 diabetes on oral glucose-lowering medications.

Burden and Risk of Depression in Patients Receiving Semaglutide: A Systematic Review and Meta-Analysis.

Gaurab Bhaduri, Shilanjan Roy, Anchin Kalia +2 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including semaglutide, are widely used for Type 2 diabetes mellitus (T2DM), obesity and related metabolic conditions. Evidence on potential neuropsychiatric effects remains inconsistent. This systematic review and meta-analysis evaluated depression risk among patients receiving semaglutide. Following PRISMA 2020 guidelines, major biomedical databases, trial registries, pharmacovigilance databases, conference abstracts and grey literature were searched from inception to January 2026. Eligible studies included randomised controlled trials, observational studies, large database analyses and pharmacovigilance disproportionality studies involving patients receiving semaglutide. Risk of bias was assessed using ROBINS-I and the Newcastle-Ottawa Scale. The pooled risk ratio for depression was 1.25 (95% CI: 0.95-1.65; I2 = 98%). For anxiety and suicidal ideation/attempt, pooled risk ratios were 1.22 (95% CI: 0.93-1.60; I2 = 99%) and 1.20 (95% CI: 0.90-1.62; I2 = 92%), respectively. No statistically significant differences were observed between semaglutide and comparator/placebo groups for outcomes. Pooled estimates did not show a statistically significant increase in depression, anxiety or suicidal ideation/attempt among patients receiving semaglutide compared with comparator groups. However, the certainty of evidence was limited by substantial heterogeneity, risk of bias and reliance on heterogeneous data sources, including spontaneous-reporting studies. These findings are reassuring but should be interpreted as the absence of a detected increased risk in the available evidence, rather than definitive proof of no psychiatric risk.

Reframing GLP-1 Therapies as Cardiometabolic Health Drugs: Beyond the Race to Weight Loss.

Harlan M Krumholz

Effectiveness and Safety of Combined Semaglutide and Dapagliflozin Therapy in Type 2 Diabetes: A Retrospective Cohort Study.

Mahmoud Alzahrani, Najlaa Alsudairy, Zahra Al Asmari +6 more

Combination therapy with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors may provide complementary metabolic, cardiovascular, and renal benefits in type 2 diabetes mellitus (T2DM). However, real-world evidence from Middle Eastern populations remains limited. This study evaluated the effectiveness and safety of combined semaglutide and dapagliflozin therapy in routine clinical practice.

Advances in Cardiovascular Pharmacotherapy. IX. Protection Against Major Adverse Cardiovascular Events by Glucagon-like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus and Obesity.

Paul S Pagel, Dustin Hang, Julie K Freed +1 more

The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of insulinotropic peptides that replicate the effects of endogenous GLP-1 but have a prolonged duration of action. GLP-1 RAs have had a remarkably profound impact on the treatment of type 2 diabetes and obesity because they substantially improve glycemic control and produce considerable weight loss. The U.S. FDA's requirement that pharmaceutical companies establish the cardiovascular safety of new type 2 diabetes medications coincided with the development of GLP-1 RAs and mandated that trials be conducted to assure that their adverse cardiovascular effect profiles were noninferior to placebo. This FDA requirement proved to be fortuitous because many of the newly developed GLP-1 RAs were shown to cause unanticipated cardiovascular and renal protective effects, which led to their expanded use beyond patients with type 2 diabetes or obesity to those with atherosclerotic cardiovascular disease, chronic kidney disease, and heart failure with preserved ejection fraction. This first of two articles on the cardiovascular pharmacology of GLP-1 RAs briefly discusses the physiology of GLP-1, describes the discovery and development of GLP-1 RAs, examines the findings of major clinical trials and their substudies showing that GLP-1 RAs reduce major adverse cardiovascular events in patients with or at high risk for atherosclerotic cardiovascular disease and type 2 diabetes, and finally, reviews the evidence indicating that the GLP-1 RA semaglutide protects against major adverse cardiovascular events in patients with obesity and established cardiovascular disease but not type 2 diabetes.

Advances in Cardiovascular Pharmacotherapy. X. Glucagon-Like Peptide-1 Receptor Agonists in Heart Failure and Mechanisms of Protection.

Paul S Pagel, Dustin Hang, Julie K Freed +1 more

The first part of this two-part article discussed the physiology of glucagon-like peptide-1 (GLP-1), described the discovery and development of GLP-1 receptor agonists (RAs), examined the findings of major clinical trials and their substudies showing that GLP-1 RAs reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes and atherosclerotic cardiovascular disease, and finally, reviewed the evidence indicating that semaglutide protects against MACE in patients with obesity and established cardiovascular disease but not type 2 diabetes. This second part reviews recent clinical trials indicating that these drugs reduce symptom burden, increase exercise tolerance, and improve quality of life in patients with heart failure with preserved but not reduced ejection fraction. The article also discusses mechanisms by which GLP-1 RAs produce cardiovascular protection in patients with atherosclerotic cardiovascular disease or heart failure.

Obesity management for kidney TRANSPLANTation: protocol for the vanguard phase of an innovative randomised controlled trial, embedded in routine care (OK-TRANSPLANT 2).

Kristin K Clemens, Jennifer Irwin, Michael Chiu +14 more

Large randomised controlled trials (RCTs) of obesity interventions have excluded those with advanced chronic kidney disease (CKD) including recipients of dialysis. Obesity management is critically important to their health and healthcare, including their ability to access kidney transplant.

GLP-1 receptor agonists, metabolic syndrome, and Alzheimer's disease: Lessons and opportunities from the EVOKE trials.

Pragati Gupta, Valeria Pozzilli, Anastasia De Giovanni +4 more

Metabolic syndrome and Alzheimer's disease (AD) are increasingly recognised as interconnected, sharing vascular, metabolic and inflammatory pathways that accelerate brain ageing and cognitive decline. This review critically examines the evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for diabetes and obesity, may influence AD related pathways or reduce AD risk in metabolically vulnerable populations. Metabolic syndrome and AD related cognitive impairment share biological mechanisms including vascular damage, insulin resistance and chronic inflammation, suggesting that therapies targeting metabolic dysfunction could influence neurological outcomes. GLP-1RAs are notable for combining systemic benefits, like weight loss, improved glycaemic control, and reduced cardiovascular risk, with possible but incompletely established central nervous system effects. Experimental studies suggest that some GLP-1RAs may reduce amyloid and tau pathology, support mitochondrial function, and limit neuroinflammation, although recent preclinical studies and limited brain penetrance argue against a direct neuroprotective effect. Observational data suggest lower dementia rates among users compared with other antidiabetic treatments. However, the recent EVOKE and EVOKE + trials showed that oral semaglutide did not slow clinical progression in early symptomatic AD, despite positive biomarker effects. This highlights the challenge of translating biological plausibility into meaningful clinical benefit and refocuses attention on disease stage, target population, and mechanism. Beyond summarising evidence, this review advocates a more cautious and mechanism specific framework: preserving cognitive health may require addressing systemic metabolic dysfunction rather than targeting the brain alone. GLP-1 RAs have failed to show an effect in symptomatic AD, but their effects on metabolism might still be beneficial at earlier stages, such as the preclinical phase of AD. Future studies should determine whether earlier intervention in metabolically enriched groups can alter AD related cognitive, vascular, and biomarker trajectories.

Semaglutide vs Metabolic and Bariatric Surgery and Cardiovascular Outcomes in Obesity.

Ting-Chun Tseng, Sunny Ssu-Yu Chen, Hui-Yuan Chen +1 more

To compare cardiovascular outcomes associated with metabolic and bariatric surgery (MBS) versus semaglutide therapy among adults with obesity, stratified by type 2 diabetes mellitus (T2DM) status.

EQ-5D Health Utility Gains with Once-Weekly Semaglutide 2.4 mg in People with MASH and F2/F3 Fibrosis: An Analysis of ESSENCE.

Margarida Augusto, Robert Bauer, Simon Clancy +3 more

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of metabolic dysfunction-associated steatotic liver. It is highly prevalent, particularly among individuals with overweight or obesity, and substantially impairs health-related quality of life. Semaglutide 2.4 mg received accelerated approval from the US Food and Drug Administration in August 2025 for adults with noncirrhotic MASH and fibrosis stages F2-F3 based on results from the ESSENCE trial. This study aimed to estimate the impact of semaglutide on health utility in this population.

Perioperative management of GLP-1 receptor agonists: a structured narrative review with considerations relevant to neurosurgical patients.

Utkan Topçu, Ferhat Oto

The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) is increasing in the treatment of obesity and type 2 diabetes mellitus. Some patients taking these medications undergo cranial or spinal surgical procedures. Delayed gastric emptying is a key mechanism of action for these medications. Despite the standard preoperative fasting period, there is a risk of residual gastric contents remaining in the perioperative period. Since neurosurgical patients face a risk of postoperative complications such as aspiration, delayed extubation, and postoperative nausea and vomiting, there is a need for a clinically focused review.

AI Patient Support and 6-Month Medication Adherence in a Digital Obesity Program: A Retrospective Analysis.

Louis Talay, Connie Xu, John Alderete +3 more

Real-world glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapies face substantial attrition rates in commercial digital weight loss services (DWLSs). Conversational artificial intelligence (AI) has been proposed to enhance patient support at production scale, but robust evidence of its effectiveness in improving medication retention is scarce.

Efficacy and safety of once-weekly semaglutide 2·4 mg in Chinese adults with overweight or obesity (STEP 12): a randomised, double-blind, placebo-controlled, multicentre, phase 3b trial.

Lixin Guo, Xiaolei Bao, Kuo-Chin Huang +6 more

Semaglutide 2·4 mg is a GLP-1 receptor agonist that reduces bodyweight, and provides other cardiometabolic benefits, among people with a BMI at least 30 kg/m2 or at least 27 kg/m2 and with weight-related comorbidities. This trial aimed to evaluate the efficacy, tolerability, and safety of semaglutide 2·4 mg in adults from mainland China and Taiwan with overweight or obesity according to locally defined, BMI thresholds.

Case Report: Oral semaglutide-associated depression in a patient with type 2 diabetes mellitus: a dose-dependent recurrence confirmed on rechallenge and managed with vortioxetine-bupropion combination therapy.

Abdulrahman S Alanazi, Basmah A Alanazi

Oral semaglutide carries a neuropsychiatric safety profile that continues to evolve. Large clinical trials have not, at the group level, demonstrated excess psychiatric adverse events-but pharmacovigilance databases and case reports have documented a signal for depression and suicidal ideation in individual patients. A dose-dependent onset with rechallenge has not, to our knowledge, been previously described for the oral formulation, though such an association cannot be established from a single observation.

Microfluidic-assisted formulation of hydrophobic ion pairing-Based solid lipid nanoparticles for semaglutide delivery.

Ilaria Arduino, Rosa Maria Iacobazzi, Alessia Pontrelli +6 more

Semaglutide is a glucagon-like peptide-1 receptor agonist widely used for the treatment of type 2 diabetes and obesity. Despite its clinical efficacy, oral administration remains challenging because of its limited gastrointestinal stability, poor epithelial permeability, and low affinity for lipid-based delivery systems. In the present study, a combined hydrophobic ion pairing (HIP) and solid lipid nanoparticle (SLN) approach was explored to improve semaglutide incorporation and delivery-related properties. Semaglutide was complexed with the cationic lipid DOTAP at different molar ratios (1:0-1:18) and subsequently incorporated into cetyl palmitate-based SLNs produced by microfluidic mixing using a herringbone device. The resulting formulations were characterized in terms of particle size, ζ-potential, encapsulation efficiency, morphology, solid-state organization, colloidal stability, release behavior, mucus interaction, cytocompatibility, and epithelial permeability. Among the various formulations prepared, the one prepared with a molar ratio semaglutide: DOTAP of 1:18 and a peptide concentration of 10% (w/w) (F10) showed the best results, combining particle sizes of less than 300 nm with almost complete encapsulation efficiency and a highly positive ζ-potential. FTIR, DSC, TGA and SAXS analyses confirmed the correct formation of the complex and its incorporation into the lipid matrix. The F10 formulation demonstrated good stability under simulated gastrointestinal conditions and a sustained-release profile. The formulation also exhibited strong interactions with mucus, whilst retaining the ability to diffuse through the mucin network. Cytocompatibility studies demonstrated acceptable cell viability at relevant concentrations, whilst permeability experiments through Caco-2 monolayers revealed an approximately 6-fold increase in apparent permeability compared to free semaglutide. Therefore, these findings indicate that the combination of DOTAP-mediated hydrophobic ion pairing and microfluidic-assisted SLN production represents a potentially promising strategy for improving semaglutide encapsulation, gastrointestinal stability, and epithelial transport, while maintaining a favorable balance between mucus interaction and mucodiffusion.

Glucagon-Like Peptide-1 (GLP-1)-Based Therapies and Heart Failure Outcomes: A Scoping Review of Contemporary Randomized Controlled Trials.

Jenika Patel, Deep Patel, Maria Pino

Glucagon-like peptide-1 (GLP-1)-based therapies have been observed to produce cardiovascular benefits in cardiometabolic diseases; however, their impact on heart failure-specific outcomes is only becoming known through dedicated randomized controlled trials (RCTs). This scoping review consolidates the most recent randomized data that examine how GLP-1-based therapies affect heart failure-specific symptoms, functional capacity, and the occurrence of clinical events. Literature searches were conducted in PubMed, Google Scholar, and CINAHL for RCTs and prespecified analyses between 2021 and 2026 evaluating GLP-1-based therapies and reporting heart failure-specific outcomes. Five RCT-based studies met inclusion criteria, including randomized trials and prespecified RCT-derived analyses evaluating semaglutide and tirzepatide. Among patients with heart failure with preserved ejection fraction (HFpEF) and obesity, semaglutide significantly improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and 6-minute walk distance compared to placebo. Tirzepatide exhibited improvements across symptoms and functional and event-based outcomes, with prespecified trajectory analyses confirming favorable shifts in New York Heart Association functional class, Patient Global Impression of Severity, health-related quality of life, and background heart failure medication use. Among patients with type 2 diabetes mellitus and chronic kidney disease, semaglutide was associated with a significantly reduced rate of cardiovascular death or worsening heart failure events. Although the available evidence comes from a small number of recent randomized and prespecified RCT-based studies, current findings suggest that GLP-1-based therapies are associated with improvements in symptoms and functional capacity and reductions in heart failure events in certain patient populations, especially those with HFpEF and obesity. These beneficial effects support a potential role for the integration of GLP-1-based therapies in population-specific heart failure management.

Role of Oral Glucagon-Like Peptide-1 Receptor Agonists in Weight Management for Individuals With Overweight or Obesity Without Diabetes: A Network Meta-Analysis of Randomized Controlled Trials.

A B M Kamrul-Hasan, Hamid Ashraf, Lakshmi Nagendra +6 more

Oral GLP-1 receptor agonists (GLP-1 RAs) offer a non-injectable option for weight management in adults with overweight/obesity without diabetes. This network meta-analysis (NMA) evaluated their effects on body weight.

Diagnostic and Management Pitfalls of SGLT2 Inhibitor-Associated Ketoacidosis in the ICU: Lessons Following Cardiac Surgery and GLP-1 Agonist Interaction.

Ana Paula García Pérez, Damián Gutiérrez-Zárate, Karina Rosas-Sánchez +2 more

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are cornerstones in the treatment of Type 2 diabetes (T2D), but their use is associated with diabetic ketoacidosis (DKA), a potentially life-threatening complication in the critical care setting. We present two cases of male patients with T2D who developed SGLT2i-associated ketoacidosis under different stressors: the first following coronary artery bypass graft (CABG) surgery and the second after the addition of semaglutide to his therapeutic regimen. Both patients presented with high anion gap metabolic acidosis, ketonuria, and plasma glucose levels < 200 mg/dL. Management required intravenous insulin protocols and glucose supplementation to reverse ketosis. This report emphasizes the need for preoperative suspension protocols and close monitoring of changes in combination therapy to avoid diagnostic delays in the intensive care unit.

The new era of MASH pharmacotherapy: a comprehensive review of FDA-approved and emerging agents.

Abeer Qasim, Rayan Alataa, Fnu Veena +1 more

Metabolic dysfunction-associated steatohepatitis (MASH), formerly nonalcoholic steatohepatitis (NASH), is a progressive liver disease and a leading cause of cirrhosis and liver-related mortality worldwide, affecting approximately 3%-5% of the global adult population and up to 30%-40% of individuals with type 2 diabetes mellitus (T2DM) or those attending dedicated diabetes and endocrine centers. For decades, treatment was limited to lifestyle interventions. The years 2024 and 2025 marked a paradigm shift with the first-ever FDA approvals of pharmacologic agents for MASH.

Effect of semaglutide on kidney outcomes in the SELECT, FLOW, and SOUL trials: a prespecified pooled analysis.

Johannes F E Mann, Sunil V Badve, Florian M M Baeres +18 more

The GLP-1 receptor agonist semaglutide reduces clinically important kidney outcomes in people with type 2 diabetes and chronic kidney disease (CKD). We aimed to assess the pooled effects of semaglutide on kidney outcomes in prespecified analyses of participant-level data from the diverse populations of the SELECT, FLOW, and SOUL randomised placebo-controlled trials.

Impact of semaglutide introduction on the use of triptans: an interrupted-time series.

Noémie Roland, Heidi Sonne, Lanfranco Pellesi +4 more

Emerging evidence suggests that glucagon-like peptide-1 receptor agonist (GLP-1RA) may be associated with reduced migraine burden. We aimed to evaluate whether semaglutide for weight management initiation is associated with changes in triptan consumption.

Effect of Oral Semaglutide on Cardiovascular Outcomes in Type 2 Diabetes by Extent of Vascular Disease.

Matthew A Cavender, Nikolaus Marx, Sharon L Mulvagh +18 more

Effects of Oral Semaglutide on Dietary Intake and Body Composition in Japanese People With Type 2 Diabetes: A Prospective Observational Study in Clinical Practice.

Mika Sawada, Naoko Nakanishi, Masakazu Aihara +7 more

Glucagon-like peptide-1 receptor agonists are effective glucose-lowering agents with established benefits on body weight and cardiometabolic outcomes. However, their precise effects on body composition and dietary intake patterns, including food group consumption and macronutrient energy distribution, particularly in clinical settings, remain incompletely understood.

Efficacy and Hypoglycaemia Outcomes With Once-Weekly IcoSema Versus Comparators in Individuals With Type 2 Diabetes by Kidney and Liver Function: A Post Hoc Analysis of the COMBINE 1-3 Trials.

Linong Ji, Jonas Dahl Andersen, Malik Benamar +4 more

This post hoc analysis of COMBINE 1-3 assessed efficacy and hypoglycaemia outcomes with IcoSema (once-weekly combination therapy of basal insulin icodec and semaglutide [a glucagon-like peptide-1 analogue]) versus comparators in adults with type 2 diabetes (T2D) by kidney and liver function subgroups.

Acute Nutritional Axonal Neuropathy in the Setting of Semaglutide-Associated Gastrointestinal Intolerance: A Case Report.

Chloe J Cohan, Liam Townley, Erik Ortega

The aim of the study was to report a unique case of severe sensorimotor polyneuropathy due to acute nutritional axonal neuropathy (ANAN) associated with thiamine and other vitamin deficiencies in the setting of semaglutide-related malnutrition, emphasizing early recognition and intervention to prevent permanent neurologic injury.

GLP-1 receptor agonists in hip, knee and shoulder arthroplasty: Implications for obesity, osteoarthritis, metabolic optimisation and complications.

George M Avram, Pier Francesco Indelli, Bruno Violante +7 more

Glucagon-like peptide-1 receptor agonists and related incretin-based therapies are rapidly changing the management of obesity and metabolic disease. Their increasing use also among patients with osteoarthritis has important implications for hip, knee and shoulder arthroplasty. Beyond weight loss, these drugs may influence systemic inflammation, glycemic control, osteoarthritic symptoms, perioperative complications and surgical candidacy. Recent retrospective studies suggest that preoperative GLP-1 receptor agonist use may be associated with lower risks of periprosthetic joint infection, hospital readmission and other adverse outcomes after total joint arthroplasty. Beyond the perioperative setting, GLP-1 receptor agonists have also been associated with reductions in blood pressure and significant improvements in cardiovascular risk among patients with chronic kidney disease or preexisting cardiovascular disease. However, the current evidence remains largely observational and is limited by residual confounding, indication bias, heterogeneity in treatment timing, and inconsistent reporting of drug class, dose, and duration. This editorial argues that GLP-1 receptor agonists should not be viewed simply as weight-loss agents before arthroplasty, but as part of a broader movement toward metabolic optimisation. Prospective studies are needed before these therapies can be incorporated into standardised arthroplasty optimisation pathways.

Semaglutide-Induced Sarcopenia via GLP-1R-mTOR-Satellite Cells Axis and Muscle-Glucose Feedback Loop Potentially Leading to Refractory Hyperglycemia in Type 2 Diabetes: A Case-Driven Hypothesis.

Amr Ahmed, Sharifa Rodini, Fahad Alrubyea +1 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide have transformed type 2 diabetes mellitus (T2DM) management, yet emerging concerns highlight potential risks of accelerated sarcopenia and subsequent metabolic disruptions. This case-driven hypothesis explores a 53-year-old male with T2DM diagnosed in 2014, who experienced progressive glycemic failure despite standard therapies, including metformin, glipizide, sitagliptin, and empagliflozin. Transition to dulaglutide 1.5 mg for 1.5 years followed by semaglutide (titrated from 0.25 to 1 mg weekly starting September 2024) resulted in weight loss from 84 kg to 70 kg by September 2025, accompanied by sarcopenic symptoms (muscle weakness, reduced mobility) and refractory hyperglycemia (fasting glucose 300 mg/dL, HbA1c 9%), persisting post-discontinuation on September 1, 2025, despite metformin and empagliflozin. We posit that semaglutide may precipitate acute sarcopenia via unexpected GLP-1R-mTOR-satellite cells axis crosstalk, disrupting AMPK-mTOR balance to suppress anabolic mTORC1/IGF-1 signaling (potentially by 25-35%) while enhancing catabolic FOXO/ubiquitin-proteasome and excessive autophagy pathways. This could extend to myokine reprogramming (elevated myostatin/GDF15, reduced irisin/IL-15), glucagon/α-cell compensation inducing hyperglucagonemia (15-25% rise), microbiome-bile acid shifts fostering low-grade inflammation (IL-6/TNF-α upregulation by 10-15%), mitochondrial mass reduction (20-25% via AMPK), and NMJ disassembly, collectively impairing muscle as the primary glucose sink (reducing GLUT4-mediated uptake by 35-45%) and initiating a «muscle-glucose feedback loop» with hepatic gluconeogenesis amplification, yielding treatment-resistant hyperglycemia.Supporting evidence from cohorts (e.g., 24-month study showing ASMI/grip strength declines in 432 patients), longitudinal analyses (NMJ degradation with CAF22/NfL elevations in 141 men), secondary trials (9.3% psoas volume loss in 51 MASLD cases), and case reports (fatigue in a 74-year-old, rhabdomyolysis in a 47-year-old) aligns with this framework, as does in vitro data linking GLP-1 excess to kinesin-1/GLUT4 inhibition and ATP depletion (20-30%). This novel hypothesis underscores sarcopenia's role in GLP-1RA-induced metabolic paradoxes, urging prospective studies on muscle-preserving interventions like resistance training or GLP-1R modulators to refine T2DM paradigms and inspire multidisciplinary research into endocrine-muscle interactions.

Glucagon Agonist Therapies and Vision Loss: Balancing Promise with Prudence in India.

Abhyuday Saxena, Anupam Prakash

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual incretin therapies such as tirzepatide have transformed the management of type 2 diabetes mellitus and obesity, with expanding cardiometabolic indications and rapid market growth globally and in India. However, emerging postmarketing evidence has raised concerns regarding ocular safety. Pharmacovigilance analyses, cohort studies, and case reports suggest an association between GLP-1-based therapies and ophthalmic adverse events, including early worsening of diabetic retinopathy and, more concerningly, nonarteritic anterior ischemic optic neuropathy (NAION)-a potentially irreversible cause of sudden vision loss in adults over 50 years. Although the absolute risk appears very low, regulatory agencies, including the WHO and European Medicines Agency, now recognize NAION as a very rare adverse effect of semaglutide, and similar signals are being explored for other agents, suggesting a possible class effect. Proposed mechanisms include altered optic nerve head perfusion, sympathetic-mediated vasoconstriction, and rapid glycemic shifts affecting vascular autoregulation; however, causality remains unproven. In India, where over 100 million adults live with diabetes and obesity rates are rising, even rare adverse events may translate into substantial public health impact, particularly given limited access to ophthalmic care and increasing unsupervised drug use. We advocate a balanced approach: baseline ophthalmic evaluation in high-risk individuals, informed consent regarding visual symptoms, early referral for visual complaints, strengthened pharmacovigilance, and coordinated endocrinology-ophthalmology surveillance systems. As newer triple agonists approach clinical use, integrating ocular safety into prescribing frameworks is imperative. Metabolic gains must not come at the cost of preventable vision loss.

Semaglutide in Practice: Insights from a Retrospective Case Series at a Jharkhand Tertiary Care Hospital.

Ajay Kumar Jha, Ashok Sunder

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated efficacy in improving glycemic control and reducing cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). However, real-world evidence from Indian populations remains limited. This study aimed to assess the effectiveness and safety of semaglutide on glycemic control, body weight, and metabolic parameters in patients with T2DM in a real-world clinical setting.

Semaglutide-associated NAION: a proposed 'two-hit' model involving buried optic disc drusen and sustained hypohydration.

Guohong Zhao, Nan Ma, Yan Yang +2 more

Semaglutide-associated non-arteritic anterior ischaemic optic neuropathy (NAION) mechanisms are unclear. We report a 28-year-old man with type 2 diabetes who developed right NAION 4-5 months after starting semaglutide. Multimodal imaging confirmed NAION and bilateral buried optic disc drusen. The affected eye was short, whereas the fellow eye was highly myopic and longer. Serial bioimpedance showed a 1.9 L decline in total body water over 7 weeks, with preserved fat mass and stable extracellular-to-total-body-water (ECW/TBW) ratio. We propose a hypothesis-generating 'two-hit' model in which anatomical susceptibility and sustained hypohydration together precipitate NAION. Heightened clinical awareness may be warranted and prospective studies are required.

Effectiveness & safety of semaglutide in weight reduction in obese nondiabetic patients: A systematic review and meta-analysis.

Faryal Naz, Fawad Qaiser, Arif Mumtaz +5 more

Obesity is a chronic multifactorial disease characterized by excess adiposity and persistent low-grade systemic inflammation, contributing substantially to cardiometabolic morbidity and mortality. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist approved for chronic weight management, promotes weight loss by reducing appetite, delaying gastric emptying, and decreasing energy intake while also demonstrating potential anti-inflammatory effects. Although semaglutide has shown promising efficacy for weight reduction, an updated evaluation of its efficacy and safety in nondiabetic individuals with overweight or obesity is warranted.

Comparative Cardiovascular Outcomes and Safety Profiles of Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Trials.

Samih Abdelmutalab Mohamed Abdalla, Hind Osman Ali Mohammed, Eltayeb Osman E Omer +6 more

Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been assessed in several large cardiovascular outcome trials (CVOTs); however, the individual agents differ in molecular structure, pharmacology, and the populations studied, and their reported effects range from neutral to clearly beneficial. This review compares the cardiovascular efficacy and safety of GLP-1 RAs across all eligible randomized, placebo-controlled CVOTs in T2DM and quantitatively pools the primary outcome. Following the PRISMA 2020 statement, ClinicalTrials.gov, MEDLINE, Embase, and the Cochrane CENTRAL were searched from inception to 15 December 2025 for randomized, double-blind, placebo-controlled CVOTs comparing a GLP-1 RA with placebo in adults with T2DM and reporting adjudicated major adverse cardiovascular events (MACE) as a primary or co-primary endpoint. The protocol was not prospectively registered. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment (Cochrane RoB 2), and certainty of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Findings were synthesized narratively and, for the primary MACE outcome, pooled using a DerSimonian-Laird random-effects model on the log-hazard-ratio scale, with heterogeneity quantified by I² and Cochran's Q, leave-one-out sensitivity analysis, and small-study assessment by funnel plot and Egger's test. Nine trials enrolling 69,730 participants met the eligibility criteria. The primary MACE hazard ratio favored the GLP-1 RA in eight of nine trials (range = 0.73-1.02) and reached statistical superiority in five. Random-effects meta-analysis yielded a pooled MACE hazard ratio of 0.86 (95% CI: 0.82-0.92; P < 0.001), corresponding to a 14% relative risk reduction, with moderate heterogeneity (I² = 37%; Cochran's Q = 12.7, P = 0.12) and a 95% prediction interval of 0.75-1.00. The pooled estimate was robust to leave-one-out analysis (0.85-0.88), and no small-study asymmetry was detected (Egger's P = 0.13). The composite benefit was driven by reductions in myocardial infarction and stroke, with a neutral effect on hospitalization for heart failure. Gastrointestinal adverse events were the most common class effect; a class-level excess of gallbladder and biliary disease was also evident, and a diabetic retinopathy signal was observed with subcutaneous semaglutide. Eight trials were judged to be at low risk of bias, and the certainty of evidence was moderate for the principal cardiovascular outcomes. In adults with T2DM, GLP-1 RAs as a class reduce the risk of MACE by approximately 14% with an acceptable safety profile, supporting their role as a cornerstone of cardiovascular risk reduction. Between-agent and between-trial heterogeneity preclude a definitive ranking of individual agents.

Incorporating estimands into meta-analyses of clinical trials.

Antonio Remiro-Azócar, Pepa Polavieja, Emmanuelle Boutmy +9 more

The estimand framework is increasingly established to pose research questions in confirmatory clinical trials. In evidence synthesis, the uptake of estimands has been modest, and the population, intervention, comparator, and outcome (PICO) framework is more often applied. While PICOs and estimands have overlapping elements, the estimand framework explicitly considers different strategies for intercurrent events. We propose a pragmatic framework for the use of estimands in meta-analyses of clinical trials, highlighting the value of estimands to systematically identify and mitigate key sources of quantitative heterogeneity, and to enhance the applicability or external validity of pooled estimates. Focus is placed on the role of strategies for intercurrent events, within the specific context of meta-analyses for health technology assessment. We apply the estimand framework to a network meta-analysis of clinical trials, comparing the efficacy of semaglutide versus dulaglutide in type 2 diabetes. We explore the impact of a treatment policy strategy for treatment discontinuation or initiation of rescue medication versus a hypothetical strategy for the corresponding intercurrent events. The specification of different target estimands at the meta-analytical level allows us to be explicit about the source of heterogeneity, the intercurrent event strategy, driving any potential differences in results. We advocate for the integration of estimands into the planning of meta-analyses, while acknowledging that potential challenges exist in the absence of subject-level data. Estimands can complement PICOs to strengthen communication between stakeholders about what evidence syntheses seek to demonstrate, and to ensure that the generated evidence is maximally relevant to healthcare decision-makers.

Adult Annular Pancreas Presenting With Gastric Outlet Obstruction Following Semaglutide Initiation: A Case Report.

Fatima Gamaleldin, Milind Raje, Solomon K John

Annular pancreas is a rare congenital anomaly that may remain clinically silent until adulthood. Its symptoms can be masked or exacerbated by glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which delay gastric emptying. We report a 55-year-old male with type 2 diabetes who developed progressive postprandial vomiting and nine-kg weight loss following semaglutide initiation. Imaging revealed a partial annular pancreas causing second-part duodenal stenosis without malignancy. Symptoms persisted despite semaglutide discontinuation, supporting a fixed mechanical obstruction as the primary aetiology. The patient underwent successful Roux-en-Y gastrojejunostomy and cholecystectomy; histopathology confirmed benign fibrotic pancreatic tissue. At follow-up, the patient was symptom-free with nutritional recovery. This case emphasises that severe gastrointestinal symptoms in patients on GLP-1 RAs should prompt evaluation for structural pathology rather than being attributed solely to medication side effects, ensuring timely surgical intervention.

GLP-1 receptor agonists in primary care: readiness, equity, and the risk of a two-tiered obesity treatment landscape.

Mohamed Mustaf Ahmed, Rahmatullah Nazari, Zhinya Kawa Othman +6 more

Glucagon-like peptide-1 receptor agonists have transformed obesity pharmacotherapy by producing substantial weight loss and, for semaglutide in patients with established cardiovascular disease, reducing major cardiovascular events. Integrating these therapies into primary care is constrained by gaps in provider training, clinical inertia, weight bias, high treatment costs, and fragmented insurance coverage. Racial and ethnic minority groups, low-income communities, and publicly insured patients are less likely to receive or fill prescriptions despite the disproportionate burden of obesity-related diseases. This narrative review examines primary care readiness, structural determinants of access, disparities in prescribing and use, real-world adherence, and policy options for these drugs. Without coordinated action, these therapies may reinforce a two-tiered treatment landscape in which access reflects socioeconomic advantages rather than clinical needs. Equitable implementation will require aligned reforms in coverage and pricing, workforce development, person-centered care, and long-term treatment support.

PYY3-36 potentiates Semaglutide‑mediated mitochondrial modulation in MASLD.

Niklas Geiger, Alexander Georg Nickel, Michael Kohlhaas +14 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a frequent comorbidity of obesity. Incretins have emerged as promising therapeutics for MASLD, but their exact mechanisms of action remain unclear. In this study with obese rats, we investigated the cellular effects of the GLP 1 receptor agonist semaglutide and the NPY 2 receptor agonist PYY3 36 on hepatic mitochondria with a focus on mitochondrial oxygen consumption and ROS emission.

Correction: Exploring factors predicting the effectiveness of oral semaglutide in Japanese individuals with type 2 diabetes switching from dipeptidyl peptidase 4 inhibitors: a pilot study.

Takao Hirotsu, Kanta Taniguchi, Rimei Nishimura

[This corrects the article DOI: 10.3389/fcdhc.2025.1520389.].

Dose-dependent effects of oral semaglutide on arterial stiffness and the additive role of SGLT-2 inhibitors in type 2 diabetes.

Takao Sato, Toshihiro Miyamoto, Ryoma Fukuoka +7 more

The cardio-ankle vascular index (CAVI) is a blood pressure-independent marker of arterial stiffness and a well-established predictor of cardiovascular (CV) events. The effects of oral semaglutide, particularly at low doses, on arterial stiffness remain unclear.

Understanding Obesity as a Multisystem Disease: Advancing Research, Redefining Diagnostic Criteria, and Establishing Modern Therapeutic Approaches.

Hala Abdallah, Mohamad Khalil, Laura Mahdi +4 more

Obesity is a complex, chronic, relapsing disease that affects nearly all physiological functions and homeostatic mechanisms, extending far beyond mere excess adiposity. Traditional clinical practice often relies on uniform interventions that fail to account for diverse patient phenotypes. This review synthesizes current evidence on personalized obesity management, dietary interventions, and advanced pharmacotherapies aligned with the new 2025 Lancet Commission framework. A comprehensive narrative review was conducted across major biomedical databases to evaluate the efficacy, safety, and mechanisms of metabolic interventions, focusing on phenotype-specific dietary matching, bioactive compounds, and modern multi-receptor glucagon-like peptide-1 (GLP-1)-based therapies across preclinical and clinical intervention tiers in adult and pediatric populations. While specific nutraceutical extracts display promising secondary metabolic benefits, their overall weight-loss efficacy remains modest due to variable clinical data and limited sample sizes. Conversely, high-potency anti-obesity medications demonstrate unprecedented weight-reduction efficacy, with semaglutide 2.4 mg and tirzepatide yielding mean body weight losses of ~14.9% and ~20.9%, respectively. Furthermore, landmark outcome data from the SELECT trial confirms that semaglutide 2.4 mg achieves a significant 20% relative risk reduction in major adverse cardiovascular events (MACE), independent of baseline glycemic status or heart failure. However, clinical extension data reveal rapid weight rebound upon drug cessation, highlighting that obesity requires continuous, long-term therapeutic strategies. Effective obesity care demands an operational shift from traditional, one-size-fits-all treatments to personalized, multi-tiered strategies. Combining phenotype-specific lifestyle modifications with potent, long-term multi-hormonal pharmacotherapies or metabolic surgery optimizes long-term therapeutic durability, systemic metabolic health, and sustained cardioprotection.

Real-World Kidney and Glycaemic Outcomes Following Semaglutide Initiation in Adults with Type 2 Diabetes and Mild Chronic Kidney Disease.

Syed Arman Rabbani, Haea Amar Alkoud, Mohamed El-Tanani +5 more

Background: Real-world kidney and metabolic responses to semaglutide in type 2 diabetes (T2D) and chronic kidney disease (CKD) remain poorly characterised, particularly in Middle East and North Africa (MENA) region. Methods: We conducted a retrospective, single-centre, paired-cohort study at a secondary care hospital in UAE. Adults with T2D and predominantly mild CKD newly initiated on subcutaneous semaglutide were included. Single-arm design without comparator; findings describe biomarker trajectories and cannot establish causality. Primary outcomes were within-participant six-month changes in serum creatinine, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (uACR). Results: A total of 324 patients were analysed (mean age 55.3 ± 12.4 years; 66.0% female; BMI 36.1 ± 6.9 kg/m2; median HbA1c 8.3% [IQR 7.2-10.0]; eGFR 87.0 ± 25.8 mL/min/1.73 m2; KDIGO G1-G2 in 82.7%; A2 92.6%, A3 4.6%). At six months, BMI fell by 2.0 kg/m2 and HbA1c by a median 2.0%; 52.0% achieved ≥5% BMI reduction and 87.2% achieved ≥0.5% absolute HbA1c reduction. Serum creatinine decreased by 3.6 µmol/L and eGFR rose by 3.7 mL/min/1.73 m2; given concurrent weight loss, these changes likely reflect reduced creatinine generation rather than true filtration improvement. A ≥30% eGFR decline occurred in only 0.9%. Geometric mean uACR fell by 19.8%; among participants with baseline uACR ≥ 30 mg/mmol, 66.7% achieved ≥30% uACR reduction. KDIGO G-category improved in 17.3% and was stable in 76.8%; the A-category remained stable in 95.7%. Conclusions: In adults with T2D, mild CKD, and substantial obesity, semaglutide was associated with clinically meaningful improvements in weight, glycaemia, and albuminuria over six months, supporting it as part of a layered cardio-renal protective strategy in routine care.

Differential Anti-Inflammatory Effects of Semaglutide and Tirzepatide in Experimental Diabetes Mellitus.

Roxana-Cristina Dobriceanu, Ianis Kevyn Stefan Boboc, Liliana Mititelu Tartau +6 more

Type 2 diabetes mellitus is associated with chronic low-grade inflammation contributing to endothelial dysfunction, metabolic imbalance, and cardiovascular complications. Although semaglutide (SEM) and tirzepatide (TIR) provide important metabolic and cardioprotective benefits, their early anti-inflammatory effects and potential sex-dependent differences remain incompletely understood. This study comparatively evaluated the effects of SEM and TIR on systemic inflammatory biomarkers in a murine model of streptozotocin-induced diabetes mellitus. Thirty BALB/c mice were allocated into six experimental groups according to sex and treatment: control, SEM, and TIR groups (n = 5/group). Diabetes was induced by intraperitoneal streptozotocin administration, followed by treatment with SEM or TIR. Circulating interleukin-1β (IL-1β) and pentraxin-3 (PTX-3) levels were measured at baseline, one week after streptozotocin administration, and after six weeks of treatment. Control groups exhibited progressive increases in IL-1β and PTX-3 levels, indicating sustained inflammatory activation. In contrast, SEM- and TIR-treated animals showed attenuated inflammatory responses characterized by transient or stabilized biomarker profiles. Differential inflammatory responses were observed between treatments and sexes. Male SEM and Male TIR groups demonstrated stable IL-1β levels, whereas female treated groups showed persistent elevations, particularly Female TIR animals. PTX-3 responses also displayed differential sex-dependent patterns, with Female SEM animals exhibiting the most stable inflammatory profile. These findings suggest differential early immunomodulatory effects of the two modern antidiabetic drugs, characterized by distinct biomarker responses according to sex and inflammatory marker profile. IL-1β and PTX-3 may represent complementary biomarkers for the assessment of early inflammatory activation associated with diabetes mellitus and its cardiometabolic complications.

Impact of semaglutide withdrawal on cardiometabolic profile and physiology of energy balance: Recovery effects after semaglutide termination - The REST trial study protocol.

Taras Yevusiak, Alanna Weisman, Ravi Retnakaran +3 more

Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide have been shown to induce substantial weight loss and improve cardiometabolic risk factors in patients living with obesity. However, most individuals regain weight after abrupt withdrawal of semaglutide, with reversal of its beneficial cardiometabolic effects.

Understanding Biased Signaling and Small-Molecule Binding for Treatment of Type 2 Diabetes Mellitus and Obesity at the Glucagon-Like Peptide-1 Receptor (GLP-1R) Based on Molecular Dynamics Simulations.

Jack Brubaker, Soo-Kyung Kim, Bo Li +2 more

Glucagon-like peptide-1 receptor (GLP-1R) is a class B1 G protein-coupled receptor expressed in multiple tissues and is a major therapeutic target for type 2 diabetes mellitus and obesity. Here, we investigate the mechanisms of GLP-1R binding and activation using molecular dynamics (MD) simulations of semaglutide, tirzepatide, danuglipron, and CHU-128bound GLP-1R-Gs complexes. We analyze these simulations as a function of temperature, ligand class (peptide vs. small molecule), and signaling profile (biased vs. non-biased) to assess how these factors affect GLP-1R interactions and conformational dynamics. Our results reveal distinct interaction patterns and structural features associated with each factor which persist over the MD trajectories. Together, these findings deepen our mechanistic understanding of GLP-1R agonism and further aid in the design of effective, orally available GLP-1R agonists with reduced side effects.

Body Composition Changes During GLP-1 Receptor Agonist Therapy in Pediatric Obesity: A Pilot Study.

Bogdan Mihai Pascu, Irina Bojoga, Anca Bălănescu +2 more

GLP-1 receptor agonists (GLP-1 RAs) are effective weight-loss therapies, but data on body composition changes in pediatric obesity remain scarce. The primary objective was to evaluate the effects of GLP-1 RAs on body composition in children with obesity.

Incretin-Based Therapies, Obesity-Associated Inflammation, and Atherosclerotic Cardiovascular Risk.

Jan Kafol, Borut Jug, Zlatko Fras

Cardiovascular disease remains a leading cause of mortality despite major advances in lipid lowering and risk-factor control, highlighting the importance of residual cardiovascular risk. Inflammation is a central driver of atherosclerosis, while obesity promotes chronic low-grade inflammation, adipose tissue dysfunction, ectopic fat accumulation, and vascular injury. This narrative review focuses on obesity-associated inflammation as an upstream contributor to residual atherosclerotic risk and evaluates whether incretin-based therapies modify this pathway through weight loss, metabolic improvement, and additional inflammatory or vascular mechanisms. Data from mechanistic studies, biomarker analyses, vascular imaging studies, and cardiovascular outcome trials are reviewed. Anti-inflammatory trials support inflammation as a modifiable therapeutic pathway, although clinical benefit depends on the therapeutic target, timing, and patient selection. Glucagon-like peptide-1 receptor agonists reduce inflammatory and oxidative stress biomarkers and show anti-atherosclerotic effects in experimental models, but human vascular imaging data remain inconclusive. Cardiovascular outcome trials establish benefit with several GLP-1 receptor agonists, including semaglutide in selected patients with overweight or obesity without diabetes. However, direct human evidence for receptor-mediated anti-inflammatory or anti-atherosclerotic effects remains limited, and the relative contributions of weight loss, metabolic improvement, and additional mechanisms remain uncertain.

Efficacy and Safety of Once-Weekly Semaglutide 2.0 mg as an Add-On to Dose-Reduced Insulin Glargine versus Dose-Titrated Insulin Glargine in People With Type 2 Diabetes and Overweight (SUSTAIN OPTIMIZE).

Helena W Rodbard, Concetta Irace, Jevitha Lobo +5 more

Type 2 diabetes (T2D) management with basal insulin can lead to hypoglycaemia and weight gain. SUSTAIN OPTIMIZE compared once-weekly semaglutide 2.0 mg as add-on to dose-reduced insulin glargine (Sema+IGlarreduced) versus dose-titrated IGlar (IGlartitrated) on glycated haemoglobin (HbA1c), body weight (BW), daily insulin dose, and participant satisfaction.

Linking pediatric obesity to youth-onset type 2 diabetes: integrated longitudinal and cross-sectional evidence from population-based studies worldwide.

Ashraf T Soliman, Fawzia Alyafei, Nada Alaaraj +3 more

Youth-onset type 2 diabetes mellitus (T2DM) is a rapidly growing pediatric metabolic disorder that parallels the global childhood obesity epidemic. Despite multiple population-based registries and a global meta-analysis documenting near-universal obesity at the time of a T2DM diagnosis, no integrated synthesis spanning 25 years and including diverse populations has been performed. Here we conducted a systematic review of PubMed and Scopus (January 2000 to March 2025) using longitudinal data from population-based registries in the USA (SEARCH), Canada (Manitoba), England and Wales (National Paediatric Diabetes Audit), Israel, Australia, and New Zealand as well as cross-sectional burden from a global meta-analysis (53 studies, n=8,942) and national audits. Study quality was appraised using the Newcastle-Ottawa Scale and A Measurement Tool to Assess Systematic Reviews v2. All registries showed a temporally parallel increase in the incidence of pediatric obesity and youth-onset T2DM. In the USA, the T2DM incidence rose 79% (3.8 → 6.8 per 100,000/yr, 2002-2018); in Manitoba, it nearly doubled (16.0 → 31.1 per 100,000/yr, 2009-2018); and Israel showed a 441% rise (0.63 → 3.41 per 100,000/yr, 2008-2019). The global pooled obesity prevalence at the T2DM diagnosis was 75.3% (95% confidence interval, 72.1%-78.5%), with approximately 41,600 new youth cases annually worldwide. Once-weekly semaglutide 2.4 mg (STEP TEENS trial) reduced the average body mass index by 16.1% at 68 weeks with concurrent glycemic improvement, while bariatric surgery achieved 95% T2DM remission at 3 years in adolescents (Teen-LABS cohort). Multicontinental evidence confirmed a robust temporally consistent obesity-T2DM link; obesity precedes T2DM at the population level and is present in approximately 75% of affected youths at diagnosis worldwide. Weight-reduction interventions, particularly glucagon-like peptide-1 receptor agonists and bariatric surgery, offer meaningful glycemic benefits; however, primary prevention of childhood obesity remains the most powerful strategy to arrest this epidemic.

The cost-effectiveness of second line diabetes medication added to standard therapy in preventing type 2 diabetes related nephropathy in Germany.

Hanni Hille, Wendelin Schramm, Ahmed Bounekkar

Type 2 diabetes and its associated complications like nephropathy impose a serious burden on health systems. Several blood glucose-lowering medications have shown to be likely to provide nephroprotective properties, delaying or preventing the onset of kidney damage. Kidney-specific health-economic evaluations, comparing different agents, remain rare for Germany.

Beyond Weight Loss: Early Real-World Evidence of Semaglutide in Obesity.

Steluța Constanța Boroghină, Amalia-Ioana Arhire, Teodora Papuc +6 more

Background: Obesity is a chronic, relapsing disease that often proves resistant to lifestyle measures alone. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are reshaping treatment, yet prospective real-world data remain limited. Objective: To prospectively assess the effects of once-weekly Semaglutide on weight, body composition, and metabolic health in obesity. Methods: An exploratory observational study of 37 patients initiating Semaglutide (mean age 31 years; 11 children and adolescents; 22 females) was conducted. All met obesity criteria (baseline BMI 34.7 kg/m2). Anthropometry, bioimpedance body composition, and fasting biochemistry were obtained at baseline and 3 months. Variables were reported as mean ± SD or median (IQR) according to normal/non-normal distribution, whether a parametric test or a Wilcoxon one was used. Parametric or non-parametric paired tests (two-sided α = 0.05) were applied. We also explored tri-ponderal mass index (TMI, kg/m3) and its correlations with metabolic markers. Results: At 3 months, body weight decreased by a median 8.0 kg (p < 0.001), BMI by 1.6 kg/m2 (p < 0.001). Body fat percentage declined: 43.4% to 42.8% (p = 0.009), with a small reduction in skeletal muscle mass (-0.6 kg; p = 0.035). Fasting glucose improved (p = 0.030) and HOMA-IR fell significantly. HbA1c changes were minimal, consistent with near-normal baseline values. Triglycerides decreased, while total cholesterol, LDL-C, HDL-C, liver enzymes, creatinine, uric acid, and 25-OH vitamin D remained stable. Baseline TMI (median 20.13 kg/m3; IQR 3.80) correlated strongly with HOMA-IR (r = 0.766, p < 0.001) and moderately-to-strongly with body fat percentage (r = 0.621, p < 0.001). Conclusions: In this real-world cohort, Semaglutide produced rapid, clinically meaningful improvements in weight, adiposity, and insulin resistance within 3 months. Findings suggest that Semaglutide may represent a promising adjunct to lifestyle therapy in obesity management.

Evaluating the Cardiovascular Benefits of Innovator Semaglutide 2.4 mg (Recombinant DNA (r-DNA)) in Patients With Overweight or Obesity: A Critical Review of Current Evidence.

Brij Teli, Sunil Sathe, Ravi Kalra +37 more

Obesity and cardiovascular (CV) disease (CVD) are tightly intertwined global epidemics, with excess adiposity now recognized as a major, modifiable driver of atherosclerotic events, heart failure, and mortality. Despite advances in cardiometabolic care, residual CV risk remains high in people with obesity, underscoring the need for therapies that both reduce body weight and directly modify CV risk. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has emerged as a pivotal agent across the cardiometabolic spectrum, culminating in the SELECT trial, which demonstrated a reduction in three-point major adverse CV events (3P-MACE) in people with obesity and established CVD but without diabetes. Complementary evidence from heart failure with preserved ejection fraction (HFpEF) trials and real-world studies further supports a broad CV and functional benefit profile. This narrative review synthesizes data from randomized controlled trials (RCTs) and real-world evidence (RWE) on Wegovy® (semaglutide 2.4 mg, a recombinant DNA-derived GLP-1RA) in obesity with CVD, with a focus on SELECT, mediation analyses suggesting weight-independent CV effects, and outcomes in obesity-related HFpEF. We also discuss guideline positioning, regulatory milestones-including the 2025 Central Drugs Standard Control Organization (CDSCO) approval in India-and the evolving competitive landscape. Overall, semaglutide 2.4 mg represents the first and only anti-obesity medication with proven CV benefit in people with obesity without type 2 diabetes (T2D), with important implications for clinical practice and health policy.

Advances in proteomics research related to semaglutide: evidence from humans and animals.

Qiannan Jia, Hua Mu, Yuqing Wang +2 more

With the advancement of proteomics technologies, an increasing number of studies have begun to examine semaglutide-associated protein expression changes and pathway alterations across different biological contexts. However, existing evidence remains fragmented across different disease backgrounds, sample types, and research platforms, lacking systematic integration.

Cardiovascular and Cerebrovascular Outcomes Risk Reduction Associated With Semaglutide vs Tirzepatide: A Target Trial Emulation.

Ahmed Y Azzam, Muhammed Amir Essibayi, Pranjal Rai +11 more

Glucagon-like peptide-1 receptor agonists demonstrate cardiovascular benefits; however, head-to-head comparisons between semaglutide and tirzepatide remain limited.

Impact of semaglutide on cognitive function in patients with type 2 diabetes and mild cognitive impairment: a 24-month observational study.

Giuliano Cassataro, Silvia Scriffignano, Giulio Geraci +7 more

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of mild cognitive impairment (MCI) and dementia. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) provide cardiovascular and metabolic benefits, and emerging data suggest neurocognitive effects. We conducted a 24-month prospective observational study of 72 adults (≥ 50 years) with T2DM and MCI treated with semaglutide (subcutaneous [SC] or oral) and assessed at baseline (T0) and every 6 months (T1-T4). Outcomes included anthropometrics, fasting glucose, HbA1c, LDL-c, and neuropsychological tests (Montreal Cognitive Assessment [MoCA], Digit Symbol Substitution Test [DSST], Beck Depression Inventory [BDI]). A control cohort of 60 patients with T2DM and MCI not receiving semaglutide was evaluated with the same protocol. Semaglutide was associated with significant reductions in body weight, BMI, waist circumference, fasting glucose, and HbA1c (all p < 0.05). Cognitive performance improved, as shown by MoCA scores (median Δ≈ + 4 points, p < 0.001) at T4 compared with T0; at T4, semaglutide recipients also had higher MoCA scores than controls (+ 4.0 vs - 1.5, p < 0.001). DSST and BDI scores also improved (p = 0.001 and p = 0.044, respectively). MoCA improved similarly with both formulations, whereas DSST improvement reached significance only with SC semaglutide. In multivariable regression, semaglutide independently predicted MoCA improvement (+ 4.76 points, p < 0.001). No semaglutide-treated patient progressed to dementia versus 14 in controls (p = 0.002). In adults with T2DM and MCI, semaglutide was associated with improved cognition and a lower risk of progression to dementia. Differences between formulations may reflect distinct central nervous system engagement. Randomized trials are warranted.

Semaglutide for prevention of type 2 diabetes in women with postpartum prediabetes after gestational diabetes: protocol for a Belgian multicentre double-blind randomised placebo-controlled trial.

Yana Vanlaer, Nina Embo, Niels Bochanen +14 more

Women with postpartum pre-diabetes following gestational diabetes mellitus (GDM) are at particularly high risk of developing type 2 diabetes mellitus (T2DM). While the implementation of effective lifestyle interventions in the early postpartum period is often difficult and has in general limited efficacy to prevent T2DM after GDM, effective preventive strategies, including medical therapies, are needed in this population. The 'semaglutide for the treatment of pre-diabetes in women with prior gestational diabetes (SERENA) study' aims to evaluate the efficacy, safety and cost-effectiveness of semaglutide in preventing progression to T2DM during the early postpartum period.

Implications of Generic Semaglutide Availability on the Cost-Effectiveness of GLP-1RA for Guideline-Indicated Patients With Type 2 Diabetes.

Ethan McNally, Abhinav Sharma, Pedro Marques +3 more

Therapeutic Potential of Incretin-Based Therapies for Alcohol Use Disorder - A narrative review of available clinical evidence.

Mette Kruse Klausen, Anders Fink-Jensen

Alcohol use disorder (AUD) remains a major global health burden, yet pharmacological treatment options are limited, and an urgent need for novel molecular targets for the treatment of AUD exists. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been used for more than two decades to treat type 2 diabetes and, subsequently, overweight and obesity. Unexpected effects, including reduced alcohol intake, have been reported by patients as well as by clinicians and these - often anecdotal - reports have been supported by a growing body of data from large registry studies, target trial emulation analyses, preclinical experiments in mice, rats, and non-human primates, and randomized clinical trials, associating the use of GLP-1RAs with reduced alcohol consumption. This convergence has sparked growing interest in GLP-1RAs as a novel therapeutic strategy for AUD. In this narrative review, we synthesize current evidence on the effects of GLP-1RAs in individuals with AUD. To date, only three randomized controlled trials have examined GLP-1RAs in AUD, showing reductions in alcohol cue brain reactivity and alcohol consumption, particularly among individuals with overweight or obesity. We will also report on observational data, including large registry studies, target trial emulation analyses, and real-world data, which consistently associate GLP-1RA use with reduced alcohol consumption. Case reports and social media analyses further corroborate reductions in alcohol craving and consumption. Mechanistically, emerging evidence points to modulation of reward circuitry, incentive salience, gastric emptying, and metabolic signaling. Overall, GLP-1RAs represent a promising and mechanistically novel approach to AUD treatment, warranting confirmation in larger, long-term randomized trials.

Oral Semaglutide and CV Benefits in the SOUL Trial: How Do Baseline or Changes in HbA1c or BMI Affect Clinical Outcomes?

Silvio E Inzucchi, Rohana Abdul Ghani, John Deanfield +20 more

In the SOUL trial (NCT03914326), oral semaglutide reduced risk of major adverse cardiovascular (CV) events (MACE) by 14%. Whether baseline or changes in HbA1c or BMI are associated with these CV benefits is not known.

From FLOW to translational positioning in chronic kidney disease: mechanistic complementarity of SGLT2 inhibitors and GLP-1 receptor agonists.

Xue Tian, Xiaoying Ma, Enxue Song +5 more

Chronic kidney disease is a central node of the cardio-kidney-metabolic continuum and carries substantial residual cardiovascular and kidney risk. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have reproducibly reduced kidney disease progression and heart failure risk in CKD outcomes trials, whereas GLP-1RAs have established cardiovascular benefit across cardiometabolic populations. The FLOW trial (Evaluate Renal Function With Semaglutide Once Weekly) established hard kidney-outcome evidence for semaglutide in type 2 diabetes with CKD, although whether this renal benefit represents a broader GLP-1RA class effect remains unresolved. This review synthesizes current evidence through a translational framework centered on mechanistic complementarity rather than simple add-on therapy. SGLT2 inhibitors predominantly provide proximal tubular and hemodynamic offloading, coupled with fasting-mimetic metabolic reprogramming that may improve oxygen-stress balance and cellular housekeeping. GLP-1RAs predominantly support an immune-vascular repair program by dampening sterile inflammation, preserving endothelial integrity, and limiting fibrotic amplification. These pathways appear to converge at mitochondrial homeostasis, autophagy, and barrier stability. We argue that the most useful clinical implication at present is not a fixed prescribing algorithm, but a phenotype-aware way to frame residual risk, sequence future studies, and define mechanistic endpoints for combination strategies across chronic kidney disease phenotypes.

GLP-1 Receptor Agonists and All-Cause Overdose Risk in Veterans With Type 2 Diabetes and Opioid Use Disorder.

Kevin P Kennedy, Ryan Bremseth-Vining, Kevin G Lynch +4 more

Objective: Overdoses remain a major public health challenge. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been proposed as a treatment for opioid use disorder (OUD) based on preclinical research. Early observational research suggests that GLP-1RAs are associated with reduced opioid overdoses but warrants replication in different patient populations. Methods: This target trial emulation study used Veterans Health Administration (VA) data to include Veterans with a diagnosis of type 2 diabetes mellitus and OUD who initiated semaglutide and tirzepatide or a comparison diabetes medication (insulin, metformin, a sulfonylurea, a sodium-glucose transport 2 (SGLT2) inhibitor, or a dipeptidyl-peptidase 4 [DPP4] inhibitor) between January 1, 2020, and December 31, 2024. Each set of comparison groups was propensity score matched on relevant variables. Cox proportional hazards regression models were used to compare the time to all-cause overdose events in the 12 months after medication initiation. Results: After propensity score matching, semaglutide and tirzepatide were associated with significantly lower risk of all-cause overdose compared to insulin (hazard ratio [HR]=0.32; 95% CI=0.14-0.71; P=.006; n=630) and SGLT2 inhibitors (HR=0.25; 95% CI=0.09-0.68; P=.006; n=432). Semaglutide and tirzepatide were not associated with significantly lower risks than metformin (HR=0.75; 95% CI=0.38-1.45; n=1,016), sulfonylureas (HR=0.82; 95% CI=0.33-1.96; n=710), or DPP4 inhibitors (HR=1.20; 95% CI=0.52-2.78; n=858). Conclusion: Collectively, semaglutide and tirzepatide were associated with lower risk of all-cause overdose compared to insulin and SGLT2 inhibitors, but not metformin, sulfonylureas, or DPP4 inhibitors. These results suggest the possible role of GLP-1RAs in OUD but underscore the need for randomized controlled trials.

Insulin, Semaglutide and Dapagliflozin in Adults With Type 1 Diabetes: Design and Methods of Triple Therapy for Type 1 Diabetes (TTT1)-An International Phase 3 Clinical Trial.

Joseph G Timmons, Husam Ghanim, James G Boyle +9 more

Attaining target glycaemia can be a challenge in Type 1 Diabetes (T1D) due to insulin-induced weight gain. Adjunct therapy with modern glucose-lowering agents developed for type 2 diabetes (T2D) has great potential but may be insufficiently efficacious and carries risks of hypoglycaemia and ketosis. We designed the first Phase 3 clinical trial to assess the efficacy and safety of adding a Glucagon-Like Peptide 1 receptor agonist (GLP-1RA) and a Sodium-Glucose Co-transporter (SGLT2) Inhibitor to insulin therapy in overweight and obese adults with T1D and glycaemia above target (HbA1c 7.5%-11.0% inclusive) (NCT03899402).

Glucagon-like peptide-1 receptor agonists in the aging population of people with HIV: emerging evidence and clinical implications.

Lara Haidar, Joseph A C Delaney

The increasing use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for type 2 diabetes and obesity has generated interest in their potential role among people with HIV (PWH), who experience a high burden of cardiometabolic disease and aging-related comorbidities. This review summarizes emerging evidence on the efficacy, safety, and implementation considerations of GLP-1RAs in PWH.

N-terminally modified GLP1R agonists drive G protein bias via extracellular loop 3 displacement.

Li-Hua Zhao, Qian He, Qingning Yuan +4 more

The glucagon-like peptide-1 receptor (GLP1R), a class B G protein-coupled receptor (GPCR), is a pivotal therapeutic target for type 2 diabetes mellitus and obesity. GLP1R agonists signal through both G protein and β-arrestin pathways, associated with distinct receptor conformational and trafficking states. Here, we develop G protein-biased GLP1R agonists through N-terminal modifications, including acetylation or amino acid substitutions, which exhibit preferential G protein signaling relative to the reference ligand. Cryo-EM structure of GLP1-Y11-GLP1R-Gs complex at 2.64 Å resolution reveals that outward displacement of extracellular loop 3 (ECL3) is the key structural feature associated with signaling bias, distinguishing the complex from β-arrestin-biased agonist-bound state. Ac-GLP1 and Ac-semaglutide display altered receptor trafficking, attenuated β-arrestin recruitment, and prolonged cAMP signaling. In diet-induced obese mice, Ac-semaglutide maintains glucose-lowering activity three days post-administration. These findings elucidate the structural basis of GLP1R biased agonism and provide mechanistic insights into class B GPCR signaling modulation.

Postshortage Compounded GLP-1 RA Market in 2 States With Potentially High Demand.

Michael J DiStefano, Adeleine Tilley, Deepika Paratane +3 more

Supply-side challenges combined with high costs and limited insurance coverage led to a robust market for compounded glucagon-like peptide-1 receptor agonists (GLP-1 RAs). However, assessment of this market since the end of the semaglutide and tirzepatide shortages is needed.

Incretin-based cardiovascular protection beyond diabetes: evidence, mechanisms, and therapeutic frontiers from GLP-1 receptor agonists to multi-agonist therapy.

Libin Qiu, Jinpeng Liu, Nana Hu

Incretin-based therapy has moved from glycaemic control into the centre of cardiometabolic medicine. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) consistently reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2DM) and established atherosclerotic cardiovascular disease (ASCVD), while semaglutide 2.4 mg has extended the evidence base to people with overweight or obesity and established cardiovascular disease in the absence of diabetes. Dedicated trials have further expanded the clinical landscape to chronic kidney disease (CKD), obesity-related heart failure with preserved ejection fraction (HFpEF), and symptomatic peripheral artery disease (PAD). Concurrently, dual and triple incretin-based agonists, oral peptide and non-peptide formulations, and combination strategies with sodium-glucose cotransporter-2 (SGLT2) inhibitors and non-steroidal mineralocorticoid receptor antagonists are reshaping treatment algorithms. This critical review synthesizes cardiovascular outcome trials (CVOTs), mechanistic studies, meta-analyses, guideline recommendations, and regulatory developments available up to 30 April 2026. The central conclusion is that incretin-based cardiovascular protection is biologically plausible and clinically reproducible. Critically, this benefit is now independent of diabetes as the defining therapeutic context-a paradigm shift with broad implications for cardiovascular practice. Nevertheless, the magnitude of benefit varies considerably by molecule, dose, population, comparator, and endpoint hierarchy; mediation analyses do not precisely quantify direct cardioprotection; and cardiovascular outcome evidence for newer multi-agonists and oral non-peptide GLP-1 RAs remains incomplete. Interpretation therefore requires a balanced evidence framework: GLP-1 RAs with proven outcome benefit should be prioritized in patients with ASCVD (e.g., LEADER, SUSTAIN-6, HARMONY Outcomes), obesity with established CVD (SELECT), CKD (FLOW), or obesity-related HFpEF (STEP-HFpEF) when supported by trial data and regulatory indications, whereas next-generation agents should be evaluated according to completed CVOTs rather than weight-loss efficacy alone. Remaining research priorities include defining weight-independent mechanisms, optimizing combination therapy, identifying biomarker-defined responders, preserving lean mass during high-efficacy weight loss, and ensuring equitable global access.

Coronary artery disease -related outcomes associated with semaglutide and tirzepatide in type 2 diabetes mellitus and obesity: a systematic review and meta-analysis.

Xiao-Yu Zhou, Chen-Hao Deng, Ji-Yuan Zhong +7 more

Semaglutide and tirzepatide are widely used drugs in the treatment of metabolic diseases based on incretin-based therapy. However, evidence on coronary artery disease (CAD)-related outcomes has largely been derived from separate randomized trials with different control groups, and focused synthesis across CAD phenotypes remains limited. This study aimed to evaluate CAD-related outcomes reported in randomized controlled trials (RCTs) of semaglutide and tirzepatide in adults with type 2 diabetes (T2DM) and/or obesity.

Do Fasting GLP-1 and GIP Levels Predict the Initial Pharmacological Response to Semaglutide and Tirzepatide?

Sandro La Vignera, Cristian Fioriglio, Rosita A Condorelli

Background/Objectives: Semaglutide and tirzepatide demonstrate substantial efficacy in obesity treatment, yet individual responses vary markedly. The incretin system-comprising glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-is frequently dysregulated in obesity, but whether fasting incretin levels predict differential pharmacological responses remains unexplored. We investigated whether combinatorial fasting GLP-1/GIP tertile profiles predict the initial weight-loss response to semaglutide versus tirzepatide in patients with severe obesity. Methods: This prospective, parallel-group, open-label pilot study enrolled 90 treatment-naïve patients with BMI > 40 kg/m2 (mean 42.5 ± 3.5 kg/m2) at the University of Catania, Italy. Fasting serum GLP-1 (0.8-50 pg/mL) and GIP (1-16 ng/mL) were measured by chemiluminescence immunoassay and distributed into tertiles, generating nine combinatorial profiles (P1-P9; n = 10 per profile). Within each profile, five patients were randomly assigned to semaglutide (escalated to 2.4 mg/week) or tirzepatide (escalated to 15 mg/week). Primary outcome was pharmacological response category at six months: low (<5% body weight reduction), intermediate (5-15%), or optimal (>15%). Results: Baseline characteristics were balanced across profiles (age 48 ± 8 years, BMI 42.5 ± 3.5 kg/m2, waist circumference 134 ± 12 cm, HOMA-IR 8.5 ± 3.0; all p > 0.05). Tirzepatide achieved optimal response in profiles with low GIP tertile regardless of GLP-1 level (P1, P6, P8), while semaglutide achieved optimal response when GLP-1 was low and GIP was intermediate-to-high (P4, P5). Both drugs showed low response in the high GLP-1/high GIP profile (P3). Mean weight loss in optimal-response groups was 18.2 ± 2.1% for tirzepatide and 16.8 ± 1.9% for semaglutide. Waist circumference reductions paralleled weight loss patterns. HOMA-IR decreased significantly in all optimal-response groups (mean reduction 4.2 ± 1.1 units). Conclusions: In this hypothesis-generating pilot study, fasting GLP-1/GIP combinatorial profiling, obtained from a single fasting blood sample, was associated with differential pharmacological responses to semaglutide and tirzepatide in severe obesity. Low GIP levels were tentatively associated with optimal tirzepatide response; low GLP-1 with intermediate-to-high GIP was tentatively associated with optimal semaglutide response. These preliminary findings provide proof-of-concept for incretin-guided personalised obesity pharmacotherapy but require confirmation in larger, adequately powered randomised trials before any clinical recommendations can be made. The inability to discriminate incretin secretory deficiency from receptor resistance using fasting measurements alone, the absence of a placebo control, and the six-month follow-up (shorter than the 12-18 months at which maximal efficacy is typically observed) remain critical limitations.

Semaglutide and Exercise Synergy in Obesity: Preserving Muscle Mass and Uncovering Organ Crosstalk.

José A Inia, Simone Droog, Jessica Snabel +6 more

Semaglutide, a glucagon-like peptide-1 receptor agonist, effectively promotes weight loss and improves metabolic parameters in individuals with obesity. However, its use is often accompanied by reductions in lean mass, raising concerns about long-term muscle health. This study explored whether combining semaglutide with exercise could preserve muscle mass and enhance metabolic outcomes.

Cancer risk of glucagon-like peptide-1 receptor agonists for obesity: comparison with bariatric surgery and other weight-loss drugs.

Elio R Bitar, Karim Besir, Kaelyn C Cummins +6 more

Obesity is associated with an increased risk of several cancers, including colorectal cancer (CRC), pancreatic cancer, and hepatocellular carcinoma (HCC). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been linked to a lower risk of certain obesity-associated cancers, but most studies have focused on patients with diabetes. Their impact on nondiabetic patients using GLP-1 RAs for weight loss remains unclear.

Comment on 'Real-World Evidence of the Effectiveness and Safety of Biosynthetic Semaglutide in Type 2 Diabetes: A Multicentre Study From Pakistan'.

Fatima Shahid, Muhammad Faizan Khan

Changes in food cravings, dietary quality, body composition, and dietary intake during GLP-1 receptor agonist therapy: The CRAVE study.

Demsina Babazadeh, Stephanie Therrien, Angela K Fitch +1 more

To evaluate changes in diet quality, food cravings, dietary intake, and body composition during 24 weeks of GLP-1 RA OMM therapy in a real-world clinical setting.

How Low Could Semaglutide Prices Fall? An Analysis of Production Cost and Implications for Global Access.

Jacob Levi, Samuel Cross, Nydile Ramesh +2 more

This study aimed to estimate potential launch prices of generic semaglutide following patent expiry in 2026 and to quantify the global obesity and type 2 diabetes (T2DM) burden in countries where generic access may become possible.

Direct effects of glucagon-like Peptide-1 receptor agonists on mitochondrial function in human-derived in vitro models: A systematic review and meta-analysis.

Zoe Lee Greenblatt, Atena Tork, Ivy Cruz +4 more

GLP-1 receptor agonists (e.g., semaglutide; GLP-1 RAs) treat Type 2 Diabetes and obesity, mainly by improving glycemic control, suppressing appetite, delaying gastric emptying, and inducing weight loss. Emerging evidence suggests they also directly affect mitochondrial function independently of systemic metabolism. To our knowledge, this is the first systematic review and meta-analysis examining direct mitochondrial effects of GLP-1 RAs in human-derived in vitro models. Of 1547 records identified (1203 screened after deduplication), 17 studies met the criteria, and only 11 contributed to the quantitative synthesis of mitochondrial outcomes. Outcomes included mitochondrial membrane potential (MMP), bioenergetics (ATP-linked oxygen consumption, respiration, ATP production), and mitochondrial reactive oxygen species (MitoROS). Meta-analysis demonstrated significantly improved bioenergetics (SMD = 1.109, 95% CI: 0.556-1.662, P < 0.001) and reduced MitoROS (SMD = -3.489, 95% CI: -6.690 to -0.288, P = 0.034) following GLP-1RA treatment. No significant effect on MMP was observed in the primary analysis (SMD = 0.997, 95% CI: -1.678 to 3.672, P = 0.459), although an exploratory sensitivity analysis excluding statistically identified outlying effect sizes suggested a potential improvement in MMP (SMD = 3.145, 95% CI: 2.147-4.144, P < 0.01); however, this finding should be interpreted cautiously. Overall certainty of the evidence was very low for the primary outcomes due to methodological limitations, substantial heterogeneity, imprecision, and publication bias in some outcomes. Only the MMP sensitivity analysis achieved low-certainty evidence. These findings suggest that GLP-1 RAs may directly promote mitochondrial health, but more rigorous, standardized, and independent studies are needed to confirm their relevance to whole-body physiology.

Lower fall and femoral fracture risks with semaglutide and tirzepatide compared with DPP-4 inhibitors in older adults with type 2 diabetes.

Hsin-Yu Chen, Jheng-Yan Wu, Yi-Hsin Chu +2 more

This retrospective cohort study evaluated whether semaglutide and tirzepatide reduce the risk of falls and femoral fractures in older adults with type 2 diabetes and overweight or obesity. The findings showed significantly lower risks of both outcomes compared with DPP-4 inhibitors.

Pharmacological Therapy for Metabolic Dysfunction-Associated Steatotic Liver Disease in a New Era for Obesity and Metabolic Medicine: A State-of-the-Art Review.

Wah-Kheong Chan, Hak-Keith Leung, Guo-Jeng Tan +4 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and a major cause of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Weight loss via positive health behavioral change is the cornerstone of management of MASLD. However, this is a huge challenge for many patients, highlighting the need for effective pharmacological therapies. Two pharmacological agents have received conditional approval for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), the progressive inflammatory form of MASLD, namely resmetirom, an oral, liver-directed, selective thyroid hormone receptor-β agonist, and semaglutide, a glucagon-like peptide-1 receptor agonist. Despite recent advances, effective pharmacological therapy for MASH-related cirrhosis remains an unmet need, underscoring the importance of early identification and intervention. This narrative review summarizes the current pharmacological therapy landscape of MASLD, including emerging incretin-based therapies and fibroblast growth factor-21 analogues, as well as current guidance on the use of non-invasive tests for treatment selection and monitoring for treatment response. It also provides a background on recent advances in obesity and metabolic medicine, highlighting the evolving paradigm of complication-centric obesity management and the potential role of incretin-based therapies as the backbone of the management of obesity and obesity-related conditions, including MASLD.

Neuropsychiatric Outcomes With Tirzepatide, Semaglutide, and Other GLP-1 Receptor Agonists.

Solomon Chih-Cheng Chen, Tso-Jen Wang, Chu-Kuang Chou +1 more

Neuropsychiatric safety concerns, including depression and suicidal ideation, have emerged during the expanding clinical use of incretin-based therapies for type 2 diabetes mellitus (T2DM) and obesity. However, whether risks differ across successive generations of incretin-based therapies remains uncertain.

Semaglutide Modulates Visceral Adipose Tissue Lipid Metabolism in Type 2 Diabetic Mice: A Lipidomics Study.

Xinlei Chen, Bingrou Tu, Zhaoyuan Li +3 more

Type 2 diabetes mellitus (T2DM) is a major public health challenge. This study aimed to explore the molecular mechanisms underlying the effects of semaglutide on lipid metabolism in visceral white adipose tissue in a mouse model of T2DM.

Role of GLP-1 receptor agonists in the prevention and treatment of obesity-related cancer.

Giovanna Muscogiuri, Guendalina Del Vecchio, Luca Colangeli +3 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become pivotal in treating type 2 diabetes and obesity due to their ability to improve glycemic control and promote weight loss. Beyond their metabolic benefits, emerging evidence suggests that GLP-1 RAs may exert anticancer effects by modulating critical biological pathways involved in tumorigenesis, including insulin signaling, inflammation, and cellular proliferation. Current evidence derived from observational and secondary analyses suggests potential protective effects of GLP-1 RAs against several cancers-including prostate, breast, pancreatic, gynecological, glioma, and oral squamous cell cancer through both weight-dependent and independent mechanisms, but the absence of large-scale randomized controlled trials (RCTs) with cancer-specific endpoints remains a critical limitation. Moreover, safety concerns remain a major challenge. Although rodent studies raised concerns regarding medullary thyroid carcinoma, human data have not substantiated a significant risk. Similarly, initial signals of pancreatitis and pancreatic cancer risk have been largely attenuated by subsequent rigorous analyses. Common side effects, such as gastrointestinal discomfort, are usually manageable and transient, but rare adverse events warrant vigilance, particularly in vulnerable patient populations. GLP-1 RAs show emerging signals for cancer prevention and treatment, but their therapeutic application in oncology should proceed cautiously. Future research must prioritize well-designed, adequately powered cancer-focused RCTs that evaluate both efficacy and safety over extended periods.

Brain Neuromodulation via Endoscopic Gastric Implant Improves Glycemic Control in Insulin-Dependent Type-2 Diabetes: First-in-Human Feasibility and Autonomic Response Study.

Valerio Cigaina, Alfredo Saggioro, Paolo Fabris +1 more

A miniaturized, self-powered Brain NeuroModulator (BNM) device, endoscopically implanted under neuroleptanalgesia in the submucosal layer of the proximal lesser gastric curvature, has the potential to consistently increase parasympathetic tone as measured by heart rate variability (HRV).

Semaglutide and Musculoskeletal Health: A Mendelian Randomization Study Based on GLP-1 Receptor Expression.

Dong Li, Xinyu Liang, Zhijun Li +2 more

Semaglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist, is clinically used for glycemic control and weight loss. However, it is still unclear whether it has any impact on bones and muscles. Does semaglutide have any impact on the musculoskeletal system of patients during its use, or does it have any negative effects on them? This study aims to assess the impact of GLP1R on bone and muscle using Mendelian Randomization.

Comparative 24-month cardiovascular outcomes and biomarker trajectories with semaglutide, empagliflozin, and sitagliptin in people with obesity and type 2 diabetes: a multicenter real-world study.

Jo-Ching Chen, Kai-Wen Liu, Yu-Nan Huang +3 more

Comparative evidence on 24-month clinical outcomes and biomarker trajectories with semaglutide, empagliflozin, and sitagliptin in adults with type 2 diabetes (T2D) and obesity remains limited.

Comparative Positioning of Orforglipron Among Selected GLP-1 Receptor Agonist Benchmarks: A Narrative Review.

José Castro-Gamboa, Jeaustin Mora-Jiménez, Sebastián Arguedas-Chacón +1 more

Orforglipron is an oral, nonpeptide, small-molecule glucagon-like peptide-1 receptor agonist developed for type 2 diabetes and obesity. This narrative review evaluates its comparative positioning among marketed GLP-1 receptor agonists by integrating structural, pharmacological, clinical, and practical evidence. A narrative literature review was conducted using PubMed/MEDLINE, Embase, Scopus, Web of Science, ClinicalTrials, official prescribing information, and citation tracking. The synthesis was organized by comparative domains, including molecular structure, receptor pharmacology, early clinical pharmacology, direct comparative evidence, contextual comparator evidence, and practical administration. From 245 screened records, 88 duplicates were removed, 157 unique records were assessed, and 35 orforglipron-focused sources were retained. Seven additional comparator trials were selected through targeted citation verification because they represented clinically relevant benchmarks for oral semaglutide in type 2 diabetes and obesity, danuglipron as another oral small-molecule GLP-1 receptor agonist, and injectable semaglutide as a high-efficacy class comparator. Current evidence identifies several domains relevant to the comparative positioning of orforglipron, including its nonpeptide small-molecule structure, receptor pharmacology, once-daily oral dosing profile, and direct comparator evidence against dulaglutide and oral semaglutide. Food-effect and prescribing-information sources describe fewer food-related administration constraints for orforglipron than for oral semaglutide. However, indirect comparisons remain limited by differences in populations, doses, follow-up duration, comparators, and endpoints. At present, orforglipron should be viewed as an oral small-molecule GLP-1 receptor agonist with emerging comparative evidence, rather than as a broadly superior replacement for existing agents. Further long-term comparative, cardiovascular, renal, safety, adherence, and real-world effectiveness data are needed to define its final place in therapy.

Semaglutide Injection Once-Weekly for Weight Management in Adults: Results From A Randomized Phase III, Active-Controlled Study.

Unnikrishnan Ambika Gopalakrishnan, Ameya Joshi, Harish Kumar +24 more

To evaluate and compare the efficacy, safety, and immunogenicity of a synthetic semaglutide injection (Test semaglutide) with Wegovy (Reference semaglutide) injection for weight management.

Cardiovascular Outcomes With Tirzepatide Versus GLP-1 Receptor Agonists in Overweight or Obesity: A Systematic Review and Meta-Analysis.

João Pedro Machado Ribeiro Jacintho Silva, Bruno Viruez Nogueira, Deborah Lomelino Sartori +4 more

To compare cardiovascular outcomes associated with tirzepatide versus glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in adults with overweight or obesity.

Protocol for Novel Perioperative Optimization of Obese Osteoarthritic Patients pending Total Knee Replacement with glucagon-like peptide-1 receptor agonist (NPO-OOPS-TKR) : a pilot randomized controlled trial.

Lawrence C M Lau, Tak W D Lui, Chunyi Wen +8 more

Obesity is associated with higher rates of perioperative complications and worse pain and functional outcomes after total knee arthroplasty (TKA). Preoperative optimization through weight management is therefore clinically appealing, but the current evidence base is mixed. No randomized controlled trial (RCT) has evaluated glucagon-like peptide-1 receptor agonists (GLP-1RAs) as a perioperative optimization strategy before TKA, and no such trial has focused on an Asian population. This pilot randomized trial therefore aims to determine the feasibility, tolerability, and acceptability of semaglutide-based optimization before and after TKA in older Asian adults with obesity.

Time to benefit of incretin-based therapies in adiposity-related heart failure with mildly reduced or preserved ejection fraction: a systematic review and meta-analysis.

Bernardo F Spiazzi, Carolina P Zingano, Amanda R Vest

Obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF). Incretin-based therapies are associated with a reduction in worsening heart failure (HF) events for patients with HF with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), although the time to clinical benefit from these therapies is unknown.

GLP-1 Agonists and Risk of Atrial Fibrillation in Non-Dialysis Chronic Kidney Disease.

Parth Dhamelia, Ninad Khandekar, Srikanth Vallurupalli +5 more

GLP1 receptor agonists (GLP-1 RAs) improve cardiorenal outcomes in chronic kidney disease (CKD) patients with obesity or type 2 diabetes. Whether GLP-1 RAs reduce risk of atrial fibrillation (AF) in CKD patients, especially in absence of diabetes or obesity, is unclear.

Current Concepts in Perioperative Guidance and Outcomes in Hand Surgery Patients Taking Glucagon-Like Peptide-1 Receptor Agonists.

Ethan Y Song, M Stephen Melton, Warren Hammert +2 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide and tirzepatide, have rapidly increased in use for diabetes management and weight loss, coinciding with the rising prevalence of obesity and diabetes among patients undergoing hand surgery. Growing perioperative concerns of delayed gastric emptying and aspiration risk have prompted evolving guideline recommendations and clinical uncertainty surrounding surgical planning. Current evidence on GLP-1 RA usage and outcomes in hand and orthopedic literature remains limited, but multiple studies report no notable increase in postoperative complications. There may be potential benefits to GLP-1 RA in surgical outcomes, possibly related to reduced systemic medical morbidity and improved metabolic control. As there still are substantial limitations in the medical literature on the effects of GLP-1 RA, questions remain regarding optimal perioperative medication management, effects on bone and wound healing in the context of rapid weight loss, and anesthesia-related risk. Yet, as GLP-1 RA exposure becomes increasingly common, hand surgeons must understand the pharmacology, risk profile, and emerging evidence to guide individualized decision-making and ensure safe perioperative management for patients.

Effect of Semaglutide on Measured vs Estimated Glomerular Filtration Rate.

Rafal Yahya, Esben Iversen, Suvanjaa Sivalingam +7 more

Semaglutide is a glucagon-like peptide-1 receptor agonist widely used for its glucose-lowering effects in people with type 2 diabetes (T2D), as well as its cardiovascular and kidney-protective properties. However, it remains unclear whether semaglutide influences blood concentrations of endogenous filtration markers like creatinine, cystatin C, beta-trace protein (BTP), and beta-2 microglobulin (B2M). We investigated the effect of semaglutide on these filtration markers and the performance of estimated glomerular filtration rate (eGFR) equations compared with measured glomerular filtration rate (mGFR).

Concurrent diabetic ketoacidosis, acute pancreatitis, and subsequent ruptured acalculous cholecystitis in a patient receiving semaglutide: A case report.

Chuan-Tai Chiu, Ya-Hui Hu, Chia-Hui Chang

A 70-year-old male with type 2 diabetes presented to the emergency department with severe abdominal pain and dyspnea after 24 weeks of treatment with weekly subcutaneous semaglutide (1 mg). He was diagnosed with acute pancreatitis and diabetic ketoacidosis (DKA) and admitted to the intensive care unit. Following 5 days of stabilization and symptom relief, he was transferred to a general ward. However, the patient subsequently developed a high-grade fever persisting for 3 days, accompanied by severe leukocytosis, despite normalized serum lipase levels. A repeat abdominal computed tomography scan revealed acute acalculous cholecystitis complicated by gallbladder rupture. The patient underwent emergency percutaneous transhepatic gallbladder drainage and antibiotic therapy, leading to gradual recovery. This clinical course illustrates a rare cascade of severe complications in a patient receiving a glucagon-like peptide-1 (GLP-1) receptor agonist. Specifically, when new-onset systemic symptoms emerge following the initial stabilization of a critical illness, clinicians should maintain vigilance for repeating imaging studies. This rare case highlights the need for further investigation into whether the pharmacological effects of GLP-1 receptor agonists, such as biliary stasis, might act as a predisposing factor for complex biliary complications in the setting of severe physiological stress.

Cost-Effectiveness of Semaglutide 2.4 mg for Obesity Disease Management in Japan: A Lifetime Economic Modeling Study Incorporating Retreatment Scenarios.

Yuta Kamada, Shogo Wada, Hiroyuki Matsuda +1 more

Obesity is a chronic disease associated with substantial morbidity and healthcare costs. In Japan, the Optimal Use Promotion Guidelines (OUG) impose restrictions on patient eligibility for semaglutide 2.4 mg and limit treatment duration. This study evaluated the cost-effectiveness of semaglutide 2.4 mg in Japan under retreatment assumptions informed by OUG requirements.

Wernicke's Encephalopathy Following Semaglutide Treatment for Obesity: A Systematic PRISMA Review of Case-Based Evidence.

Janice Bidesie, Erik Oudman

Glucagon-like peptide-1 receptor agonists are increasingly prescribed for obesity. Although generally considered safe, marked appetite suppression and persistent gastrointestinal adverse effects may increase the risk of nutritional deficiencies. Wernicke's encephalopathy (WE), caused by thiamine deficiency, is a rare but potentially fatal neurological disorder that may result in irreversible cognitive impairment if not promptly recognized and treated. Recently, cases of WE associated with semaglutide use have been reported. This study aimed to systematically review published case reports of WE occurring after semaglutide treatment for obesity from an endocrinological drug safety perspective.

Pharmacological mechanisms and clinical impacts of antidiabetic drugs on colorectal cancer risk: a systematic review.

Yu Yang, Kan Wang

Type 2 diabetes mellitus (T2DM) significantly increases colorectal cancer (CRC) risk, driven by shared metabolic and inflammatory pathways. As lifelong glucose-lowering medications are routinely used in T2DM, their pharmacological activities and associated oncological effects have become critical for safety and repurposing. This review systematically summarizes the pharmacological mechanisms, epidemiological evidence, and clinical outcomes of eight antidiabetic drug classes in modulating CRC risk. We highlight drug-specific effects: metformin may act via AMPK/mTOR and immune reprogramming; SGLT-2 inhibitors may exert direct cytotoxicity and indirect metabolic benefits; GLP-1 RAs show class-wide neutrality except high-dose semaglutide; DPP-4 inhibitors display dual pro- and anti-tumor effects; insulin and most secretagogues elevate CRC risk via hyperinsulinemia; while TZDs and AGIs offer modest chemopreventive effects. We conclude that antidiabetic drugs possess pharmacological properties that can inform CRC risk stratification and drug repurposing. Future research should prioritize mechanistic validation and precision pharmacology to translate these findings into clinical practice.

Beyond weight loss: predictors of treatment satisfaction and patient-reported outcomes in incretin-based therapies. A cross-sectional study.

Ali Kapan, Othmar Moser, Richard Felsinger +1 more

Incretin-based therapies, including glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists, have demonstrated substantial efficacy in weight management. However, real-world treatment experience, tolerability, and treatment continuation remain important challenges, and the determinants of patient satisfaction are not fully understood.

Rebooting blood vessel repair: implications of the SEMA-VR CardioLink-15 trial.

Raj Verma, Meena Verma, Brady Park +4 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events (MACE), heart failure, and mortality through undetermined mechanisms independent of glycemic control. This review examines emerging evidence that GLP-1RAs overcome vascular regenerative cell exhaustion (VRCE), a pathological depletion of bone marrow-derived progenitor cells that mediate vessel repair.

Efficacy and Safety of Intensifying Once-Weekly Insulin Icodec Treatment With Once-Weekly Semaglutide in Adults With Type 2 Diabetes: A Single-Arm, Open-Label, Treat-to-Target, Phase 3b Trial (ONWARDS 8).

Krzysztof Strojek, Andreas Liebl, Neha Narendra Mumbaikar +3 more

To investigate the efficacy and safety of intensifying once-weekly insulin icodec (icodec) with once-weekly semaglutide in adults with type 2 diabetes (T2D).

Enhanced Stability and Transdermal Delivery of Semaglutide Using an L-Arginine Based Dissolving Microneedle System.

Priyanka Panchal, Snehal Daware, Yi Guo +4 more

Glucagon-like peptide-1 agonists, especially Semaglutide (SMG), have revolutionized the management of diabetes and obesity, yet its clinical application is hindered by challenges in oral bioavailability and patient adherence to injectable formulations. Transdermal delivery offers a promising alternative, and this study explores dissolving microneedle (DMN) technology for SMG administration. PETOX is a water-soluble polymer utilized for the fabrication of dissolving microneedles and unique stabilization of SMG by incorporating L-arginine. Our study presents the first comprehensive investigation of L-arginine as an excipient in dissolving microneedles to enhance peptide integrity and stability. This study focuses on the development and characterization of DMN arrays formulated with a polymeric blend of hyaluronic acid, PETOX, and L-arginine, designed for the transdermal delivery of SMG. The SMG loaded microneedles (SMG-DMNs) exhibit robust mechanical strength (3.47 N/needle; fracture force), excellent Parafilm M® insertion (> 50% at 450 μm depth), and drug release over 12 h. Extensive SMG-DMNs characterization include ex-vivo porcine skin insertion, scanning electron microscopy, confocal microscopy, and unique agarose-based dissolution model showed effective optimization of polymeric matrix for SMG, ensuring better insertion capabilities. The florescence imaging verified efficient transdermal deposition and penetration of dye suggesting potential transdermal delivery of SMG upon insertion. While the DMN approach addresses key barriers such as low oral bioavailability, injection-related discomfort and patient compliance; challenges persist regarding loss of therapeutic activity and stability of peptide. Nevertheless, DMN technology presents a promising, patient-friendly alternative for peptide therapeutics, with the potential to significantly improve outcomes in T2DM and obesity management.

Weekly and Biweekly Treatment With Bofanglutide Versus Semaglutide in Chinese Patients With Type 2 Diabetes : A Phase 2b Randomized Clinical Trial.

Ming Liu, Zhifeng Cheng, Li Lu +12 more

Bofanglutide is a novel glucagon-like peptide-1 receptor agonist under development for type 2 diabetes mellitus (T2DM) and overweight and obesity.

Ease of Use, Ease of Learning, and Convenience of the CagriSema Dual-Chamber Pen: Results From a Usability Study in Adults With Overweight, Obesity, or Type 2 Diabetes.

Walter Gulisano, Gitte Ter-Borch, Paul Brown +6 more

This study evaluated the usability of the CagriSema dual-chamber pen, a single-dose, single-use, pre-filled autoinjector for once-weekly subcutaneous administration of a fixed-dose combination of cagrilintide and semaglutide. Adults with overweight/obesity (n = 85) or type 2 diabetes (n = 65) performed simulated injections after standardized training. Endpoints included injection completeness, task durations, and user feedback via the Injection Device Experience and Acceptability-Ease of Use and Convenience Questionnaire (IDEA-ECQ; content validity supported by cognitive interviews, n = 50). All but one participant completed the injection successfully. Median training time was 3 minutes, and time to prepare and inject was 15 seconds. Participants rated the device easy/very easy to use (100%), easy/very easy to learn (98.7%), and an injection with the pen convenient (99.3%). Results were consistent across populations and unaffected by prior device experience.

Real-World Evidence of the Effectiveness and Safety of Biosynthetic Semaglutide in Type 2 Diabetes: A Multicentre Study From Pakistan.

Arshad Hussain, Muhammad Umar Wahab, Saleem Qureshi +7 more

To evaluate the real-world effectiveness, safety and patient-reported outcomes of biosynthetic semaglutide in adults with type 2 diabetes mellitus (T2DM) receiving routine outpatient care in a cost-constrained setting.

Chronic semaglutide alters ingestive behavior without impairing taste function in mice.

Alisha A Acosta, Hillary Ellis, Fang-Yu Hsu +3 more

Glucagon-like peptide-1 receptor (GLP-1R) agonists such as semaglutide are highly effective treatments for obesity, yet the mechanisms by which they reduce food intake remain incompletely understood. Because taste plays a critical role in guiding food intake, several clinical studies have investigated whether GLP-1R agonists alter taste function, but these reports have yielded conflicting results. Here, we systematically tested the effects of chronic semaglutide treatment on taste responsivity in diet-induced obese mice. Mice were evaluated using brief-access gustometer tests to assess responses to sweet, bitter, sour, salty, and fatty tastants. Chronic semaglutide treatment produced robust weight loss but did not alter lick rates for any tastant, indicating intact taste-driven orosensory evaluation across modalities. Psychophysical analysis using a broad range of sucrose concentrations revealed similar concentration-response functions and comparable EC50 values between vehicle- and semaglutide-treated mice, demonstrating unchanged sweet taste sensitivity. However, semaglutide modestly increased total licking and trial initiation for sucrose, suggesting enhanced behavioral engagement rather than altered taste perception. Consistent with the behavioral findings on taste, semaglutide did not affect the abundance of taste receptor cell subtypes in the circumvallate papilla or the expression of genes involved in taste receptor signaling and neurotransmission. Together, these results indicate that chronic semaglutide does not detectably impair peripheral taste function in mice under our experimental conditions. Instead, GLP-1R agonists likely influence ingestive behavior through mechanisms independent of taste signaling, potentially involving alterations in motivational processes.

Clinical Effectiveness and Safety of Oral Semaglutide in a Real-World Cohort of Patients with Heart Failure with Reduced Ejection Fraction, Type 2 Diabetes and Obesity: A Propensity Score-Matched Analysis.

Alicia Trenas-Calero, Nuria Prieto-Laín, Miguel A Pérez-Velasco +6 more

Bacground/Objectives: There is limited evidence on the role of glucagon-like peptide-1 receptor agonists in heart failure. We aimed to analyze the clinical efficacy of oral semaglutide in terms of health status and change in body weight in patients with heart failure with reduced ejection fraction, type 2 diabetes, and obesity. Methods: This observational, retrospective, real-world study included patients treated with oral semaglutide (Oral-Sema Group) and without glucagon-like peptide-1 receptor agonists (Control Group). The primary outcome was heart failure status, defined as a ≥5 point difference in the Kansas City Cardiomyopathy Questionnaire total symptom score, and change in body weight at 24 months. Results: After 1:1 propensity score matching, 162 patients were included in each group (mean age 71.0 years, mean body mass index 32.1, 52.9% females). Patients in the Oral-Sema Group were more likely to have improvement in heart failure health status from baseline to 24 months (OR: 2.45; 95%CI: 1.25-3.65; p = 0.012). The mean change in body weight was -8.0 ± 2.1 kg in patients with oral semaglutide and -1.9 ± 1.0 kg in control patients (p < 0.01). After treatment, there were negative correlations between the Kansas City Cardiomyopathy Questionnaire total symptom score and body weight (r = -0.558, p < 0.01) and glycated hemoglobin (r = -0.491, p = 0.017). It had good tolerability and safety. Conclusions: Oral semaglutide was associated with an improvement in heart failure health status and weight loss in patients with heart failure with reduced ejection fraction, type 2 diabetes, and obesity. Further research on glucagon-like peptide-1 receptor agonists in heart failure with reduced ejection fraction is needed.

Effects of Semaglutide on Cardiometabolic Risk in People with Obesity, With and Without Type 2 Diabetes: A Retrospective Observational Study.

Loredana Deaconu, Oana Albai, Bogdan Timar +6 more

Background and Objectives: Obesity and insulin resistance are major contributors to cardiometabolic disease and type 2 diabetes mellitus (T2DM). This study evaluated the real-world effects of semaglutide on metabolic parameters, body composition, and cardiometabolic risk factors in people with obesity, with and without T2DM, and explored predictors of treatment response. Materials and Methods: This retrospective longitudinal observational study included 70 adults with obesity (42 with T2DM and 28 without T2DM) treated with semaglutide according to current clinical guidelines. The primary outcomes were changes in body weight, waist circumference, fasting plasma glucose, and glycated hemoglobin (HbA1c). Secondary outcomes included changes in lipid profile, insulin resistance indices, inflammatory markers, hepatic parameters, and body composition assessed by bioelectrical impedance analysis (InBody770). Results: Semaglutide treatment was associated with significant reductions in body weight (-9 kg), waist circumference (-8 cm), HbA1c (-1.1%), systolic blood pressure (-7.5 mmHg), visceral fat area (-30.1 cm2), and insulin resistance markers. Improvements in glycemic parameters were more pronounced in participants with T2DM. Skeletal muscle mass (SMM) was relatively preserved during treatment. Baseline HbA1c and visceral adiposity were independently associated with metabolic response. Conclusions: In this real-world observational cohort, semaglutide was associated with significant improvements in metabolic parameters, body composition, and cardiometabolic risk markers in people with obesity, with and without T2DM. Baseline metabolic characteristics may influence treatment response.

From dual to quintuple agonism for next-generation pharmacology to treat obesity and type 2 diabetes: synergistic incretin and nuclear receptor signaling.

Gaetano Santulli

Receptor-targeted polypharmacology is emerging as a promising strategy for the treatment of obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis. GLP-1-GIP-lanifibranor, a unimolecular conjugate combining GLP-1R/GIPR co-agonism with pan-PPAR activation, enables receptor-guided intracellular delivery of lanifibranor to incretin receptor-expressing cells while limiting systemic off-target exposure. In obese mouse models, the conjugate produced greater reductions in body weight, adiposity, food intake, and hyperglycemia than semaglutide, GLP-1-GIP co-agonism, or lanifibranor alone, while significantly improving insulin sensitivity. Mechanistic analyses demonstrated receptor-dependent delivery and identified PPARδ signaling as a principal mediator of glycemic improvement independent of weight loss. Unlike unconjugated lanifibranor, the conjugate did not induce anemia, fluid retention, renal dysfunction, or adipocyte differentiation, supporting the concept that tissue-restricted PPAR activation may mitigate classical adverse effects of systemic PPAR agonism. These findings establish peptide-directed nuclear receptor targeting as a potentially important platform for next-generation metabolic therapeutics, although substantial translational uncertainties remain regarding clinical efficacy, safety, and long-term applicability.

From evidence to practice: Identifying candidates for semaglutide in chronic atherosclerotic disease.

Aldo P Maggioni, Francesco Orso, Donata Lucci +2 more

Randomised clinical trials (SELECT and SOUL) demonstrated that semaglutide, a GLP-1 receptor agonist, reduces the combined outcome measure of atherothrombotic events or cardiovascular mortality in patients with coronary artery disease, both with and without diabetes. Because real-world populations may differ from trial cohorts, we assessed the proportion of patients potentially eligible for semaglutide using the criteria set out by the regulatory authorities based on the SELECT and SOUL results.

High-yield recombinant production of the semaglutide main chain P29 intermediate using SNAC-tagged enterokinase-cleavable fusion peptides.

Qingyu Qi, Ge Gao, Guodong Li +1 more

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insufficient insulin secretion or impaired cellular response to insulin, resulting in increased blood sugar levels and persistent hyperglycemia. The diabetes-related health expenditure worldwide is estimated to have surpassed 1,000 billion USD according to the new data from the International Diabetes Federation. Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated high efficacy in glycemic control and body weight loss, is approved for T2DM and obesity treatment. However, up to now, industrial production of semaglutide remains constrained by limited yield and high cost associated with conventional approaches. Therefore, improving production efficiency while reducing manufacturing cost remains a challenge. In this study, we report a new strategy for obtaining semaglutide main chain P29, also known as Arg34GLP-1 (9-37), which is a key intermediate precursor in semaglutide synthesis. The method employs a series of semaglutide-derived helical fusion pro-peptides containing the sequence GSHHWHHHSSGDDDDK, which could be cleaved by a 2-step processing via sequence-specific nickel-assisted chemical protein cleavage followed by enterokinase cleavage. Using this strategy, semaglutide main chain P29 was highly expressed and purified to 98% purity, with yields exceeding 5 grams per liter of broth. This process provides improved productivity compared with previously reported strategies. The work establishes an efficient and scalable platform for semaglutide intermediate production and shows potential for large-scale industrial production.

Personalized Combination of a Ketogenic Diet and Low-Dose Semaglutide for Cardiometabolic Health: A Retrospective Case Series.

Genevieve Parker, Madeline D Morris, Jeter R Heggie +9 more

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have demonstrated efficacy for weight loss in obesity; however, up to 40% of weight lost may derive from lean body mass. The ketogenic diet independently improves insulin sensitivity and promotes fat oxidation while preserving lean tissue. This study aimed to describe changes in body composition, insulin sensitivity, and cardiometabolic markers in patients who followed a personalized ketogenic dietary protocol while receiving low-dose semaglutide over a 6-month insulin resistance reversal program. Methods: Seven analyzed adults (six female, one male) with overweight or obesity (baseline BMI 25.6-47.2 kg/m2) participated in a clinician-supervised 6-month program combining a whole-food ketogenic diet with semaglutide (≤1.0 mg/week). Body composition and fasting metabolic markers were assessed at 1, 3, and 6 months. Results: Mean total weight loss was 21.9 kg, of which a mean of 92% was attributable to BIA-estimated fat mass. Skeletal muscle mass was largely preserved as measured by BIA (mean loss 1.2 kg), and one patient gained lean tissue. Fasting insulin declined by a mean of 15.6 µIU/mL. Visceral fat decreased by a mean of 37.0%. Six of seven patients showed reductions in high-sensitivity C-reactive protein. Triglycerides decreased in six of seven patients, and HDL cholesterol increased in all seven. LDL cholesterol responses were heterogeneous. Conclusions: In this small, uncontrolled case series, combining a ketogenic diet with low-dose semaglutide was associated with substantial fat loss, apparent preservation of lean mass as measured by BIA, and improvements in insulin sensitivity and cardiometabolic markers. Because the semaglutide dose and dietary protocol were individualized to each patient's response, the program illustrates a personalized approach to insulin resistance. These preliminary findings are hypothesis-generating and warrant confirmation in controlled prospective studies.

Lean Mass and Musculoskeletal Preservation in GLP-1-Based Obesity Treatment: Nutrition, Exercise, Supplementation, and Monitoring Strategies.

Roko Šantić, Lovre Martinović, Nikola Pavlović +5 more

Background/Objectives: GLP-1-based obesity pharmacotherapy has shifted clinical attention from the magnitude of weight loss to the quality of weight loss. This review evaluates whether body composition changes during treatment with GLP-1-based agents represent clinically meaningful muscle loss and identifies nutrition, supplementation, exercise, and monitoring strategies that may help preserve lean mass, function, bone health, and nutritional adequacy. Methods: A comprehensive narrative review was performed using focused searches of PubMed, publisher-hosted journal platforms, and reference lists of key primary studies and recent evidence syntheses through March and May 2026. Evidence was organized around body composition, muscle quality and function, dietary protein and micronutrient adequacy, exercise, supplementation, bioelectrical impedance analysis, imaging, and emerging biomarkers. Results: Semaglutide and tirzepatide preferentially reduce fat mass, including visceral and ectopic adiposity, while producing smaller but consistent reductions in lean mass or lean soft tissue. However, DXA-derived lean mass and BIA-derived fat-free mass are not equivalent to skeletal muscle, and lean tissue loss does not necessarily indicate impaired strength or physical performance. The most defensible supportive care model combines food-first nutritional counseling, adequate protein intake, structured resistance exercise, management of gastrointestinal adverse effects, and risk-based monitoring of micronutrient inadequacy. Protein supplementation and nutritionally complete meal replacements may be useful when intake is insufficient, whereas creatine, essential amino acids or leucine, beta-hydroxy-beta-methylbutyrate, fiber, probiotics, omega-3 fatty acids, and multi-ingredient products remain adjunctive options supported mainly by indirect or phenotype-specific evidence. Conclusions: Future GLP-1 trials and clinical care should move beyond body weight and total lean mass toward integrated assessment of muscle quantity, muscle quality, function, bone, and nutritional adequacy, and standardized BIA-based clinical monitoring where advanced imaging is not feasible.

Papillary thyroid carcinoma discovered in a patient on semaglutide therapy for metabolic syndrome: a case presentation and review of current evidence.

Jawad Haddadin, Aus Haddad, Lina Nahar +2 more

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is widely used for the management of type 2 diabetes, metabolic syndrome, and obesity. Concerns regarding its potential association with thyroid cancer, particularly medullary thyroid carcinoma, have emerged, although current human evidence remains inconclusive. Reports of papillary thyroid carcinoma (PTC) while using semaglutide therapy are exceedingly rare.

Hydrophobic ion pairing formed semaglutide designed for oral self-microemulsifying delivery in diabetes treatment.

Yuhuan Zhang, Jinghan Cheng, Hanming Wang +4 more

Semaglutide (SET) is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes. Although injectable formulations offer high bioavailability, they are associated with poor patient compliance. In contrast, oral tablets are more convenient but suffer from limited absorption due to SET's hydrophilicity and enzymatic instability in the gastrointestinal tract. To address these challenges, we developed a hydrophobic ion pair (HIP) complex of SET and sodium docusate (SET-DOC), which was further incorporated into a self-emulsifying drug delivery system (SD@SEDDS) to facilitate oral delivery. The optimized SD@SEDDS produced a clear emulsion upon dilution, with a uniform particle size of 85.55  nm, high drug loading (2.64  mg/g), and excellent stability. In vitro transport studies using a Caco-2/HT-29 co-culture model demonstrated enhanced permeability and reduced P-glycoprotein-mediated efflux. In vivo studies in a type 2 diabetic rat model showed that SD@SEDDS significantly reduced blood glucose levels, improved lipid profiles, and exhibited good biocompatibility without observable toxicity. These findings suggested that the combination of HIP technology and SEDDS represented a promising strategy for enhancing the oral delivery efficiency of peptide drugs such as SET.

The risk of retinal vascular events in patients using semaglutide: a scoping review.

Salma Choujaa Goudira, Kurt Højlund, Jakob Grauslund

Background This scoping review aims to explore existing clinical trials on the association between semaglutide use and the occurrence of retinal vascular events to detect any potential safety concern. Summary The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines. A search was performed across PubMed, Embase via Ovid, ClinicalTrials.gov, and Google Scholar on April 16th, 2025, and Marts 5th, 2026. We aimed to detect clinical trials reporting retinal vascular events while investigating the effect of semaglutide in patients with type 2 diabetes or obesity. Reports on optic ischemic neuropathy were included as a reference outcome, to evaluate whether the method used in the review might be capable of detecting rare ophthalmic vascular adverse events, and thereby a potential safety signal. Key Messages Thirteen randomized clinical trials (predominantly double-blind and placebo-controlled) were included, comparing 17,478 individuals treated with semaglutide and 17,334 placebos. A total of 15 retinal vascular events were reported in the semaglutide groups compared with four events in placebo arms. In large, long-term trials (SELECT, SOUL, FLOW), incidence rates were consistently low but numerically higher in semaglutide-treated patients, ranging from 0 to 0.33 events per 1,000 person-years versus 0 to 0.05 in placebo groups. In trials with active comparators, rates ranged from 0 to 5.99 events per 1,000 person-years in semaglutide groups and 0 to 3.52 in comparator groups. For ischemic optic neuropathies, six events were reported among 11,757 semaglutide-treated patients versus one event among 11,105 placebo-treated individuals; in trials with active comparators, two versus one event were reported. In conclusion, retinal vascular events, especially retinal arterial occlusions, showed a higher pattern of reporting in the semaglutide arm across clinical trials, the majority of which were randomized placebo-controlled-trials. Optic ischemic neuropathies were also found to be higher on the semaglutide-arm. These findings support the need for further investigation through large-scale registry studies.

Long-Term Safety and Renal Outcomes of Semaglutide in Non-Diabetic Obesity with Chronic Kidney Disease or Hypertension: A Systematic Review and Meta-Analysis.

Mohamed Kamal ElSayed Elganyny, Abdelhakim Kamal ElSayed Elganyni, Hib Alla Maskji +12 more

Semaglutide, a GLP-1 receptor agonist, has demonstrated metabolic and renal benefits in diabetic populations. However, its efficacy and safety in non-diabetic individuals with obesity and chronic kidney disease (CKD) remain largely unstudied. Given the high cardiometabolic risk in this group and limited therapeutic options, evaluating semaglutide's role is crucial.

The systems medicine view of semaglutide: from clinical trials to molecular mechanisms.

Rui Vitorino

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is a key therapy in managing type 2 diabetes (T2D), offering significant improvements in glycemic control, weight loss, and cardiovascular protection. Beyond these clinical benefits, multi-omics research is clarifying the molecular mechanisms underlying its systemic metabolic effects.

Semaglutide and major adverse cardiovascular events in patients with and without DM: A systematic review and meta-analysis.

Yanhua Li, Chunmei Lv, Lianlian Cao +2 more

Semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA), has been associated with cardiovascular benefits, whereas the consistency of its effect across various clinical settings, as well as its safety-economic profile, remains uncertain. MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform were searched up to January 2025 and identified 11 randomized controlled trials (12 comparisons; 25,067 participants) comparing semaglutide with placebo or active control. Using a DerSimonian-Laird random-effects model, semaglutide reduced major adverse cardiovascular events by 32% [pooled odds ratio (OR)=0.68; 95%; confidence interval 0.52-0.91; 95% prediction interval 0.44-1.04]. Point estimates remained unchanged after censoring all STEP obesity trials (OR=0.70) or both heart-failure trials (OR=0.66), indicating a negligible institution-level effect. Mixed-effects meta-regression analysis revealed greater benefit with lower body weight, LDL- and total cholesterol levels, and lesser benefit with higher age, HbA1c and blood pressure (all P<0.01). Safety pooling found higher risks of any gastrointestinal (GI) disorder [relative risk (RR)=1.47], gallbladder events (RR=2.37), and discontinuation due to GI intolerance (RR 2.32). A total of seven out of 11 trials enrolled ≥75% White patients, none of whom were from low-income countries, limiting generalizability. Besides, U.S. cost-utility models published in the literature report incremental cost-effectiveness ratios of US$ 180,000-260,000 per quality-adjusted life-year, above conventional willingness-to-pay thresholds. Overall, semaglutide demonstrated marked cardiovascular risk reduction at all doses and across all populations, with low statistical heterogeneity. However, this benefit must be weighed against GI intolerance, limited racial and geographic representation and uncertain cost-effectiveness outside high-income regions. Future trials must oversample underrepresented minorities, extend to low- and middle-income regions, and include formal economic evaluations to further refine population-specific benefit-risk profiles and value estimates.

Hepatic Safety of Orforglipron in Adults With Obesity or Overweight and/or Type 2 Diabetes: A Pooled Analysis of the Orforglipron Phase 3 Clinical Trials.

Sean Wharton, Adam Stefanski, Jiaxun Chen +3 more

Orforglipron is a novel small-molecule, once daily oral non-peptide GLP-1 receptor agonist. The hepatic safety profile in adults with obesity or overweight and/or type 2 diabetes (T2D) across seven orforglipron Phase 3 clinical trials was assessed.

The Impact of Missed Doses on Pharmacokinetic Concentrations for Oral Semaglutide in Comparison to Other Glucagon-Like Peptide-1-Based Therapies.

Rune Viig Overgaard, Henrik Agersø, Christian Hollensen +2 more

Real-world weight loss with injectable semaglutide vs dulaglutide for diabetes.

Allison Spitery, Alison Lobkovich, Emily Thomas

To compare the real-world effects of weekly injectable semaglutide (Ozempic) vs dulaglutide (Trulicity) on weight loss in an urban, predominantly African American patient sample with type 2 diabetes (T2D).

Erratum.

In the Abstract entitled "GLP-1 Receptor Agonist Use in Children and Young People with Severe and Complicated Obesity in 35 Specialist Weight Management Clinics in England" [Obes Facts. 2026;19(suppl 1):295. https://doi.org/10.1159/000551826] by Madeley et al., the following is being corrected.The submitted Abstract was an earlier draft based on data that was still subject to updates at that time. The revised results presented at the conference draw on a more recent version of the dataset.Therefore, the Results section of this Abstract has been updated by the authors as follows:"Results: 406 CYP (53.2% female, mean age 15.3 ± 1.7 years, range 11.3-19.5) receiving semaglutide were matched to 787 comparator patients. Mean baseline %BMIp95 was 172.9 (±29.5; BMI-SDS 3.77 ± 0.47), indicating a cohort with very severe obesity. Across all participants (n = 1,193), there was a high burden of obesity-related complications; 43.0% had metabolic dysfunction-associated steatotic liver disease, 23.2% had dysglycaemia (type 2 diabetes mellitus 4.7%, impaired glucose tolerance 18.5%), 18.9% had obstructive sleep apnoea, and 12.0% had hypertension. 19.6% of females had polycystic ovary syndrome. 56.7% had documented depression, anxiety, or self-harm. At 6, 12, and 18 months, %BMIp95 was 13.8, 19.0, and 22.9 percentage points lower in the semaglutide group than in matched comparators (95% CI: -15.4 to -12.3; -21.3 to -16.9; -27.8 to -18.1), representing relative reductions of 8.8%, 12.5%, and 14.4%. Corresponding between-group differences in BMI were -2.7, -4.0, and -5.2 kg/m2 (95% CI: -3.1 to -2.3; -4.6 to -3.5; -6.5 to -3.9), representing relative reductions of 7.4%, 10.2%, and 11.2%."

Semaglutide for Primary Prevention of Major Adverse Cardiac and Cerebrovascular Events in Patients with Type 2 Diabetes and Comorbid Rheumatoid Arthritis: A Target-Trial Emulation.

Farheen Malik, Mandar Shah, Yu Chang +10 more

Rheumatoid arthritis (RA)-related physical limitations often hinder sustained physical activity and weight management, thereby amplifying cardiovascular risk through adverse metabolic profiles and chronic inflammation. We aimed to assess the effectiveness of semaglutide on the risk of incident major adverse cardiovascular and cerebrovascular events (MACCE) in obese adults with type 2 diabetes mellitus (T2DM) and RA in a primary-prevention setting.

Obesity Management Pharmacotherapies and Lifestyle Treatment for Pediatric Obesity Management: A Systematic Review and Network Meta-Analysis.

Ke-Wen Wan, Evander Fung-Chau Lei, Ying Liu +6 more

Pediatric obesity is a global health challenge. Although health behavior and lifestyle treatment (HBLT) is foundational, the comparative effectiveness of HBLT, various pharmacotherapies, and their combinations remains unclear.

Prescribing of GLP-1 and GIP/GLP-1 Receptor Agonists and Other Glucose-Lowering Drugs Requiring Special Caution in Elderly Japanese People With Type 2 Diabetes: A Preliminary Report.

Manaka Sato, Riku Takemura, Masahiro Yuki +4 more

Adverse drug events are more common in elderly people, prompting the Japan Geriatrics Society to update its "Guidelines for Safe Pharmacotherapy in the Elderly" in 2025. In this revision, glucagon-like peptide-1 receptor agonist (GLP-1RA) and glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA) were newly added to the list of drugs requiring special caution. This study aimed to descriptively investigate real-world prescribing patterns of GLP-1RAs and their concomitant use with other glucose-lowering drugs (GLDs) requiring special caution among elderly people with type 2 diabetes (T2D).

Perinatal Semaglutide Treatment Improves Maternal Health and Mitigates Offspring Metabolic Dysfunction in a Mouse Model of Maternal Obesity.

Ananthi Rajamoorthi, Taylor Hollingsworth, Yuxia Guan +2 more

Early-life exposures during critical periods of development significantly impact lifelong metabolic risk and likely contribute to the rising rates of obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) in children. Here, we evaluated the safety and metabolic effects of semaglutide, a GLP-1 receptor agonist (GLP-1 RA), administered from preconception through lactation in dams fed a high-fat diet (HFD) or standard diet, and assessed metabolic outcomes in dams and their offspring. Offspring were weaned to a standard diet. We found that semaglutide improved body composition and glucose metabolism in HFD-fed dams during pregnancy. These maternal changes persisted 10 weeks after weaning despite discontinuation of semaglutide treatment. HFD exposure impaired glucose homeostasis and promoted hepatic steatosis in offspring at 18 weeks. These effects were ameliorated by maternal semaglutide treatment. Importantly, metabolic improvements in dams and offspring occurred without adverse effects on conception rate or fetal viability. These findings suggest that GLP-1 RA during the perinatal period can improve maternal and offspring metabolic health in a mouse model of obesity and support further investigation of GLP-1-based therapies to mitigate maternal metabolic dysfunction and improve metabolic risk in children.

Quality of life, morbidity, mortality, and long-term prognosis after craniopharyngioma.

Hermann L Müller

During the first months following diagnosis and treatment of childhood-onset craniopharyngioma, a substantial proportion of patients experience rapid and marked weight gain. This frequently progresses to severe hypothalamic obesity, which results from hypothalamic injury caused either by the tumor itself or by therapeutic interventions. Hypothalamic obesity should be regarded as one manifestation within the broader clinical spectrum of hypothalamic syndrome. Given the pivotal role of hypothalamic nuclei in maintaining physiological homeostasis, hypothalamic syndrome encompasses a wide range of disturbances, including hypothalamic-pituitary hormone deficiencies, disruption of circadian rhythms, impaired regulation of hunger, satiety, and thirst, as well as thermoregulatory dysfunction and cognitive, sleep-related, and psychosocial impairments. Consequently, affected individuals often develop persistent obesity, chronic fatigue, excessive daytime sleepiness, and mood disturbances, which may contribute to social withdrawal, academic challenges, reduced participation in daily activities, and impaired quality of life. Over time, these patients are at increased risk for metabolic syndrome, cardiovascular disease, sustained reductions in quality of life, and premature mortality. Historically, the management of hypothalamic syndrome has been challenging for both patients and clinicians, as conventional obesity treatments, including lifestyle modification, dietary interventions, and physical activity, have shown limited long-term efficacy. Pharmacological approaches have likewise been unsatisfactory, either due to insufficient effectiveness or unacceptable adverse effects leading to their withdrawal from clinical use. The therapeutic impact of central nervous system stimulants and glucagon-like peptide-1 receptor agonists in acquired hypothalamic obesity remains inconsistent and subject to ongoing debate. Recent findings from a randomized controlled trial provide, for the first time, encouraging evidence that setmelanotide, a melanocortin-4 receptor agonist, may substantially improve outcomes in patients with hypothalamic dysfunction associated with hypothalamic obesity. The emergence of a safe and effective pharmacological therapy that addresses not only metabolic abnormalities but also key psychosocial features, such as hyperphagia and overall quality of life, may represent a significant advancement in the management of this complex condition and offers the potential to meaningfully improve outcomes in this highly burdened and underserved patient population.

Dual Glucagon and GLP-1 Receptor Agonist Survodutide Improves Biomarkers of Beta-Cell Function and Insulin Sensitivity in People With Type 2 Diabetes or Living With Overweight/Obesity.

Elif I Ekinci, Sandra González Maldonado, Anna Unseld +3 more

This post hoc analysis evaluated the effect of survodutide on beta-cell function, insulin sensitivity, and glucose biomarkers in two phase 2 trial populations.

Cardiovascular outcomes of semaglutide and tirzepatide in type 2 diabetes mellitus and obesity: a systematic review and meta-analysis.

Xiao-Yu Zhou, Qi Wu, Hao-Lan Lu +5 more

To systematically evaluate cardiovascular outcomes associated with semaglutide and tirzepatide in adults with type 2 diabetes mellitus (T2DM), overweight or obesity.

Effect of GLP-1 receptor agonists at doses for obesity management on muscle health: systematic review and meta-analysis of randomized controlled trials (RCTs).

Ligia Patricia Laverde, Oscar Mauricio Muñoz-Velandia, Diana Alfonso +1 more

The impact of GLP-1 receptor agonists (GLP1-RA) treatment on lean mass and body composition in patients with obesity is not fully understood.

Real-world experience of semaglutide 2.4 mg in the US: a retrospective analysis of profiles, satisfaction, and treatment patterns in people with obesity and overweight.

Yiqiao Zhang, Zhenxiang Zhao, Victoria Higgins +1 more

To characterize treatment experiences, compliance with dosing frequency, and adherence to treatment regimen, and to assess factors associated with adherence and compliance among patients with obesity or overweight (PwO) receiving semaglutide 2.4 mg for weight management.

Semaglutide and Follow-On Peptide Therapeutics: Balancing Innovation, Regulation, and Clinical Outcomes.

Brij Teli, Shrikant Somani, Vivek Arya +7 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as an important therapeutic class for the management of type 2 diabetes mellitus (T2DM) and obesity owing to their ability to improve glycemic control, promote weight loss, reduce cardiometabolic parameters, and have the added advantage of a low risk of hypoglycemia due to glucose-independent insulin secretion. Semaglutide, a long-acting GLP-1 RA developed using a semi-recombinant process, has demonstrated significant benefits across metabolic and cardiovascular outcomes. Amid the increasing need for affordable therapies, there has been a rising interest in developing synthetic peptide versions of glucagon-like peptide-1 (GLP-1)-based drugs originally produced using recombinant deoxyribonucleic acid (rDNA) technology. However, the transition from recombinant production to chemical peptide synthesis raises important considerations about regulatory pathways, manufacturing processes, and potential clinical implications. Regulatory approaches for synthetic peptides vary across regions. The European Union and the United States follow distinct frameworks, with India adopting a risk-based regulatory approach that may require extensive quality, safety, and clinical data. Manufacturing processes can influence impurity profiles, stability, and immunogenicity, potentially affecting clinical outcomes. Therefore, the approval of follow-on versions of semaglutide requires a rigorous demonstration of both quality and clinical comparability with the originator, consistent with principles applied to biosimilars. Online databases such as PubMed, Scopus, and Google Scholar were used to source relevant research articles. This narrative review aims to discuss the development of semaglutide, examine global and national regulatory perspectives on synthetic and recombinant peptides, and explore the clinical implications of manufacturing variability. It also highlights the expanding therapeutic potential of semaglutide beyond obesity and T2DM.

Semaglutide and Risk of Adult-Onset Seizure: A Target Trial Emulation.

Yong Eun, Suhwan Bong, Hyun Yong Koh +4 more

Adult-onset seizure reflects the burden of acquired brain insults, but established disease-modifying preventive strategies are limited. We evaluated whether semaglutide initiation is associated with a lower incidence of adult-onset seizure compared with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other glucose-lowering drugs (GLDs) in adults with type 2 diabetes.

Effects of Semaglutide on Body Composition and GFR: A Prespecified Analysis of the SMART Trial.

Hiddo J L Heerspink, Maria Soler, Jelle M Beernink +16 more

Treatment with semaglutide compared with placebo for 24 weeks reduced lean body mass and fat mass in adults with CKD and overweight or obesity. Changes in lean body mass or fat mass during semaglutide treatment did not correlate with changes in creatinine or cystatin C‑eGFR or measured GFR. Semaglutide significantly reduced extracellular water and BP, and changes in BP correlated with extracellular water.

CGM-derived postprandial glucose with IcoSema versus other insulin regimens: a post hoc analysis of COMBINE 1 and 3.

Christophe De Block, Malik Benamar, Ariel Fu +2 more

Impaired insulin and incretin responses, alongside elevated postprandial glucose (PPG) levels after meals, are hallmarks of type 2 diabetes (T2D) and can lead to postprandial hyperglycaemia. This post hoc analysis used PPG levels derived from continuous glucose monitoring (CGM) to investigate the effect of IcoSema versus other insulin-based regimens on PPG control in T2D.

A Computational Trial of Dermal Mechanotransduction in GLP-1 Receptor Agonist-Associated Premature Facial Ageing.

Eqram Rahman, William Richard Webb, Jean D A Carruthers

The efficacy of non-invasive ultrasound skin tightening (e.g., Sofwave) relies on fibroblast mechanotransduction, a process impaired in obesity. The widespread use of GLP-1 receptor agonists (GLP-1RAs) like semaglutide for weight loss introduces a dynamic metabolic variable that may further alter dermal tissue state. The optimal timing between these interventions is unknown and difficult to study clinically.

Adjunctive GLP1 Receptor Agonists in Patients with Inflammatory Bowel Diseases and Obesity and/or Diabetes: A Target Trial Emulation.

Kuan-Hung Yeh, Dhruv Ahuja, Sagar B Patel +11 more

We conducted a target trial emulation study to examine the effect of two glucagon-like peptide-1 receptor agonists (GLP1RAs) (semaglutide and tirzepatide) on clinical outcomes in patients with inflammatory bowel diseases (IBD) with obesity and/or diabetes.

Association between GLP-1 receptor agonist use and NAION with optic disc drusen.

Ibrahim Abboud, Rami Madani, Joseph G Chacko +3 more

In adults with optic disc drusen and type-2-diabetes or obesity, glucagon-like peptide-1 receptor agonists exposure was not associated with increased nonarteritic anterior ischemic optic neuropathy hazard, though moderate risk increases could not be excluded statistically.

Cardiometabolic Effects of Semaglutide in Individuals with Type 2 Diabetes in the United Arab Emirates: Real-World 12-Month Outcomes and Predictors of Response.

Muhammad Hamid Siddique Mian, Kholood Abdulla Hasan Abdulla Janahi, Afnan Tayeb +9 more

There is little real-world evidence on semaglutide effectiveness in the United Arab Emirates (UAE), despite the high local burden of type 2 diabetes (T2DM) and obesity. The aim of this study was to evaluate real-world cardiometabolic outcomes and predictors of response following initiation of semaglutide in a tertiary endocrine clinic.

Comparative Effectiveness and Safety of Once-Weekly Injectable Semaglutide Versus Dulaglutide in Individuals with Type 2 Diabetes Managed in UK Primary Care: A Population-Based Cohort Study.

Franziska S Ulrich, Morten Frost Nielsen, Nicola Napoli +1 more

The SUSTAIN-7 trial demonstrated greater HbA1c and bodyweight reductions with once-weekly semaglutide versus dulaglutide in type 2 diabetes, but strict eligibility criteria limit external validity. We evaluated the comparative real-world effectiveness and safety of these agents in UK primary care.

GLP-1 Receptor Agonists in Aesthetic Surgery: A Narrative Review on Perioperative Safety, Sarcopenic Morphologies, and Adapted Body Contouring Strategies.

Mario Venza, Isabella Venza

GLP-1 receptor agonists (GLP-1 RAs) are increasingly used for obesity and for weight management in individuals seeking aesthetic improvement. Their pharmacologic effects (delayed gastric emptying and reduced appetite) and the rapidity of weight loss may create perioperative and morphologic challenges for aesthetic and body contouring surgery.

The Effect of Semaglutide on Quality of Life in Adults With Overweight or Obesity: A Brief Systematic Review and Meta-Analysis.

Naseem Eisa, Mira Khoury

Semaglutide 2.4 mg causes substantial weight loss, but its average effect on patient-reported physical function requires interpretation against clinically meaningful thresholds and routine clinical expectations. This systematic review and meta-analysis aimed to evaluate the effects of once-weekly subcutaneous semaglutide 2.4 mg on patient-reported physical functioning and weight-related quality-of-life outcomes in adults with overweight or obesity.

Weight Changes With Lower Doses of Semaglutide in Clinical Practice: Findings From the Chinese HARMONY Cohort.

Shuang Liu, Baige Cao, Chuwen Lin +5 more

To evaluate 24-week weight changes with lower-dose semaglutide in routine care among Chinese adults with obesity and to examine whether diabetes and ectopic fat in the liver and pancreas are associated with heterogeneity in weight-loss response.

The Effect of Semaglutide on Antipsychotic-Induced Weight Gain and Other Metabolic Parameters, among a Cohort of Inpatients.

Riddhita De, Yasser Amin Alfatwa, Pruntha Kanagasundaram +8 more

Antipsychotic use in severe mental illnesses (SMI) is associated with metabolic dysregulation, including antipsychotic-induced weight gain (AIWG), type 2 diabetes (T2D), and dyslipidemia. In the case of non-response to metformin which is currently recommended for AIWG mitigation, no clear alternatives exist. Semaglutide, a weekly injectable glucagon like peptide-1 receptor agonist, represents a promising option. However, effectiveness and safety data in SMI are lacking. With initiation of semaglutide, we hypothesized weight loss, improvements in metabolic indices, and good tolerability.

Current trends in semaglutide therapy and strategies to improve its bioavailability.

Swasthik Nayak, Akanksha D Dessai, Usha Y Nayak

A GLP-1 Receptor Agonist, semaglutide, is given in the management of type 2 diabetes mellitus and obese individuals. However, oral semaglutide exerts very low bioavailability due to multiple gastrointestinal and biopharmaceutical barriers. Delivery of oral semaglutide becomes difficult due to instability in GI fluids, degradation through proteolysis by various enzymes, and mucus diffusion limitation; epithelial permeability restricts the oral absorption of the drug, due to which the oral bioavailability of semaglutide is exceedingly low. This review identifies methods that enhance oral bioavailability as well as treatment efficacy of semaglutide.

Evidence-informed guidance for the clinical use of oral semaglutide in obesity management.

Domenica Rubino, Sean Wharton, Michael G Knight +1 more

Oral semaglutide, the first oral glucagon-like peptide-1 (GLP-1) receptor agonist therapy approved for the treatment of type 2 diabetes, is now approved for obesity management and cardiovascular risk reduction in adults, demonstrating weight loss comparable to that of subcutaneous GLP-1 therapies, alongside improvements in cardiometabolic risk factors. The availability of oral semaglutide for the treatment of obesity provides healthcare professionals with additional opportunities to individualize therapy based on patient preferences, lifestyle, and clinical circumstances. However, the oral semaglutide formulation requires specific administration conditions to optimize absorption and effectiveness. Notably, oral semaglutide tablets should be taken first thing in the morning on an empty stomach with no more than half a glass of plain water (up to 120 mL or 4 fl oz), followed by 30 min before eating food, drinking additional fluids, or ingesting other oral medications. Person-centered clinical discussions between healthcare professionals (HCPs) and patients prior to treatment initiation are important to ensure patients understand administration requirements and why they are necessary, establish realistic expectations for obesity treatment targets, and cover approaches to maintain adherence. HCP-patient consultations should also include discussion of strategies to help patients minimize, prepare for, and manage adverse events. In this article, we provide practical guidance for incorporating oral semaglutide into obesity management, drawing on evidence from clinical trials, including the OASIS 4 trial, and the authors' clinical insights.

Boerhaave's syndrome associated with glucagon-like peptide-1 receptor agonist use: a case report.

Jason M Aubrey, Chance Benner, Geoffrey T Lam

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are increasingly prescribed for type 2 diabetes and weight loss, with well known gastrointestinal side effects including nausea, vomiting, and delayed gastric emptying. While mucosal injuries such as Mallory Weiss tears have been reported, full thickness esophageal perforation has not previously been described. We report the first documented case of Boerhaave's syndrome associated with GLP-1 RA use, highlighting the potential for rare but life threatening complications following abrupt reinitiation at high doses.

Evaluation of the Efficacy of Semaglutide Dose Escalation in Reducing HbA1c Levels and Insulin Dose in Type 2 Diabetes Patients: Real-World Semaglutide Data from Türkiye, SEMA-TR Study.

Hilmi Erdem Sumbul, Bektas Isik, Ahmet Gazi Mustan +16 more

Background: Several studies have demonstrated that adding semaglutide to the treatment of patients with type 2 diabetes mellitus (T2DM) reduces insulin requirements and glycated hemoglobin (HbA1c) levels. This study aimed to investigate real-world evidence for the effects of semaglutide dose escalation on HbA1c, body weight, dyslipidemia, and insulin dose reduction in patients with T2DM in the Cukurova region of Türkiye. Methods: This retrospective cohort study enrolled 500 patients (255 male, 245 female; mean age 56.1 ± 10.8 years) who initiated semaglutide therapy for T2DM between 2024 and 2025. Patients were grouped according to their maximum semaglutide dose: 0.25 mg (Group I), 0.50 mg (Group II), and 1.00 mg (Group III). The primary endpoint was the change in HbA1c from baseline to end of study (30 weeks) across semaglutide dose escalation groups. Secondary endpoints included changes in body weight, frequency of insulin dose reduction, and effects on lipid parameters. Results: A total of 117 patients (23.4%) discontinued semaglutide therapy, while 383 patients (76.6%) completed the study. The primary endpoint revealed a mean HbA1c reduction of -1.03 ± 0.35% from baseline to end of study (95% CI 0.99-1.07; t = 58.644; p < 0.001). Reductions in HbA1c increased progressively from Group I to Group III (HbA1c: -0.72 ± 0.28, -1.02 ± 0.26, -1.27 ± 0.34%). Insulin dose reduction frequency increased significantly from Group I to Group III (40%, 41%, and 51%, respectively; p = 0.010), with a statistically significant difference only between Group I and Group III. At the end of follow-up, rates of hypoglycemic episodes and gastrointestinal (GI) adverse events were similar across groups. Conclusions: In a real-world population from the Cukurova region of Türkiye, semaglutide dose escalation in T2DM patients achieved clinically meaningful glycemic control, body weight reduction, LDL-cholesterol lowering, and a significant increase in insulin dose reduction frequency, without a significant increase in GI adverse events.

Retrospective Comparative Study of Oral Versus Subcutaneous Semaglutide in Patients with Type 2 Diabetes Mellitus.

Barbara Toffoli, Matteo Michieletto, Stella Bernardi +1 more

Semaglutide represents a unique therapeutic option for patients with type 2 diabetes mellitus (T2DM), being the first and currently only glucagon-like peptide-1 receptor agonist (GLP-1RA) available in both subcutaneous and oral formulations. This study aimed to compare the effectiveness of oral versus subcutaneous (sc) semaglutide on metabolic parameters and cardiovascular risk factors in T2DM patients. This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center. We analyzed data from 434 patients (median age 70 years, diabetes duration 13 years), treated with oral (n = 232) or sc (n = 202) semaglutide. The oral formulation had a higher discontinuation rate. Among these patients, 130 patients in the oral group and 145 in the sc group had an 18-month follow-up. When comparing these groups, patients taking sc semaglutide had a significantly higher baseline BMI. However, multivariate linear regression models suggested that both formulations were comparably effective in reducing HbA1c and BMI, with baseline values being the primary predictors of response. To address BMI imbalances, propensity score matching was performed, identifying 55 matched pairs. Both oral and sc semaglutide reduced HbA1c and BMI and there were no significant differences in the median change in HbA1c and BMI between groups. Interestingly, oral semaglutide was associated with a significantly greater reduction in diastolic blood pressure compared to the sc formulation. Furthermore, concomitant therapy with SGLT2 inhibitors significantly enhanced the reduction in total and LDL cholesterol. Oral and subcutaneous semaglutide show comparable effectiveness in lowering HbA1c and BMI in a real-world setting.

Efficacy and Safety of Oral Semaglutide in the Management of Diabetes and Obesity: A Comprehensive Meta-analysis of Real-world Evidence.

Sweekruti Jena, Radhika Jindal, Deep Dutta +2 more

Oral semaglutide is the only oral glucagon-like peptide-1 receptor agonist approved for type 2 diabetes (T2D) management. Although its efficacy and safety are established from randomized controlled trials (RCTs), real-world evidence (RWE) may differ. No comprehensive systematic review and meta-analysis (SRM) has holistically analysed the RWE on oral semaglutide. This SRM analysed the RWE outcomes of oral semaglutide.

Risk Factors for Hypoglycemia in Type 2 Diabetes Mellitus Patients Using Once-Weekly Semaglutide: A Matched Case-Control Study.

Palanisamy Amirthalingam, Fawaz Ahmed Alarawi, Loay Mohammed Jassas Alagwar +11 more

The semaglutide once-weekly injection (Sema-OWI) is widely accepted for managing type-2 diabetes mellitus (T2DM) patients, particularly those seeking weight loss. However, hypoglycemia is continually challenging healthcare practitioners, and the underlying factors have yet to be conclusively reported. The study aimed to investigate the underlying characteristics of T2DM patients undergoing sema-OWI treatment.

Patient Experiences With GLP-1 Receptor Agonists.

Isabella de Vere Hunt, Mariana Ramirez-Posada, Christopher Sam Babu +3 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are transformational therapies in the treatment of obesity; yet discontinuation rates are high, and patients experience rapid weight regain after stopping treatment. Few scientific publications have reported patients' experiences of taking GLP-1 RAs in a variety of health contexts outside its use as treatment for type 2 diabetes.

Cost-effectiveness of semaglutide versus dulaglutide for Type 2 Diabetes in China: A Markov Model analysis.

Qiying Chen, Tianyu Chen, Weicheng Lin +1 more

From the perspective of China's basic medical insurance, to evaluate the cost-effectiveness of semaglutide versus dulaglutide for type 2 diabetes mellitus (T2DM) in China, informing clinical and health policy decisions.

Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters.

Yasser Abuetabh, Mya A Schmidt, Masaaki Naganuma +18 more

While glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide are effective in treating obesity, up to 45% of the resulting weight loss can be attributed to skeletal muscle loss. Given the critical role of skeletal muscle in health and mobility, this may have long-term adverse consequences. Herein we investigated whether oral ketone ester supplementation could prevent semaglutide-induced muscle loss and explored the underlying molecular mechanisms. Obese, glucose-intolerant mice received vehicle, semaglutide, or semaglutide plus a β-hydroxybutyrate-generating ketone ester for three weeks. Body composition, muscle strength, and endurance were assessed longitudinally. Semaglutide monotherapy reduced lean mass, impaired muscle strength, and suppressed mitochondrial gene expression while elevating atrophy-related genes in skeletal muscle samples. Co-administration with ketone ester preserved skeletal muscle mass and function without compromising fat loss. Mechanistically, ketone ester co-treatment prevented semaglutide-induced changes in mitochondrial and atrophy-related gene expression, suggesting mitochondrial defects and impaired ketone metabolism contribute to GLP-1RA-induced muscle loss. Together, these findings demonstrate that ketone ester supplementation can maintain muscle mass and performance during semaglutide-driven weight loss. These preclinical findings support ketone therapy as a promising strategy to counteract the sarcopenia-promoting effects of GLP-1RAs and warrant clinical evaluation to assess its translational potential.

The efficacyand safety of once weekly injectable semaglutide (Ozempic) among patients with Type 2 diabete sintertiary care hospital: A Retrospective Study.

Misbah Jabeen, Umar Yousaf Raja, Osama Istiaq +1 more

To assess the efficacy and safety of weekly injectable semaglutide in obese type 2 diabetes mellitus patients.

Nationwide Real-World Retrospective Study of Oral Semaglutide Use in Adults Living With Type 2 Diabetes in Finland.

Atte Vaden, Mari Lahelma, Lalli Nurmi +5 more

This Finnish nationwide retrospective 'real-world' study evaluated the effects of oral semaglutide on glycaemic control, body weight, lipid profile, and liver enzymes in adults living with type 2 diabetes (T2D) and naïve to any GLP-1 receptor agonists in Finland.

Semaglutide and weight loss in obese patients with and without type 2 diabetes.

Harish Gupta, Rajeev Verma

Efficacy and safety of novel formulation of semaglutide injection: A multicentre, randomized, comparative, active controlled, phase 3 study in comparison with reference biologic in Indian patients with type 2 diabetes mellitus.

Prabhat Kumar Sharma, V Viswaprasad, Animesh Choudhary +24 more

Type 2 diabetes mellitus (T2DM) is the most common non-communicable disease affecting over 89.8 million adults in India. Evidence suggests long-acting glucagon-like peptide-1 (GLP-1) receptor agonist improves glycaemic control in the patients with T2DM. This phase 3 trial compared a novel semaglutide injection developed by Zydus Lifesciences Ltd. with the reference biologic in Indian adults with T2DM inadequately controlled on metformin.

Spinal Implant-Associated Infection in Type 2 and Type 1 Diabetes: Phenotype-Specific Inflammatory Features and Therapeutic Response to Semaglutide.

Thomas E Olson, Trevor S Lloyd, Christopher D Hamad +14 more

Diabetes mellitus (DM) is a major risk factor for postoperative infection and wound complications in spine surgery, yet distinctions between Type 2 (T2DM) and Type 1 (T1DM) pathophysiology are rarely addressed. This study compares infectious burden, wound healing, and immune response among a murine model of spinal implant-associated infection of T2DM, T1DM, and nondiabetic control mice before and after metabolic intervention with the GLP-1 receptor agonist (GLP-1RA), semaglutide.

Elecoglipron, an oral small molecule GLP-1 receptor agonist in adults with type 2 diabetes (SOLSTICE): a multicentre, phase 2b, randomised, placebo-controlled trial.

Vanita R Aroda, Melanie J Davies, Jill Maaske +10 more

Elecoglipron is an oral, small molecule glucagon-like peptide (GLP)-1 receptor agonist currently in development for the management of type 2 diabetes. Elecoglipron is orally administered once daily with no food or fluid restrictions. SOLSTICE, a phase 2b study, evaluated the efficacy, safety, and tolerability of elecoglipron versus placebo in participants with type 2 diabetes.

Efficacy and safety of once-weekly cagrilintide-semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study.

Vanita R Aroda, Raffaella Buzzetti, Stine-Mathilde Dalskov +7 more

Cagrilintide-semaglutide (CagriSema) is a novel, once-weekly combination of the amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide. We aimed to assess the efficacy and safety of cagrilintide-semaglutide for people with type 2 diabetes inadequately controlled with diet and exercise.

Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study.

John B Buse, Harpreet S Bajaj, Stine-Mathilde Dalskov +8 more

The amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide have complementary effects on glycaemic control and bodyweight. We aimed to investigate the efficacy and safety of a fixed-dose combination of cagrilintide and semaglutide (cagrilintide-semaglutide; known as CagriSema) versus semaglutide or cagrilintide for glycaemic control in people with type 2 diabetes and overweight or obesity.

Cagrilintide-semaglutide: a new option for patients with type 2 diabetes.

André J Scheen

Cagrilintide-semaglutide (CagriSema) as an add-on to basal insulin in adults with type 2 diabetes (REIMAGINE 3): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.

Julio Rosenstock, Liana K Billings, Reena Gajria +6 more

Basal insulin treatment for type 2 diabetes often results in inadequate glycaemic control and is associated with weight gain and increased risk of hypoglycaemia. We aimed to compare the efficacy and safety of a once per week combination of cagrilintide with semaglutide (CagriSema) versus placebo as an add-on to basal insulin in individuals with type 2 diabetes.

Once-Weekly Subcutaneous Semaglutide 2.4 mg Injection is Cost-Effective for Weight Management in Spain.

Andreu Altés, Óscar Moreno-Pérez, Miquel Sastre-Belío +6 more

A current major challenge for national health systems (NHS) is the increase of obesity and overweight among populations. Subcutaneous semaglutide 2.4 mg, a glucagon-like peptide 1 analogue, has been approved by the European Medicines Agency as an adjunct to a reduced-calorie diet and increased physical activity (diet and exercise [D&E]) for the treatment of obesity. The aim of this study was to evaluate the cost-effectiveness of semaglutide 2.4 mg in combination with D&E compared with D&E alone in the treatment of patients with obesity in Spain.

[Semaglutide-induced acute-on-chronic liver failure: A case report and literature review].

Rao Fu, Huizhi Wu, Haiying Huang +1 more

Semaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA), primarily used for the treatment of type 2 diabetes mellitus and obesity. Common adverse drug reactions (ADRs) include nausea, vomiting, diarrhea, abdominal pain, and constipation, whereas liver function-related ADRs are relatively rare. We report a rare and severe case of semaglutide-induced acute-on-chronic liver failure (ACLF) in a 47-year-old male patient who was successfully treated. The patient was admitted to the Department of Infectious Disease at the Second Xiangya Hospital of Central South University on December 1, 2023. He had a history of chronic hepatitis B and had discontinued antiviral therapy for more than two years without medical supervision. Due to weight loss requirements, he initiated subcutaneous semaglutide therapy. Approximately three months after treatment initiation, he developed severe liver dysfunction, which rapidly progressed to profound jaundice, coagulopathy, and hepatic encephalopathy. Drug-induced liver injury (DILI) was considered the primary precipitating factor of liver failure, and the final diagnosis was ACLF. Following confirmation of the diagnosis, semaglutide was discontinued, and comprehensive management, including hepatoprotective therapy, artificial liver support, plasma exchange, and liver transplantation, was implemented. The patient's clinical symptoms and liver function parameters improved significantly. This report describes the successful management of semaglutide-induced ACLF and reviews the relevant literature. For individuals with underlying chronic liver disease (e.g., chronic viral hepatitis), thorough baseline liver assessment should be performed prior to initiating semaglutide or similar agents. Close monitoring during treatment is essential to identify potential severe drug-induced liver injury at an early stage.

Diabetic Status, Advanced Age, and Hispanic Ethnicity Predict Poorer Weight Loss in Patients with Obesity on Semaglutide.

Nicole C Cornet, Adam P Buckholz, Michele Yeung +7 more

Define demographic and clinical predictors of weight loss outcomes in patients with obesity prescribed semaglutide in real-world practice.

Semaglutide in Metabolic Medicine: A Review on Clinical Applications and Emerging Therapeutics.

Abdulrahman A Aljabri

Obesity and type 2 diabetes mellitus affect over 800 million and 537 million individuals worldwide. Semaglutide, a weekly glucagon-like peptide-1 receptor agonist, has advanced treatment of pathophysiological processes linked to metabolic dysregulation. This review consolidates evidence on its mechanisms of action, clinical effectiveness across established and emerging applications, safety, and prospects for personalized therapy. Clinical studies have shown that semaglutide sustains glycemic control, promotes substantial weight loss, and provides cardiovascular and renal protection. Recent FDA clearance marks the first therapeutic alternative for metabolic dysfunction-associated steatohepatitis among the emerging applications. Pharmacogenomic insights facilitate personalized therapy; however, clinical applications remain in experimental stage. Gastrointestinal side effects are the main tolerability concern, but the risk-benefit profile underscores its increasing significance in metabolic therapy. Therapies for diabetes and obesity are cost-effective; however, global accessibility challenges persist. Future priorities include refining combination medicines, promoting precision medicine, and addressing healthcare inequities to augment population-level effects.

Kidney and Survival Benefits of Semaglutide in Diabetes With Chronic Kidney Disease: FLOW Trial Cardiovascular Subgroup Analyses.

Katherine R Tuttle, George L Bakris, Florian M M Baeres +16 more

Cardiovascular disease increases risks of chronic kidney disease (CKD) progression and mortality in type 2 diabetes.

Optimization of nursing strategies for semaglutide treatment in overweight type 2 diabetes based on gene polymorphism.

Xing Chen, Miaoqing Zhou, Liang Guo +1 more

To evaluate the impact of a gene polymorphism-based individualized nursing strategy on the efficacy of semaglutide in overweight type 2 diabetes (T2DM) patients and to assess its role in mitigating genotype-driven outcome disparities.

Real-world use of submaximal doses of long-acting GLP-1 receptor agonist semaglutide in patients with obesity: a prospective observational study.

Zuzana Miertová, Patrik Lecký, Boris Focko +7 more

Obesity is a global health problem with numerous metabolic and mechanical complications. In previous studies, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide has been identified as one of the most promising medications for treating obesity. We carried out a prospective observational study investigating the effect of submaximal doses of semaglutide in 56 adult patients with obesity (mean age 49 ± 12 years, 42 female and 14 male). We evaluated the effects on body weight, waist circumference, height/waist ratio, and BMI during 3-month follow-up. 30 patients in our group also reached a 6-month follow-up. Our patients achieved a weight loss of 6.45 ± 0.31% (p < 0.01) in 3 months of semaglutide therapy, and in the subgroup of 30 patients where semaglutide was administered for 6 months, weight loss was 11.35 ± 0.47% (p < 0.01). Regarding waist circumference, patients achieved a 7 cm decrease in waist circumference in 3 months, and an additional 6 cm at 6 months, respectively (p < 0.01). The mean height/waist ratio decreased from 0.71 ± 0.08 to 0.67 ± 0.09 after 3 months of treatment (p < 0.01) and to 0.63 ± 0.09 (p < 0.01) after 6-month of semaglutide treatment. Mean BMI decreased from 40.3 ± 6.7 to 37.5 ± 6.83 kg/m2 (p < 0.01) after 3 months of treatment and to 35.5 ± 7.73 kg/m2 in the subgroup with 6 months of therapy (p < 0.01). Our study showed a significant decrease in body weight, waist circumference, height/waist ratio, and BMI in patients with obesity treated with submaximal doses of semaglutide.

Semaglutide in Adolescents Living With Obesity: A Real-World Data Study Exploring Predictors of Treatment Response.

Valeria Cimador, Sophie Robertson, Christine Desmond +4 more

15-PGDH inhibition promotes muscle repair and strength recovery during GLP-1 receptor agonist-induced weight loss.

Minas Nalbandian, Jameel Lone, Emmeran Le Moal +9 more

Glucagon-like peptide-1 receptor agonists, including long-acting semaglutide, are transformative anti-obesity therapies. However, emerging evidence indicates that weight loss may come at the expense of skeletal muscle mass, a tissue essential for mobility, metabolic regulation, and overall health. Here, we show that inhibition of the gerozyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme that increases with injury and aging, improves muscle repair and strength recovery in the presence of semaglutide. In a high fat diet-induced mouse model of obesity, semaglutide alone caused significant loss of muscle mass, while preserving contractile function. Following injury, obese mice exhibited pathological calcifications previously reported for the heritable myopathy, Duchenne Muscular Dystrophy. Semaglutide had both beneficial and deleterious effects, reducing calcific remodeling, but causing reduced regenerated myofiber sizes. This impaired regenerative myofiber growth in semaglutide-treated mice was surmounted by cotreatment with a 15-PGDH inhibitor (PGDHi), which stimulated muscle stem cell function and myofiber growth, leading to enhanced strength. Importantly, PGDHi synergizes with semaglutide to boost postinjury muscle quality and muscle force without compromising weight loss.

Renal or Hepatic Impairment Does Not Affect Pharmacokinetics, Safety, or Tolerability of Subcutaneous Cagrilintide.

Mette J F Nielsen, Niels-Peter Becker, Helene H Hansen Duus +6 more

Cagrilintide is a long-acting amylin agonist under development as monotherapy for weight management and as a fixed-dose combination with the glucagon-like peptide-1 receptor agonist semaglutide (CagriSema) for weight management and treatment of type 2 diabetes. Two studies were conducted to assess the effects of renal or hepatic impairment on pharmacokinetics, safety and tolerability following single doses of cagrilintide.

Quadruple Non-Insulin Therapy for Advanced Type 2 Diabetes Mellitus With Cognitive Impairment: A Case Report.

Stjepan Skudar

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder that often requires treatment intensification over time. In complex patients with multiple comorbidities and cognitive impairment, therapeutic decisions must balance glycemic control with safety and feasibility. We present a 59-year-old male with long-standing T2DM, marked body weight fluctuations, and emerging neurocognitive decline. Baseline glycated hemoglobin (HbA1c) was 9.4%, with progressive improvement to 7.1% under quadruple non-insulin therapy consisting of metformin, sitagliptin, glimepiride, and semaglutide. Insulin therapy was avoided due to cognitive impairment and a high risk of dosing errors. Sustained glycemic control was achieved without severe hypoglycemia. This case highlights the importance of individualized, multidisciplinary management in advanced T2DM and demonstrates that non-insulin strategies may be a viable and safe alternative in selected high-risk patients.

Glucagon-like peptide 1 receptor agonist use and risk of arthroplasty for knee osteoarthritis: retrospective database analysis.

Victoria Carter, Ethan Desverreaux, Idris Amin +4 more

Knee osteoarthritis (OA) is a leading cause of chronic pain and disability, with limited disease modifying therapies. While glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have established cardiometabolic benefits and have been associated with reductions in knee OA related pain, it is unclear whether they can reduce progression to total knee arthroplasty (TKA).

Mixed Medullary and Papillary Thyroid Carcinoma in a Patient on Tirzepatide.

Lauren H Beshay, Jitin Makker, Susan Ahern

Medullary thyroid cancer (MTC) stems from thyroid parafollicular C cells and is considered a rare type of neuroendocrine tumor. It can be inherited as part of syndromes, such as familial medullary thyroid cancer (FMTC) and multiple endocrine neoplasia type 2 (MEN 2), or it can arise sporadically. GLP-1 receptor agonist drugs (GLP1 RA), like semaglutide and tirzepatide, carry an FDA black box warning against using them in patients who have a prior history or a family history of MTC or MEN2. This recommendation stems from rodent studies showing thyroid C-cell tumors. Current studies have not confirmed an association between GLP1RAs and risk of differentiated thyroid cancer in human studies. In addition, there is no consensus on screening or evaluating patients for thyroid cancer prior to or during treatment with GLP1 RA. Here, we report a case of mixed medullary and papillary thyroid carcinoma newly diagnosed in a 68-year-old female on tirzepatide for type 2 diabetes who presented with a neck mass.

Atypical retrobulbar optic neuropathy after semaglutide escalation.

Shivaprasad Channabasappa, Riddhi Das Gupta, Vidhya Chandran +1 more

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is widely used to manage type 2 diabetes and obesity. Recent pharmacovigilance signals have reported an increased incidence of nonarteritic anterior ischemic optic neuropathy (NAION) among semaglutide users, although the absolute risk remains low. We report a man in his early 30 seconds with class III obesity, obstructive sleep apnea, and prediabetes who developed acute, painless, asymmetric bilateral visual dysfunction four weeks after semaglutide escalation to 1 mg per week. Evaluation revealed retrobulbar optic neuropathy with asymmetric visual field defects, a central scotoma in the left eye, an altitudinal defect in the right eye, preserved optic disc appearance, and markedly delayed visual evoked potentials. Optical coherence tomography and neuroimaging were unremarkable. The presentation was atypical for NAION but did not fully align with classical demyelinating optic neuritis, yielding a mixed clinical picture. Semaglutide was discontinued immediately, and visual function remained stable over serial follow-up with adaptation to a persistent left central scotoma but no further deterioration. This case illustrates an atypical retrobulbar optic neuropathy in close temporal proximity to semaglutide dose escalation and underscores the need for clinical vigilance and strengthened pharmacovigilance as GLP-1RA use expands globally.

GLP-1 RAs in Substance Use Disorders: Emerging Evidence and Future Directions.

Jason Macanian, William H Frishman

Substance use disorders (SUDs) are the leading causes of both global mortality and morbidity, and alcohol, nicotine, and opioids account for most of this burden. Existing pharmacotherapies are only moderately effective, have inconsistent compliance and regular relapse, and therefore, new treatment modalities are required. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), which have been licensed to treat type 2 diabetes and obesity, have emerged as potential therapeutic candidates for SUDs due to their central action on neural reward circuits. GLP-1 receptors are expressed in mesolimbic regions, and preclinical studies show decreases in drug use, suppression of nucleus accumbens efflux of dopamine, and inhibition of relapse-like behaviors in models of alcohol, nicotine, and opioids. Early clinical findings, particularly those from semaglutide, indicate reductions in both alcohol and cigarette consumption, although the results remain inconsistent and are limited by small sample size. Subgroup analysis and observational findings suggest that GLP-1RAs may have potentially larger effects in individuals with obesity and metabolic disease, which could also be due to metabolic modes of action. In opioid use disorder, evidence is currently limited to animal models but demonstrates comparable efficacy to established therapies. Collectively, GLP-1RAs represent an emerging and mechanistically novel therapeutic option for SUDs. Future research should prioritize large-scale randomized controlled trials, patient stratification, and long-term safety assessments to define their potential role as adjunct or standalone treatments in addiction medicine.

Oral Semaglutide 25 mg Versus Orforglipron 36 mg in Obesity: A Population-Adjusted Indirect Treatment Comparison.

Wojciech Michalak, Martin Bøg, Theiss Bendixen +5 more

This study aimed to indirectly compare the effects of oral semaglutide 25 mg versus orforglipron 36 mg on body weight loss, other cardiometabolic biomarkers, and tolerability in adults with overweight (body mass index [BMI] ≥ 27 kg/m2 and at least one obesity-related complication) or obesity (BMI ≥ 30 kg/m2), without diabetes, using data from OASIS 4 and ATTAIN-1.

Semaglutide 25 mg Oral Versus Semaglutide 2.4 mg Injectable: An Indirect Treatment Comparison of Weight Loss Outcomes.

Molly Plotkin, Milana Ivkovic, Inger Smith +4 more

Semaglutide, a GLP-1 receptor agonist, has demonstrated significant weight loss benefits for patients with overweight or obesity in both oral and subcutaneous (s.c.) formulations. Given comparable systemic exposure between formulations, an indirect treatment comparison (ITC) was conducted to confirm comparable efficacy.

The Impact of GLP-1-Based Therapies on Cardiovascular Outcomes in Type 2 Diabetes: A Comprehensive Systematic Review and Network Meta-Analysis.

Shih-Ming Chuang, Sung-Chen Liu, Kuo-Liong Chien +3 more

To provide updated agent-level comparative estimates of GLP-1-based therapies for cardiovascular outcomes in adults with Type 2 diabetes mellitus (T2DM) using a hazard ratio (HR)-based systematic review and network meta-analysis (NMA).

Semaglutide Injection in Indian Patients With Type 2 Diabetes Mellitus: A Randomised, Phase III, Active-Controlled Study.

Unnikrishnan Ambika Gopalakrishnan, Ameya Sudhakar Joshi, Richa Giri +31 more

To evaluate the efficacy, safety and immunogenicity of semaglutide injection (synthetic) (Test group) compared with the Reference semaglutide injection [Ozempic, (Reference group)] in Indian patients with Type 2 diabetes mellitus (T2DM).

Evaluation of the Safety, Efficacy and Pharmacokinetics of BGM0504 in Chinese Adults With Type 2 Diabetes: A Multicentre, Randomised, Controlled and Double-Blind Phase II Trial.

Ping Jin, Linong Ji, Yangqing Huang +7 more

This study aimed to evaluate its safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy in Chinese adults with T2DM and to preliminarily compare its efficacy and safety with semaglutide through multiple subcutaneous injections.

IgG Fc-Binding Motif-Conjugated Exendin-4: A Long-Acting Hypoglycemic Agent via Broad-Spectrum Antibody Engagement for Type 2 Diabetes Therapy.

Baojing Mi, Shengjie Ding, Ziyu Tian +6 more

Type 2 diabetes mellitus requires therapies that optimize both efficacy and durability. Although incretin mimetics such as exendin-4 (Ex4) enhance glycemic control, their short half-life restricts their clinical utility. Current extension strategies (e.g., Fc fusion) encounter challenges including immunogenicity and manufacturing complexity. Here, we engineered a series of site-specific IgG Fc-binding motif-modified Ex4 analogues using two orthogonal conjugation methods, leveraging Fc-III-4C-mediated IgG binding (human IgG: KD = 20.1 nM) to achieve a significantly extended plasma half-life. Structure-activity relationship studies revealed that the lead candidate, conjugate 7, retained robust GLP-1R activation and acute glucose-lowering efficacy. In human IgG-preconditioned db/db mice, conjugate 7 achieved a hypoglycemic duration comparable to that of semaglutide. Chronic once-daily dosing of the lead conjugate rivaled semaglutide in reducing HbA1c and protecting pancreatic islets, without toxicity. This strategy leverages >80% of endogenous circulating IgG as a biological reservoir to overcome peptide therapy limitations, offering a translatable platform for long-acting antidiabetic agents.

After the Prescription: The Clinical Support Gap in Telehealth-Based GLP-1 Care.

Anna Zucker

GLP-1 medications offer promise for obesity management and are increasingly accessible via digital platforms. In this News and Perspectives article, JMIR Correspondent Anna Zucker reports on the gap in clinical support that could undermine their potential benefits.

Lifestyle First and Lifestyle Always, Does Not Mean Lifestyle Only: Reimagining Cardiometabolic Care in the Era of GLP-1 Receptor Agonists.

Elizabeth Joy, Jonathan Bonnet

The rapid uptake of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including semaglutide and tirzepatide, has transformed the management of obesity, diabetes, and cardiometabolic disease, producing substantial weight loss, improved glycemic control, and reduced cardiovascular and renal risk. This article advances a guiding principle for contemporary care: "lifestyle first and lifestyle always, but not lifestyle only." While GLP-1 RAs have reshaped clinical practice and reinforced recognition of obesity as a biologically mediated disease, pharmacotherapy alone cannot resolve the complex behavioral, physiologic, and social drivers of cardiometabolic risk. Discontinuation of GLP-1 RAs without structured lifestyle support commonly results in weight regain, and medication does not address sarcopenia, physical deconditioning, sleep, stress, psychosocial determinants, or social connection. Lifestyle behaviors, high-quality nutrition, regular physical activity including resistance training, restorative sleep, stress management, social connectedness, and a sense of purpose, constitute the physiological and behavioral foundation for durable health gains. GLP-1 RAs are therefore positioned not as substitutes for lifestyle change, but as catalysts that create metabolic and psychological conditions that are favorable to adopting and sustaining healthy behaviors. Integrated, interprofessional models that combine pharmacologic and lifestyle strategies, supported by policy and systems change, are proposed as the emerging standard for long-term cardiometabolic health.

Semaglutide Inhibits Osteoblast Ferroptosis Induced by Diabetic Periodontitis via Modulating the Wnt5a/Ror2/p38 MAPK Signaling Pathway.

Zhen Zhang, Delong Niu, Wenjie Qiu +3 more

Type 2 diabetes mellitus (T2DM) is a major risk factor for periodontitis, often leading to exacerbated alveolar bone loss. Ferroptosis, an iron-dependent regulated cell death pathway, contributes to osteoblast dysfunction under diabetic conditions. The non-canonical Wnt5a/Ror2 pathway is pivotal in inflammation and bone metabolism. Semaglutide, a long-acting GLP-1 receptor agonist, may modulate this pathway and protect osteoblasts from ferroptosis, however, its role in diabetic periodontitis remains unclear.

Safety, tolerability and efficacy of GLP-1 receptor agonists (GLP-1 RA) in the management of post-liver transplant weight gain: A multicenter, observational study.

Mohammad Qasim Khan, Chiara Becchetti, Mahmoud Riyam Jouid +13 more

Post-liver transplant (LT) weight gain and metabolic dysfunction predispose to cardiovascular (CV) morbidity, allograft steatosis, and reduced long-term survival. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) promote weight loss and improve cardiometabolic health, yet evidence in liver transplant recipients (LTR) is limited. We aimed to evaluate the safety, tolerability, and efficacy of GLP-1 RAs in post-LT weight management.

Comparative Effectiveness of CagriSegma, Semaglutide, Cagrilintide and Tirzepatide in the Management of Overweight and Obesity: A Network Meta-Analysis of Randomized Clinical Trials.

Sultan Hamarsheh, Abdel Rahman Jaber, Omar Abu-Khazneh +4 more

Obesity is a chronic, progressive disease affecting over 1 billion adults worldwide, linked to serious comorbidities, including diabetes, hypertension, and cardiovascular disease and associated with increased mortality. Achieving clinically meaningful weight loss is critical to reducing cardiometabolic risk. Tirzepatide, semaglutide, cagrilintide and their combination (CagriSema) have demonstrated efficacy in clinical trials; however, no direct head-to-head studies have compared all advanced anti-obesity medications. This network meta-analysis examines their comparative efficacy and safety.

Semaglutide and risk of Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION) in type 2 diabetes mellitus: A systematic review and meta-analysis.

Stamatios Lampsas, Chrysa Agapitou, Evangelos Oikonomou +5 more

The use of Glucagon-like peptide-1 receptor agonists (GLP-1RAs) has expanded dramatically worldwide, with semaglutide being one of the most widely utilized agents. Nonarteritic anterior ischemic optic neuropathy (NAION) has been associated with GLP-1RAs use from emerging pharmacovigilance data. This systematic review and meta-analysis sought to evaluate the risk of NAION in patients with type 2 diabetes mellitus (T2DM).

Glucagon-like Peptide-1 Therapy in Obesity-Related Heart Failure with Preserved Ejection Fraction: Mechanisms, Clinical Evidence, and Implications.

Malak Moones Abedi, Ibrahim Alabid, Wasim I I Alghoul +7 more

Background: Glucagon-like peptide-1 (GLP-1)-based therapies offer significant cardiometabolic benefits. Obesity-related heart failure with preserved ejection fraction (HFpEF) arises from a complex interplay of increased lipids, chronic inflammation, and metabolic disturbances. These factors not only exacerbate the disease but also affect GLP-1 pathways, supporting the potential role of GLP-1-based therapies in targeting this condition. Objective: This review aimed to synthesize the current evidence on GLP-1-based therapy in HFpEF, focusing on mechanisms of action, clinical outcomes, and practical significance. Methodology: A narrative review using PubMed and Scopus was conducted, including studies published between January 2020 and March 2026. Evidence from randomized trials, pooled analyses, mechanistic studies, and observational data was incorporated. Results: GLP-1-based therapies, including semaglutide and tirzepatide, demonstrated significant improvements in symptoms, exercise capacity, and quality of life. These benefits are closely linked to weight loss, reduced inflammation, and improved congestion indices. Tirzepatide use has also been associated with a reduction in heart failure-related complications. The underlying mechanisms likely involve coordinated effects on metabolism, inflammation, hemodynamics, and cardiac remodeling. Current evidence suggests that its efficacy in improving morbidity rates is stronger than its efficacy in reducing mortality rates. Conclusions: GLP-1-based therapies offer a promising, phenotypically targeted approach to managing obesity-associated HFpEF. However, their long-term effects on mortality remain unclear, highlighting the need for further research. Further studies should refine patient selection and define optimal clinical integration.

Angioedema After Accidental Semaglutide Dosing Error: A Case Report.

Bryan D Kraft, Sarah Matuszak

Background: Glucagon-like peptide-1 receptor agonist (GLP-1 RA) use has increased exponentially as studies show significant benefits in cardiovascular and renal diseases and obesity. Accessibility to the public also increased after compounding pharmacies began direct-to-consumer distribution. Gastrointestinal side effects are common; however, hypersensitivity reactions are rare. Case Presentation: A 50-year-old female with a history of obesity, hypertension, and lisinopril-induced angioedema presented to the Emergency Department with swelling of the lips, tongue, and throat developing four hours after her first injection of compounded semaglutide for weight loss. She was treated with epinephrine, corticosteroids, and antihistamines, but due to progressive airway edema, she required intubation and mechanical ventilation for four days. After extubation, she reported accidentally injecting a ten-fold higher dose (2 mg) of semaglutide than was appropriate for the first dose. The hospitalization was complicated by hypoglycemia requiring dextrose infusion, but was otherwise unremarkable, and she was discharged home on day 7. Based on the temporal onset after semaglutide injection, this presentation was most consistent with GLP-1 RA-induced angioedema. While she also had a history of lisinopril-induced angioedema five years earlier, and had been taking valsartan for hypertension, the remoteness of the lisinopril exposure made this less likely. Conclusions: Semaglutide use may be associated with severe angioedema within hours of administration. Given the overlapping indications and patient populations, angioedema appearing in patients taking both GLP-1 RAs and ACE inhibitors may become increasingly common and present a diagnostic dilemma. Diagnosis of hypersensitivity to GLP-1 RAs can be supported with history and positive skin testing. Clinicians should be aware that inexperienced patients are at the highest risk of dosing errors.

The Effects of GLP-1 Receptor Agonists on Retinal Microvascular Alterations.

Stamatios Lampsas, Gerasimia-Marina Chardalia, Chrysa Agapitou +6 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the management of type 2 diabetes mellitus (T2DM) by providing robust glycemic control alongside significant cardioprotective and renoprotective benefits. This review synthesizes current mechanistic, preclinical, and clinical evidence regarding the impact of GLP-1RAs on retinal microvasculature and summarizes the current clinical evidence of GLP-1RA-induced retinal complications. GLP-1RAs exert pleiotropic effects on the retinal microvasculature, offering protection by amelioration of endothelial function, reduction in oxidative stress, inflammation, microvascular remodeling, and preservation of the blood-retinal barrier (BRB). Despite these mechanistic advantages, emerging clinical data have raised concerns regarding potential retinal adverse events associated with GLP-1RA therapy. Observational studies and pharmacovigilance analyses have suggested possible associations with non-arteritic anterior ischemic optic neuropathy (NAION), diabetic macular edema (DME), vitreous hemorrhage, retinal detachment, macular hole formation, and progression of diabetic retinopathy (DR), particularly in the context of semaglutide use. Most evidence comes from retrospective studies or secondary endpoints, limiting causal inference. Retinal complications associated with GLP-1RAs remain heterogeneous and inconclusive, requiring careful evaluation of potential risks across diverse patient populations. Future research should conduct large, randomized trials with standardized ocular endpoints, detailed imaging, and stratified analyses to clarify GLP-1RA retinal safety.

Real-World Effectiveness and 12-Month Persistence of a Semaglutide-Supported Digital Weight-Loss Service: A Retrospective Cohort Study in Germany.

Louis Talay, Jason Hom, Marilyn Tan +1 more

To evaluate the 12-month effectiveness and patient persistence of a semaglutide-supported digital weight-loss service (DWLS) in a real-world German cohort.

Correction: Discontinuation of oral semaglutide due to adverse effects: a database study on Japanese individuals with type 2 diabetes.

Mizuki Ishiguro, Rimei Nishimura

[This corrects the article DOI: 10.1007/s13340-025-00868-0.].

Phenome-wide analysis of downstream health outcomes following second-line antidiabetic agent prescriptions in All of Us.

Maxwell Salvatore, Bingyu Zhang, Huilin Tang +7 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for type 2 diabetes (T2D) and weight management, yet their real-world health impacts remain understudied. Using a retrospective cohort design with electronic health record data from 17,267 adults with type 2 diabetes in the All of Us Research Program, we conduct propensity score-matched phenome-wide association studies comparing diagnoses following GLP-1 RA prescription (including semaglutide-specific analyses) to those following sodium-glucose cotransporter-2 inhibitor (SGLT2i) and dipeptidyl peptidase-4 inhibitor (DPP4i) prescriptions between January 2018 and October 2023. We employ both intention-to-treat and per-protocol Cox proportional hazards models alongside restricted mean survival time analyses evaluating up to 974 phenotypes. We identify multiple phenome-wide significant and suggestive associations, including for cardiovascular, genitourinary, dental, and metabolic outcomes. Compared to SGLT2i, semaglutide demonstrates reduced risk for genitourinary infections in women (e.g., candidiasis of vulva and vagina (per-protocol hazard ratio 0.31, 95% confidence interval (0.17-0.55)). Compared to DPP4i, GLP-1 RAs are associated with reduced risk of diseases of hard tissues of teeth (0.45 (0.33-0.61)). Time-to-event analyses reveal modest delays for key diagnoses. These findings underscore differences in downstream diagnostic associations across second-line T2D therapies and highlight semaglutide's distinct profile, with implications for clinical decision-making and personalized prescribing.

Glycaemic changes during early semaglutide treatment: a case of pancreatic adenocarcinoma.

Işılay Taşkaldıran, Püren Gökbulut, Hasan Yiğit +1 more

Glucagon-like peptide-1 receptor agonists are widely used for the management of obesity and dysglycaemia, and current evidence does not support a causal association with pancreatic cancer. We report a 55-year old woman with obesity and prediabetes who started once-weekly semaglutide 0.25 mg for weight management and glycaemic control. Baseline fasting plasma glucose was 107 mg/dL and glycated haemoglobin was 6.0%. After one month, despite a 4 kg weight loss and no significant gastrointestinal symptoms, fasting plasma glucose increased to 169 mg/dL and glycated haemoglobin to 6.6%. Latent autoimmune diabetes in adults was excluded by negative autoantibodies and preserved C-peptide. Further evaluation revealed markedly elevated carbohydrate antigen 19-9 and pancreatic magnetic resonance imaging demonstrated a 4 × 3 cm irregular mass in the pancreatic head. Surgical exploration identified liver metastases, and biopsy confirmed metastatic pancreatobiliary adenocarcinoma. This case highlights that atypical glycaemic changes during early semaglutide treatment should be interpreted cautiously, particularly during subtherapeutic dose escalation. Such observations do not imply causality, but may warrant individualized assessment when accompanied by additional clinical suspicion.

Short-term comparative effects of semaglutide, either alone or in conjunction with canagliflozin, on early diabetic kidney disease.

Wang Long, Li Ningning, Huang Weijun

Diabetic kidney disease (DKD) is a common complication of type 2 diabetes mellitus and an important cause of end-stage renal disease. Metabolic dysfunction, albuminuria, and chronic low-grade inflammation characterize early DKD, leading to progressive renal impairment. To date, SGLT2 inhibitors and GLP-1 receptor agonists are known to provide renoprotective and metabolic benefits; however, there is limited evidence available regarding the combined use of these treatments in early DKD.

Projected reduction in major adverse cardiovascular events among high-risk U.S. adults with type 2 diabetes eligible for oral semaglutide: a SOUL trial-based analysis using NHANES (1988-2018) cycles.

Mustafa Al-Jarshawi, Andrew Cole, Rodrigo Bagur +5 more

Semaglutide drives weight loss through cAMP-dependent mechanisms in GLP1R-expressing hindbrain neurons.

Claire Gao, Isabelle C Geneve, Shakira Rodriguez-Gonzalez +5 more

Glucagon-like peptide 1 receptor (GLP1R) agonists, such as semaglutide, drive weight loss by binding to GLP1Rs-classically described as Gs-coupled G-protein-coupled receptors-in the brain; however, the intracellular signalling mechanisms underlying these effects remain poorly defined. Here, we find that semaglutide engages both Gs- and Gq-dependent signalling pathways in Glp1r-expressing neurons in the area postrema (APGlp1r), the primary site of semaglutide action in the brain, and differentially regulates neuronal activation across distinct neuronal clusters. Semaglutide also drives graded increases of the essential secondary messenger cyclic adenosine monophosphate (cAMP) in APGlp1r neurons through the Gs pathway. Inhibition of the cAMP-degrading enzyme phosphodiesterase 4 (PDE4) enhances and sustains these cAMP responses, and disruption of Gs or cAMP signalling in APGlp1r neurons abolishes semaglutide-induced weight loss and downstream brain-wide activation. Our systematic characterization of semaglutide's signalling mechanisms in the hindbrain reveals the intracellular signalling architecture through which semaglutide engages cAMP and calcium to regulate body weight, providing avenues for improving obesity therapeutics.

Effects of a 6-week subcutaneous infusion of native GIP alone or as add-on to semaglutide in people with type 2 diabetes: a single-centre, double-blind, parallel-group, randomised, placebo-controlled trial.

Mads M Helsted, Christiane Fonnesbech-Wulff, Nina L Schaltz +11 more

The long-term glycaemic effects of glucose-dependent insulinotropic polypeptide (GIP) remain unclear. We aimed to assess whether a 6-week subcutaneous infusion of GIP alone and in combination with the GLP-1 receptor agonist semaglutide would enhance glycaemic control in individuals with type 2 diabetes.

Semaglutide-associated risk of nonarteritic anterior ischemic optic neuropathy in patients with type 2 diabetes: A systematic review and meta-analysis of observational studies.

Jędrzej Chrzanowski, Magdalena Walicka, Jacek Burzyński +3 more

Semaglutide, a glucagon-like peptide-1 receptor agonist, is widely used for the management of type 2 diabetes (T2DM). Recent case reports have raised concerns about a potential association between semaglutide use and the development of nonarteritic anterior ischemic optic neuropathy (NAION), a rare but vision-threatening condition. We aimed to evaluate whether semaglutide use is associated with an increased risk of NAION in patients with T2DM.

ICER report demonstrates both the value and challenges in financing of weight loss medications.

Sujith Ramachandran, Ben Urick, Tara Thomas

Two out of 5 US adults live with obesity, generating substantial clinical and economic burden. Recent glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including semaglutide and tirzepatide, demonstrate significant weight loss and cardiometabolic benefits and were found by the Institute for Clinical and Economic Review (ICER) to be cost-effective compared with lifestyle modifications alone. However, even limited uptake exceeds ICER's annual budget impact threshold, prompting access concerns. The latest real-world evidence demonstrates that persistence for these drugs is lower than in clinical trials, resulting in frequent weight regain after discontinuation, tempering expectations of long-term medical cost offsets. Evidence on medical spending impact is mixed, with cost-offset signals only observed among patients with obesity and diabetes receiving high-potency injectable agents, whereas obesity-only populations often show spending increases. Given current coverage restrictions, this commentary recommends combining drug coverage with lifestyle management programs, avoiding arbitrary duration limits, using targeted prior authorization, and exploring innovative payment models to improve access while managing budget impact.

Glucagon-like peptide-1 receptor agonists for weight loss in end-stage heart failure patients considered for heart transplantation.

Sambavan Jeyakumar, Ragavi Jeyakumar, Hunter Eckford +11 more

Severe obesity is a relative exclusion criterion for heart transplantation. This study assessed glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for weight loss as a bridge to heart transplantation candidacy. A retrospective study of end-stage heart failure (ESHF) outpatients commenced on semaglutide compared demographic, metabolic, and transplant listing data pre- and post-treatment. Nine patients (median pre-GLP-1 RA body mass index [BMI]: 35.9 kg/m2 [IQR 1.3]) received semaglutide for a median of 4 months (IQR 9). Seven patients (78%) had an initial BMI >35 kg/m2; an exclusion criterion for transplantation. Post-treatment, median BMI decreased to 32.2 kg/m2 (IQR 4.1), representing a 5.0 kg (IQR 6.3) median weight loss. All patients were subsequently transplant-listed, and 7 (78%) patients underwent transplantation. No significant adverse effects were reported. These preliminary findings suggest semaglutide may facilitate heart transplantation eligibility in ESHF patients with severe obesity, warranting larger studies to guide GLP-1 RA use in transplant protocols.

Weight trajectories after last tirzepatide or semaglutide prescription across a federated health network.

Karthik Murugadoss, Gowtham Varma, A J Venkatakrishnan +2 more

GLP-1 receptor agonist (GLP-1RA) discontinuation has been associated with weight regain. However, weight trajectories following the last documented GLP-1RA prescription in the real-world clinical setting have not been explored. Here, we assessed weight trajectories of 4182 patients in the 6 months following their last semaglutide or tirzepatide prescription. Approximately two-thirds of patients showed stable weight or continued weight loss during this period. In a representative subset of 300 patients whose clinical notes were curated using a large language model, treatment discontinuation was documented for 119 patients (40%) around the time of the last prescription. Among these 119 patients, a similar pattern of weight trajectories was observed, with 72% of patients not demonstrating weight regain. Exercise counseling was documented more frequently among patients with durable weight loss after the last GLP1-RA prescription than among those with weight regain (26.2% vs. 14.7%; P = .04). Further studies are warranted to evaluate the mechanisms underlying these real-world patterns.

Comment on Mann et al. Impact of Oral Semaglutide on Kidney Outcomes in People With Type 2 Diabetes: Results From the SOUL Randomized Trial. Diabetes Care 2026;49:257-265.

Songbei Li

Response to Comment on Mann et al. Impact of Oral Semaglutide on Kidney Outcomes in People With Type 2 Diabetes: Results From the SOUL Randomized Trial. Diabetes Care 2026;49:257-265.

Johannes F E Mann, Ole Kleist Jeppesen, Nicolas Belmar +2 more

Plain language summary: the evoke(+) studies of semaglutide for early Alzheimer's disease.

Jeffrey L Cummings, Alireza Atri, Mary Sano +9 more

What is this summary about?This article presents a plain language summary of the results from the evoke and evoke+ phase 3 clinical studies, collectively known as the evoke(+) studies, which were published in The Lancet in March 2026.The primary goal of the evoke(+) studies was to understand if oral treatment with up to 14 mg of the drug semaglutide (normally used for the treatment of type 2 diabetes and/or obesity) delayed decline of memory and thinking in people with the early stages of Alzheimer’s disease.A delay in the onset of Alzheimer’s disease has been observed in some previous studies among patients with type 2 diabetes treated with semaglutide, suggesting that this could be a potential treatment for Alzheimer’s disease.The evoke(+) studies compared the effects of semaglutide treatment taken once per day by mouth with a placebo group using clinical tests and blood and cerebral fluid samples that can measure the course of Alzheimer’s disease. People in the trial did not know if they were receiving semaglutide or placebo (e.g. the trials were ‘blinded’).The main test used was change in Clinical Dementia Rating–Sum of Boxes score which assesses thinking, memory, and everyday activities.Change in Alzheimer’s Disease Cooperative Study Activities of Daily Living–Mild Cognitive Impairment score, a measure of activities of daily living in everyday life, was also included in the study. Activities of daily living include those inside and outside the home.What are the key takeaways?Oral semaglutide taken once per day by mouth up to 14 mg did not slow cognitive or functional decline in people with the early stage of Alzheimer’s disease. Therefore, it is not effective as a treatment for the early stages of Alzheimer’s disease.Safety information collected during the studies showed that adverse effects are similar to those observed when semaglutide is taken for other diseases and no new adverse effects were identified.The evoke(+) studies provide information on disease progression and safety that could be used in the future.

Semaglutide use for hypothalamic obesity and type 2 diabetes mellitus after suprasellar germinoma treatment.

Kenichi Yokota, Tomoko Nakagawa, Yuta Nakamura +3 more

Hypothalamic obesity (HO) is a severe complication of suprasellar tumors characterized by hyperphagia, rapid weight gain, and resistance to lifestyle interventions. We describe a case of a woman diagnosed with suprasellar germinoma at 16 years of age who was treated with chemotherapy and radiotherapy. Subsequently, she experienced progressive weight gain, increasing from 57 kg to a peak of 138 kg by age 37 years, and developed type 2 diabetes mellitus at age 28 years. At age 38 years, she presented with polydipsia, polyuria, and fatigue, and was admitted for the management of hyperglycemia with class III obesity (123.5 kg; body mass index [BMI], 51.4 kg/m2). Intensive insulin therapy (up to 100 units/day) resolved glucotoxicity. After initiation of semaglutide (titrated from 0.25 to 0.5 mg/week), appetite markedly decreased, and subsequent weight loss was achieved. Three months after discharge, her weight decreased from 131 kg to 112.1 kg, representing an approximate 14% reduction, accompanied by optimized glycemic control. Body composition analysis revealed that weight loss was primarily due to fat mass reduction with relative preservation of muscle mass. This case demonstrates the potential efficacy of semaglutide in patients with HO and type 2 diabetes mellitus after suprasellar germinoma treatment.

[Value and benefit of basic insulin/GLP-1RA weekly preparation in clinical treatment of type 2 diabetes in adults].

S C Zhang, L Zang, Y Cheng +2 more

The prevalence of type 2 diabetes mellitus has been rising continuously in China. However, glycemic control rates remain suboptimal, posing a significant public health challenge. Although traditional intensive insulin strategies are effective in improving glycemic control, they are often associated with risks such as hypoglycemia and weight gain. Fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) offer complementary mechanisms of action, enhancing efficacy and safety while simplifying treatment regimens, making them a key focus of clinical development. Insulin icodec/semaglutide fixed-ratio combination (IcoSema), the first once-weekly dual-component preparation combining a basal insulin and a GLP-1RA, utilizes advanced formulation technology to achieve stable co-formulation of the ultra-long-acting once-weekly basal insulin and the once-weekly GLP-1RA, with the two components acting in a complementary and synergistic manner. The Phase 3 COMBINE clinical trial program demonstrated that, compared with insulin icodec, semaglutide(1.0 mg), or basal-bolus insulin regimens, IcoSema provides superior or equivalent glycemic control, and the risk of clinically significant or severe hypoglycemic events is comparable to that of semaglutide(1.0 mg). Once-weekly administration helps to simplify the treatment regimen and improve treatment adherence. The clinical application of IcoSema is expected to alleviate the dilemma in Chinese type 2 diabetes management of balancing effective glycemic control with safety and simplicity, offering a new therapeutic option for patients requiring insulin intensification that combines efficacy, safety, and convenience.

Pharmacovigilance of semaglutide: A descriptive analysis of WHO-VigiAccess reports.

Nasser M Alorfi, Mansour M Alourfi, Ammar Aldabbagh +7 more

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is widely prescribed for type 2 diabetes mellitus and chronic weight management. With its growing global use, continuous pharmacovigilance is essential to detect emerging patterns of adverse drug reactions (ADRs). To describe the global ADRs profile of semaglutide using data from the World Health Organization's (WHO) VigiAccess pharmacovigilance database. A retrospective descriptive analysis was conducted using publicly available ADR data retrieved from the WHO-VigiAccess portal on October 18, 2025. The total number and proportion of ADRs were summarized according to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC). Demographic information, including age group, sex, geographic region, and reporting year, was reviewed descriptively. A total of 81,770 ADR reports associated with semaglutide were identified. The most frequently reported SOCs were gastrointestinal disorders (28%, n = 42,574), general disorders and administration site conditions (12%, n = 19,200), and injury, poisoning and procedural complications (11%, n = 16,601). Additional categories included nervous system disorders (8%), investigations (7%), and metabolism and nutrition disorders (7%). The majority of ADRs were reported among adults aged 45 to 64 years, with most originating from Europe and the Americas. Annual reporting increased markedly between 2018 and 2025, corresponding with expanded clinical use and obesity-related approvals. Global pharmacovigilance data indicate that semaglutide ADRs are primarily gastrointestinal and systemic in nature, consistent with its known pharmacological effects. Continuous monitoring is warranted to identify emerging safety signals and support optimized patient management as use expands worldwide.

American Society for Metabolic and Bariatric Surgery statement on the treatment options for patients with non-response and weight recurrence after metabolic and bariatric surgery.

Vosburg Ralph Wesley, Carter Jonathan, Azagury Dan +5 more

Metabolic and bariatric surgery (MBS) is the most effective treatment for severe obesity, producing durable weight loss and improvement in obesity-related comorbidities. However, a subset of patients experience inadequate weight loss (non-response, NR) or weight recurrence (WR), which can lead to persistence or recurrence of metabolic disease, diminished quality of life, and warrants for further treatment interventions.

Synthesis of scarless circular RNAs expressing long-acting GLP-1RAs for type 2 diabetes therapy.

Yude Lin, Zhibo Huang, Zhiwei Xiao +8 more

Glucagon-like peptide-1 (GLP-1) is a prominent therapeutic agent capable of normalizing fasting blood glucose levels in diabetic patients. While GLP-1-expressing mRNA encapsulated in lipid nanoparticles (LNPs) has been evaluated for diabetes treatment in primate models, circular RNAs (circRNAs) represent a more stable alternative to linear mRNA, offering significant potential for the development of next-generation GLP-1-encoding RNA therapeutics.

GLP-1 RA semaglutide for alcohol use disorder: a potential multi-target therapy.

Sergio Maimone, Antonio Galante, Carlotta Castoro +2 more

Unmasking counterfeit semaglutide: analysis of real-world safety data from EudraVigilance.

Alessia Zinzi, Mario Gaio, Rosanna Ruggiero +7 more

The spread of counterfeit drugs represents a serious threat to public health because they may be ineffective or cause the onset of severe suspected adverse drug reactions (ADRs). To date, the traceability of semaglutide-based products, widely used off-label for weight loss, is not a well-studied area.

Esophageal Motility Patterns Are Not Impacted By Glucagon-Like Peptide-1 Receptor Agonist Use.

Annie L Wang, Laura Bach, David A Leiman

Glucagon-like peptide-1 receptor agonist (GLP-1RA) use is associated with delayed gastric emptying. It is unknown whether GLP-1RAs affect esophageal motility. We aimed to assess the relationship between GLP-1RA use and esophageal function test results.

Implications of Glucagon-Like Peptide-1 Receptor Agonists in Otolaryngology - Head and Neck Surgery: A Review.

Brady J Anderson, Douglas J Van Daele, Alexander D Claussen +2 more

The number of patients taking glucagon-like peptide-1 receptor agonists (GLP-1RAs) is increasing. Beyond diabetes and weight management, these medications have various effects within the head and neck with both beneficial and potentially adverse clinical implications. Delayed gastric emptying may contribute to reflux, chronic cough, and potential aspiration in the perioperative setting; as such, physicians should be aware of anesthetic guidelines (duration of pre-operative cessation, pre-operative fasting or liquid diet) to improve safety and avoid operative delay. GLP-1RAs have shown benefit in treating obstructive sleep apnea in those with obesity or overweight and may become increasingly relevant in multimodal treatment of sleep disorders. GLP-1 receptor signaling is involved in sinopulmonary inflammatory cascades and recent evidence suggests clinical implications for chronic sinusitis and olfactory disorders. Previously reported neuroprotective effects have led to investigation regarding potential benefit in neurotoxicity-associated hearing loss. Muscle atrophy with weight loss may contribute to a gaunt, aged appearance leading patients to seek facial rejuvenation, or to a patulous eustachian tube and changes in conductive hearing. Animal studies suggested an increased risk of thyroid cancer, but population studies have been inconclusive and will require long-term investigation to determine any causal relationship.

Baseline vitamin D status is associated with glycemic and weight loss outcomes in patients with type 2 diabetes treated with semaglutide.

Ariel Israel, Mahmud Moed, Hala Abo Fanne +6 more

Semaglutide, a glucagon-like peptide-1 receptor agonist, is an established therapy for type 2 diabetes (T2D), offering robust glycemic control and weight reduction. Vitamin D has been implicated in metabolic regulation, yet its influence on semaglutide-induced outcomes remains unclear.

GLP-1 Receptor Agonist Combination Therapy Before and After Metabolic and Bariatric Surgery: A Review of Outcomes.

Chang Seok Ko

The paradigm of obesity treatment is rapidly evolving with the introduction and widespread adoption of glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Semaglutide, the representative agent, has demonstrated substantial weight reduction and cardiometabolic benefits across multiple pivotal clinical trials, reshaping societal perceptions of anti-obesity pharmacotherapy. In parallel, sleeve gastrectomy (SG) has become the most commonly performed metabolic and bariatric surgical procedure worldwide due to its technical simplicity, strong safety profile, and durable outcomes. The use of anti-obesity medication in the preoperative setting of metabolic and bariatric surgery has been previously explored; however, its clinical benefit has long remained controversial and inconsistent. Recent evidence suggests that GLP-1 RAs can safely achieve greater preoperative weight loss than earlier pharmacologic agents. Furthermore, GLP-1 RAs have emerged as an effective treatment option for postoperative weight regain, demonstrating significant weight-loss benefits in both SG and gastric bypass patients compared with conventional therapies. As GLP-1-based therapies continue to advance, future strategies should shift toward a multimodal treatment model analogous to oncology, integrating pharmacologic and surgical interventions throughout all phases of obesity care. Further research is needed to establish the ideal timing, duration, safety, and long-term weight loss and metabolic effects of GLP-1 RA administration in both pre- and postoperative phases.

15-PGDH Inhibition Overcomes Muscle Regenerative Deficit Seen With GLP1-Receptor Agonist-Induced Weight Loss.

Minas Nalbandian, Jameel Lone, Emmeran Le Moal +8 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including long-acting semaglutide, are revolutionary anti-obesity therapies. However, emerging evidence indicates that weight loss may come at the expense of skeletal muscle mass, a tissue essential for mobility, metabolic regulation, and overall health. Here, we show that an inhibitor of the gerozyme 15-hydroxyprostaglandin dehydrogenase (PGDHi), which boosts PGE2 levels, increases skeletal muscle mass, strength, and regeneration in the presence of semaglutide. We find that in a high fat diet-induced mouse model of obesity, semaglutide alone induces significant loss of muscle mass, while retaining contractile function. However, muscle regeneration and recovery of strength post-injury are hindered by semaglutide. This regenerative deficit is due to impeded stem cell function, which is overcome if mice are treated with a combination of PGDHi and semaglutide. Our data show that GLP-1-mediated weight loss interferes with this key muscle-building function, which PGDHi co-treatment counteracts to promote proper muscle regeneration and restored strength.

Tirzepatide Versus Semaglutide and Cardiovascular Outcomes in Type 2 Diabetes With Established Cardiovascular Disease: An Indirect Treatment Comparison Meta-Analysis.

Ronald M Goldenberg, Jill Trinacty, Christine Ibrahim

Estimated Oral Semaglutide Exposure Has Distinct Relationships With Glycaemic Response, Weight Loss and Gastrointestinal Tolerability.

Gian Paolo Fadini, Mario Luca Morieri, Carlotta Boscaro +2 more

Oral semaglutide absorption is subject to inter-individual variability. We investigated whether estimated individual exposure (eCavg) provides predictive information beyond the prescribed dose in a real-world cohort of patients with type 2 diabetes (T2D).

The impact of automated insulin delivery on glucose management in people with diabetes and advanced chronic kidney disease.

Jean C Lu, Christine L Meyer-Olesen, Bella Halim +15 more

Chronic kidney disease (CKD) complicates insulin dosing and increases glycaemic instability in diabetes. We aimed to compare feasibility, safety and efficacy of automated insulin delivery (AID) with usual care in people with diabetes and advanced CKD.

Semaglutide and Cardiovascular Outcomes in People with Type 2 Diabetes: A SUSTAIN-6 Post Hoc Analysis by Weight Loss Category.

Angelo Navas, Joshua Noone, Nathan Laney +5 more

Type 2 diabetes (T2D) is a known risk factor for cardiovascular (CV) disease. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, improve glycemic control and are associated with weight loss, but the impact of weight loss on major adverse cardiovascular events (MACE) when taking semaglutide is not fully understood. This post hoc analysis of the SUSTAIN-6 trial aimed to examine the correlation between weight loss with semaglutide and the occurrence of MACE (nonfatal myocardial infarction, nonfatal ischemic stroke, and CV death).

Semaglutide-associated Twiddler syndrome.

Thomas Seiler, Fabian Noti, Markus Laimer +2 more

52-year-old woman with cardiac sarcoidosis and a dual-chamber implantable cardioverter defibrillator (ICD) was treated with semaglutide for refractory obesity (body mass index (BMI) of 40.1 (kg/m2)). After rapid weight loss of 25 kg, she developed painful device mobility and right ventricular lead dysfunction. Chest x-ray revealed lead entanglement consistent with Twiddler syndrome, which is a mechanical complication in which a pacemaker or ICD rotates within its pocket, causing the leads to twist or dislodge and resulting in device malfunction. Lead extraction was complicated by cardiac tamponade. After recovery, she underwent successful reimplantation of a single-chamber ICD. Patients with cardiac implantable electronic devices who are treated with glucacon-like-peptide-1 receptor agonists may have an increased risk of Twiddler syndrome, as substantial weight loss can increase generator mobility in the subcutaneous pocket. Clinicians should recognize this rare but potentially life-threatening complication.

Semaglutide 2.4 mg for Obese Patients with MASH: A Cost-Effectiveness Analysis from the Italian NHS Perspective.

Enrico Torre, Sergio Di Matteo, Chiara Martinotti +7 more

Metabolic dysfunction-associated liver disease (MASLD) and its progression to steatohepatitis (MASH) are highly prevalent among obese patients, contributing substantially to healthcare costs. Semaglutide, a GLP-1 receptor agonist, has shown metabolic and hepatic benefits in this population. This study assessed the cost-effectiveness of Wegovy® (semaglutide 2.4 mg) versus no pharmacological treatment in obese patients with MASH ≤F3 without diabetes, from the perspective of the Italian National Health Service (NHS).

Exploring Weight Loss Medication Discourse: Mixed Methods Analysis of US-Based Facebook Posts.

Elizabeth Dennard, Katrina Makres, Amrutha Alibilli +9 more

Despite the documented clinical efficacy of weight loss medications, few large-scale mixed methods studies have captured the experiences of individuals taking these medications.

Real-world Impact of GLP-1 Receptor Agonists on Health-related Quality of Life in Type 2 Diabetes and Obesity (SEVERAL Study).

José Seijas-Amigo, Ángel Salgado-Barreira, Carlota Roca-Martinez +20 more

To evaluate the real-world impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on health-related quality of life (HRQoL) and metabolic outcomes in adults with type 2 diabetes and obesity.

Beyond GLP-1 Monotherapy: Novel Multi-Agonists, Amylin Analogues, and Combination Strategies in Obesity and Type 2 Diabetes.

Mikhail Khachaturov, Dimitrios G Goulis

To provide a clinically oriented narrative review of recently reported human trial data on emerging pharmacotherapies for obesity and type 2 diabetes beyond glucagon-like peptide-1 receptor agonist (GLP-1RA) monotherapy.

Semaglutide vs. Bariatric Surgery: Comparing Costs and Clinical Outcomes in Patients With Diabetes and Obesity.

Karan R Chhabra, Nihan Gencerliler, Babak J Orandi +9 more

We compared health care spending and utilization associated with semaglutide relative to bariatric surgery in patients with obesity and type 2 diabetes (T2D).

Effect of Semaglutide Combined With Conventional Insulin Therapy on Blood Glucose Control and Renal Function in Elderly Patients With Type 2 Diabetes.

Lan Ye, Ying Yín

Poor glycemic control in elderly diabetes patients leads to complications like nephropathy. Semaglutide (SEM), a GLP-1 receptor agonist, may improve both blood glucose (BG) control and renal function (RF). This study evaluates the effects of SEM combined with insulin therapy on BG and RF.

Dulaglutide-associated body odor with dechallenge and rechallenge in a patient with type 2 diabetes.

Srecko Marusic, Matea Staresinic, Maja Cigrovski Berkovic

Although uncommon, medications may induce unpleasant body odor, potentially leading to psychosocial distress and reduced treatment adherence. To date, unpleasant body odor has not been recognized as an adverse effect of dulaglutide. We report a novel case of dulaglutide-associated body odor, confirmed by dechallenge and rechallenge.

[Current and future medical treatments for metabolic dysfunction-associated steatohepatitis].

Rodolphe Anty, Marwin A Farrugia

Drug treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) is undergoing a revolution. The fight against cardiovascular risk factors, the optimization of the treatment of type 2 diabetes, the screening of common extra-hepatic cancers, personalized dietary measures, therapeutic physical exercise programs and the fight against a sedentary lifestyle remain fundamental to propose to all patients. For patients with metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis (F2-F3), resmetirom is the first effective and well-tolerated drug marketed in the USA and Europe. Semaglutide or double or triple incretin receptor/glucagon receptor agonists could constitute the future cornerstone of drug management for patients with MASLD, due to the achievement of very significant weight loss (from 10 to more than 24% of the initial weight). Semaglutide has been shown to reduce cardiovascular and renal events, and has been approved for marketing in the USA, for MASH without cirrhosis. The choice of the best drug combination, the optimal prescription duration and the best drug option in the case of MASH-related cirrhosis remain to be determined.

Computational phenotyping of effort-based decision-making in type-2 diabetes on and off semaglutide.

Sara Z Mehrhof, Hugo Fleming, Camilla L Nord

Motivation plays a fundamental role in human behaviour. Dopaminergic pathways have long been implicated in individual differences in motivation. Emerging evidence suggests such neural mechanisms interact with metabolic processes to coordinate energy expenditure with energy resources, thereby linking motivation with metabolic health. We ask whether a cognitive-computational index of motivation-reliably linked to neuropsychiatric symptoms-is altered in the context of type-2 diabetes and treatment with a GLP-1 agonist (semaglutide). In a pre-registered experiment, we quantified computational effort-based decision-making parameters in participants with diabetes on (N = 58) or off (N = 54) semaglutide treatment, compared to two groups of matched controls without diabetes (N = 58 each). Subjects with type-2 diabetes showed a blunted acceptance bias, a computational parameter describing the bias to accept effort for reward. This effect was not driven by neuropsychiatric comorbidity or antidepressant use. Across all participants, we found that increasing diabetes risk linearly predicted reduced acceptance bias. Participants with diabetes treated with semaglutide did not show restored motivation. Metabolic ill-health is associated with reduced acceptance bias during motivational decision-making. This blunting mirrors-but is largely independent of-neuropsychiatric motivational deficits. This suggests metabolic ill-health is accompanied by a cognitive shift towards energy conservation, potentially contributing to comorbidity between metabolic ill-health and mental illness.

Acute Contractile Effects of Glucagon-like-Peptide-1 Receptor Agonists in the Human Heart.

Joachim Neumann, Uwe Kirchhefer, Britt Hofmann +1 more

Glucagon-like-peptide-1 receptor (GLP-1R) agonists are under development as new drugs to treat type 2 diabetes, liver disease, obesity and cardiovascular diseases. Some of these drugs are solely agonists of the GLP-1R. It turned out that their benefit could be improved when they also stimulated the glucagon receptor (GCGR) and/or the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR). Stimulation of GLP-1R in cell cultures but also in neonatal atrial and/or ventricular cardiomyocytes and adult atrial cardiomyocytes raised the activity of adenylyl cyclase and thus augmented the 3',5'cyclic adenosine monophosphate (cAMP) levels. We discuss here the acute contractile effects of such agonists on isolated human atrial and ventricular cardiac preparations from failing and non-failing hearts. We address the receptors involved, GLP-1R expression in various cardiac regions of the human heart, single and multiple receptor agonists and the post-receptor signal transduction system of the GLP-1R in the human heart. Some of the new drugs addressed are still in the early phases of clinical development. We critically discuss the experimental and clinical data available and we also define research needs for experimental and clinical studies.

Quality by Design-Based Formulation Development of an Oral Semaglutide Tablet.

Ji-Hyeon Yoon, Do-Hyub Kim, Joo-Eun Kim

Background: This study aimed to investigate, from a scientific and formulation perspective, an oral semaglutide tablet incorporating sodium caprate (C10) as an intestinal absorption enhancer and to optimize its formulation performance using a Quality by Design (QbD)-based approach. Semaglutide-a peptide-based therapeutic-provides effective glycemic control and weight reduction; however, its extremely low oral bioavailability has limited administration to subcutaneous injection. Although various attempts have been made to improve peptide absorption, achieving consistent delivery through oral routes remains a significant challenge due to enzymatic degradation and poor membrane permeability. Methods: To overcome these limitations, an absorption enhancer (sodium caprate) was incorporated to enhance oral absorption, and a Quality by Design (QbD)-based approach was applied to systematically guide formulation development. Following the definition of the Quality Target Product Profile and critical quality attributes, risk assessments (Preliminary Hazard Analysis and Failure Mode and Effects Analysis) were conducted to identify key formulation factors. A design of experiments approach was then employed to determine the optimal tablet composition. Results: Consequently, the resulting formulation met all predefined quality criteria, including hardness, disintegration, friability, and content uniformity. In addition, the in vitro dissolution profile demonstrated a release pattern comparable to that of the reference product, with similarity factor values of 74.4, 74.7, and 71.3 at pH 1.2, 4.0, and 6.8, respectively. Conclusions: These findings indicate that the formulation can achieve consistent and reproducible quality performance as an oral semaglutide dosage form. The QbD-based formulation design strategy presented in this study provides a robust and broadly applicable approach for developing oral delivery systems for peptide drugs, including semaglutide, and ultimately provides useful formulation insight for future peptide-based oral delivery research.

Once-Weekly Semaglutide in Patients with Cardiovascular-Kidney-Metabolic Syndrome: A Real-World Study.

Alicia Trenas-Calero, Nuria Prieto-Laín, Ana I Gómez-Hernández +6 more

Introduction and Objectives: There is limited evidence on the role of glucagon-like peptide-1 receptor agonists in the interplay between cardiovascular disease, chronic kidney disease, and metabolic dysfunction. This work analyzed the efficacy and safety of once-weekly semaglutide in patients with cardiovascular-kidney-metabolic syndrome. Patients and Methods: This observational, real-world study included patients with heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus treated with once-weekly semaglutide (Sema-CKM Group) and patients not treated with glucagon-like peptide-1 receptor agonists (Control-CKM Group). A 1:1 propensity score matching analysis was performed. The two primary outcomes were heart failure events and major kidney disease events at 24 months. Results: After matching, 302 patients were included in each group. A heart failure event occurred in 63 patients (20.9%) in the Sema-CKM Group and 121 (40.1%) in the Control-CKM Group (OR: 0.80; 95%CI: 0.62-0.98; p < 0.01). The number of major kidney disease events was lower in the Sema-CKM Group than the Control-CKM Group (36 vs. 65; OR: 0.85; 95%CI: 0.72-0.98; p = 0.014). Patients in the Sema-CKM Group were more likely to have an improvement in heart failure health status from baseline to 24 months (OR: 2.80; 95%CI: 1.30-4.30; p < 0.01). Semaglutide also improved glycemic control (glycated hemoglobin -0.7%) and reduced body weight (-9.3 kg). Conclusions: Once-weekly semaglutide was associated with reductions in heart failure events and major kidney disease events in patients with heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. Further research on glucagon-like peptide-1 receptor agonists in cardiovascular-kidney-metabolic syndrome is needed.

Management of Obese Patients with Cardiovascular Disease with Emerging Weight-Lowering Drugs: A Narrative Review.

Alessandro Ciarloni, Gianmaria Salvio, Monia Bordoni +2 more

Background/Objectives: Obesity has a huge impact on global healthcare and economy. Consequently, the pharmaceutical industry has recently introduced novel anti-obesity drugs such as semaglutide and tirzepatide, which can yield remarkable weight reduction in patients, while also having significant cardiovascular benefits. Methods: Other weight-lowering medications are currently under investigation, and this narrative review provides an overview of the main novel drugs that are being tested. Results: These novel agents have different mechanisms of action, e.g., calorie intake reduction, increase in basal metabolism, and increase in muscle mass. Conclusions: In the future, obesity treatment is likely to become increasingly personalized, and further cardiovascular benefits could be expected. The combined use of different molecules could minimize their side effects, for instance, by minimizing muscle wasting observed during glucagon-like peptide 1 receptor agonists (GLP1-RAs) therapy. In our opinion, these highly effective drugs could represent a valuable addition to healthy lifestyle, as the evidence linking increases in muscle mass and basal metabolic rate to improved cardiovascular health is strongest when these changes are achieved through diet and regular physical activity.

An Ionic Liquid-Based Enteric Formulation for Enhanced Oral Delivery of Semaglutide in Type 2 Diabetes Mellitus.

Juan Tao, Xinrui Lu, Yuning Wei +3 more

Oral delivery of peptide therapeutics remains challenging due to gastrointestinal degradation, poor epithelial permeability, and extremely low bioavailability. To address these limitations, we developed an enteric solid formulation based on sorbic acid-choline ionic liquids (ILs) for the oral delivery of semaglutide (Sema), a glucagon-like peptide-1 (GLP-1) analogue. The IL-based enteric system was designed to enhance peptide stability, reduce gastric degradation, and promote intestinal absorption. In vitro studies demonstrated strong resistance to acidic conditions and pH-responsive release in simulated intestinal fluid. In vivo imaging further revealed prolonged intestinal retention of the IL-loaded enteric particles. Pharmacokinetic evaluation showed a 2.3-fold increase in maximum plasma concentration compared to the reference Rybelsus. In type 2 diabetes mellitus (T2DM) mice, the formulation achieved glucose-lowering efficacy comparable to subcutaneous Sema administration, with additional improvements in hepatic histology. Importantly, repeated-dose studies indicated favorable systemic and gastrointestinal tolerability under the tested conditions. Collectively, these results demonstrate that IL-based enteric formulation enhances oral peptide exposure while maintaining safety, offering a promising strategy for noninvasive T2DM management.

Semaglutide in obesity and type 2 diabetes: A review of clinical trial evidence from 1 to 5 semaglutide treatment effect in people with obesity program.

Aastha Khanna, Vipin Kumar, Sahil Gola

Obesity and type 2 diabetes mellitus (T2DM) are widespread health concerns that often coexist, contributing to increased cardiometabolic risks and premature death. Despite advancements in both lifestyle interventions and medical treatments, achieving lasting weight reduction and stable glycemic control remains a major clinical challenge. This review examines findings from the semaglutide treatment effect in people with obesity 1 (STEP) 1-5 trials, which assessed the effectiveness, safety, and long-term outcomes of once-weekly semaglutide 2.4 mg for weight management in adults. These trials included individuals with and without T2DM, enabling comparison across different populations and interventions. In nondiabetic participants (STEP 1, 3, and 4), semaglutide led to average weight reductions between 10% and 17%, while in patients with T2DM (STEP 2), the reduction was around 10%. The inclusion of intensive behavioral therapy in STEP 3 further enhanced weight loss outcomes. Results from STEP 4 highlighted notable weight regain following treatment withdrawal, reflecting the relapsing nature of obesity. STEP 5 confirmed semaglutide's ability to maintain significant weight loss (~15%) and improve metabolic health over a 2-year period. The most common side effects were gastrointestinal in nature but were generally manageable and nonsevere. Collectively, these trials support semaglutide 2.4 mg as an effective and sustainable option for managing obesity and overweight, including in people with T2DM. The data also emphasize the importance of combining pharmacological therapy with lifestyle modifications and recognize obesity as a long-term condition that necessitates continuous treatment.

Cardiometabolic and Renal Outcomes in Semaglutide Users with Type 2 Diabetes Achieving Glycemic and Weight Goals: An Observational Cohort Study.

Xi Tan, Wan-Lun Tsai, Yuanjie Liang +4 more

Within the cardiovascular-kidney-metabolic syndrome (CKM) framework, semaglutide has demonstrated benefits beyond glycemic control and weight loss in clinical trials. However, most real-world studies in type 2 diabetes (T2D) have limited assessment of broader cardiometabolic and renal outcomes. We evaluated CKM-relevant outcomes among individuals with T2D who achieved substantial hemoglobin A1c (HbA1c) and weight improvements after initiating semaglutide in real-world settings.

Assessment of Carbon Emission Impact of Semaglutide in Patients with Type 2 Diabetes in the United Kingdom using an Innovative Modelling Approach.

Niels Lund, Andreas Rasche, Matthew Taylor +5 more

To evaluate the carbon footprint and clinical outcomes of once-weekly subcutaneous semaglutide in patients with type 2 diabetes mellitus (T2DM) in the United Kingdom.

Euthyroid Sick Syndrome Precipitated By Rapid Weight Loss Following Semaglutide Initiation: A Case Report.

Ziad W Elmezayen, Farah Qrareya, Abdallah Abdallah +2 more

Euthyroid sick syndrome (ESS) is characterized by abnormal thyroid function tests, most notably a low triiodothyronine (T3) level, occurring in the absence of intrinsic thyroid disease. A 54-year-old woman presented to the endocrinology clinic with a 4-month history of progressive fatigue, lethargy, and new-onset cold intolerance after initiation of semaglutide for weight management. The dose was titrated monthly over 4 months, during which she experienced significant weight loss of 22 kg. Laboratory evaluation revealed a thyroid function profile classic for ESS, with low free T3, low-normal free T4, and a normal thyroid-stimulating hormone (TSH) level that was inappropriately low relative to the reduced T3. After exclusion of primary thyroid and pituitary disorders, a diagnosis of ESS secondary to the catabolic state induced by rapid weight loss was made. The patient was counseled that this represented a physiological adaptation rather than intrinsic thyroid disease. Semaglutide was continued given its metabolic benefits, and nutritional optimization with adequate caloric and protein intake was advised.

GLP-1R-GIPR-PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice.

Daniela Liskiewicz, Aaron Novikoff, Ahmed Khalil +50 more

There are increasing numbers of effective drugs to improve obesity-linked metabolic dysfunction; GLP-1R-GIPR co-agonism is effective in the management of obesity and type 2 diabetes1,2, and lanifibranor-a nuclear-acting small-molecule triple agonist of PPARα, PPARγ and PPARδ-is in clinical phase 3 trials for the treatment of metabolic dysfunction-associated steatohepatitis3. Here, seeking to further improve the metabolic efficacy of GLP-1R-GIPR co-agonism, we report the development of a unimolecular quintuple agonist that combines the body weight-reducing and blood glucose-lowering effects of GLP-1R-GIPR co-agonism with the insulin-sensitizing and anti-inflammatory effects of lanifibranor via its targeted delivery into GLP-1R- and GIPR-expressing cells. In vitro, GLP-1-GIP-lanifibranor is indistinguishable from GLP-1-GIP in relation to incretin receptor signalling and shows equal stimulation of insulin secretion in isolated mouse islets. In vivo, however, GLP-1-GIP-lanifibranor outperforms GLP-1R-GIPR co-agonism and semaglutide, further decreasing body weight, food intake and hyperglycaemia in obese and insulin-resistant mice through synergistic incretin and PPAR action. The metabolic action of GLP-1-GIP-lanifibranor is blunted in mice with genetic or pharmacological inhibition of GLP-1R, GIPR or PPARδ and is absent in DIO double incretin receptor-knockout mice, collectively suggesting that GLP-1-GIP-lanifibranor has substantial therapeutic value in the treatment of obesity and diabetes.

Semaglutide 2.4 mg Cardiometabolic Long-Term Effects in Patients With Obesity or Overweight in a Real-World Setting: A Retrospective Cohort Study in the United States (SMILE).

Aleksandrina Ruseva, Wojciech Michalak, Matthew Bassan +9 more

To evaluate the real-world associations between semaglutide 2.4 mg and cardiometabolic comorbidities, biomarkers and cardiovascular risk among adults with overweight or obesity.

Efficacy and safety of semaglutide injection in Indian patients with type 2 diabetes mellitus inadequately controlled on metformin: a phase 3, randomized, active-controlled trial (SIZE-DM study).

Nitin Kapoor, Shehla Shaikh, Saptarshi Bhattacharya +26 more

This study evaluated the efficacy and safety of generic semaglutide compared with innovator Semaglutide in Indian adults with type 2 diabetes mellitus (T2DM).

Efficacy, Safety and PK of Once-Daily Oral Semaglutide 25 mg for Obesity With and Without Type 2 Diabetes in Comparison With Subcutaneous Semaglutide 2.4 mg: A Model-Informed Drug Development Approach.

Rune Viig Overgaard, Oscar Birkhan, Naveen Rathor +4 more

Semaglutide has previously been approved for weight management and cardiovascular disease as a subcutaneous formulation, and more recently also as an oral formulation. However, there is limited information across oral dose levels, and there are no studies for the 25 mg dose in people with obesity and type 2 diabetes (T2D). To fulfil health authority approval requirements, population pharmacokinetic and exposure-response analyses were used to extrapolate efficacy and safety data from subcutaneous to oral semaglutide.

Liver benefits of early initiation of low-dose GLP-1 receptor agonists in newly diagnosed type 2 diabetes - A case report.

Joyce Y Lee, Huy Nguyen, Tan Nguyen

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to exert favorable effects on hepatic biomarkers and liver-related conditions, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. However, the optimal dosage and duration of GLP-1RA therapy necessary to achieve these extrapancreatic hepatic benefits remain unclear. In this case report, we presented a 28-year-old White Hispanic female with Class I obesity and newly diagnosed type 2 diabetes who demonstrated a marked and rapid normalization of persistently elevated alanine aminotransferase levels following the initiation of subcutaneous semaglutide therapy. This case report highlighted the potential for immediate hepatic improvement with GLP-1RA treatment, exceeding commonly anticipated clinical outcomes in primary care.

Semaglutide-Associated Acute Pancreatitis in a Patient With Type 2 Diabetes Mellitus: A Case Report.

Piyush Puri, Michael Akhavan, Jonathan Shadan +2 more

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist widely prescribed for type 2 diabetes mellitus and obesity, is generally well tolerated but can be associated with gastrointestinal adverse effects and, rarely, pancreatitis. As its use grows, clinicians must remain aware of potential complications, particularly in patients with additional risk factors. We report the case of a 57-year-old woman with diabetes, hypertension, and hyperlipidemia who presented with acute severe epigastric pain and persistent vomiting shortly after consuming a large, fatty meal. She had been receiving semaglutide for several months. Laboratory studies showed marked leukocytosis, hyperglycemia with an anion gap metabolic acidosis, and a lipase level exceeding 3000 U/L. CT imaging demonstrated acute interstitial edematous pancreatitis with peripancreatic fluid and early concern for necrosis. She was treated conservatively with aggressive intravenous hydration, bowel rest, electrolyte repletion, and analgesia. Her condition improved with supportive care, and she was discharged with close outpatient follow-up. This case highlights the importance of recognizing pancreatitis as a possible multifactorial complication in patients using GLP-1 receptor agonists. This case highlights the need for clinicians to maintain awareness of pancreatitis as a potential adverse effect in patients receiving semaglutide, especially those with additional risk factors such as biliary pathology or dietary triggers. As the use of GLP-1 receptor agonists continues to grow, careful assessment of abdominal symptoms and early recognition of pancreatic inflammation are essential for optimizing outcomes and guiding safe prescribing practices.

Is There a Causal Link Between GLP-1 Receptor Agonists and Non-Arteritic Anterior Ischaemic Optic Neuropathy? A Critique of the Clinical Evidence.

Helen V Danesh-Meyer, Joseph F Rizzo

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for managing Type 2 diabetes and obesity, with well-documented and significant cardiometabolic benefits. Recent observational reports and pharmacovigilance data have raised concerns about a possible association between GLP-1RAs-particularly semaglutide- and non-arteritic anterior ischaemic optic neuropathy (NAION), a rare cause of sudden vision loss. While case reports and spontaneous reporting systems suggest a potential signal, these sources are subject to confounding and reporting bias. Observational studies offer mixed findings, with some Scandinavian registry studies reporting elevated risks while large electronic health record EHR) analyses from the U.S. and multi-national databases have reported null or weak associations. Meta-analyses of randomised controlled trials- the gold standard for causal inference- currently lack power to reliably assess this rare outcome but suggest, at most, a comparatively moderate increase in risk (e.g., odds ratio of 2-3). Overall while a causal link cannot be excluded, the numerous studies that assert an 'association' between GLP-1 RA exposure and NAION should motivate larger pooled analyses of RCTs with adjudicated ocular outcome to definitely assess risk.

Evaluating the Efficacy, Safety, and Practical Considerations of Semaglutide for Weight Loss in Non-Diabetic Adults: A Narrative Review.

Ayesha Laraib, Uswa Ahmad, Syeda Iman Laraib +4 more

The rising global prevalence of obesity has catalyzed the development of potent glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review evaluates the efficacy, safety, and practical considerations of injectable semaglutide for weight management, specifically in non-diabetic adults, a population where weight loss outcomes often differ from those seen in diabetic cohorts.

Metabolic and Bariatric Surgery vs Glucagon-like peptide-1 Receptor Agonist Therapy: A Head-to-Head Comparison in Improvement of Cardiometabolic Risk Profiles.

Wissam Ghusn, Robert A Vierkant, Noura Jawhar +11 more

To compare 1-year changes in estimated 10-year and lifetime atherosclerotic cardiovascular disease (ASCVD) risk following metabolic and bariatric surgery (MBS) versus glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy among adults with obesity.

Associations of Semaglutide With Skeletal Outcomes in People With Obesity, With and Without Type 2 Diabetes: A Target Trial Emulation.

Yu-Nan Huang, Min-Yu Tsou, Pin-Hung Li +6 more

To evaluate the associations between semaglutide initiation and long-term skeletal outcomes in people with obesity, stratified by type 2 diabetes (T2D) status, using target trial emulation.

Efficacy and safety of co-administered cagrilintide and semaglutide versus semaglutide alone in adults with overweight or obesity with or without type 2 diabetes in Japan and Taiwan (REDEFINE 5): a multicentre, randomised, active-controlled, phase 3a trial.

Toshimasa Yamauchi, Niels-Peter Becker, Christoffer Andersen Hagemann +7 more

The combination of cagrilintide and semaglutide has been shown in global studies to induce reductions in bodyweight. We assessed the efficacy and safety of a fixed-dose combination of cagrilintide 2·4 mg and semaglutide 2·4 mg versus semaglutide 2·4 mg for weight management in an east Asian population.

Impact of GLP-1 RA plus progestin therapy on fertility-sparing management of endometrial intraepithelial neoplasia and endometrial cancer.

Tina Yi Jin Hsieh, Ting-Tai Yen, Michele R Hacker +2 more

We examined whether the addition of GLP-1RA to progestin therapy reduced the risk of hysterectomy in patients with endometrial intraepithelial neoplasia (EIN) and endometrial cancer (EC) in the U.S. managed with fertility-sparing management.

Leucine supplementation modulates body composition and early weight rebound during GLP-1 receptor agonist therapy in diet-induced obese mice.

Ze-Wei Zhao

GLP-1 receptor agonists (GLP-1RAs) like semaglutide are effective for obesity treatment but may cause lean mass loss and post-discontinuation weight rebound. This study aimed to explore whether leucine supplementation alone or combined with semaglutide optimizes body composition in diet-induced obese (DIO) mice.

Semaglutide Treatment in Young Adults Living With Type 2 Diabetes: A Post Hoc Analysis From the SUSTAIN and PIONEER Clinical Trials.

Francesco Zaccardi, Vanita R Aroda, Ecenur Guder Arslan +6 more

Young adults (aged ≤ 40 years) are underrepresented in clinical trials that investigate interventions for those living with Type 2 diabetes (T2D). This study evaluated the efficacy of semaglutide treatment in young adults with T2D by examining the effects on HbA1c and body weight (BW) during the SUSTAIN and PIONEER programmes compared to placebo and active comparators, according to age at study enrolment. This study also assessed aggregated safety data across age subgroups.

Hemodynamic Changes in Response to GLP-1 Treatment in ICD and CRT Patients: Insights From HeartLogic Sensor Data.

Frederik Holme Fussing, Lise Witten Davodian, Danny Witten Davodian +24 more

Glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy is increasingly used, but the physiological effects in patients with heart failure and reduced ejection fraction (HFrEF) remain uncertain. Continuously collected data from implantable cardiac devices may enable evaluation of drug effects in a real-world setting.

Complex clinical encounter series: Glucagon-like peptide-1 receptor agonists-induced weight loss: are we paying attention to bone health?

Elena Ambrogini

A sixty-five-year-old white woman with obesity class II, hypertension, hyperlipidemia, obstructive sleep apnea, osteoarthritis, and pre-diabetes was started on subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), for weight loss. Her DXA BMD 3 months prior to the initiation of semaglutide showed osteopenia. She did not have personal or family history of fractures. She had gone into menopause at the age of 52 with no other risk factors for osteoporosis. She maintains an adequate intake of calcium and cholecalciferol and she is active but does not exercise regularly. After 1 year on semaglutide, she lost ~15 % of her weight with improvement of blood pressure, lipid profile, and sleeping pattern. She reports two recent falls. The initial recommendation was to repeat DXA in two-three years. However, recent evidence suggests that in elderly patients experiencing ~ 9% weight loss with semaglutide, monitoring bone remodeling markers and BMD after 1 year of treatment is justified. Counseling on adequate protein intake and strengthening exercise to preserve muscle mass should also be provided.

A Multicentre, Prospective, Non-Interventional Single-Arm Study Investigating the Impact of Once-Daily Oral Semaglutide in a Real-World Adult Population With Type 2 Diabetes in Mexico.

Guillermo González-Gálvez, Juan C Garnica-Cuellar, Miguel Ángel Colín-García +5 more

To investigate the oral semaglutide use among Mexican adults with type 2 diabetes.

Widespread exposure to GLP-1RAs and weight loss-related discourse: Considering potential public health implications.

Marilou Côté, Ximena Ramos Salas, Kimberly Carrière +1 more

Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), are approved for the treatment of type 2 diabetes, obesity, and related conditions, and have demonstrated significant benefits for individuals with these conditions. However, in recent years, public interest and demand for GLP-1RAs-often driven by media, social media influencers, advertising, and public discourse-have increased beyond the populations for whom these medications are medically indicated. The ripple effects of widespread public exposure to GLP-1RAs and weight-loss-related discourse on public health have received very little research attention and remain poorly understood. This widespread exposure may contribute to a perception that GLP-1RAs are intended as weight loss solutions for non-medical use, rather than an effective treatment for specific chronic conditions like obesity. Such perceptions could influence demand and affect equitable access for people with medical indications for these medications. Widespread exposure to discourse that highlights GLP-1RAs as weight loss solutions may inadvertently reinforce social desirability for thinness and body image concerns. Despite the established clinical efficacy of GLP-1RAs for medically indicated conditions, this commentary highlights the potential public health risks associated with their growing portrayal as weight loss solutions for non-medical use in the public sphere and calls for research to better understand these broader implications to inform balanced public health communication strategies.

The weight-loss-independent hepatoprotective benefits of semaglutide are orchestrated by intrahepatic sinusoidal endothelial GLP-1 receptors.

Maria J Gonzalez-Rellan, Cristina Riobello, Susanna Fang +7 more

Glucagon-like peptide-1 (GLP-1) medicines improve metabolic liver disease through weight-loss-dependent and -independent actions. Here, we interrogated semaglutide's action in mice with metabolic dysfunction-associated steatohepatitis (MASH). In Glp1rWnt1-/- mice resistant to GLP-1RA-induced weight loss, semaglutide improved steatosis, fibrosis, and immune remodeling. GEM-X Flex-seq localized Glp1r expression to pericentral liver sinusoidal endothelial cells (ECs) (LSECs) and CD8+ T cells. EC Glp1r deletion in Glp1rTie2-/- mice or AAV8-Cre-mediated hepatic EC Glp1r knockdown substantially abrogated semaglutide's hepatic benefits despite preserved weight loss. Transcriptomic profiling revealed that Glp1r+ LSECs adopt a stress-responsive phenotype in MASH that is reversed by semaglutide. Glp1r+ LSECs function as dominant contributors to semaglutide-regulated circuits linked to injury and repair involving VWF, SELE, CEACAM, and BMP. Molecular profiling revealed semaglutide-coordinated transcriptional and protein-level reversal of disease signatures. Together, the data using mouse models of MASH reveal an EC-specific, weight-loss-independent, semaglutide-regulated, GLP-1R-dependent intrahepatic network for improving liver health.

GLP-1 Receptor Agonist Semaglutide and SGLT2 Inhibitors after Acute Coronary Syndrome in Patients with Diabetes: Real-World Comparative Outcomes from an Observational Registry.

Ivana Jurin, Karlo Gjuras, Dijana Bešić +9 more

Patients with type 2 diabetes (T2D) remain at high cardiovascular risk after acute coronary syndrome (ACS), particularly after myocardial infarction (MI). Evidence on the early post-ACS use of glucagon-like peptide-1 receptor agonists (GLP-1RA), particularly semaglutide, and sodium-glucose cotransporter-2 inhibitors (SGLT2i) is limited.

Real-world use of semaglutide in patients with type 2 diabetes and end-stage renal disease: a multicenter retrospective cohort study.

Omar Alkhezi, Lama Alfehaid, Amal Alanezi +2 more

Semaglutide and other Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular and renal benefits in patients with type 2 diabetes mellitus (T2DM); however, individuals with end-stage renal disease (ESRD) have been systematically excluded from landmark outcome trials. Consequently, real-world data evaluating the safety and effectiveness of GLP-1 RAs in this high-risk population remain limited.

SemaGBA: A System Dynamics Model of the Semaglutide-Responsive Gut-Brain Axis A Model of How the Brain and Semaglutide Regulate Appetite and Weight.

Vivan C W Kennis, Natal A W van Riel

Semaglutide is a GLP-1 receptor agonist for the treatment of type 2 diabetes and obesity. Its clinical effects are well established, but the underlying mechanisms remain unclear. This study aims to use computational modelling to generate hypotheses about semaglutide's long-term metabolic (body weight, net energy intake, blood glucose, insulin, insulin sensitivity, glucotoxicity, leptin, leptin sensitivity, lipotoxicity, GLP-1 and βcell function) and neural (AgRP, POMC, and dopamine neural activity) effects.

Association of Semaglutide Treatment With Liver Cirrhosis and Hepatocellular Carcinoma in Type 2 Diabetes: A Population-Based Cohort Study.

Assaf Issachar, Talish Razi, Ilya Borochov +2 more

Metabolic dysfunction-associated steatotic liver disease is common among individuals with type 2 diabetes mellitus and substantially increases the risk of liver cirrhosis and hepatocellular carcinoma. Effective therapies that improve metabolic control while preventing advanced liver outcomes are limited.

Differential Impact of Metabolic Bariatric Surgery Versus Semaglutide on Adverse Hepatic and Extrahepatic Outcomes in Individuals With Metabolic Dysfunction-Associated Steatotic Liver Disease and Type 2 Diabetes.

Weronika Stupalkowska, Alex E Henney, David R Riley +3 more

We compared the impact of metabolic bariatric surgery (MBS) versus semaglutide on clinical outcomes in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D).

Geriatric Pharmacotherapy Case Series: GLP-1 RA for Weight Management in Older Adults.

Lauren Toma, Kelsey Buckley, Nicole Early

Background: This case study reviews the use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) for weight management in older adults. A 69-year-old male patient discusses weight loss goals with his health care provider and seeks pharmacotherapy options in addition to lifestyle modifications. His medical history includes type 2 diabetes mellitus (T2D), coronary artery disease (CAD), prior coronary artery bypass graft, heart failure with reduced ejection fraction (HFrEF), hypertension, hyperlipidemia, and allergic rhinitis. He initiated weight loss efforts following a myocardial infarction; however, dietary and physical activity changes alone have not resulted in substantial weight reduction. Assessment: This patient is an appropriate candidate for GLP-1 RA therapy given his T2D, obesity, CAD, and a recent elevation in serum creatinine (SCr). The patient will initiate semaglutide, a medication approved for weight management with demonstrated cardiovascular benefit. The dose will be titrated to a maintenance dose of 2 mg once weekly, with ongoing monitoring of tolerability and weight loss.Given his age, there is concern for sarcopenia associated with excessive weight loss. The patient will be advised to maintain a balanced diet with an emphasis on protein intake and to engage in regular physical activity to minimize loss of muscle mass. Outcome: The patient experiences weight reduction within the first few weeks of therapy and tolerates treatment well. He has incorporated additional strength training into his exercise routine and increased his intake of vegetables and protein. The patient has insurance coverage for semaglutide due to his comorbid T2D; therefore, medication cost is not a barrier to treatment. Conclusion: When evaluating the use of GLP-1 RA agents in older adults, these agents demonstrate benefits beyond glycemic control and weight loss, including cardiovascular and renal outcomes. However, GLP-1 RA-associated weight loss may contribute to muscle loss, which is of particular concern in older adults who are at risk for frailty or falls. Patients receiving GLP-1 RA therapy should be encouraged to maintain adequate protein intake and engage in regular physical activity, particularly resistance training, to preserve muscle mass. Additionally, the high cost of GLP-1 RA agents may limit access for patients without insurance.

Oral Health Considerations and Dental Management Guidelines for Semaglutide Medications.

Karina Kofman, Aviv Ouanounou

Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated clinically meaningful weight loss effects in patients with Type 2 diabetes and high BMI, and dental practitioners and physicians are often encountering patients who take these medications. Semaglutide is known to be associated with several systemic side effects, including delayed gastric emptying, belching, reflux and nausea, nutritional changes, and gastrointestinal discomfort. Systemic effects secondarily manifest in the oral cavity, and as a result, patients taking semaglutide may present with xerostomia (dry mouth), halitosis (bad breath), enamel erosion tied to vomiting, altered taste, among other oral signs and symptoms. It is important for dental professionals and physicians to become informed of possible symptoms and corresponding management strategies, given the multiple potential indirect effects on the oral cavity and relevance to dental treatment planning. This article reviews the pharmacodynamics of semaglutide and dives into the current evidence on oral manifestations of the drug family and implications for dental and oral health. It outlines practical management recommendations for dentists and the broader interdisciplinary healthcare team.

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.