Semaglutide

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.