While glucagon-like peptides 1 receptor agonists (GLP-1RAs) grow in popularity, their potential for presurgical weight optimization in spine surgery remains unclear. We examined the influence of semaglutide prescription on one- to three-level transforaminal lumbar interbody fusion (TLIF) outcomes.

Retrospective analysis of obese, non-diabetic patients was conducted from 2018 to 2022. A 1:1 exact match paired semaglutide users with non-users based on age, gender, surgical levels, and comorbidities. The primary outcome were the rates of surgical and medical complications at 30 days following TLIF. A sub analysis assessed outcomes after stratifying by prescription duration (greater or less than nine months). Kaplan-Meier survival analyses evaluated the need for additional lumbar fusion. The alpha was set to 0.05, but with the Bonferroni correction the significance threshold was set to 0.0045.

471 semaglutide users were matched with 471 non-users with no baseline differences. Semaglutide users had higher rates of pneumonia (2.97 % vs 0.85 %, p < 0.05) compared to nonusers. When stratified by prescription duration, patients with longer semaglutide use had a higher incidence of urinary tract infection (4.03 % vs 1.27 %, p < 0.05) and acute kidney injury (3.18 % vs 0.85 %, p < 0.05). The need for additional lumbar fusion was associated with both semaglutide use (17.0 % vs. 6.4 %, p < 0.0001) and duration (28.3 % vs. 4.8 %, p < 0.0001).

Semaglutide may adversely affect lumbar fusion outcomes and necessitate additional surgery, possibly secondary to its systemic effects on bone metabolism and weight loss patterns. Further research into optimal drug formulation, dosage, and weight loss protocols will be required before mainstream use.

The association between GLP-1 receptor agonists (GLP-1RA) and nonarteritic anterior ischemic optic neuropathy (NAION) remains unclear. Given the debilitating sequelae of NAION and rapid increase of GLP-1RA use, further research is essential to investigate this potential relationship. This study seeks to determine the risk of NAION and ischemic optic neuropathy (ION) in patients prescribed GLP-1RAs.

Retrospective matched cohort study.

TriNetX United States collaborative network.

Patients ≥12 years old with type 2 diabetes (T2DM) and considered overweight or obese (high BMI), with at least one ophthalmology or neurology visit. Among T2DM patients, approximately 120,000 patients with a semaglutide prescription and 220,000 prescribed any GLP-1RA were compared to matched T2DM controls. Among high BMI patients, approximately 58,000 on semaglutide and 66,000 on any GLP-1RA were compared to matched controls.

Patients prescribed semaglutide or any GLP-1RA were compared with those on non-GLP-1RA medications. Populations were propensity matched (1:1) on various demographic and risk factors to balance baseline cohorts.

Cumulative incidence and risk of NAION and ION. Risk ratios (RR) with 95% confidence intervals (CI) were reported, with significance defined as CI <0.9 or > 1.1.

In T2DM patients prescribed semaglutide, the risk of NAION (RR = 0.7, 95% CI: 0.523-0.937) and ION (RR = 0.788, 95% CI: 0.609-1.102) after 5 years was not significantly increased compared to matched T2DM controls. Similarly, T2DM patients on any GLP-1RA demonstrated no significant difference in the risk of NAION (RR = 0.887, 95% CI: 0.735-1.071) or ION (RR = 0.969, 95% CI: 0.813-1.154) compared to controls. Furthermore, no increased risk of either outcome was found in the high BMI groups prescribed semaglutide or any GLP-1RA. The cumulative 5-year risk of NAION and ION in T2DM patients on semaglutide was 0.065% and 0.08%, respectively. In those with high BMI prescribed semaglutide, the risk of NAION and ION after 2 years was 0.038% and 0.404%, respectively.

There was no significant increase in risk of NAION or ION in patients taking semaglutide or GLP-1RAs compared to T2DM or high BMI controls.

The vagus nerve, as an important component of the gut-brain axis, plays a crucial role in the communication between the gut and brain. It influences food intake, fat metabolism, and emotion by regulating the gut-brain axis, which is closely associated with the development of gastrointestinal, psychiatric, and metabolism-related disorders. In recent years, significant progress has been made in understanding the vagus-mediated regulatory pathway, highlighting its profound implications in the development of many diseases. Here, we summarize the latest advancements in vagus-mediated gut-brain pathways and the novel interventions targeting the vagus nerve. This will provide valuable insights for future research on treatment of obesity and gastrointestinal and depressive disorders based on vagus nerve stimulation.

Obesity is considered a chronic disease and is influenced by biological, environmental, and behavioral factors that can contribute to its progression. Although lifestyle changes are integral to treating obesity and maintaining a healthful weight, weight reduction from behavioral intervention alone is often insufficient because neurophysiologic factors may work against such changes in lifestyle and behavior. Research suggests that the mechanisms underlying food cravings and obesity overlap with dopaminergic signaling in the brain and pathways involved in addiction. As a result, patients who are differentially impacted by food cravings may have better outcomes with treatments targeting neural systems implicated in both homeostatic and hedonic food consumption or addictive behaviors.

In this clinical review, we describe the safety and efficacy data for the fixed-dose, extended-release combination of naltrexone and bupropion (NB-ER) compared with its monotherapy constituents (naltrexone and bupropion), as well as discuss the appropriate use of NB-ER to treat patients with obesity.

NB-ER is approved for the treatment of patients with obesity, with studies showing that patients can achieve significant weight reduction compared with placebo when treatment is combined with a reduced-calorie diet and increased physical activity. Across NB-ER phase 3 trials, responders to treatment had a mean body weight reduction of 11.7 % at 56 weeks. Of note, the unique combination of naltrexone, an opioid receptor antagonist, and bupropion, a norepinephrine-dopamine reuptake inhibitor associated with stimulating pro-opiomelanocortin cells (POMC), in NB-ER may work together to target POMC cells to prevent endogenous negative feedback, thereby decreasing appetite and improving weight-related outcomes.

Unlike monotherapy with its component drugs, NB-ER is optimized for the treatment of obesity. The appropriate use of NB-ER should consider the specific characteristics and adiposity-related complications of an individual.

Obesity is a pandemic problem that correlates with a cluster of metabolic factors leading to poor cardiovascular outcomes, morbidity, and an increased risk of overall mortality. It is necessary to approach obesity with a comprehensive treatment plan, which may involve lifestyle modifications (diet, exercise, and behavioral therapy) and pharmacological interventions. This article provides an overview of the mechanisms of action, efficacy, and safety of available long-term anti-obesity drugs and introduces other potential agents under investigation.

Metabolic syndrome (MetS) is defined by the presence of at least three of five clinical parameters including abdominal obesity, insulin resistance, elevated triglycerides, reduced high-density lipoprotein (HDL) and hypertension. Major features describing MetS have been recognized risk factors for cancer onset, with an alarming impact on gastrointestinal (GI) tumors. Intriguingly, therapeutic administration of drugs to improve glycemic control and dyslipidemia (including metformin, statins) has been shown to have a preventive role in the development and in prognosis improvement of several cancer types. Overall, these observations highlight the key role of altered metabolism prevalently in cancer risk development and unveil anti-MetS agent repurposing potential beyond their conventional pharmacological action. The objective of this review is to summarize the current knowledge about the antitumor activity of anti-diabetic and anti-lipemic agents in GI cancer onset and progression. Here, pre-clinical evidence of their therapeutic potential and of their integration in novel compelling therapeutic strategies will be discussed. Possible clinical outcomes of these novel therapeutic combined protocols specifically dedicated to GI cancer patients will be put under the spotlight. In the future, these novel therapeutic options should be considered to improve conventional chemotherapy response and prognosis of this group of patients.

Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.

Single molecules that combine complementary modes of action with glucagon-like peptide-1 receptor (GLP-1R) agonism are best-in-class therapeutics for obesity treatment. NN1706 (MAR423, RO6883746) is a fatty-acylated tri-agonist designed for balanced activity at GLP-1R and glucose-dependent insulinotropic peptide receptor (GIPR) with lower relative potency at the glucagon receptor (GcgR). Obese mice, rats and non-human primates dosed with NN1706 showed significant body weight reductions and improved glycemic control. In human participants with overweight or obesity, daily subcutaneous NN1706 treatment resulted in substantial body weight loss in a dose-dependent manner without impairing glycemic control (NCT03095807, NCT03661879). However, increased heart rate was observed across NN1706 treatment cohorts, which challenges further clinical development of NN1706.

Stroke is a leading cause of disability and mortality worldwide. It has been estimated that more than 90% of the risk of stroke is associated with modifiable factors, including diabetes, hypertension, obesity, and heart disease. Glucagon-like peptide 1 receptor agonists (GLP1RAs) have been shown to have a beneficial effect on these major risk factors. In this review, we discuss the evidence supporting the use of GLP1RAs on brain health, particularly in relation to stroke prevention.

The results of multiple randomized clinical trials demonstrate that, among patients with type 2 diabetes, GLP1RAs reduce body weight and improve glucose levels and lipid metabolism. In high-risk populations, GLP1RAs also reduce the risk of major adverse cardiovascular events, including all stroke and non-fatal stroke. Mechanistically, GLP1RAs have a beneficial effect on different stroke risk factors, support microvascular function, and reduce inflammation and oxidative stress. GLP1RAs are recommended for the primary prevention of stroke in patients with diabetes and elevated cardiovascular risk.

Objective: Available data comparing the efficacy of liraglutide and semaglutide in managing weight loss is limited. The objective of this study was to compare efficacy of both drugs on weight loss. Methods: A retrospective observational cohort study conducted at our quaternary care hospital from June 2018 to July 2022. The study included adults who received either liraglutide or semaglutide during the study period. The primary outcome was weight loss, while secondary outcomes included effects on HbA1c levels and lipid profile. Results: A total of 366 patients were analyzed (122 on liraglutide, 244 on semaglutide). The groups were comparable in mean age (51.00 ± 11.55 vs 51.16 ± 12.35 years, P = 0.521) and baseline mean weight (94.7 ± 19.5 vs 94.6 ± 19.9 kg, P = 0.989). After a median follow-up of 10 (6-17) months for the liraglutide group and 7.5 (6-11) months for the semaglutide group (P < 0.001), the resultant weights were 90.8 ± 19.6 kg for the liraglutide group and 91.1 ± 19.8 kg for the semaglutide group (P < 0.001) when comparing each group to its baseline separately. When comparing the weight loss achieved in each group, liraglutide achieved a median weight loss of -4 (-7 to 0) kg versus -3 (-6 to 0) kg for semaglutide (P = 0.867). The reduction in HbA1c levels with liraglutide was significantly less than with semaglutide: -0.2 (-0.5 to 0.3) versus -0.5 (-1.1 to 0.1), respectively, (P = 0.003). Both drugs significantly lowered LDL and triglycerides. Multivariable linear regression analysis confirmed no significant difference between the drugs [B -0.577, 95% CI -1.87 to 0.7; P = 0.38], while baseline weight, diabetes, and SGLT2 inhibitors were significant factors affecting weight. Conclusion: Both liraglutide and semaglutide were effective in reducing weight, with no significant difference between the two drugs. However, semaglutide was more effective in reducing HbA1c levels.

The obesity epidemic is a major public health problem nowadays. The pathophysiology of obesity, which underlies its chronic, progressive, self-sustaining course, determines the difficulties in developing effective and safe methods for body weight control. The article is dedicated to the consideration of the evolution of conservative treatment of obesity, in particular, the history of pharmacotherapy of this disease, characterized by many ups and downs, is presented. The paper discusses, in chronological order, the emergence, efficacy, mechanisms of action, and described side effects of drugs that were investigated and used for weight loss at one time or another, as well as the reasons why many of them were subsequently withdrawn from the market. Until recently, long-term effective and safe pharmacotherapy of obesity remained an insurmountable challenge. Only in the last two decades has the understanding of the molecular mechanisms of appetite control reached a level that allows for a more productive search and development of promising drugs aimed at the pathogenetic treatment of obesity. This article discusses the status of currently available drugs for weight loss, as well as the prospects for drug treatment of obesity. The results of clinical trials of advanced therapeutic molecules, including gastrointestinal hormone receptor agonists, reinforce the belief that a breakthrough in the drug treatment of obesity is possible.

Childhood obesity is a major public health concern, associated with early-onset comorbidities and a high likelihood of persisting into adulthood. Anti-obesity medications (AOMs) may serve as an adjunct to lifestyle modifications for managing pediatric obesity.

To evaluate prescribing patterns, weight outcomes, and cardiometabolic impacts of AOMs among children and adolescents aged 10-18 years within Clalit Health Services (CHS), the largest health maintenance organization in Israel.

This retrospective observational study analyzed data from CHS's electronic database (2017-2024). The study cohort included 307 208 children with BMI measurements exceeding World Health Organization (WHO)-defined thresholds for overweight or obesity. Among these, 2236 (0.7%) were prescribed AOMs (metformin, GLP-1 receptor agonist, or orlistat). A secondary analysis assessed longitudinal changes in BMI z-scores and cardiometabolic parameters among individuals who purchased at list two prescriptions of AOMs.

AOMs prescriptions were more common among females, younger patients, those with higher BMI z-scores, and medium-to-high socioeconomic position (SEP) levels. Children prescribed AOMs exhibited a higher prevalence of obesity-related comorbidities and greater engagement with dietitians and endocrine specialists. Metformin was the most commonly prescribed medication (73.8%), followed by GLP-1 receptor agonist (24.5%) and orlistat (1.7%). Females demonstrated higher rates of medication adherence and longer treatment durations than males. Among the 1717 participants with ≥2 AOMs purchases, BMI z-scores significantly declined during treatment, accompanied by reductions in blood glucose, HbA1c, triglycerides, and total cholesterol, and increases in HDL cholesterol. BMI z-scores and cardiometabolic parameters partially regressed after treatment cessation but remained improved compared to baseline.

AOMs demonstrate potential for weight management and cardiometabolic improvement in children with obesity, particularly among those with severe obesity and comorbidities, within real-world settings. However, the modest utilization rate highlights the need for improved accessibility and further real-world evidence to optimize treatment strategies for pediatric obesity.

Most forms of obesity are associated with chronic diseases that remain a global public health challenge.

Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation.

This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood.

The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies.

The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity.

This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.

The global rise in obesity and type 2 diabetes mellitus (T2DM) presents significant challenges in musculoskeletal care, contributing to increased perioperative complications, impaired bone health, and compromised muscle function. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for glycemic control in T2DM, have demonstrated substantial benefits in weight reduction and metabolic regulation. The purpose of this review is to understand the musculoskeletal biologic and clinical implications of GLP-1RAs.

Evidence suggests that GLP-1RAs may impact musculoskeletal health through anti-inflammatory effects, bone metabolism modulation, and alterations in muscle composition. GLP-1RAs may promote osteoblastogenesis while dampening osteoclast activity to maintain bone mineral density. The result on fracture risk is unclear. Additionally, while GLP-1RAs cause lean mass loss, GLP-1RAs appear to preserve skeletal muscle, reduce fatty infiltration, and enhance fiber formation and function. Further, GLP-1Rs are present in synovial tissue and cartilage, demonstrating downregulation of inflammatory molecules and chondrocyte apoptotic pathways, though clinical studies show variable effects in the setting of osteoarthritis. Overall, the heterogeneity in findings underscores the need for further research to delineate the long-term musculoskeletal effects of GLP-1RAs. Understanding the musculoskeletal impact of GLP-1RAs is critical for optimizing their integration into orthopedic practice. This review explores the orthopedic implications of GLP-1RAs, highlighting their biologic mechanisms and clinical effects on obesity-related joint inflammation and arthropathy, bone mineral density and fracture risk, and skeletal muscle preservation.

Obesity is associated with an increased cardiovascular risk. Drugs with glucagon-like peptide-1 receptor agonist (arGLP-1) action for overweight/obesity, such as liraglutide, semaglutide, and tirzepatide, have shown improvements in weight and body composition, as well as in parameters related to glucose metabolism, hypertension, dyslipidemia (reduction of triglycerides and increase in HDL cholesterol), and metabolic dysfunction-associated steatotic liver disease. Additionally, semaglutide 2.4mg sc has shown a reduction in cardiovascular mortality, non-fatal myocardial infarction or stroke, and symptoms of heart failure, while tirzepatide has demonstrated a reduction in cardiovascular mortality and heart failure symptoms in patients with obesity and heart failure. The availability of these new drugs with arGLP-1 action represents a paradigm shift in the treatment of obesity, as they achieve greater weight loss and improvements in cardiometabolic comorbidities.

Overweight and obese breast cancer (BC) survivors face higher risks of recurrence and all-cause mortality, including from cardiovascular disease (CVD). Weight management therapy (WMT) may reduce cardiovascular events (CVE). We assessed trends in WMT in BC survivors and evaluated rates of CVE.

We conducted a retrospective cohort study using the MarketScan Database, including overweight and obese patients (18-95 years) with invasive BC (2009 -2021), who underwent breast surgery. Exclusions were prior bariatric surgery or secondary cancers. Patients were categorized by weight status and by WMT, including nutrition counseling, medications, and bariatric surgery. We utilized descriptive statistics, univariate analysis for factors associated with WMT receipt and rates of CVE, and a multivariable logistic regression model to determine WMT-associated factors.

We identified 35,206 patients: 18.8% overweight, 53.7% obese class I/II/unspecified, and 27.4% obese class III. WMT was utilized by 5.3%, 6.4%, and 9.6%, respectively (p < 0.001). Among 2,484 patients who received WMT, 72.7% had nutrition counseling, 26.7% received weight loss medication, and 4.9% underwent bariatric surgery. From 2009 to 2021, WMT use increased from 3.7% to 11.3% (p < 0.001), and use of weight loss medication increased from 0.3% to 5.1% (p < 0.001). Factors associated with receipt of WMT included younger age, greater degree of obesity, more recent year of surgery, lumpectomy, higher comorbidity score, and prior WMT. CVE incidence was lower in WMT recipients (0.8% vs.1.3%, p = 0.02).

In patients with BC, WMT has increased over time, and most markedly weight loss medication use. WMT is associated with lower incidence of CVE.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily managed through diet and lifestyle modifications. However, these behavioural interventions alone may not achieve disease regression or remission, and maintaining long-term adherence is challenging. Incretin mimetics and other gastrointestinal hormones targeting the pleiotropic pathophysiological pathways underlying MASLD have now emerged as promising disease-modifying therapies.

This is a comprehensive review summarising the role of glucagon-like peptide-1 (GLP-1) receptor agonists and glucagon/glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor dual or triple agonists in the treatment of metabolic dysfunction-associated steatohepatitis (MASH).

Only clinical trials with endpoints assessed by liver histology were included for a robust evaluation of therapeutic efficacy.

Recent evidence from phase 2 clinical trials for MASH demonstrated that pharmacological agents based on GLP-1 receptor agonism are effective in improving disease activity. Additionally, tirzepatide and survodutide showed potential clinical benefits in reducing fibrosis. Other cardiometabolic benefits observed include weight loss and improvements in glycaemic control and lipid profile. Adherence to treatment may be limited by gastrointestinal side effects, though they were found to be generally mild to moderate in severity. An interim analysis of the semaglutide phase 3 trial confirmed its efficacy in improving steatohepatitis and demonstrated its potential to improve fibrosis.

GLP-1 receptor agonists, alone or in combination with GIP and/or glucagon receptor agonists, represent promising, effective pharmacotherapies for the treatment of MASLD/MASH. Larger and longer-duration clinical trials are needed to further evaluate the efficacy and safety of GIP receptor and glucagon receptor agonism.

Lifestyle interventions are the cornerstone of obesity treatment. However, insufficient long-term effects are observed in patients with genetic obesity disorders, as their hyperphagia remains untreated. Hence, patients with genetic obesity often require additional pharmacotherapy to effectively manage and treat their hyperphagia and obesity. Recent advancements in antiobesity pharmacotherapy have expanded the range of available antiobesity medications (AOM). This includes the targeted AOM setmelanotide, approved for specific genetic obesity disorders, as well as nontargeted AOMs such as naltrexone-bupropion and glucagon-like peptide-1 analogues. Targeted AOMs have demonstrated significant weight loss, reduced obesity-related comorbidities, and improved hyperphagia and quality of life in patients with specific genetic obesity disorders. Small observational studies have shown that similar benefits from nontargeted AOMs or off-label pharmacotherapies can be achieved in patients with specific genetic obesity disorders, compared to common multifactorial obesity. In the future, novel and innovative pharmacotherapeutical options, including combination therapies and possibly gene therapy, will emerge, offering promising effects on body weight, hyperphagia, and, most importantly, quality of life for patients with a variety of genetic obesity disorders.

To examine the evidence and continuing role of strategies for the primary prevention and treatment of obesity in the context of effective obesity pharmacotherapies, through a narrative review.

Global policies to improve nutritional labelling and reduce sugar-sweetened beverages consumption have been implemented worldwide (> 45 countries) with some success which varies by population and environment. Tailored behavioural interventions are effective and essential to reduce individual risk of progression from preclinical to clinical obesity. Pharmacotherapies are powerful treatment agents for clinical obesity but must consider nutritional and metabolic risks of use and discontinuation. The obesogenic environment continues to undermine individual agency to adopt healthier dietary and physical activity patterns. Population health informatics tools could inform tailored interventions based on real-time risk and contribute to obesity prevention and treatment. Efforts to rebalance investment towards obesity prevention must continue to improve population health and reduce healthcare burden.

Obesity and heart failure (HF) represent two growing pandemics. In the general population, obesity affects one in eight adults and is linked with an increased risk for HF. Obesity is even more common in patients with HF, where it complicates the diagnosis of HF and is linked with worse symptoms and impaired exercise capacity. Over the past few years, new evidence on the mechanisms linking obesity with HF has been reported, particularly in relation to HF with preserved ejection fraction. Novel therapies inducing weight loss appear to have favourable effects on health status and cardiovascular risk. Against the backdrop of this rapidly evolving evidence landscape, HF clinicians are increasingly required to tailor their preventive, diagnostic, and therapeutic approaches to HF in the presence of obesity. This scientific statement by the Heart Failure Association of the European Society of Cardiology provides an up-to-date summary on obesity in HF, covering key areas such as epidemiology, translational aspects, diagnostic challenges, therapeutic approaches, and trial design.

Limited data exist on the association of glucagon-like peptide 1 receptor agonists (GLP-1RAs) with the risk of venous thromboembolism. This meta-analysis aimed to investigate the association between GLP-1RAs and the risk of venous thromboembolism including deep vein thrombosis (DVT) and pulmonary embolism.

A systematic search of PubMed, Web of Science, EMBASE, and Cochrane library was conducted from inception until July 3, 2024, to identify randomized controlled trials comparing GLP-1RAs with placebo or other anti-iabetic drugs, with reported data on DVT and pulmonary embolism. The primary outcome was venous thromboembolism, and secondary outcomes included DVT and pulmonary embolism. Pooled odds ratios (ORs) were calculated using fixed-effects models with Mantel-Haenszel method and treatment arm continuity correction for zero-event trials. A total of 39 randomized controlled trials involving 70 499 participants were included. A nonsignificant upward trend in the risk of venous thromboembolism was observed among participants using GLP-1RAs (OR, 1.19 [95% CI, 0.94-1.50]). GLP-1RAs were significantly associated with an increased risk of DVT (OR, 1.64 [95% CI, 1.14-2.36]); risk difference 25 (5-52) more events per 10 000 person-years). Subgroup analyses revealed that increased risk of DVT was particularly prominent in randomized controlled trials with treatment duration >1.5 years (OR, 2.32 [95% CI, 1.49-3.60]) and in cardiovascular outcome trials (OR, 2.18 [95% CI, 1.36-3.49]). No significant association was observed between GLP-1RAs and risk of pulmonary embolism.

GLP-1RAs might increase the risk of DVT, especially for long-term use of GLP-1RAs. Clinicians should be aware of this potential risk when prescribing GLP-1RAs.

To assess the association of tirzepatide use with a 10-year predicted risk of type 2 diabetes (T2D) among Chinese participants with obesity or overweight from the SURMOUNT-CN trial.

In this post hoc analysis, the QDiabetes-2018 risk engine was used to calculate the 10-year predicted T2D risk at baseline, week 24 and week 52 among SURMOUNT-CN participants randomized to receive tirzepatide 10 mg, 15 mg or placebo. A mixed model for repeated measures was used to compare mean predicted risk changes from baseline to weeks 24 and 52 between tirzepatide and placebo. Subgroup analyses were conducted by baseline body weight mass index (BMI) status and baseline prediabetes status.

Demographic and baseline clinical characteristics were similar among tirzepatide10 mg (n = 59), 15 mg (n = 53) and placebo (n = 57). From baseline to week 52, the least square (LS) mean predicted T2D risk changed from 5.3% to 1.2% for tirzepatide 10 mg, from 4.9% to 1.0% for tirzepatide 15 mg and from 5.8% to 4.5% for placebo. The difference in LS mean risk change from baseline to week 52 was significant between both tirzepatide 10 mg (-3.2%, 95% confidence interval [CI]: -4.2%, -2.2%) and 15 mg (-3.4%, 95% CI: -4.4%, -2.4%) and placebo. Significantly greater predicted risk reductions for tirzepatide than placebo were observed in all subgroups.

Tirzepatide was associated with significantly reduced predicted 10-year risk of T2D among SURMOUNT-CN participants with obesity or overweight, irrespective of baseline BMI and prediabetes status.

The prevalence of diabetes and obesity continues to rise in women of reproductive age, with significant implications for both mother and foetus. Glucagon-like peptide-1 receptor agonists are effective treatments of diabetes and obesity. However, no Glucagon-like peptide-1 receptor agonists are currently approved for use during pregnancy. We describe the outcomes of unplanned pregnancies during regulatory clinical trials of Glucagon-like peptide-1 receptor agonists submitted to the Food and Drug Administration and European Medicines Agency.

A search was conducted of the regulatory documentation published by the European Medicines Agency and the Food and Drug Administration on unplanned pregnancies during regulatory clinical trials of Glucagon-like peptide-1 receptor agonists. Clinical and Medical Reviews published by the Center for Drug Evaluation and Research at the Food and Drug Administration for every Glucagon-like peptide-1 receptor agonist prior to market authorisation were assessed to gather information on unplanned pregnancies that occurred while females were partaking in the clinical development programmes of such drugs.

Evidence in women having planned pregnancies is lacking, and the only evidence thus far relies on pregnancies occurring inadvertently during Glucagon-like peptide-1 receptor agonist trials. The incidence of congenital abnormalities in humans appears relatively low following Glucagon-like peptide-1 receptor agonist use during pregnancy.

Key knowledge gaps must be addressed before the introduction of the Glucagon-like peptide-1 receptor agonist class of drugs for pregnant women. Currently, Glucagon-like peptide-1 receptor agonists should be stopped as soon as the patient becomes aware of a pregnancy. The establishment of patient registries designed to capture data relating to cases of Glucagon-like peptide-1 receptor agonist exposure during pregnancy is a high priority, and where data already exist, the findings need to be published.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as groundbreaking therapeutic agents in managing a spectrum of metabolic disorders, demonstrating remarkable efficacy across multiple organ systems and disease states. These compounds are not only well-established in the treatment of type 2 diabetes (T2D) and obesity-conditions for which they have received widespread approval-but also exhibit promising potential in addressing cardiovascular disease (CVD) and Metabolic dysfunction-associated steatotic liver disease (MASLD). Recent investigations have begun to illuminate the utility of GLP-1RAs in the management of type 1 diabetes (T1D), as well as neurodegenerative disorders such as Alzheimer's and Parkinson's disease and various behavioral disorders. A plethora of clinical trials have consistently validated the capacity of GLP-1RAs to improve glycemic control, promote weight loss, and mitigate cardiovascular risk factors in individuals with T2D and obesity. While their application in T1D remains limited due to safety concerns-particularly regarding the risks of hypoglycemia and hyperglycemic ketoacidosis-emerging data suggest that GLP-1RAs may offer hepatoprotective benefits, potentially reducing liver fat content and decelerating the progression of MASLD. The neuroprotective attributes of GLP-1 RAs have garnered significant interest, with research indicating their potential to alleviate cognitive decline associated with neurodegenerative diseases. Furthermore, preliminary findings highlight the role of GLP-1 RAs in addressing behavioral disorders, emphasizing their extensive therapeutic promise. This comprehensive review synthesizes the current evidence supporting the diverse therapeutic applications of GLP-1RAs, positioning them as "magic drug" therapies for metabolic and neurological disorders. As ongoing research continues to explore innovative applications and combinations of GLP-1RAs, the landscape of disease management in metabolic and neurological contexts is poised for transformative advancements. This review will also critically assess safety considerations and underscore the need for personalized treatment strategies to optimize patient outcomes in these complex and often comorbid conditions.

Healthy "environment-sleep-emotion-exercise-diet" intervention [E(e)SEEDi] lifestyle can improve the quality of life, prolong aging and promote longevity due to improvement of human immunity and prevention of cardiovascular diseases (CVD). Here, the author reviewed the associations between these core elements with CVD and cardiovascular aging, and developed a new scoring system based on the healthy E(e)SEEDi lifestyle for prediction and evaluation of life expectancy. These core factors are assigned 20 points each (120 points in total), and a higher score predicts healthier aging and longevity. The E(e)SEEDi represents "a tree of life" bearing the fruits of longevity as well as "a rocket of anti-ageing" carrying people around the world on a journey of longevity. In conclusion, the E(e)SEEDi can delay aging and increase the life expectancy due to the role of a series of cellular and molecular "mechanisms-hallmarks-biomarkers". It's believed that the novel scoring system has a huge potential and beautiful prospects.

Glucagon-like peptide-1 (GLP-1) receptor agonists, increasingly used for diabetes management and weight loss, have been linked to lower readmission rates after knee and hip arthroplasty. However, their impact on total shoulder arthroplasty (TSA) outcomes remains unclear. This study investigates the effects of GLP-1 receptor agonists on major complications and revisions following TSA.

A retrospective query of the TriNetX database from 2010 to 2023 was performed to identify patients who underwent anatomic or reverse TSA and were prescribed GLP-1 receptor agonists. GLP-1 receptor agonist users were 1:1 propensity score-matched to controls for demographic factors and comorbidities, yielding 1259 patients in each group. Outcomes included 90-day postoperative medical complications and readmission and revision surgery at 2 years. Odds ratios (ORs), 95% confidence intervals, and P values were calculated. After Bonferroni correction, P < .005 was considered significant.

GLP-1 receptor agonist users (n = 1259) experienced significantly higher rates of deep vein thrombosis (1.6% vs. 0.9%; OR 3.0; P = .001), myocardial infarction (1.60% vs. 0.9%; OR 2.84; P = .003), pneumonia (3.34% vs. 1.50%; OR 2.25; P = .003), transfusion (7.1% vs. 4.3%; OR 1.7; P = .003), and readmission (8.1% vs. 5.2%; OR 1.6; P = .004) in the 90-day postoperative period compared to patients not taking GLP-1 receptor agonists. There were no differences in the rates of stroke, pulmonary embolism, postoperative anemia, or renal failure. In patients with a minimum 2-year follow-up (n = 776), there was no difference in revision rate (3.2% vs. 1.8%; OR 1.8; P = .07).

GLP-1 receptor agonist use during TSA was associated with an increased risk of deep vein thrombosis, myocardial infarction, pneumonia, need for transfusion, and readmission. Further investigation into the perioperative risk assessment and medical optimization of patients utilizing GLP-1 receptor agonists may be warranted.

Metabolic disease, including obesity and type 2 diabetes, are amongst the most significant health issues facing women of reproductive age. To date, no antenatal weight management tools have reduced the risk of adverse health outcomes for women with obesity and their offspring, resulting in a shift in focus to the pre-conception period. Although not yet recognised in most international weight management guidelines, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are being increasingly used for weight management prior to conception.

A literature search of PubMed, Medline, and Embase databases identified relevant articles describing the use of GLP-1 RAs prior to and during pregnancy. Papers were selected based on relevance and originality, with clinical trials, large observational studies and meta-analyses being preferentially included.

This narrative review summarises the mechanism of action of GLP-1 RAs and the clinical effects observed in non-pregnant adults. It synthesises the available data from human and animal studies regarding the safety and efficacy of GLP-1 RAs prior to pregnancy, and the consequences of inadvertent drug exposure in early pregnancy. In considering the need to balance the risks of metabolic disease with the risks posed by inadvertent drug exposure, it highlights the areas where further research is needed to guide clinical decision-making.

GLP-1 RAs may have a role in facilitating weight loss and improving the metabolic health of women prior to pregnancy. However, there is currently insufficient evidence to demonstrate that the use of this class of drugs prior to pregnancy improves pregnancy outcomes.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as blockbuster drugs for treating metabolic diseases. Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and acting on the central nervous system to regulate satiation and satiety. This review summarizes the discovery of GLP-1 and the development of GLP-1RAs, with a particular focus on their central mechanisms of action. Human neuroimaging studies demonstrate that GLP-1RAs influence brain activity during food cognition, supporting a role in pre-ingestive satiation. Animal studies on hypothalamic feed-forward regulation of hunger suggest that cognitive hypothalamic mechanisms may also contribute to satiation control. We highlight the brain mechanisms of GLP-1RA-induced satiation and satiety, including cognitive impacts, with an emphasis on animal studies of hypothalamic glucagon-like peptide-1 receptor (GLP-1R) and GLP-1R-expressing neurons. Actions in non-hypothalamic regions are also discussed. Additionally, we review emerging combination drugs and oral GLP-1RA formulations aimed at improving efficacy and patient adherence. In conclusion, the dorsomedial hypothalamus (DMH)-a key GLP-1RA target-mediates pre-ingestive cognitive satiation, while other hypothalamic GLP-1R neurons regulate diverse aspects of feeding behavior, offering potential therapeutic targets for obesity treatment.

Pharmacotherapy is part of a comprehensive guideline-conform treatment concept for people with obesity. The foundation of obesity treatment is initially a conservative multimodal basic treatment and consists of a low-energy diet, increased physical activity and behavioral changes. If the individual treatment goals are not achieved with this approach, medications can support the basic treatment. The concept is that drugs should not only achieve weight reduction and stabilization of the reduced body weight but also provide better long-term treatment for the chronic multisystem disease obesity. The incretin-based pharmacotherapy with liraglutide, semaglutide and tirzepatide, which have been introduced in recent years, have not only pronounced weight-reducing but also beneficial cardiometabolic effects. These include improvements in obesity-related comorbidities, such as type 2 diabetes, hypertension, fatty liver disease, obstructive sleep apnea, cardiovascular risk factors, chronic kidney disease and others. In contrast, incretin-based pharmacotherapy is typically associated with mild to moderate gastrointestinal side effects. With the marketing launch of setmelanotide, a medication became available for the treatment of rare monogenic forms of obesity. In addition, numerous incretin-based active agents and new substance classes are in advanced phases of clinical development. Due to their favorable efficacy and side effect profiles and also with respect to the positive cardiometabolic effects, the new drugs have the potential to significantly increase the importance of pharmacotherapy of obesity in Germany.

Obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF) and contributes through multiple pathophysiological pathways, including systemic inflammation, neurohormonal activation, and mechanical inhibition. The treatment of obesity has shown significant potential for improving HFpEF outcomes. Sodium-glucose cotransporter 2 inhibitors have emerged as effective treatments for improving symptoms and quality of life in patients with HFpEF while aiding in weight control. Furthermore, a recent demonstration of the clinical benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in HFpEF showed promising results in reducing weight loss, and improving symptoms and clinical outcomes. In this review article, we discuss the association between HFpEF and obesity, the emerging role of GLP-1 RAs, and future directions for medical therapies targeting obesity-associated HFpEF.

Obesity, a chronic and progressive disease with a complex etiology, remains a significant global health challenge. Despite advancements in lifestyle interventions, pharmacological therapies, and bariatric surgery, substantial barriers to effective and sustained obesity management persist. Resistance to weight loss and gradual weight regain are commonly reported, limiting the long-term success of both non-pharmacological and pharmacological strategies. A possible contributor is metabolic adaptation, a phenomenon characterized by reduced metabolic rate and energy expenditure following weight loss, which hinders therapeutic efficacy. To address these challenges, increasing attention has been directed toward strategies that counteract maladaptive mechanisms by modulating metabolic rate and enhancing energy expenditure. One promising approach involves mitochondrial uncoupling, where electron transport and oxygen consumption are disconnected from ATP synthesis, promoting energy dissipation. Preclinical studies have demonstrated the potential of various chemical compounds with uncoupling activity as anti-obesity agents. Additionally, carbon monoxide (CO) has emerged as a significant gaseous signaling molecule in human physiology, with anti-inflammatory, antioxidative, and cytoprotective properties. Advances in CO-based pharmacology have led to the development of controlled-release CO donors, enabling precise therapeutic application. Experimental studies suggest that CO modulates mitochondrial bioenergetics, induces mild mitochondrial uncoupling, and regulates mitochondrial biogenesis. By integrating these findings, this review uniquely connects scientific threads, offering a comprehensive synthesis of current knowledge while proposing innovative directions in mitochondrial, metabolic and CO-based pharmacological research. It highlights the potential of CO-based pharmacology to regulate metabolic rate, support weight loss, and address obesity-related dysfunctions, thus suggesting novel pathways for advancing obesity treatment.

There is a pressing requirement to formulate innovative approaches for addressing inadequate weight loss or recurrence in individuals following metabolic bariatric surgery (MBS). Glucagon-like peptide- 1 (GLP- 1) analogues such as liraglutide and semaglutide have been formulated for treating type 2 diabetes or managing obesity. In this systematic review and meta-analysis, we aimed to pool the results from all available studies on GLP- 1 agonists to assess the efficacy of these drugs in weight recurrence or suboptimal clinical response of patients who underwent MBS.

We searched PubMed, Scopus, and Web of Science from inception till October 2024 for articles that fulfil our eligibility to be included in the systematic review and meta-analysis investigating the use of GLP- 1 agonists in the management of weight recurrence or suboptimal clinical response in patients who underwent MBS. The search strategy was as follows: "Liraglutide" OR "Semaglutide" OR "Tirzepatide" OR "GLP- 1" OR "Glucagon like peptide" AND "Weight" AND "Bariatric" OR "Sleeve" OR "Banding" OR "Roux-en-Y bypass. We used the mean difference (MD) to compare between continuous variables at a confidence interval (CI) of 95%, and p-value of 0.05.

The use of GLP- 1 agonists (liraglutide, semaglutide, and tirzepatide) was associated with a statistically significant decrease in the weight of the included patients showing an overall MD = 8.07 kg (95%CI: 5.5, 10.64, p < 0.00001) and I2 = 44%, p = 0.04. Moreover, these drugs (liraglutide, and semaglutide) showed significantly reduced body mass index (BMI) after treatment with overall MD = 4.42 kg/m2 (95%CI: 3.42, 5.42, p < 0.00001), and I2 = 67%, p = 0.0005. Compared with control group, the use of GLP- 1 agonists was associated with reduced weight with MD = - 9.19% (95%CI: - 10.81, - 7.58, p < 0.00001) and I2 = 0%. However, no difference was observed between both groups regarding BMI change with MD = - 1.97% (95%CI: - 4.65, 0.71, p = 0.15).

GLP- 1 agonists such as liraglutide and semaglutide effectively lower body weight and BMI in patients who suffer from weight recurrence or suboptimal clinical response after undergoing MBS. However, future studies are still warranted to investigate the most appropriate protocols for management.

Obesity is a leading cause of morbidity and mortality with health consequences that crosscut most medical specialties. Despite the emergence of effective and promising new therapies, many impediments to comprehensive obesity care remain. As part of their commitment to improving obesity care, the American College of Physicians (ACP) and its Council of Subspecialty Societies (CSS) held a summit on 24 October 2023 to identify barriers to and opportunities for collaborative action in the domains of physician education, health care policy and care delivery, and addressing weight bias. This report summarizes the summit proceedings and provides a postsummit synthesis from ACP and CSS. Key themes were centered on knowledge, advocacy, action, and compassion, including the need for culture change, paradigm shifts, and stakeholder engagement and collaboration; a focus on empowerment of both clinicians and patients; the importance of knowing patients as people to help address social determinants of health; the need to address learned helplessness; and the importance of embracing artificial intelligence and technology as disruptive innovations. Recommendations for next steps for collaborative action include leveraging and improving already available educational and clinical resources, developing obesity education and care standards that incorporate patients' perspectives and address social determinants of health, developing community and public-private partnerships to improve access and public awareness, and coordinating messaging and policy advocacy efforts that align with mitigating the longstanding obesity epidemic.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are the major contributors to the liver disease burden globally. The rise in these conditions is linked to obesity, type 2 diabetes, metabolic syndrome and increased alcohol consumption. MASLD and ALD share risk factors, pathophysiology and histological features but differ in their thresholds for alcohol use, and the ALD definition does not require the presence of metabolic dysfunction. A recent multi-society consensus overhauled the nomenclature of liver steatosis and introduced the term MetALD to describe patients with metabolic dysfunction who drink more than those with MASLD and less than those with ALD. This new terminology aims to enhance the understanding and management of liver disease but poses challenges, such as the need to accurately measure alcohol consumption in research and clinical practice settings. Recent studies show that MetALD has significant implications for patient management, as it is associated with increased mortality risks and more severe liver outcomes compared to MASLD alone. MetALD patients face increased risks of liver disease progression, cancer and cardiovascular disease. The diagnosis of MetALD involves the adequate quantification of alcohol use through standardised questionnaires and/or biomarkers as well as proper assessment of liver disease stage and progression risk using non-invasive tools including serologic markers, imaging, elastography techniques and genetic testing. Effective management requires addressing both metabolic and alcohol-related factors to improve outcomes. This review intends to provide a comprehensive overview of MetALD, covering pathogenesis, potential diagnostic approaches, management strategies and emerging therapies.

Glucagon-like peptide-1 receptor agonists and their analogues have emerged as effective pharmacotherapies for obesity.

To assess the short-term cost-effectiveness of subcutaneous tirzepatide, semaglutide, liraglutide, and oral semaglutide for managing obesity or overweight in patients without diabetes.

A decision tree model was developed using a 68-week time window with consideration of serious adverse events and treatment discontinuation from a US payer's perspective. The study population were adults with obesity or overweight with at least 1 weight-related comorbidity but without diabetes. Clinical data were obtained from clinical trials. Model utilities, disutilities, and the costs of serious adverse events were sourced from published literature. Medication costs were assigned from Red Book. All costs were calculated in 2024 US dollars. The incremental cost-effectiveness ratio was calculated based on the cost per quality-adjusted life-year (QALY) gained. A willingness-to-pay threshold of $150,000 per QALY was used. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the effect of parameter uncertainty on the results.

In the base-case analysis, both subcutaneous tirzepatide and oral semaglutide were cost-effective vs subcutaneous liraglutide and subcutaneous semaglutide. Compared with oral semaglutide, subcutaneous tirzepatide was cost-effective, with an incremental cost-effectiveness ratio of $34,212 per QALY gained. Sensitivity analyses indicated the results were highly sensitive to medication costs and the effectiveness of medications. The probabilistic sensitivity analysis suggested that subcutaneous tirzepatide was most likely to remain cost-effective, with a 98% probability at a willingness to pay of $150,000 per QALY compared with other medications.

Subcutaneous tirzepatide and oral semaglutide were cost-effective therapies compared with subcutaneous liraglutide and subcutaneous semaglutide for the short-term management of obesity in adults without diabetes. At or under a willingness-to-pay threshold of $150,000 per QALY, subcutaneous tirzepatide was most cost-effective, surpassing oral semaglutide. These findings provide valuable insights for health care decision-makers in selecting antiobesity medications.

Data on tirzepatide in Asian patients with obesity are limited. This study aimed to gain a better understanding of tirzepatide for treatment of Japanese patients with obesity disease (BMI ≥25 kg/m2 with excessive fat accumulation) as defined by the Japanese Society for the Study of Obesity.

This was a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial of the efficacy and safety of tirzepatide as an adjunct to lifestyle modifications. Japanese adults with obesity disease (BMI ≥27 kg/m2 accompanied by ≥2 obesity-related health disorders or ≥35 kg/m2 accompanied by ≥1 obesity-related health disorders), excluding diabetes, were assigned 1:1:1 via computer-generated random sequence to receive once weekly subcutaneous tirzepatide (10 mg or 15 mg) or placebo. Coprimary endpoints were the mean percent change in bodyweight and the proportion of participants achieving at least 5% bodyweight reduction at week 72, using the efficacy estimand. Efficacy and safety were assessed in the modified intention-to-treat (mITT) population. This study is registered with ClinicalTrials.gov, NCT04844918.

Between May 10, 2021, and June 24, 2023, 413 participants were screened, and 267 were randomly assigned. Due to exclusion of one study site, the mITT population was 225 participants (133 [59%] men and 92 [41%] women, mean age 50·8 [SD 10·7] years), with 73 in the tirzepatide 10 mg group, 77 in the tirzepatide 15 mg group, and 75 in the placebo group, of whom 192 (85%) completed both study and treatment. Estimated treatment differences relative to placebo in change in bodyweight at week 72 were -16·1% (95% CI -18·7 to -13·5; p<0·0001) and -21·1% (95% CI -23·6 to -18·5; p<0·0001) following tirzepatide 10 mg and 15 mg, respectively. At week 72, a higher proportion of participants achieved at least 5% bodyweight reduction with tirzepatide 10 mg (67 [94%] of 71) and 15 mg (73 [96%] of 76) compared with placebo (15 [20%] of 75; both p<0·0001). Cardiometabolic and body composition indices were also improved with tirzepatide. Participants treated with tirzepatide experienced treatment-emergent adverse events more frequently (10 mg: n=61 [84%]; 15 mg: n=66 [86%]) than those who received placebo (52 [69%]), most commonly gastrointestinal symptoms. Study discontinuations due to adverse events were infrequent (placebo: n=3 [4%]; tirzepatide 10 mg: n=1 [1%]; tirzepatide 15 mg: n=0).

In Japanese adults with obesity disease, tirzepatide provided clinically a meaningful reduction in bodyweight compared with placebo over 72 weeks, with a safety profile consistent with that observed in global populations.

Eli Lilly and Company.

For the Japanese translation of the abstract see Supplementary Materials section.

Researchers and clinicians have increasingly recognized the importance of investigating and considering sex differences in obesity treatment. In this narrative review, we first summarized sex differences in select obesity-related conditions that have been the focus of studies of second-generation anti-obesity medications (i.e., semaglutide and tirzepatide) including type 2 diabetes, obstructive sleep apnea, knee osteoarthritis, and heart failure. We next described sex differences related to obesity treatments with a focus on the second-generation anti-obesity medications, semaglutide and tirzepatide.

Type 2 diabetes, obstructive sleep apnea, knee osteoarthritis, and heart failure demonstrated sex-specific pathways influenced by factors such as hormones and body composition. Lifestyle modification, on average, resulted in larger weight losses in males. In contrast, second-generation AOMs produced higher mean weight losses among females. Females reported more adverse events (e.g., nausea, vomiting) with second-generation anti-obesity medications. The few studies that have performed analyses of changes in obesity-related comorbidities stratified by sex have shown consistent improvements between males and females in heart failure and cardiovascular outcomes. Studies are needed to evaluate the effect of sex on the efficacy of anti-obesity medications including on mental health, investigate the mechanisms underlying these effects, and develop interventions to improve the availability and access of these medications.

Over a third of the global population is affected by obesity, fatty liver disease (Metabolic Dysfunction-Associated Steatotic Liver Disease, MASLD), and its severe form, MASH (Metabolic Dysfunction-Associated Steatohepatitis), which can ultimately progress to hepatocellular carcinoma (HCC). Recent advancements include therapeutics such as glucagon-like peptide 1 (GLP-1) agonists and neural/vagal modulation strategies for these disorders. Among the many pathways regulating these conditions, emerging insights into transforming growth factor-β (TGF-β) signaling highlight potential future targets through its role in pathophysiological processes such as adipogenesis, inflammation, and fibrosis. Vagus nerve innervation in the gastrointestinal tract is involved in satiety regulation and energy homeostasis, and vagus nerve stimulation has been applied in weight loss and diabetes. This review explores clinical trials in obesity, novel therapeutic targets, and the role of TGF-β signaling and vagus nerve modulation in obesity-related liver diseases and HCC.

Bariatric surgery (BS) has emerged as a crucial and effective treatment for severe obesity (SO), providing significant and sustained weight loss and improving comorbidities. Optimizing perioperative careparticularly through structured prehabilitation is crucial for improving surgical outcomes and long-term weight management. This review examines the role of prehabilitation, nutrition, psychological support, physical activity, and pharmacologic treatment in improving the effectiveness of BS.

Despite the benefits of prehabilitation, there are significant differences in the way it is implemented in different healthcare centers. Protocols vary widely in terms of duration, components and intensity, leading to inconsistencies in patient preparation and postoperative recovery. Many patients still do not receive multidisciplinary support from dietitians, psychologists or physiotherapists prior to surgery, which can affect long-term outcomes. Barriers to effective prehabilitation include a lack of standardized guidelines, insufficient healthcare resources and limited patient adherence due to lack of awareness, low motivation or logistical constraints. Despite its proven benefits, structured prehabilitation lasting at least 3-6 months is not available to all patients, as access remains unequal and suboptimal in many healthcare settings. Prehabilitation is an important but underutilized component of BS preparation. Standardizing protocols and ensuring multidisciplinary, patient-centered support are essential to maximizing surgical benefit. Overcoming barriers such as healthcare system limitations, patient motivation and knowledge gaps is critical to integrating prehabilitation into routine bariatric care. This review emphasizes the need for evidence-based, multimodal prehabilitation strategies to improve perioperative care and long-term outcomes for BS patients.

Patients with atherosclerotic cardiovascular disease (ASCVD), such as those with a history of MI or stroke, are at high risk for morbidity and mortality associated with future cardiovascular events. Ideal management of these patients requires a multifactorial strategy for risk factor mitigation and prevention of additional cardiovascular events. Traditional management of secondary prevention patients involves lipid-lowering with statins, blood pressure control, and anti-platelet treatment. Several additional targets have been identified to optimize the secondary prevention of ASCVD, such as further lipid control, inflammation management, lifestyle and weight optimization, strict diabetes control, use of β-blockers, use of renin-angiotensin-aldosterone system inhibitors, vaccinations, and additional considerations of anti-thrombotic therapies. This review will describe the interventions associated with these targets, as well as the relevant research and indications for these therapies.

Glucagon-like peptide- 1 receptor agonists (GLP- 1 RA) are a rapidly expanding class of medications used to treat many chronic diseases. This review explores factors that may contribute to accelerated muscle loss among higher-risk patient populations and describes tailored interventions to reduce the risk of accelerated sarcopenia and frailty.

While GLP- 1 RA can result in total weight loss upwards of 25%, recent studies show that they can also lead to significant loss of lean body mass, reaching as high as 15-40% of total weight lost. This rapid and significant decline in muscle mass while taking GLP- 1 RA places certain patient populations already predisposed to sarcopenia at higher risk for muscle loss and adverse events. Currently, there is insufficient evidence delving into the impact of GLP- 1 RA on body composition among older adults, patients with chronic kidney disease, liver disease, and inflammatory bowel disease. However, research suggests that a high protein diet and resistance training may help prevent loss of muscle mass during GLP- 1 RA usage. A targeted and individualized nutrition and physical activity regimen should be instituted for each patient with a focus on optimizing protein intake and performing frequent resistance training in order to minimize loss of muscle mass while promoting the loss of fat mass. Future research should evaluate the impact of GLP- 1 RA on sarcopenia in high-risk patient populations.

To assess real-world use of Saxenda® (liraglutide 3.0 mg) and off-label use of Victoza® (liraglutide 1.2 mg/1.8 mg) for weight management and Saxenda® posology in the United Kingdom. Their similar doses and formulation pose a risk of inadvertent use due to their use for different indications.

This retrospective, non-interventional drug utilization cohort study (DUS), based on anonymized patient data from the Clinical Practice Research Datalink databases (CPRD Aurum, GOLD), included adult liraglutide initiators without prior prescription 12 months before the index date. Descriptive statistics were used to characterize Saxenda® and Victoza® user demographics and drug utilization.

Totally 604 Saxenda® and 4853 Victoza® patients were included. Approximately half of the Saxenda® initiators (Si's) (N = 306) had available body weight, of which 96.4% initiated treatment according to the weight loss indication. Si's were more likely female than Victoza® initiators (Vi's) (86.4% vs. 52.1%), younger (mean age ± SD: 46.5 ± 11.7 years) versus (57.5 ± 12.0 years) and with shorter duration of follow-up observation (18.8 ± 13.9 months) versus (32.9 ± 15.9 months). N < 5 of 16 patients with 24-weeks body mass index (BMI) data did not adhere to the Saxenda® stopping rule. N < 5 of 92 patients with valid dose used Victoza® outside the diabetes indication.

This DUS provides descriptive data for initiators of liraglutide in the initial 5-year period following the launch of Saxenda® in the United Kingdom. Real-world use of Saxenda® and Victoza® raised no new safety concerns. Where assessment was possible, Saxenda® and Victoza® were mostly prescribed by physicians according to their approved indications.