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BACKGROUND: Obesity is an independent risk factor for complications after abdominal hernia repair. Glucagon-like-peptide-1 (GLP-1) receptor agonists are gaining popularity as pharmacologic weight loss adjuncts and may help patients reach weight loss goals for surgery. We examine our early experience utilizing GLP-1 agonists versus lifestyle modifications alone to achieve weight loss in patients before elective hernia repair. METHODS: This single-center, retrospective review identified obese patients who underwent elective hernia repair from 2014 to 2023. Patients were asked to achieve a BMI ≤ 33 kg/m2 before surgery. Patients who lost weight with GLP-1 therapy in addition to lifestyle changes were compared to a control cohort that achieved similar preoperative weight loss without GLP-1 therapy. Primary outcome was mean time from GLP-1 agonist initiation and initial surgery clinic visit to surgery. Secondary outcomes were 30-day morbidity, mortality, and reoperation rates, and hernia recurrence. RESULTS: Forty-six patients with ventral/incisional, flank, umbilical, parastomal, inguinal, and hiatal hernias were identified (GLP-1 N = 24, control N = 22). 81.8% (N = 18) of controls had a ventral/incisional hernia, compared to 45.8% (N = 11) of GLP-1 patients (p = 0.03). Mean BMI at GLP-1 agonist initiation was similar to mean BMI at initial clinic visit for controls (38.1 ± 4.9 vs 38.2 ± 2.7 kg/m2, p = 0.66). Preoperative mean percentage total weight loss (14.9 ± 7.5 vs 12.4 ± 6.9 kg, p = 0.39) and mean BMI reduction (6.0 ± 3.8 vs 4.9 ± 2.3 kg/m2, p = 0.43) were similar between groups. The mean time from GLP-1 agonist initiation to surgery was significantly shorter than initial clinic visit to surgery for controls (6.3 ± 4.0 vs 14.7 ± 17.6 months, p = 0.03). There was no statistically significant difference in time from initial clinic visit to surgery between groups (7.6 ± 4.4 vs 14.7 ± 17.6 months, p = 0.06). There was no significant difference in 30-day morbidity between groups (8.3 vs 27.3%, p = 0.13). CONCLUSION: GLP-1 agonists accelerate preoperative weight loss for obese hernia patients without negatively impacting postoperative outcomes.

Background and aims: Type 2 diabetes mellitus (T2DM) is usually complicated by cardiovascular diseases, hyperglycemia, and obesity, which worsen the outcome for the patient. Since recent evidence underlines the epigenetic role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the management of these comorbidities, this study compared the effects of these agents, namely liraglutide, semaglutide, dulaglutide, and exenatide, on miRNA regulation in the management of T2DM. Results: GLP-1RAs modify the expression of miRNAs involved in endothelial function, sugar metabolism, and adipogenesis, including but not limited to miR-27b, miR-130a, and miR-210. Baseline miR-15a-5p predict weight loss, while higher miR-378-3p and miR-126-3p levels are related to better glycemic control and lower HbA1c and FPG at one year post-treatment. miR-375-5p was also reported as a predictor of HbA1c levels. Liraglutide has a protecting effect against pancreatic β-cell apoptosis by downregulating miR-139-5p. The highly-expressed miR-375 in pancreatic islets can be considered as a biomarker for assessing the cytoprotective action of GLP-1RAs on β-cells. GLP-1RAs also enhance β-cell responsiveness by promoting GLP-1 receptor expression through the suppression of miR-204. While semaglutide, semaglutide, and dulaglutide reduce both systolic and diastolic blood pressures, lixisenatide and exenatide QW did not reveal such an effect. The long-acting exenatide-induced miR-29b-3p is required for the protection against diabetic cardiomyopathy. Liraglutide modulates critical regulators of endothelial cell function and atherosclerosis, including miR-93-5p, miR-26a-5p, and miR-181a-5p. Eventually, GLP-1RAs regulation of exosomal miRNAs, such as miR-192, implicated in the development of fibrosis and inflammation in T2DM micro-cardiovascular outcomes like DKD and DR. Conclusion: Additional studies will be needed in the elucidation of the relations between GLP-1RA-induced miRNAs and clinical-laboratory findings concerning the diverse populations, gender, and presence of other comorbid states in treated patients with T2DM. [ABSTRACT FROM AUTHOR]

Introduction: Traditionally, obstructive sleep apnea (OSA) management has focused on continuous positive airway pressure therapy, oral appliances, and in some cases, surgical interventions. However, these treatments do not directly address the underlying metabolic issues contributing to OSA. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for type 2 diabetes management, have demonstrated substantial efficacy in promoting weight. Areas covered: This review aims to summarize the potential impact of liraglutide, semaglutide, and tirzepatide in managing obese patients with OSA. Expert opinion: The introduction of GLP-1 RAs has gained attention not only for their ability to produce significant and sustained weight loss but also for their potential to improve OSA symptoms by reducing fat deposition around the upper airway and decreasing systemic inflammation. Emerging clinical trials suggest that GLP-1 RAs may enhance traditional OSA treatments, offering an integrated approach targeting the root cause of obesity in OSA. Additionally, GLP-1 RAs may provide benefits for other obesity-related comorbidities, including hypertension and cardiovascular disease, which are commonly associated with OSA. The future integration of GLP-1 RAs into OSA treatment protocols could mark a paradigm shift toward more comprehensive management strategies, ultimately improving patient outcomes in this complex patient population. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the risk factors for gastrointestinal side effects (GISEs) in patients with type 2 diabetes mellitus (T2DM) during treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) based on real-world data and to develop a prediction model for GLP-1RA-related GISEs. Methods: A total of 855 patients who attended the First Affiliated Hospital of Shandong First Medical University from January 2020 to May 2023 were selected as the study participants, who were divided into the training set (598 cases) and the validation set (297 cases) using a simple random sampling method at a ratio of 7:3. The general information and biochemical indicators of the participants were collected to assess the risk factors for GLP-1RA-related GISEs, and multifactorial logistic regression analysis was used to obtain the best predictors. A nomogram prediction model was constructed. The Hosmer–Lemeshow test was used to assess the differentiation and calibration of the nomogram model, and decision curve analysis (DCA) was used to evaluate the clinical utility of the model. Results: Age, gender, history of gastrointestinal disorders, and number of combined oral medications were found as risk factors for the occurrence of GISEs in patients with T2DM using GLP-1RAs (p < 0.05). The nomogram prediction model based on these four factors had good discriminability (AUC values of the training and validation sets of 0.855 and 0.836, respectively) and accuracy (Hosmer–Lemeshow test: p > 0.05 for the validation set). DCA showed that the prediction model curve had clinical utility in the threshold probability interval of >5%. Conclusions: The established nomogram model has an excellent predictive effect on GISEs induced by GLP-1RAs in patients with T2DM. [ABSTRACT FROM AUTHOR]

Increasing infertility rates represent a growing medical challenge in modern societies resulting from a complex interplay of sociocultural trends, lifestyle factors, exposure to environmental toxins, and underlying health problems. Women's fertility is particularly vulnerable to these shifts. The obesogenic lifestyle not only accelerates weight gain, but also disrupts ovulation driving the rise in infertility. Among several medications used for treating obesity and type 2 diabetes, glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) show promising improvement in female fertility most likely by stimulating ovulation. However, the effects of GLP‐1RAs on the endometrium remain unclear. Further studies are needed to investigate the impact of GLP‐1RAs on endometrial receptivity and embryo implantation and early development. The aim of this study is to address the knowledge gap regarding the effects of GLP‐1RAs on human reproduction, with special focus on the endometrium. Understanding these mechanisms may help to develop new strategies for improving fertility treatment, reduce implantation failure and address potential safety concerns regarding teratogenicity and adverse developmental outcomes for children born to women conceiving during or soon after GLP‐1RA treatment. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion The use of (GLP‐1 RAs) among pregnant women is escalating, yet safety data remain insufficient. This study aims to comprehensively assess adverse drug reactions (ADRs) associated with GLP‐1 RAs in pregnant women using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.FAERS data from 2004 to 2023 were analysed, focusing on pregnant women aged 15–55 years exposed to GLP‐1 RAs. Descriptive analysis covered patient demographics, clinical aspects and annual trends. Disproportionality analysis used reporting odds ratio and Bayesian confidence propagation neural network to detect ADR signals.Among 354 cases with 1671 ADR reports, an exponential rise in reported cases since 2012 was observed. The median age of the affected women was 36 years, with 50.56% classified as advanced age pregnant. The disproportionality analysis revealed significant ADR signals in the reproductive (n = 199) and gastrointestinal systems (n = 155), with spontaneous abortion and pre‐eclampsia being the most concerning. Additionally, while no significant dose‐related differences were found, the age subgroup analysis indicated heightened risk across most age groups, except for those aged 20–24 years, highlighting the need for careful monitoring of GLP‐1 RAs used during pregnancy.This study highlights increasing GLP‐1 RA use in pregnant women and identifies potential pregnant ADRs. GLP‐1 RAs are not recommended for use during pregnancy. In cases of unintentional exposure, close monitoring is advised to ensure maternal and foetal safety. These findings provide valuable insights for clinicians making informed decisions and regulators considering using GLP‐1 RA in pregnancy. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a potent therapeutic option for the management of obesity, demonstrating exceptional efficacy in several large-scale clinical trials. Despite their promising therapeutic outcomes, the rising popularity of these agents raises significant concerns, particularly regarding their off-label use by individuals seeking weight loss for aesthetic reasons rather than addressing underlying metabolic health conditions. This article critically evaluates the efficacy and safety of GLP-1 RAs in obesity management. Additionally, it explores the economic implications and ethical challenges associated with the increasing demand for GLP-1 RAs. By addressing these dimensions, this article aims to facilitate informed and responsible decision-making in clinical practice, highlighting the need for individualized patient assessments and careful consideration of both short- and long-term safety risks. [ABSTRACT FROM AUTHOR]

Objective: Glucagon-like peptide-1 receptor agonists (GLP1RAs), originally developed for the treatment of type 2 diabetes mellitus, have attracted attention for their potential therapeutic benefits in asthma due to their anti-inflammatory properties and effects on airway smooth muscle function. However, concerns have been raised about the possibility of GLP1RAs inducing or exacerbating asthma symptoms. Methods: We reviewed data from the US Food and Drug Administration's (FDA) adverse event (AE) reporting system (FAERS) to examine reports of cases of asthma observed in the real-world during treatment with GLP1RAs. Results: Analysis of the FAERS reporting system database has shown that certain GLP1RAs, particularly exenatide, semaglutide and liraglutide, were associated with a higher proportion of respiratory AEs, particularly asthma or asthma-like events. This association was statistically significant at least for semaglutide and liraglutide. Serious asthma-related events and deaths were also reported, with exenatide having the highest proportion of deaths. Conclusions: The reasons for the observed differences in the AE profiles of the GLP1RAs remain unclear and may involve various factors such as pharmacological properties, patient characteristics and reporting biases. The complex interplay between the therapeutic benefits of GLP1RAs and the potential respiratory risks requires careful monitoring by clinicians, underpinned by ongoing research efforts to improve patient care and safety. [ABSTRACT FROM AUTHOR]

Background: Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are new anti‐hyperglycaemic drugs with proven cardiovascular (CV) benefit in diabetic and non‐diabetic patients at high CV risk. Despite a neutral class effect on arrhythmia risk, data on semaglutide suggest a possible drug‐specific benefit in reducing atrial fibrillation (AF) occurrence. Objective: To perform a meta‐analysis of randomized clinical trials (RCTs) to assess the risk of incident AF in patients treated with semaglutide compared to placebo. Methods and Results: Ten RCTs were included in the analysis. Study population encompassed 12,651 patients (7285 in semaglutide and 5366 in placebo arms), with median follow‐up of 68 months. A random effect meta‐analytic model was adopted to pool relative risk (RR) of incident AF. Semaglutide reduces the risk of AF by 42% (RR.58, 95% CI.40–.85), with low heterogeneity across the studies (I2 0%). At subgroup analysis, no differences emerged between oral and subcutaneous administration (oral: RR.53, 95% CI.23–1.24, I2 0%; subcutaneous: RR.59, 95% CI.39–.91, I2 0%; p‐value.83). In addition, meta‐regression analyses did not show any potential influence of baseline study covariates, in particular the proportion of diabetic patients (p‐value.14) and body mass index (BMI) (p‐value.60). Conclusions: Semaglutide significantly reduces the occurrence of incident AF by 42% as compared to placebo in individuals at high CV risk, mainly affected by type 2 diabetes mellitus. This effect appears to be consistent independently of the route of administration of the drug (oral or subcutaneous), the presence of underlying diabetes and BMI. [ABSTRACT FROM AUTHOR]

The article published in the Journal of Internal Medicine explores the increased risk of hypereosinophilia following the initiation of glucagon-like peptide 1 receptor agonists (GLP1-RA) using Danish health registries. The study found that individuals who initiated GLP1-RA were three times more likely to experience hypereosinophilia compared to before initiation, with no similar association observed for other antidiabetic drugs. The research highlights the need for larger studies to further investigate the potential link between GLP1-RA and clinically manifest hypereosinophilic syndrome. [Extracted from the article]

Aims: To conduct a meta‐analysis of randomized controlled trials (RCTs) to evaluate the effect of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) on glycated haemoglobin (HbA1c) and continuous glucose monitoring (CGM) metrics as an adjunct to insulin therapy in adults with type 1 diabetes mellitus (T1D). Methods: A systematic literature search was conducted through Medline (via PubMed), Cochrane Library, and Google Scholar up to 27 May 2024. Dual‐independent study selection, data extraction, and quality assessment were performed. Results were summarized using random‐effects meta‐analysis. Results: Six RCTs were identified, involving a total of 378 individuals with T1D. The use of GLP‐1RAs in addition to standard insulin therapy was associated with a significant reduction in HbA1c (mean difference [MD] −0.21%, 95% confidence interval [CI] −0.36 to −0.06; p = 0.007) and a similar time in range (TIR) compared to placebo (MD −0.22%, 95% CI −2.39 to 1.95; p = 0.84). GLP‐1RA therapy resulted in a significantly higher time below range (MD 1.13%, 95% CI 0.50 to 1.76; p < 0.001) and a lower time above range compared with placebo (MD −1.83%, 95% CI −2.51 to −1.15; p < 0.001). Nonsignificant differences were noted for the secondary outcomes, including the mean amplitude of glucose excursion, continuous overall net glycaemic action for 60 min, mean daily glucose, coefficient of variation, and mean standard deviation of weekly glucose levels. Conclusion: Our findings suggest that, in individuals with T1D, add‐on therapy with GLP‐1RAs does not confer significant benefits in terms of CGM metrics and is associated with a longer time below the target glycaemic range. [ABSTRACT FROM AUTHOR]

Metabolic-associated fatty liver disease (MALFD) is a highly prevalent and progressive disease, strongly related to obesity, metabolic syndrome, and cardiovascular disease. It comprises a spectrum of liver pathology from steatosis (fat accumulation in the hepatocytes) to steatosis with inflammation (metabolic-associated steatohepatitis, MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. There is currently only one medication, resmetirom, US Food and Drug Administration approved for the treatment of MALFD. Evidence from randomized trials supports the efficacy of hypocaloric diets and exercise in MASH resolution. Moreover, substantial weight loss after bariatric surgery can lead to significant and longitudinally sustained MASH resolution, improvement in liver fibrosis, and decrease in the risk of major cardiovascular adverse events. Pioglitazone, an insulin sensitizer, initiated at the early stages, before the progression to fibrosis, may be effective in resolution of MASH in patients with or without type 2 diabetes. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), semaglutide and liraglutide, may also be effective in resolution of MASH but not of fibrosis. Preliminary data from interventions with tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide RA, and sodium-glucose cotransporter 2 inhibitors are encouraging, but more data based on liver biopsy are needed. [ABSTRACT FROM AUTHOR]

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been widely used for type 2 diabetes (T2D) and weight management. However, the causal relationship of GLP-1RAs with erectile dysfunction (ED) was still unclear. Methods: Mendelian randomization (MR) analysis was conducted to reveal the association of genetically proxied GLP-1RAs with ED. The proportion of potential mediators mediating GLP-1RAs to ED was also assessed by two-step MR. Finally, a series of sensitivity analyses and Two-Sep cis-MR (TSCMR) were performed to evaluate the robustness of the results. Results: MR evidence suggested that genetically proxied GLP-1RAs reduced the risk of ED [odds ratio (OR): 0.493; 95% confidence interval (95% CI): 0.430 to 0.565; P <0.001]. Further mediation analysis via two-step MR showed that this effect was partly mediated through reduced T2D, obesity, hypertension and cardiovascular disease (CVD), with mediated proportions of 2.89% (95% CI: 1.28% to 4.49%), 6.83% (95% CI: 2.25% to 11.41%), 3.22% (95% CI: 1.21% to 5.23%), and 3.06% (95% CI: 0.51% to 5.62%), respectively. Conclusions: GLP-1RAs were associated with a reduced risk of ED, and to a lesser extent, T2D, obesity, hypertension and CVD mediated this effect. Nevertheless, the potential implications of our results for ED prevention policies required validation in further clinical randomized controlled trials. [ABSTRACT FROM AUTHOR]

BACKGROUND: GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose cotransporter 2) inhibitors both improve cardiovascular and kidney outcomes in people with type 2 diabetes. We conducted a systematic review and meta-analysis to assess the effects of GLP-1 receptor agonists on clinical outcomes with and without SGLT2 inhibitors. METHODS: We searched MEDLINE and Embase databases from inception until July 12, 2024, for randomized, double-blind, placebo-controlled outcome trials of GLP-1 receptor agonists in type 2 diabetes that reported treatment effects by baseline use of SGLT2 inhibitors, with findings supplemented by unpublished data. We estimated treatment effects by baseline SGLT2 inhibitor use using inverse variance-weighted meta-analysis. The main cardiovascular outcomes were major adverse cardiovascular events (nonfatal myocardial infarction, stroke, or cardiovascular death) and hospitalization for heart failure. Kidney outcomes included a composite of ≥50% reduction in estimated glomerular filtration rate, kidney failure or death caused by kidney failure, and annualized rate of decline in estimated glomerular filtration rate (estimated glomerular filtration rate slope). Serious adverse events and severe hypoglycemia were also evaluated. This meta-analysis was registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024565765). RESULTS: We identified 3 trials with 1743 of 17 072 (10.2%) participants with type 2 diabetes receiving an SGLT2 inhibitor at baseline. GLP-1 receptor agonists reduced the risk of major adverse cardiovascular events by 21% (hazard ratio [HR], 0.79 [95% CI, 0.71–0.87]), with consistent effects in those receiving and not receiving SGLT2 inhibitors at baseline (HR, 0.77 [95% CI, 0.54–1.09] and HR, 0.79 [95% CI, 0.71–0.87], respectively; P -heterogeneity=0.78). The effect on hospitalization for heart failure was similarly consistent regardless of SGLT2 inhibitor use (HR, 0.58 [95% CI, 0.36–0.93] and HR, 0.73 [95% CI, 0.63–0.85]; P -heterogeneity=0.26). Effects on the composite kidney outcome (risk ratio, 0.79 [95% CI, 0.66–0.95]) and estimated glomerular filtration rate slope (0.78 mL/min/1.73 m2/y [95% CI, 0.57–0.98]) also did not vary according to SGLT2 inhibitor use (P -heterogeneity=0.53 and 0.94, respectively). Serious adverse effects and severe hypoglycemia were also similar regardless of SGLT2 inhibitor use (P -heterogeneity=0.29 and 0.50, respectively). CONCLUSIONS: In people with type 2 diabetes, the cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Materials and Methods Results Conclusions Developing a more effective treatment for the global impact of diabetic kidney disease is crucial. This study examined the renoprotective effects of combining glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) with sodium–glucose cotransporter 2 inhibitors (SGLT2i) compared to SGLT2is alone in type 2 diabetes (DM).This retrospective cohort study used data from the TriNetX Global Collaborative Network. Type 2 DM patients with estimated glomerular filtration rates ≥60 mL/min/1.73 m2 who used GLP‐1 RA or SGLT2i between January 1, 2013, and December 31, 2023. Propensity score matching balanced baseline characteristics, resulting in 71,186 patients in each group (combined GLP‐1 RA and SGLT2i therapy vs SGLT2i alone). Cox regression model was adopted to compare outcomes over a 5‐year period, including major adverse kidney events (MAKE), acute kidney injury (AKI), end‐stage kidney disease (ESKD), and all‐cause mortality.After matching, the average age was 57.1 ± 10.8 years for the GLP‐1 RA plus SGLT2i group and 57.2 ± 11.7 years for the SGLT2i‐only group. The GLP‐1 RA plus SGLT2i group had significantly lower risk of MAKE (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.69–0.77), AKI (HR: 0.82, 95% C0I: 0.77–0.87), ESKD (HR: 0.61, 95% CI: 0.47–0.78), and all‐cause mortality (HR: 0.54, 95% CI: 0.50–0.58) compared to the SGLT2i‐only group. Moreover, subgroup analyses showed consistent benefits across different subgroups.Dual therapy with GLP‐1 RA and SGLT2i is supported to enhance renal outcomes and address the growing burden of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide, with increased prevalence in individuals with chronic liver conditions and type 2 diabetes mellitus (T2DM). Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) have shown promise in diabetes management and may influence liver disease progression. This systematic review and meta-analysis aimed to assess the efficacy of GLP-1 RAs in reducing the risk of HCC in patients with T2DM. Methods: We conducted a literature search of PubMed, EMBASE, and Web of Science up to August 1, 2024. Studies that evaluated the incidence of HCC in T2DM patients treated with GLP-1 RAs compared to other therapies were included. Meta-analyses were performed using a random-effects model to compute pooled hazard ratios (HRs) and 95% confidence intervals (CIs), and heterogeneity was assessed using the I² statistic. All statistical analyses were performed in R software version 4.3. Results: Eight studies met the inclusion criteria. The pooled analysis demonstrated that GLP-1 RA treatment was associated with a significant reduction in HCC risk compared to insulin or no GLP-1 RA treatment (pooled HR = 0.41, 95% CI: 0.28 to 0.55), with considerable heterogeneity (I² = 74%). Compared to metformin and DPP-4 inhibitors, GLP-1 RAs did not significantly alter HCC risk (HR = 0.99, 95% CI: 0.79 to 1.27 for metformin; HR = 1.05, 95% CI: 0.80 to 1.39 for DPP-4 inhibitors). However, GLP-1 RAs were associated with a reduced risk compared to sulfonylureas (HR = 0.78, 95% CI: 0.65 to 0.93). Conclusion: GLP-1 RAs may offer protective benefits against HCC in T2DM patients compared to insulin or no GLP-1 RAs, but not significantly over other antidiabetic medications. This review indicates the need for further randomized controlled trials to clarify the role of GLP-1 RAs in HCC risk mitigation and to explore their mechanistic pathways in liver disease management. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD) are common complications of diabetes, arising from insulin resistance, inflammation, and other pathological processes in the central nervous system. The potential of numerous antidiabetic agents to modify neurodegenerative disease progression, both preclinically and clinically, has been assessed. These agents may provide additional therapeutic benefits beyond glycemic control. Introduced in the twenty-first century, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of antidiabetic drugs noted not only for their potent glucose-lowering effects but also for their cardiovascular and renal protective benefits. Various GLP-1RAs have been demonstrated to have significant benefits in in vitro and in vivo models of neurodegenerative diseases through modulating a variety of pathogenic mechanisms, including neuroinflammation, autophagy, mitochondrial dysfunction, and the abnormal phosphorylation of pathognomonic proteins. These agents also have substantial protective effects on cognitive and behavioral functions, such as motor function. However, clinical trials investigating GLP-1RAs in diseases such as AD, PD, mild cognitive impairment, psychiatric disorders, and diabetes have yielded mixed results for cognitive and motor function. This review examines the link between diabetes and neurodegenerative diseases, explores the effects of antidiabetic agents on neurodegeneration, provides a concise overview of the GLP-1 pathway, and discusses both preclinical and clinical trial outcomes of GLP-1RAs for neurodegenerative diseases, including their effects on cognition in AD and PD. This review also proposed new strategies for the design of future clinical trials on GLP-1 RAs for both AD and PD. [ABSTRACT FROM AUTHOR]

Aim: We aimed to investigate the long‐term impact of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) on thyroid function, cardiovascular health, renal outcomes and adverse events in individuals with obesity and without type 2 diabetes (T2D). Materials and Methods: In this observational cohort study, we used propensity score matching to construct comparable cohorts of individuals with obesity and without T2D who were new to GLP‐1 RA treatment and those who did not receive glucose‐lowering medications. In total, 3,729,925 individuals with obesity were selected from the TriNetX Global Network, with an index event between 1 January 2016 and 31 March 2024. The primary outcomes were safety, cardiovascular, thyroid and clinical biochemical profile outcomes occurring within 5 years following the index event. Results: After propensity score matching, the study included 12,123 individuals in each group. GLP‐1 RA treatment was associated with a significantly lower risk of all‐cause mortality (hazard ratio 0.23; 95% confidence interval 0.15–0.34) and several cardiovascular complications, including ischaemic heart disease, heart failure, arrhythmias, hypertension, stroke and atrial fibrillation (all p < 0.05). GLP‐1 RAs were also associated with a lower risk of acute kidney injury and allergic reactions. These protective effects were consistent across various subgroups and regions. Conclusions: In this large observational study, GLP‐1 RAs showed long‐term protective effects on cardiovascular health, renal outcomes and adverse events in individuals with obesity and without T2D. Our findings suggest that GLP‐1 RAs may offer a comprehensive approach to managing obesity and its related comorbidities, potentially improving overall health and survival in this population. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a prevalent condition associated with increased cardiovascular risk, particularly in individuals with comorbid obesity and type 2 diabetes (T2D). Despite the widespread use of continuous positive airway pressure (CPAP) for OSA management, adherence remains suboptimal, and CPAP has not consistently demonstrated reductions in surrogate cardiovascular events. Recently, attention has focused on glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors as potential therapeutic agents for mitigating cardiovascular risk in OSA patients. These agents, originally developed for T2D management, have demonstrated pleiotropic effects, including significant weight loss, blood pressure reduction, and amelioration of endothelial dysfunction and arterial stiffness, along with anti-inflammatory benefits, which may be particularly beneficial in OSA. Emerging clinical evidence suggests that GLP-1RAs and SGLT2 inhibitors can reduce OSA severity and improve daytime sleepiness, potentially reversing the adverse cardiovascular effects observed in OSA. This review explores the pathophysiological mechanisms linking OSA with cardiovascular disease and evaluates the potential therapeutic roles of GLP-1RAs and SGLT2 inhibitors in addressing cardiovascular risk in OSA patients. Further research, including long-term clinical trials, is necessary to establish the effectiveness of these therapies in reducing cardiovascular events and improving patients' reported outcomes in this population. [ABSTRACT FROM AUTHOR]

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Tobacco use represents the leading preventable risk factor for premature deaths worldwide. A meta-analysis of 74 epidemiological studies, including 3.2 million individuals with type 2 diabetes mellitus (T2DM) from 33 countries, reported a pooled prevalence of smoking of 20.8% among individuals with T2DM. Cigarette smoking further aggravates existing deleterious vascular effects of T2DM. Namely, chronic hyperglycemia and exposure to cigarette smoke cause additive injurious effect on the endothelium, leading to an acceleration of vascular complications seen in persons with T2DM and tobacco use disorders (TUD). In a recent study, Wang and colleagues found that semaglutide use was associated with a significantly lower risk for medical encounters for TUD, when compared to other antidiabetic drug classes; indeed, this effect was strongest compared with insulins and weakest compared with other glucagon-like peptide-1 receptor agonists. Semaglutide was associated with reduced smoking cessation medication prescriptions and counseling. Similar findings were observed irrespective of the presence of obesity. Therefore, semaglutide use might be useful in terms of smoking cessation among individuals with T2DM, thus offering an additional benefit for this constantly growing population. However, those interesting findings should be confirmed through dedicated, large-scale randomized controlled trials. [ABSTRACT FROM AUTHOR]

Haihao Yan,1,2 Wenjing Yao,2 Yanhong Li,1 Tianxing Li,3 Kexin Song,1 Pan Yan,4 Yi Dang2 1Department of Internal Medicine, Graduate School of Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of China; 2Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China; 3Department of Graduate School of Hebei North University, Zhangjiakou, Hebei, 075000, People’s Republic of China; 4Department of Internal Medicine, Yongnian District Traditional Chinese Medicine Hospital, Handan, Hebei, 057150, People’s Republic of ChinaCorrespondence: Yi Dang, Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China, Tel +86-0311-85988645, Email dangyiemail@sina.comBackground: Acute myocardial infarction (AMI) is a significant clinical challenge. Semaglutide has therapeutic potential in cardiovascular disease management, but its specific impact and mechanisms in AMI are not fully understood.Methods: Twenty-four male Sprague-Dawley rats were divided into three groups: control (Control), infarction-only (MI), and semaglutide-treated (SEMA). Weight, blood glucose, and lipid profiles were analyzed. Cardiac function was evaluated via echocardiography. Histopathological assessment and immunohistochemical analysis were performed. Untargeted metabolomic analysis using LC-MS/MS was utilized.Results: Semaglutide treatment was associated with a reduction in body weight, blood glucose, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), as well as an enhancement in the left ventricular ejection fraction (Control vs MI vs SEMA, 69.13± 4.30 vs 30.16± 3.17 vs 39.81± 6.13, P < 0.05). It also had a lower collagen volume fraction (3.05 vs 34.05 vs 17.73, P < 0.05) and ameliorated the accumulation of glycogen in the myocardium. Metabolomic profiling revealed differentially expressed metabolites between the control/MI and MI/SEMA groups, predominantly within benzenoid, lipid, and organic acid categories. Pathway enrichment analysis highlighted amino sugar and nucleotide sugar metabolism, chlorocyclohexane and chlorobenzene degradation, and phenylalanine, tyrosine, and tryptophan biosynthesis. Random forest analysis identified key metabolites, including downregulated Docusate sodium, 1-(2-Thienyl)-1-heptanone, and Adenylyl-molybdopterin, alongside upregulated Methylenediphosphonic acid, Choline sulfate, and Lactosamine.Conclusion: Semaglutide significantly ameliorated myocardial fibrosis and metabolic dysregulation in rats post-myocardial infarction. Its mechanism involves modulating glucose metabolism, lipid metabolism, and organic acid metabolism. Targeted metabolites, including Docusate sodium, 1-(2-Thienyl)-1-heptanone, Adenylyl-molybdopterin, Methylenediphosphonic acid, Choline sulfate, and Lactosamine, are implicated in the metabolic reprogramming induced by semaglutide.Keywords: semaglutide, myocardial infarction, cardiometabolic, untargeted metabolomic analysis, glucagon-like peptide-1 receptor agonists

Abstract Background Glucagon-like peptide-1 receptor agonists are a viable option for the prevention of Alzheimer’s disease (AD) but the mechanisms of this potential disease modifying action are unclear. We investigated the effects of once-weekly exenatide (EQW) on AD associated proteomic clusters. Methods The Exenatide Study of Cardiovascular Event Lowering study compared the cardiovascular effects of EQW 2 mg with placebo in 13,752 people with type 2 diabetes mellitus. 4,979 proteins were measured (Somascan V0.4) on baseline and 1-year plasma samples of 3,973 participants. C-reactive protein (CRP), ficolin-2 (FCN2), plasminogen activator inhibitor 1 (PAI-1), soluble vascular cell adhesion protein 1 (sVCAM1) and 4 protein clusters were tested in multivariable mixed models. Results EQW affected FCN2 (Cohen’s d -0.019), PAI-1 (Cohen’s d -0.033), sVCAM-1 (Cohen’s d 0.035) and a cytokine-cytokine cluster (Cohen’s d 0.037) significantly compared with placebo. These effects were sustained in individuals over the age of 65 but not in those under 65. Conclusions EQW treatment was associated with significant change in inflammatory proteins associated with AD. Trial Registration EXSCEL is registered on ClinicalTrials.gov: NCT01144338 on 10th of June 2010.

Doyoung Kwak,1 Yuanjie Liang,2 Xu Shi,3 Xi Tan2 1Department of Electrical & Computer Engineering, Texas A&M University, College Station, TX, USA; 2Novo Nordisk Inc, Plainsboro, NJ, USA; 3Department of Biostatistics, University of Michigan, Ann Arbor, MI, USACorrespondence: Xi Tan, Email mxtz@novonordisk.comPurpose: Observational research provides valuable insights into treatments used in patient populations in real-world settings. However, confounding is likely to occur if there are differences in patient characteristics associated with both the exposure and outcome between the groups being evaluated. One approach to reduce confounding and facilitate unbiased comparisons is inverse probability of treatment weighting (IPTW) using propensity scores. Machine learning (ML) and entropy balancing can potentially be used in generating propensity scores for IPTW, but there is limited literature on this application. We aimed to assess the feasibility of applying these methods for reducing confounding in observational studies. These methods were assessed in a study comparing cardiovascular outcomes in adults with type 2 diabetes and established atherosclerotic cardiovascular disease taking once-weekly glucagon-like peptide-1 receptor agonists or dipeptidyl peptidase-4 inhibitors.Methods: We applied advanced methods to generate the propensity scores compared to the original logistic regression method in terms of covariate balance. After calculating weights, a weighted Cox proportional hazards model was used to calculate the sample average treatment effect. Support Vector Classification, Support Vector Regression, XGBoost, and LightGBM were the ML models used. Entropy balancing was also performed on features identified in the original cardiovascular outcomes study.Results: Accuracy (range: 0.71 to 0.73), area under the curve (0.77 to 0.79), precision (0.53 to 0.60), recall (0.66 to 0.68), and F1 score (0.60 to 0.64) were similar between all of the advanced propensity score methods and traditional logistic regression. Among ML models, only XGBoost achieved balance in all measured baseline characteristics between the two treatment groups, closely approximating the performance of the original logistic regression. Entropy balancing weights provided the best performance among all models in balancing baseline characteristics, achieving near perfect balancing.Conclusion: Among the advanced methods examined, entropy balancing weights performed the best for optimizing balancing and can produce similar results compared to traditional logistic regression.Keywords: propensity score, machine learning, entropy balancing, type 2 diabetes, glucagon-like peptide-1 receptor agonists

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to provide cardiovascular benefits in patients with type 2 diabetes mellitus (T2DM). However, their cardiovascular protective efficacy in high-risk T2DM patients, particularly those with a history of cardiovascular events or severe chronic kidney disease, remains uncertain. Methods A comprehensive search was conducted in PubMed, Embase, Web of Science, and The Cochrane Library to identify randomized controlled trials (RCTs) that evaluated the effects of GLP-1 RAs on cardiovascular outcomes in high-risk patients with T2DM. A random-effects model was used to calculate pooled hazard ratios (HRs) for cardiovascular outcomes. Subgroup analyses and GRADE assessment were also performed. Results Nine RCTs involving 63,613 patients were included. GLP-1 RAs significantly reduced the risk of the primary composite outcome (HR: 0.86, 95% CI: 0.80–0.92), cardiovascular death (HR: 0.85, 95% CI: 0.78–0.93), all-cause death (HR: 0.87, 95% CI: 0.82–0.93), myocardial infarction (HR: 0.90, 95% CI: 0.82–0.98), stroke (HR: 0.85, 95% CI: 0.77–0.95), and heart failure (HF) hospitalization (HR: 0.90, 95% CI: 0.83–0.97). No significant difference in unstable angina (UA) hospitalization was observed (HR: 1.04, 95% CI: 0.95–1.15). Subgroup analyses indicated greater benefits with combination therapy, particularly in patients with chronic kidney disease. The quality of evidence was rated as “High” for six outcomes and “Moderate” for UA hospitalization. Conclusions GLP-1 RAs significantly reduce cardiovascular risk in high-risk T2DM patients, especially with combination therapy and in those with chronic kidney disease. However, further research is needed to confirm their long-term effects.

INTRODUCTION: The aim of this meta-analysis was to investigate the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on blood glucose and weight in adolescents with overweight/obesity and/or type 2 diabetes mellitus (T2DM) aged