Glucagon-like Peptide-1 Agonists Research Articles

Use of Obesity Medications in the Era of GLP-1 Agonists: An Expert Panel Discussion.

Use of Obesity Medications in the Era of GLP-1 Agonists: An Expert Panel Discussion.

Consideraciones Perioperatorias de los Análogos GLP-1.

GLP-1 agonists are novel medications. Its relationship with the decrease in gastric motility is clear; this presents a challenge when performing an induction under general anesthesia. Therefore, knowing its pharmacokinetics and the current recommendations described by the American Society Anesthesiologists (ASA) to evaluate perioperative risk during elective surgery are important. The objective is to review pharmacokinetics of GLP-1 analogues and evaluate current recommendations for perioperative management in patients undergoing elective surgery. We searched for articles using the keywords and medical topic titles: incretins; glucagon-like peptide-1; GLP-1; glucagon-like peptide 1 receptor agonists; GLP-1 RA; perioperative period; perioperative; perioperative; stomach emptying; gastric emptying; pulmonary aspiration; aspiration of gastric content; regurgitation of food; and regurgitation. The evidence was analyzed, synthesized and reported narratively. The elimination half-life of GLP-1 agonists determines the suspension time prior to the surgical procedure. Gastric ultrasound is a potentially quantitative tool to evaluate gastric contents prior to elective surgery.

An exploratory analysis of glucagon-like peptide-1 (GLP-1) agonists and biosimilars: A literature review.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are at the forefront of treating the global health crisis of diabetes mellitus (DM) and obesity. However, the demand for GLP-1 RAs has far outstripped its supply and comes with a high monthly cost. Thus, the development of GLP-1 RA biosimilars can potentially address these barriers by providing greater access to medications that provide clinical outcomes similar to those of the reference products. A narrative review was conducted to examine the current and future developments for GLP-1 RA biosimilars. Liraglutide and semaglutide are the predominant GLP-1 RAs being investigated for the development of biosimilars. Preliminary liraglutide biosimilar comparisons to reference liraglutide have demonstrated similar clinical efficacy and safety profiles. Semaglutide and beinaglutide biosimilars are currently under investigation as well. With the growing popularity of GLP-1 RAs, accessibility and affordability remain a challenge as monthly costs without insurance for liraglutide, semaglutide and tirzepatide are $1418, $892, and $974 respectively. This trend negatively impacts patients with obesity and DM as well as patients who can utilize it for off-label indications for conditions that benefit from weight loss such as obstructive sleep apnoea and non-alcoholic fatty liver disease. A substantial number of pharmaceutical and healthcare companies worldwide are conducting clinical trials on their GLP-1 RA biosimilars. Preliminary results from liraglutide biosimilars are promising, and several semaglutide biosimilars are currently being investigated. Future research should focus on conducting comparative head-to-head trials to determine the clinical outcomes between biosimilars and reference products.

The Role of GLP-1 Agonists in Esthetic Medicine: Exploring the Impact of Semaglutide on Body Contouring and Skin Health.

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, have revolutionized the treatment of diabetes and obesity by promoting significant weight loss through incretin effects. However, rapid weight reduction induced by these medications often leads to esthetic challenges, including facial volume loss, skin laxity, and body contour irregularities. This commentary reviews the esthetic consequences of GLP-1-induced weight loss and explores solutions for managing these concerns in clinical practice. This review synthesizes available literature and clinical observations to identify key esthetic concerns associated with GLP-1-induced weight loss. It examines various treatment modalities, including dermal fillers, biostimulatory agents, energy-based devices, and surgical procedures. The discussion highlights gaps in empirical data, optimal timing for interventions, and the need for personalized, multimodal treatment strategies. Imaging tools and psychological support are also considered as complementary approaches. As GLP-1 agonists become a cornerstone in obesity management, their esthetic implications necessitate a proactive response from esthetic practitioners. Effective management of facial volume loss, skin laxity, and body contour challenges requires a combination of injectable treatments, energy-based devices, and, in some cases, surgical interventions. Future research should focus on understanding the molecular mechanisms of skin and fat changes and developing standardized guidelines for treating this unique patient population. Additionally, a holistic approach that addresses both physical and psychological outcomes is critical to ensuring patient satisfaction and long-term well-being.

SGLT2 inhibitors reduce epicardial adipose tissue more than GLP-1 agonists or exercise interventions in patients with type 2 diabetes mellitus and/or obesity: A systematic review and network meta-analysis.

Epicardial adipose tissue (EAT) plays a significant role in several cardiovascular diseases. As a correctable risk factor and potential therapeutic target, reducing EAT has multiple cardiovascular benefits, especially in those with abnormal glucolipid metabolism. The objective of this research was to compare the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and exercise on the thickness of EAT and indicators of glucolipid metabolism in people with type 2 diabetes mellitus (T2DM), obesity, and T2DM with obesity. We searched four electronic databases: PubMed, EMBASE, the Cochrane Library, and Web of Science for articles before 31 January 2024, regardless of language. We included randomized controlled trials and a small number of case-control studies in this network meta-analysis. Differences in mean changes in EAT, body mass index, and glucolipid metabolism-related metrics were assessed. A comprehensive analysis was conducted on 16 trials (15 randomized controlled trials and one case-control study), comprising a total of 867 people. SGLT2 inhibitors were significantly better at reducing EAT than placebo (standard mean different [SMD] = -0.85 cm [95% confidence interval (CI) -1.39, -0.31]); a similar result was observed for exercise compared with placebo (SMD = -0.78 cm [95% CI -1.37, -0.18]). SGLT2 inhibitors were also significantly better at reducing EAT than GLP-1 agonists and conventional hypoglycaemic therapy (e.g., metformin or insulin; SMD = -0.74 cm [95% CI -1.45, -0.02] and SMD = -1.69 cm [95% CI -2.38, -0.99], respectively). SGLT2 inhibitors were significantly better than placebo at reducing body mass index (MD = -0.90 kg/m2 [95% CI -1.14, -0.66]) and glycosylated haemoglobin (MD = -0.52% [95%CI -0.86, -0.18]). A similar result was observed when comparing GLP-1 agonists and placebo (MD = -0.48% [95% CI -0.93, -0.03]). Changes in total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were not statistically significant between interventions. SGLT2 inhibitors have a distinct advantage over both placebo and other therapies at lowering EAT thickness, a result supported by direct comparisons and surface under the cumulative ranking curve analysis. Therefore, SGLT2 inhibitors should be prioritized as a treatment to reduce EAT in individuals with aberrant glucolipid levels, such as patients with T2DM and/or obesity.

Comparative Effects of GLP-1 Agonists, Sleeve Gastrectomy and Roux-en-Y Gastric Bypass on Diabetes Mellitus Outcomes.

The purpose of this review is to assess the effects of glucagon-like peptide-1 (GLP-1) agonists, sleeve gastrectomy (SG), and Roux-en-Y gastric bypass (RYGB) on type 2 diabetes mellitus (T2DM) remission. This review explores the efficacy, safety, and durability of these surgical and medical modalities of diabetes management. Studies have shown that GLP-1 agonists achieve higher rates of T2DM remission compared to standard glucose-lowering medications and lifestyle changes. In addition to weight loss, bariatric surgery has been found to be highly effective in treating and inducing remission of T2DM. Studies suggest that post-surgical patients see enhanced glycemic control. Both surgical interventions and GLP1 agonists are effective in achieving T2DM remission. Long-term follow-up and randomized controlled trials comparing bariatric surgery and GLP-1 agonists are necessary to evaluate their relative effectiveness in T2DM control. Further research is also needed to assess the combined effects of these treatment modalities.

The role of glucagon-like peptides in osteosarcopenia.

Various metabolic abnormalities including obesity, insulin resistance, hypertension, dyslipidemia, hyperthyroidism, and low vitamin D levels have been linked to both osteopenia and sarcopenia. Osteo-sarcopenia is also commonly observed due to aging that notably include postmenopausal women. GLP-1, a labile incretin secreted from the intestinal L-cells stimulates insulin secretion and sensitivity, making it an effective anti-diabetic medication. GLP-1 binds to its receptor, the GLP-1 receptor, a G-protein-coupled receptor, and leads to the stimulation of adenylate cyclase, increasing the levels of cyclic AMP (cAMP). Elevated cAMP then activates protein kinase A and other downstream signaling pathways. These signaling cascades result in various cellular responses, such as enhanced insulin secretion from pancreatic beta cells, improved insulin sensitivity, and modulation of appetite and gastric emptying. Additionally, GLP-1 signaling can promote cell growth and survival, contributing to its effects on muscle and bone health. Its role as an anti-diabetic medication has been enhanced through various modifications to extend its half-life, thereby improving its effectiveness and druggability. GLP-1 analogs, initially developed for diabetes management, have also been harnessed for obesity treatment due to the effect of GLP-1 to induce satiety and slow gastric emptying. Beyond their well-known anti-diabetic and anti-obesity effects, GLP-1 agonists can enhance muscle mass and bone density, making them valuable in addressing conditions like sarcopenia and osteoporosis. This review focuses on the effects of GLP-1 analogs on musculoskeletal health, by critically assessing the underlying signaling mechanisms in order to understand their translational potential for the treatment of osteo-sarcopenia.

Management of obesity with semaglutide or metformin in patients with antipsychotic-induced weight gain (MOSA): a non-randomised open-label pilot study

BackgroundAntipsychotic-induced weight gain (AIWG) represents a significant clinical challenge for both patients and clinicians, requiring appropriate interventions to prevent or reverse weight gain in patients using antipsychotics. Glucagon-like peptide 1 (GLP-1) agonists represent a novel approach to the management of obesity that has recently attracted considerable attention. Semaglutide (a GLP-1 agonist) has been demonstrated to result in notable weight loss. The present study investigates whether semaglutide is equally effective in achieving weight loss in patients with AIWG.MethodsA prospective, non-randomised cohort study was conducted with the objective of evaluating the efficacy and safety of oral semaglutide for the treatment of AIWG in routine outpatient clinical practice. Subsequently, the results were compared with those of a control group of AIWG patients taking metformin.ResultsAfter 16 weeks, the mean body weight loss was 4.5 kg (95% confidence interval (CI), -6.7 to -2.3 kg; p < 0.001) in the semaglutide group (n = 10) versus 2.9 kg (95% CI, -4.5 to -1.4 kg; p < 0.001) in the metformin group (n = 26). This corresponds to an average body weight loss of 4% for semaglutide, and 2.5% for metformin. The respective reductions in body mass index (BMI) and waist circumference were -1.7 kg/m2 (95% CI, -2.4 to -1.0 kg/m2; p < 0.001) and -6.8 cm (95% CI, -9.7 to -3.8 cm; p < 0.001) for semaglutide. The observed reductions for metformin were -0.8 kg/m2 (95% CI, -1.4 to -0.3 kg/m2; p = 0.001) and -3.4 cm (95% CI, -5.4 to -1.3 cm; p = 0.001). The differences between the two groups were not statistically significant. In both groups, adverse effects were typically mild and transient, predominantly nausea. Furthermore, psychiatric symptoms were reduced, and quality of life improved.ConclusionsOral semaglutide represents a viable, effective, and safe treatment option for psychiatric patients. However, further investigation is required to corroborate these findings.

GLP‐1 receptor agonists for Parkinson's disease: An updated meta-analysis

IntroductionTreatments for Parkinson's disease (PD) focus on symptom reduction through dopaminergic therapies, without clear evidence of disease-modifying effects. Glucagon-like peptide-1 (GLP-1) receptor agonists may reduce neuroinflammation by decreasing microglia activation in PD. Clinical trials suggest these agents have disease-modifying potential in PD. ObjectiveEvaluate the efficacy of GLP-1 receptor agonists in PD. MethodsPubMed, Embase and Cochrane Library were searched to identify randomized controlled trials (RCTs) of GLP-1 agonists for PD, up to July 2024. The risk of bias was assessed using the RoB-2 tool, and statistical analysis was performed with RevMan 5.4.1 software. ResultsGLP-1 receptor agonists showed a beneficial effect on MDS-UPDRS part III motor scores compared to placebo. Off-medication state, there was a −1.22 point improvement (95%CI -2.46, 0.22; P = 0.05). On-medication state, scores improved by −2.52 points (95%CI -4.02, −1.01; P = 0.001). The global MDS-UPDRS score showed a −3.43-point difference (95%CI -6.48, −0.48; P = 0.02). Cognitive performance, assessed via the Mattis DRS-2, improved by 1.32 points (95%CI 0.16, 2.52; P = 0.03). There were no significant differences in the NMSS (−0,19; 95%IC -3,44, 3,05; P = 0.91), in MADRS (−1,04; 95%IC -2,57, 0,48; P = 0.18), or PDQ-39 (−0,91; 95%IC -2,22, 0,39; P = 0.17). ConclusionGLP-1 receptor agonists improved motor and cognitive performance in PD, suggesting potential symptomatic benefits. However, further studies are needed to evaluate their long-term effects and their role in disease modification, especially considering ethnic and disease severity variations.

Why does GLP-1 agonist combined with GIP and/or GCG agonist have greater weight loss effect than GLP-1 agonist alone in obese adults without type 2 diabetes?

Obesity is a chronic condition demanding effective treatment strategies, among which pharmacotherapy plays a critical role. As glucagon-like peptide-1 (GLP-1) agonist approved by the Food and Drug Administration (FDA) for long-term weight management in adults with obesity, liraglutide and semaglutide have great weight loss effect through reducing food intake and delaying gastric emptying. The emergence of unimolecular polypharmacology, which utilizes single molecules to simultaneously target multiple receptors or pathways, marked a revolutionary improvement in GLP-1-based obesity pharmacotherapy. The dual agonist tirzepatide activates both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors and has shown enhanced potency for weight loss compared to conventional GLP-1 mono agonist. Furthermore, emerging data suggests that unimolecular GLP-1/glucagon (GCG) dual agonist, as well as GLP-1/GIP/GCG triple agonist, may offer superior weight loss efficacy over GLP-1 agonist. This review summarizes the comprehensive mechanisms underlying the pronounced advantages of GLP-1/GIP dual agonist, GLP-1/GCG dual agonist and GLP-1/GIP/GCG triple agonist over GLP-1 mono agonist in weight reduction in obese adults without type 2 diabetes. A deeper understanding of these unimolecular multitargeting GLP-1-based agonists will provide insights for their clinical application and guide the development of new drugs for obesity treatment.

Bridging the Gap Between Diabetes and Cardiovascular Disease: A Comparative Review of Different Glucagon-Like Peptide-1 (GLP-1) Agonists: Efficacy, Safety, and Patient Outcomes

Bridging the Gap Between Diabetes and Cardiovascular Disease: A Comparative Review of Different Glucagon-Like Peptide-1 (GLP-1) Agonists: Efficacy, Safety, and Patient Outcomes

Protective effect of Dulaglutide, a GLP1 agonist, on acetic acid-induced ulcerative colitis in rats: involvement of GLP-1, TFF-3, and TGF-β/PI3K/NF-κB signaling pathway.

A chronic inflammatory condition of the colon called ulcerative colitis (UC) is characterized by mucosal surface irritation that extends from the rectum to the near proximal colon portions. The rationale of this work was to conclude if dulaglutide (Dula) could protect rats from developing colitis caused by exposure to acetic acid (AA). Rats were randomly divided into seven groups (each with eight rats): Normal control, Dula control, AA (received 2 milliliters of 3% v/v AA through the rectum), Sulfasalazine (SLZ); given SLZ (100 mg/kg) orally from day 11 to day 21 then AA intrarectally on day 22 and Dula groups ( pretreated with 50, 100 or 150 μg/kg subcutaneous injection of Dula - once weekly for three weeks and AA on day 22 to induce ulcerative colitis, colon tissues and blood samples were taken on day 23. By generating colonic histological deviations such as inflammatory processes, goblet cell death, glandular hyperplasia, and mucosa ulcers, Dula dropped AA-induced colitis. Additionally, these modifications diminished blood lactate dehydrogenase (LDH), C-reactive protein (CRP), colon weight, and the weight/length ratio of the colon. In addition, Dula decreased the oxidative stress biomarker malondialdehyde (MDA) and increased the antioxidant enzymes (total antioxidant capacity (TAC), reduced glutathione (GSH), and superoxide dismutase (SOD) concentrations). Dula also significantly reduced the expression of transforming growth factor-1 (TGF-β1), phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT) signaling pathway, and the inflammatory cytokines: nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), and interferon-γ (IFN-γ) in colonic cellular structures. In addition, Dula enforced the levels of glucagon-like peptide-1 (GLP-1) and trefoil factor-3 (TFF-3) that were crucial to intestinal mucosa regeneration and healing of wounds. By modulating TGF-β1 in conjunction with other inflammatory pathways like PI3K/AKT and NF-κB, regulating the oxidant/antioxidant balance, and improving the integrity of the intestinal barrier, Dula prevented AA-induced colitis in rats.

PNPLA3 I148M Interacts With Environmental Triggers to Cause Human Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects up to 30% of Western populations. While obesity is a recognized risk factor, MASLD does not develop in all obese individuals, highlighting the need to understand genetic and environmental interactions. The PNPLA3 I148M variant has been identified as a key genetic risk factor, significantly increasing the likelihood of MASLD development and progression. We reviewed current literature on the role of PNPLA3 I148M in MASLD, focusing on gene-environment interactions involving diet, physical activity, obesity, and insulin resistance. We included studies analysing ethnic differences in PNPLA3 I148M prevalence and its association with MASLD. Additionally, we reviewed data on how PNPLA3 I148M influences the response to therapies, including lipid-lowering medications and GLP-1 agonists. The PNPLA3 I148M variant markedly heightens MASLD risk, particularly in Hispanic populations, where a higher prevalence of MASLD is observed. Lifestyle factors such as high sugar intake, alcohol consumption, and physical inactivity exacerbate MASLD risk among I148M carriers. Evidence shows that insulin resistance amplifies MASLD risk associated with the I148M variant, especially in non-diabetic individuals. Moreover, the PNPLA3 I148M variant interacts with other genetic loci, further modifying MASLD risk and disease course. The variant also influences treatment response, with variability observed in effectiveness of lipid-lowering therapies and GLP-1 agonists among carriers. The interplay between PNPLA3 I148M and environmental factors underscores the need for personalized MASLD prevention and treatment strategies. Targeting both genetic and lifestyle contributors may enhance MASLD management, offering a tailored approach to reducing disease burden.

Impact of glucagon-Like peptide-1 agonists in optimizing abdominal wall Reconstruction patients.

Pre-optimization of obese patients prior to abdominal wall reconstruction (AWR) is essential in mitigating their increased preoperative risks. Traditionally diet, exercising, bariatric surgery are the tools typically prescribed for weight loss. The advent of glucagon-like peptide-1 agonists (GLP-1A) which stimulate insulin secretion and inhibit gastric emptying have improved the weight loss armamentarium. However, there is a limited amount of literature on GLP-1A effectiveness and postoperative outcomes in AWR patients. This study compares the efficacy of GLP-1A to Bariatric Surgery (BAS) in perioperative AWR patient. A prospectively maintained database was retrospectively reviewed to identify all patients undergoing AWR at our institution between January 2021 and March 2024. We included patients who required GLP-1A or BAS for weight optimization prior to AWR. We excluded patients on GLP1-A or history BAS not performed for AWR preoptimization. Basic demographics such as age, sex, race, weight and BMI at initial clinic visit and at surgery were compared. Primary endpoints included time to surgery, time to bowel recovery and length of stay (LOS). Time to surgery was defined as the number of months between the initial clinic visit and AWR. Time to bowel recovery was defined as the number of days it took for the first postoperative bowel function. Secondary endpoints included standard 30-days postoperative variables. Nominal variables were analyzed using a Fisher exact test and continuous variables were analyzed with Student's T test. 35 patients were included in this study (GLP-1A: 17, BAS: 18). The GLP-1A cohort had a lesser BMI at the initial clinic visit (40.8 vs 43.4, p = 0.188). GLP-1A cohort made it to the operating room faster (9.1 months vs 13.5 months, p = 0.06) from the first clinic visit; and (7.9 months vs 9.7 months, p = 0.4) from initiation of weight loss intervention. Albeit losing less weight (14.9 kg vs 27.1 kg, p = 0.008) with a lesser reduction in the BMI (4.69 vs 9.23, p = 0.004). The GLP-1A cohort showed a non-significant elevated LOS (5.2 days vs 3.6 days, p = 0.25) and an increased ileus rate (17.6% vs 0%, p = 0.1). However, there were no differences noted in time to bowel recovery (2.9 days vs 3.1 days, p = 0.76). GLP-1A is effective in optimizing patients needing weight loss before AWR. They shorten the timeline to AWR intervention and have comparable peri-operative outcomes to BAS patients.

Pharmacologic Treatment of Pulmonary Hypertension Due to Heart Failure with Preserved Ejection Fraction: Are There More Arrows on Our Bow?

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF) represents a frequent form of PH related to left ventricular dysfunction. The pathophysiology of PH-HFpEF is intricate, and varied and includes vascular, cardiac, and pulmonary factors that contribute synergistically to developing this clinical syndrome. Improved knowledge of the pathophysiology of PH-HFpEF has paved the way for the use of new drugs such as angiotensin receptor neprilysin inhibitors (ARNIs), non-steroidal mineral corticoid receptor antagonist (nsMRA), sodium-glucose cotransporter inhibitors (SGLT2is), levosimendan, and glucagon-like peptide 1 (GLP-1) agonists. ARNIs are a widely used drug for the treatment of PH associated with heart failure with reduced ejection fraction. They have also recently been used in PH-HFpEF patients with hemodynamic benefits that need to be confirmed in future research. Finerenone is an innovative non-steroidal mineralocorticoid receptor antagonist that exhibits notable cardioprotective and renoprotective properties in individuals suffering from chronic diabetic kidney disease. It also enhances outcomes for patients with heart failure, whether they have mildly reduced or preserved ejection fraction. Moreover, in experimental studies, finerenone has been found to lower pulmonary artery pressure, reduce muscularization, and decrease the wall thickness of pulmonary arteries. SGLT2i have revolutionized the treatment of patients with heart failure irrespective of left ventricular ejection fraction, and their treatment is also associated with an improvement in the hemodynamics profile in patients with PH-HFpEF. Levosimendan is a widely used inodilator in the treatment of acute and advanced heart failure. In addition, its use in patients with PH-HFpEF (supported by the positive effects on pulmonary hemodynamics that levosimendan exerts) has recently demonstrated hemodynamic benefit in a small phase 2 study that paved the way for phase 3 studies and the creation of an oral formulation of levosimendan. Finally, GLP1 agonists are a class of drugs that, in preliminary evidence, have shown a positive effect on cardiac hemodynamics, mainly by facilitating left ventricular unloading. These effects, along with the reduction in insulin resistance and weight loss, likely lead to beneficial outcomes for PH-HFpEF patients, especially those with obesity as a comorbidity.

Abstract 4138604: Impact of GLP-1 Agonist on the Incidence of Atrial Fibrillation in Obese Patients Following Heart Failure Hospitalization

Introduction: Atrial fibrillation (AF) in patients with heart failure (HF) is associated with increased morbidity and mortality. Glucagon-like peptide-1 (GLP-1) agonists have been shown to reduce cardiovascular risk in patients with obesity and diabetes, respectively. Meta-analysis of prospective trials looking at GLP-1 agonist use on the incidence of AF suggest benefit in patients with diabetes but is of unclear benefit in this regard for patients with obesity. Hypothesis: GLP-1 agonists reduce atrial fibrillation incidence in patients with diabetes and obesity. Aims: The goal of the study is to assess the effects of GLP-1 agonist on incidence of new AF in patients with obesity and diabetes following heart failure hospitalization. Methods: The study included consecutive patients who were admitted to an academic tertiary care center over three years with a primary diagnosis of heart failure exacerbation and no prior diagnosis of AF. The primary outcome was incidence of AF within 12 months after hospitalization. Demographic, comorbidity, echocardiography, and medications were obtained. Cox-regression analysis was performed to identify the predictors of new-onset AF following HF hospitalization. Results: Of the patients included in our study, 1668 (42.9%) have a BMI greater than or equal to 30, 574 (14.5%) have BMI greater than or equal to 40, and 2300 (58.2%) have diabetes mellitus. GLP-1 use is associated with a significantly lower incidence of AF at one year in obese patients (p=0.042; RR 0.73; 95% CI: 0.54-.99) (Figure), while in non-obese individuals, GLP-1 receptor agonist was not associated with a decreased incidence of AF (p=0.674; RR 1.08; 95% CI: 0.76-1.53). In patients with diabetes, GLP-1 receptor agonist use did not reach statistical significance for reduced AF incidence following heart failure hospitalization ( p=0.091; RR 0.80; 95% CI 0.62-1.04 ). Conclusion: GLP-1 receptor agonist use is associated with a statistically significant reduction of incidence of new atrial fibrillation at one year following hospitalization for heart failure in obese patients.

Safety and Efficacy of GLP-1 Agonists in a Cohort of Patients with Fontan Circulation.

There are a growing number of adult patients palliated to a Fontan circulation. As these patients age, many develop symptomatic heart failure (d'Udekem et al in Circulation 130:S32-S38, 2014) that is exacerbated by acquired comorbidities such as obesity and hypertension. Increased body mass index (BMI) and adiposity have been associated with worse hemodynamics and clinical outcomes in these patients (Yogeswaran et al in J Am Hear Assoc: Cardiovasc Cerebrovasc Dis 12:e026732, 2023). Recently, glucagon-like peptide-1 (GLP-1) agonists, originally developed to treat diabetes mellitus, received FDA approval for weight loss and have been shown to reduce the risk of cardiovascular events in the general population (Vilsbøll et al in BMJ 344:d7771, 2012). There are limited data on these medications in patients with a Fontan circulation. We conducted a retrospective review of adults with Fontan circulation followed in our adult congenital heart disease (ACHD) clinic between 2009 and 2023 and identified 8 patients prescribed GLP-1 agonists. We found that GLP-1 agonists were well-tolerated and led to modest reduction in weight and blood pressure. Further study of the use of these medications in this population is warranted.

Abstract 4134637: Impact of Glucagon-Like Peptide-1 Agonists on Cardiovascular Outcomes in Chronic Kidney Disease Stage 5: A Propensity Score-Matched Analysis

Background: Patients with chronic kidney disease stage 5 (CKD-5) face heightened risks of cardiovascular (CV) complications and mortality. Glucagon-like peptide-1 agonists (GLP-1a), primarily used in type 2 diabetes, are being investigated for potential CV benefits in this population. This study aims to evaluate the impact of GLP-1a treatment on CV outcomes and survival among CKD-5 patients. Methods: This retrospective cohort study utilized data of adult patients diagnosed with CKD-5 between January 2014 and August 2023 from the TriNetX global research network. A propensity score matching analysis of those treated with GLP-1a for at least six months versus those never exposed to GLP-1a therapy was conducted. Results: Our analysis showed significantly reduced odds for the composite primary outcome of acute myocardial infarction (AMI), stroke, and mortality (OR = 0.66, 95% CI: 0.57-0.78, p&lt;0.001), and other CV outcomes such as cardiac arrest, hypertensive crisis, and hypertensive urgency, among the GLP-1a cohort compared with the non-GLP-1a cohort. Kaplan-Meier survival analysis revealed a significantly higher five-year incidence-free probability for the composite primary outcome (63.5% vs. 50.5%, p&lt;0.001) and for other CV outcomes such as hypertensive events, AMI, cardiac arrest, and hemorrhagic stroke for the GLP-1a cohort. Conclusion: The study suggests that GLP-1a therapy in CKD 5 patients may confer certain CV benefits. Further investigations are warranted to elucidate the underlying mechanisms and confirm the therapeutic efficacy of GLP-1a in this patient population.

Efficacy and Safety of GLP-1 Agonists on Metabolic Parameters in Non-diabetic Patients with Inflammatory Bowel Disease.

Obesity in patients with IBD is increasing, accompanied by an increase in metabolic comorbidities. Although GLP-1 agonists have shown promise in weight reduction, their efficacy and safety in patients with IBD are underexplored. This study evaluated the impact of GLP-1-based therapies on weight loss and metabolic parameters in non-diabetic patients with IBD. We conducted a single-center observational cohort study that included adult patients with IBD who were started on GLP-1-based therapy (semaglutide or tirzepatide) for weight loss from January 2021 to April 2024. The primary outcomes were changes in BMI and total body weight. Secondary outcomes included tolerability, safety, and changes in metabolic risk factors. The study included 36 patients with IBD, predominantly female (64%), with a median age of 45.5 years (IQR 41-51.5 years). The majority (67%) had Crohn's disease (CD) and on advanced therapy (86%). BMI significantly decreased from 34.0 (IQR 31.0-38.2) to 31.0 (IQR 29.0-36.1) with GLP-1-based therapy (p < 0.0001). Total body weight (TBW) significantly decreased by a median of 8.15 kg (IQR 15.9-2.2 kg; p < 0.0001). Although a decrease in total cholesterol and glycated hemoglobin was seen, this was not statistically significant (p = 0.0634 for total cholesterol, p = 0.0536 for glycated hemoglobin). No significant changes were observed in ALT or CRP levels. The most common side effects were nausea (31%) and constipation (25%). Semaglutide and tirzepatide can effectively reduce BMI in non-diabetic patients with IBD with manageable side effects. However, further studies are required to explore the long-term safety of GLP-1 agonists in the IBD population.

Semaglutide Ameliorates Diabetic Neuropathic Pain by Inhibiting Neuroinflammation in the Spinal Cord.

Male Wistar rats, each weighing between 300 and 350 g, were categorized into four groups: one non-diabetic sham group and three diabetic groups. The diabetic group received a single intraperitoneal injection of streptozotocin (STZ) at a dosage of 60 mg/kg to induce diabetic neuropathy. After 4 weeks of STZ injection, one diabetic group was given saline (vehicle), and the other two were treated with either 1× SEMA (1.44 mg/kg, orally) or 2× SEMA (2.88 mg/kg, orally). Following a 4-week course of oral drug treatment, behavioral, biochemical, and immunohistochemical analyses were carried out. The mechanical allodynia, thermal hyperalgesia, blood glucose, advanced glycation end products (AGEs), plasma HbA1C, and spinal inflammatory markers were evaluated. SEMA treatment significantly reduced both allodynia and hyperalgesia in the diabetic group. SEMA therapy had a limited impact on body weight restoration and blood glucose reduction. In diabetic rats, SEMA lowered the amounts of pro-inflammatory cytokines in the spinal cord and dorsal horn. It also lowered the activation of microglia and astrocytes in the dorsal horn. SEMA significantly reduced HbA1c and AGE levels in diabetic rats compared to the sham control group. These results indicate SEMA's neuroprotective benefits against diabetic neuropathic pain, most likely by reducing inflammation and oxidative stress by inhibiting astrocyte and microglial activity. Our findings suggest that we can repurpose GLP-1 agonists as potent anti-hyperalgesic and anti-inflammatory drugs to treat neuropathic pain without serious side effects.