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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]

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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. [ABSTRACT FROM AUTHOR]

Obesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown. In this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function. Echocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values. Overall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, −6.13 mL; 95% CI: −9.85 to −2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: −1.99 cm2; 95% CI: −3.60 to −0.38 cm2; P = 0.016; EMD in RV end-systolic area: −1.41 cm2; 95% CI: −2.42 to −0.40] cm2; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: −5.63 cm/s; 95% CI: −9.42 to −1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: −0.14; 95% CI: −0.24 to −0.04; P = 0.0075), and E/e′ (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: −0.79; 95% CI: −1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (P interaction = 0.033) but not with changes in E-wave velocity, E/e′ average, or RV end-diastolic area. In the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511 ; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470) [ABSTRACT FROM AUTHOR]

Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have gained increasing attention for their potential benefits in people with type 2 diabetes mellitus (T2DM) with chronic kidney disease (CKD). Most supportive evidence of a kidney‐protective effect of the GLP‐1RA class of medications has been derived from kidney‐related outcomes reported from cardiovascular outcome trials (CVOTs). GLP‐1RAs have been shown to reduce albuminuria, mitigate cardiovascular risk, and possibly attenuate estimated glomerular filtration rate (eGFR) decline. The kidney‐protective effects of GLP‐1RAs are thought to be attributed to their anti‐inflammatory, antioxidant, and vasodilatory properties. Despite these promising findings, the use of GLP‐RAs has yet to be definitively shown to slow progression to chronic kidney failure in people with T2DM. The Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW trial) is the first major trial assessing the potential of a GLP‐1RA to slow progression of kidney disease in people with established CKD to clinically important kidney end points. On March 5, 2024, the top line result from FLOW was announced with semaglutide 1.0 mg being reported to reduce the primary end point of the trial by a significant 24% compared with placebo. Here, we summarize the kidney outcomes reported from CVOTs for the GLP‐1RA class of medication and briefly describe kidney outcomes from other major GLP‐1RAs trials. We also discuss a potential role of the dual GLP‐1/glucose‐dependent insulinotropic polypeptide (GIP) receptor agonist, tirzepatide, as a kidney‐protective agent. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is a prevalent disease in the general population and also a well-established risk factor for the development of ischemic stroke. Patients who have been diagnosed with diabetes have a 20% higher risk for developing ischemic stroke in comparison to non-diabetic individuals. The aim of the current systematic review is to provide the latest evidence regarding the association between antidiabetic treatment and the prevention of ischemic stroke. Methods: A comprehensive search in scientific literature databases PUBMED, COCHRANE, and SCOPUS was conducted. The studies that were deemed as eligible for this review were those that examined the clinical benefits of therapeutic strategies in terms of preventing ischemic strokes. Results: A total of 32 studies met the established selection criteria. The included studies showed that pioglitazone treatment significantly reduced the risk for recurrent stroke in patients with DM. Furthermore, in the context of primary prevention, the improvement in glycemic control after treatment with the glucagon-like peptide-1 receptor agonists (GLP-1RA) semaglutide and dulaglutide was associated with a reduction in the risk of ischemic stroke in diabetic subjects. Metformin monotherapy may reduce stroke risk, while dipeptidyl peptidase 4 inhibitors, sodium-glucose co-transporter 2 inhibitors, and insulin do not seem to affect the incidence of stroke. Conclusions: The findings of the present systematic review suggest that pioglitazone and GLP-1RA may decrease the risk of stroke. Further studies are needed to provide additional data regarding the preventive effect of novel antidiabetic drugs, such as dual glucose-dependent insulinotropic polypeptide/GLP-1RA agents, on stroke. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Obesity is a disease of epidemic proportions in the United States and contributes to morbidity and mortality for a large part of the population. In addition, the financial costs of this disease to society are high. Lifestyle modifications are key to prevention and treatment but adherence and long‐term success have been challenging. Bariatric surgery has been available and pharmacologic approaches, first developed in the 1950s, continue to be an option; however, existing formulations have not provided optimal clinical efficacy and have had many concerning adverse effects. Over the last decade, glucagon‐like peptide‐1 (GLP‐1) receptor agonists, a novel group of medications for the treatment of type 2 diabetes, were found to produce significant weight loss. Several formulations, at higher doses, received FDA approval for the treatment of obesity or those overweight with weight‐related co‐morbidities. More hormone‐based therapies were and are being developed, some with dual or triple‐receptor agonist activity. Their use, however, is not without questions and concerns as to long‐term safety and efficacy, problems with cost and reimbursement, and how their use may intersect with public health efforts to manage the obesity epidemic. This review will focus on the GLP‐1 receptor agonists currently used for weight loss and discuss their pharmacology, pertinent research findings establishing their benefits and risks, issues with prescribing these medications, and a perspective from a public health point of view. [ABSTRACT FROM AUTHOR]

Background: In patients surviving stroke, approximately 15% and 60% exhibit concurrent diabetes mellitus and overweight/obesity, respectively, necessitating heightened secondary prevention efforts. Despite glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrating improved outcomes for those with diabetes mellitus or obesity, their underutilization persists among eligible individuals. This systematic review and meta-analysis investigated the impact of GLP-1 RAs on stroke risk. The findings aim to optimize the implementation of this therapeutic strategy in patients surviving stroke with diabetes mellitus or obesity. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we systematically reviewed MEDLINE and Scopus until 15 November 2023. Eligible studies included randomized cardiovascular outcome trials (CVOTs) with individuals, with or without type 2 diabetes, randomized to either GLP-1 RA or placebo. The outcomes were total strokes, non-fatal strokes, and fatal strokes. Analyses were conducted using RevMan 5.4.1. Results: Among 1369 screened studies, 11 were eligible, encompassing 82,140 participants (34.6% women) with a cumulative follow-up of 247,596 person-years. In the GLP-1 RAs group, the stroke rate was significantly lower compared to placebo (RR: 0.85, 95% CI: 0.77–0.93; NNT: 200), showing no heterogeneity or interaction with administration frequency (daily vs weekly). In addition, the GLP-1 RAs group exhibited a significantly lower rate of non-fatal strokes compared to placebo (RR: 0.87, 95% CI: 0.79–0.95; NNT: 250), with no heterogeneity or interaction based on administration frequency, route (oral vs subcutaneous), or diabetes presence. Conclusion: In this meta-analysis of 11 CVOTs with 82,140 participants, GLP-1 RAs demonstrated a 16% relative reduction in stroke risk compared to placebo. This finding may increase implementation of GLP-1 RAs by stroke specialists in individuals with stroke and comorbid diabetes mellitus or obesity. Data access statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 receptor agonists (GLP1Ra) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce major adverse cardiovascular events (MACE). We assessed whether the effect differs in patients with and without cardiovascular (CV) disease, and rated the certainty of evidence by conducting a systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials. Certainty of the evidence (CoE) was rated using the Grading of Recommendations, Assessment, Development, and Evaluation guidelines. The reduction in the risk of MACE was significant for both medications (high CoE), and the effect was similar in patients with and without CV disease (moderate CoE). GLP1Ra and SGLT2i reduced the risk of CV death (with high and moderate CoE, respectively), and the effects were consistent in the subgroups, but with very low CoE. While SGLT2i reduced the risk of fatal or non-fatal MI with a consistent effect in the subgroups, GLP1Ra reduced the risk of fatal or non-fatal stroke (with high CoE). In conclusion, GLP1Ra and SGLT2 inhibitors reduce the MACE to a similar extent in patients with and without CV disease, but have a differential effect on the reduction of fatal or non-fatal MI and stroke. [ABSTRACT FROM AUTHOR]

Aim: Glucagon‐like peptide 1 receptor agonists (GLP1RA) and sodium‐glucose cotransporter 2 inhibitors (SGLT2i) are both recommended for patients with diabetes, yet their effects on the development or progression of diabetic retinopathy (DR) are largely unknown. Methods: In this retrospective cohort study, data were collected from a nationwide database. Patients with diabetes who initiated treatment with a GLP1RA or SGLT2i between 1 May 2016 and 31 December 2017, were identified. Patients were divided into those with or without a previous diagnosis of DR and then categorized into the GLP1RA and the SGLT2i groups according to drug use. The primary outcome of interest in the DR group was the composite of new‐onset proliferative DR, vitreous haemorrhage and tractional retinal detachment (RD). In the non‐DR group, the primary outcome was the composite of newly diagnosed DR of any severity, vitreous haemorrhage and RD. Results: In total, 97 413 patients were identified. After matching, 1517 patients were treated with a GLP1RA and 3034 with an SGLT2i in the DR cohort. In the non‐DR cohort, 9549 initiated a GLP1RA and 19 098 initiated an SGLT2i. In patients with pre‐existing DR, the incidence of any DR progression event was significantly higher in the GLP1RA group than the SGLT2i group (subdistribution hazard ratio 1.50, 95% confidence interval 1.01‐2.23), primarily because of the increased risk of tractional RD. In patients without DR at baseline, the risks of all ocular outcomes were similar between the GLP1RA and SGLT2i groups. Conclusions: In patients with diabetes mellitus and established DR, GLP1RA treatment was associated with increased risks of DR progression compared with SGLT2i use. [ABSTRACT FROM AUTHOR]

Aim: To synthesize the evidence on the effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) in adolescents with overweight or obesity. Materials and Methods: For this systematic review and network meta‐analysis, we searched five databases and registries until 2 March 2024 for eligible randomized controlled trials (RCTs). The primary outcome was weight change. We did a pairwise meta‐analysis to compare GLP‐1RAs and placebo, followed by a drug‐wise network meta‐analysis (NMA) to compare GLP‐1RAs against each other. Results: We screened 770 records to include 12 RCTs with 883 participants. The evidence suggests that GLP‐1RAs reduced weight (mean difference −4.21 kg, 95% confidence interval [CI] −7.08 to −1.35) and body mass index (BMI; mean difference −2.11 kg/m2, 95% CI −3.60 to −0.62). The evidence on waist circumference, body fat percentage and adverse events (AEs) was very uncertain. The results remained consistent with subgroup analyses for coexisting type 2 diabetes. Longer therapy duration led to a greater reduction in weight and BMI. In the NMA, semaglutide led to the greatest weight reduction, followed by exenatide, liraglutide and lixisenatide. Conclusions: The evidence suggests that GLP‐1RAs reduce most weight‐related outcomes in adolescents, with semaglutide being the most efficacious. There is uncertain evidence on body fat and serious AEs, probably due to fewer studies and low incidence, respectively. Larger RCTs with head‐to‐head comparisons, pragmatic design, adiposity‐related outcomes, and economic evaluation can further guide the use and choice of GLP‐1RAs. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion To determine if glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) are associated with the development and progression of diabetic retinopathy (DR).A systematic search was conducted on PubMed, Cochrane Library, and Embase from inception to February 2024 to identify clinical studies reporting the development of and changes in DR as the primary outcome in patients with type 2 diabetes taking GLP‐1RA, insulin, or oral antidiabetic medication (OAD). Two researchers independently completed the search and referred to a third as necessary. Data for meta‐analysis was pooled using a random‐effects model.Analysis of seven studies representing 242 537 patients showed a significantly decreased risk of incidence of DR between GLP‐1RA and insulin use (RR = 0.66, 95% CI (0.48, 0.91), p = 0.01). There was no difference in the risk of DR complications (e.g., vitreous haemorrhage, retinal detachment, or requiring treatment with intravitreal injections, lasers, vitrectomy). Between GLP‐1RA and OAD use, there was no difference in the risk of incidence of DR, while there was a significantly increased risk of DR complications (RR = 1.39, 95% CI (1.07, 1.80), p = 0.01).Our findings indicate no elevated risk of incidence of DR linked to GLP‐1RA compared to insulin. In fact, GLP‐1RA may offer potential advantages over insulin regarding the overall incidence of DR. The increased risk of DR requiring treatment and associated complications in the GLP‐1RA group compared to OAD may be due to the transient progression of DR associated with a rapid decrease in HbA1c – a phenomenon not specific to GLP‐1RA and warrants further investigation. [ABSTRACT FROM AUTHOR]

This document is a position paper from the American College of Clinical Pharmacology (ACCP) discussing the use of GLP-1 receptor agonists for chronic weight management therapy. The paper emphasizes the need for healthcare professionals to ensure that these medications are appropriately prescribed, supplied, and filled per approved labels. It also encourages comprehensive treatment plans that include coaching for positive lifestyle changes and health literacy. The paper highlights potential risks and calls for regulatory agencies to prevent the manufacturing and importation of unapproved GLP-1 receptor agonists. The paper includes conflicts of interest disclosures and funding information. [Extracted from the article]

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become one of the most popular medications for patients with diabetes and obesity. Due to their effects on gut motility via central or parasympathetic pathways, there have been concerns about an increased incidence of retained gastric contents and risk of aspiration in the perioperative period. Hence, the American Society of Anesthesiologists (ASA) recommends holding GLP-1 RAs on the procedure day or a week before the elective procedure based on the respective daily or weekly formulations, regardless of the dose, indication (obesity or diabetes), or procedure type. On the contrary, the American Gastroenterological Association (AGA) advises an individualized approach, stating that more data are needed to decide if and when the GLP-1 RAs should be held prior to elective endoscopy. Several retrospective and prospective studies, along with meta-analyses, have been published since then evaluating the role of GLP-1 RAs in patients scheduled for endoscopic procedures. In this review, we discuss the current clinical guidelines and available studies regarding the effect of GLP-1 RAs on GI endoscopies. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials. The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis. Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]). In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To systematically review the efficacy and safety of glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of obesity in children and adolescents. METHODS: PubMed, Embase, Web of Science, the Cochrane Library, CNKI, Wanfang Data, and VIP databases were retrieved for randomized controlled trials (RCT) of GLP-1 receptor agonists and placebo in the treatment of obesity in children and adolescents (from database establishment to Dec. 31st, 2023). Literature screening and data extraction were performed based on inclusion and exclusion criteria, and Meta-analysis was performed using RevMan 5. 3 software. RESULTS: A total of 11 RCT were enrolled, including 981 children and adolescents with obesity. There were 542 cases in the study group (227 cases of liraglutide, 78 cases of exenatide, 134 cases of semaglutide, 103 cases of duraglutide) and 439 cases in the control group. The risk of literature bias was moderate. Meta-analysis results showed that compared with the placebo, GLP-1 receptor agonists can reduce body mass (MD = -3. 83, 95%CI = -5. 94--1. 71, P = 0. 000 4), body mass index (BMI) (MD =-1. 94, 95%CI =-3. 17--0. 70, P =0. 002), BMI-Z score (MD =-0. 18, 95%CI = -0. 33- -0. 03, P =0. 02), glycated hemoglobin (HbA1c) (MD = -0. 22, 95%CI = -0. 38--0. 07, P = 0. 005), and fasting blood glucose (MD = - 4. 43, 95% CI = - 8. 18-- 0. 68, P = 0. 02) in children and adolescents with obesity, with statistically significant differences. Subgroup analysis showed that weekly preparations may not have statistical significance in reducing body mass, yet weekly preparations could better reduce BMI and BMI-Z scores compared with daily preparations. Meanwhile, GLP-1 receptor agonists significantly lower fasting blood glucose and HbA1c levels in obese children and adolescents with type 2 diabetes compared with those without type 2 diabetes. Compared with the control group, GLP-1 receptor agonists increased the incidence of nausea (OR = 3. 13, 95% CI = 2. 23-4. 39, P < 0. 000 01), vomiting (OR = 5. 97, 95%CI = 3. 79-9. 41, P<0. 000 01), diarrhea (OR = 1. 45, 95%CI = 1. 02-2. 06, P = 0. 04), and dizziness (OR = 2. 68, 95% CI = 1. 36-5. 26, P = 0. 004), with statistically significant differences. CONCLUSIONS: GLP-1 receptor agonists can reduce body mass, BMI, HbA1c, and fasting blood glucose in children and adolescents with obesity, but the incidence of gastrointestinal adverse drug reactions is high, and attention should be paid to the clinical use. [ABSTRACT FROM AUTHOR]

In recent years, there has been a growing emphasis on the relationship between obesity and diabetes. An analysis of Korean data revealed that more than 75% of diabetic patients were overweight or obese, with two-thirds having abdominal obesity. Traditional treatment goals for diabetes have primarily focused on lowering blood glucose levels to prevent and treat microvascular and macrovascular complications, which is known as the glucocentric approach. However, with the recognition of the shared pathophysiology of insulin resistance in both diabetes and obesity, a weight-centric approach has emerged, particularly beneficial for patients in whom insulin resistance is a primary driver of type 2 diabetes. Of note, the overlap of various physiological aspects in diabetic patients necessitates a multicentric approach for effective type 2 diabetes management. Recent guidelines now recommend weight loss as a primary treatment goal alongside blood glucose control for overweight and obese diabetic patients, highlighting the significance of weight management in diabetes care. Medications such as glucagon-like peptide-1 (GLP-1) receptor agonist or dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonist with weight-loss effects are recommended for this patient population. Ongoing research is exploring the potential of various gut hormone-based therapies, offering hope for effective weight management and improved diabetes outcomes in the growing population of obese diabetic individuals. [ABSTRACT FROM AUTHOR]

Introduction: Type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) share a bidirectional link, and the innovative antidiabetic molecules GLP-1 Ras and SGLT-2is have proven cardiac and renal benefits, respectively. This study aimed to evaluate CV risk categories, along with lipid-lowering and antidiabetic treatments, in patients with T2DM from a real-life setting in Romania. Material and Methods: A cross-sectional evaluation was conducted on 405 consecutively admitted patients with T2DM in an ambulatory setting, assessing them according to the 2019 ESC/EAS guidelines for moderate, high, and very high CV risk categories. Results: The average age of the group was 58 ± 9.96 years, with 38.5% being female. The mean HbA1C level was 7.2 ± 1.7%. Comorbidities included HBP in 88.1% of patients, with a mean SBP and DBP of 133.2 ± 13.7 mm Hg and 79.9 ± 9 mm Hg, respectively, and obesity in 66.41%, with a mean BMI of 33 ± 6.33 kg/m2. The mean LDL-C levels varied by CV risk category: 90.1 ± 34.22 mg/dL in very high risk, 98.63 ± 33.26 mg/dL in high risk, and 105 ± 37.1 mg/dL in moderate risk. Prescribed treatments included metformin (100%), statins (77.5%), GLP-1 Ras (29.4%), and SGLT-2is (29.4%). Conclusions: In Romania, patients with T2DM often achieve glycemic control targets but fail to meet composite targets that include glycemic, BP, and lipid control. Additionally, few patients benefit from innovative glucose-lowering therapies with proven cardio-renal benefits or from statins. [ABSTRACT FROM AUTHOR]

Objective: 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 <18 years. Methods: PubMed, Embase, Web of Science, and Cochrane Library were searched for all randomized controlled trials (RCTs) up to August 2023 comparing GLP-1RAs with placebo in overweight/obese and/or T2DM adolescents and extracted relevant data for meta-analysis. Results: Fourteen RCTs were included in the meta-analysis with a total of 1,262 participants. Results revealed that the GLP-1RAs group had a more significant reduction in glycosylated hemoglobin A1c (HbA1c; risk difference (RD)=-0.34%, p<0.001) than the control group. However, there was no difference in fasting plasma glucose [fasting plasma glucose (FPG); RD=-2.07 mg/dL, p=0.065] between the two groups. Nonetheless, the experimental group that received exenatide showed no significant reduction in HbA1c (p=0.253) and FPG (p=0.611) between the two groups. The GLP-1RAs group had a more significant decline in body weight (RD=-4.28 kg, p=0.002) and body mass index (BMI) (RD=-1.63 kg/m2, p=0.002) compared to the control group. The experimental group was given liraglutide (RD=-2.31 kg, p=0.038) or exenatide (RD=-2.70 kg, p<0.001). Compared to the control group, the experimental group had a more significant drop in body weight than the control group. However, for the experimental group that received liraglutide, the BMI had a no significant reduction between the two groups (RD=-0.81 kg/m2, p=0.260). For the experimental group using exenatide, BMI declined more significantly in the intervention group than in the control group (RD=-1.14 kg/m2, p<0.001). Conclusion: This study showed that GLP-1RAs reduced HbA1c, FPG, and weight loss in overweight/obese and/or T2DM adolescents. Liraglutide was better than exenatide in terms of glucose reduction. Nevertheless, in terms of weight control, exenatide was more effective than liraglutide. [ABSTRACT FROM AUTHOR]

Aim: To compare the incidence of adverse events (AEs) related to antiobesity medications (AOMs; glucagon‐like peptide‐1 receptor agonists [GLP‐1RAs] vs. non‐GLP‐1RAs) after bariatric surgery. Methods: This single‐centre retrospective cohort included patients (aged 16–65 years) who had undergone laparoscopic Roux‐en‐Y gastric bypass or sleeve gastrectomy (cohort entry date) and initiated AOMs. Participants were categorized as users of US Food and Drug Administration (FDA)‐approved, off‐label, or GLP‐1RA AOMs if documented as receiving the medication on or after cohort entry date. Non‐GLP‐1RA AOMs were phentermine, orlistat, topiramate, canagliflozin, dapagliflozin, empagliflozin, naltrexone, bupropion/naltrexone and phentermine/topiramate. GLP‐1RA AOMs included: semaglutide, dulaglutide, exenatide and liraglutide. The primary outcome was AE incidence. Logistic regression was used to determine the association of AOM exposure with AEs. Results: We identified 599 patients meeting our inclusion criteria, 83% of whom were female. Their median (interquartile range [IQR]) age was 47.8 (40.9–55.4) years. The median duration of surgery to AOM exposure was 30 months. GLP‐1RAs use was not associated with higher odds of AEs: adjusted odds ratio (aOR) 1.1 (95% confidence interval [CI] 0.5–2.6) and aOR 1.1 (95% CI 0.6–2.3) for GLP‐1RA versus FDA‐approved and off‐label AOM use, respectively. AOM initiation ≥12 months after surgery was associated with lower risk of AEs compared to <12 months (aOR 0.01 [95% CI 0.0–0.01]; p < 0.001). Conclusion: Our results showed that GLP‐1RA AOMs were not associated with an increased risk of AEs compared to non‐GLP‐1RA AOMs in patients who had previously undergone bariatric surgery. Prospective studies are needed to identify the optimal timeframe for GLP‐1RA initiation. [ABSTRACT FROM AUTHOR]

Aim: To compare the effectiveness of different basal insulins (BI) prescribed as an add‐on to or switch from glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) therapy. Materials and Methods: Retrospective, real‐world data from electronic medical records of 32 Italian diabetes clinics were used, after propensity score adjustment, to compare effectiveness after 6 months of treatment with second‐ versus first‐generation BI (2BI vs. 1BI) or glargine 300 U/ml versus degludec 100 U/ml (Gla‐300 vs. Deg‐100), when added to (ADD‐ON) or in substitution of (SWITCH) GLP‐1 RA. Only comparisons, including a minimum of 100 patients per group, were performed to ensure adequate robustness of the analyses. Results: In the ADD‐ON cohort (N = 700), greater benefits of 2BI versus 1BI were found in glycated haemoglobin {HbA1c; estimated mean difference: −0.32% [95% confidence interval (CI) −0.62; −0.02]; p =.04} and fasting blood glucose [FBG; −20.73 mg/dl (95% CI −35.62; −5.84); p =.007]. In the SWITCH cohort (N = 2097), greater benefits of 2BI versus 1BI were found in HbA1c [−0.22% (95% CI −0.42; −0.02); p =.03], FBG [−10.15 mg/dl (95% CI −19.04; −1.26); p =.03], and body weight [−0.67 kg (95% CI −1.30; −0.04); p =.04]. In the SWITCH cohort starting 2BI (N = 688), marked differences in favour of Gla‐300 versus Deg‐100 were documented in HbA1c [−0.89% (95% CI −1.26; −0.52); p <.001] and FBG [−17.89 mg/dl (95% CI −32.45; −3.33); p =.02]. Using propensity score matching as a sensitivity analysis, the benefit on HbA1c was confirmed [−0.55% (95% CI –1.02; −0.08); p =.02]. BI titration was suboptimal in all examined cohorts. Conclusions: 2BI are a valuable option to intensify GLP‐1 RA therapy. Switching to Gla‐300 versus Deg‐100 was associated with greater HbA1c improvement. [ABSTRACT FROM AUTHOR]

To examine the association between glucagon-like peptide-1 receptor agonist (GLP-1RA) use and the development of glaucoma in individuals with type 2 diabetes. Nationwide, nested case-control study. From a nationwide cohort of 264 708 individuals, we identified 1737 incident glaucoma cases and matched them to 8685 glaucoma-free controls, all aged more than 21 years and treated with metformin and a second-line antihyperglycemic drug formulation, with no history of glaucoma, eye trauma, or eye surgery. Cases were incidence-density–matched to 5 controls by birth year, sex, and date of second-line treatment initiation. Conditional logistic regression was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for glaucoma, defined by first-time diagnosis, first-time use of glaucoma-specific medication, or first-time glaucoma-specific surgical intervention. Compared with the reference group, who received treatments other than GLP-1RA, individuals who were exposed to GLP-1RA treatment exhibited a lower risk of incident glaucoma (HR, 0.81; CI, 0.70–0.94; P = 0.006). Prolonged treatment extending beyond 3 years lowered the risk even further (HR, 0.71; CI, 0.55–0.91; P = 0.007). Treatment with GLP-1RA for 0 to 1 year (HR, 0.89; CI, 0.70–1.14; P = 0.35) and 1 to 3 years (HR, 0.85; CI, 0.67–1.06; P = 0.15) was not significant. Exposure to GLP-1RA was associated with a lower risk of developing glaucoma compared with receiving other second-line antihyperglycemic medication. Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

Introduction: Both glucagon-like peptide-1 receptor agonists (GLP-1 RA) and continuous glucose monitoring (CGM) improve glycemia in patients with type 2 diabetes (T2D). However, it is unknown whether adding CGM to GLP-1 RA therapy further improves A1c. We evaluated changes in A1c levels 6 months after initiation of FreeStyle Libre (FSL) in adults with sub-optimally controlled T2D already on GLP-1 RA therapy. Methods: This retrospective, observational study used Optum's de-identified Market Clarity Data, a linked electronic health record-claims database to assess changes in A1c after FSL acquisition. Inclusion criteria were T2D diagnosis, ≥ 18 years, baseline A1c ≥ 8%, with the first FSL acquisition between 2018 and 2022. Patients were required to be on GLP-1 RA prior to FSL with at least one GLP-1 RA prescription within 90 days of FSL acquisition. GLP-1 RA initiation was defined as the earliest GLP-1 RA prescription from 2017 onwards. Paired changes in A1c were assessed at 6 months after initial FSL acquisition. Results: The study cohort included 1454 adults with T2D (age 55 ± 10 years, 52% male, 38% with intensive insulin therapy, median 471 days from GLP-1 RA initiation to FSL, and baseline A1c 9.8 ± 1.5%). After FSL acquisition, patients experienced an A1c decrease of 1.5 ± 1.9% (p < 0.001). Patients with a baseline A1c > 10% had the largest reduction (n = 497, − 2.7 ± 2.2%, p < 0.001). Significant improvements were observed in subgroups based on insulin therapy and GLP-1 RA formulation. Those initiating GLP-1 RA therapy > 24 months before FSL acquisition also showed improvements in A1c (n = 478; − 1.3 ± 1.7%, p < 0.001). Conclusions : In a large, real-world study of adults with T2D, those on prior GLP-1 RA therapy experienced significant A1c improvements after acquiring FSL, irrespective of GLP-1 RA duration, GLP-1 RA formulation, or insulin therapy type. These findings support the use of FSL in adults with T2D treated with GLP-1 RA. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a leading cause of cancer death. HCC is preventable with about 70% of HCC attributable to modifiable risk factors. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), Food and Drug Administration–approved medications for treating type 2 diabetes mellitus (T2DM), have pleiotropic effects on counteracting risk factors for HCC. Here we evaluate the association of GLP-1RAs with incident HCC risk in a real-world population. This retrospective cohort included 1,890,020 patients with a diagnosis of T2DM who were prescribed GLP-1RAs or other non-GLP-1RA anti-diabetes medications and had no prior diagnosis of HCC. Incident (first-time) diagnosis of HCC and hepatic decompensating events during a 5-year follow-up was compared between cohorts of patients prescribed GLP-1 RAs vs other anti-diabetes medications. Time-to-first-event analysis was performed using Kaplan-Meier survival analysis with hazard ratio and 95% confidence interval calculated. GLP-1RAs were associated with a lower risk of incident HCC with hazard ratio of 0.20 [0.14–0.31], 0.39 [0.21–0.69], 0.63 [0.26–1.50] compared with insulin, sulfonylureas, and metformin, respectively. GLP-1RAs were associated with a significantly lower risk of hepatic decompensation compared with 6 other anti-diabetes medications. Reduced risks were observed in patients without and with different stages of fatty liver diseases, with more profound effects in patients without liver diseases. Similar findings were observed in patients with and without obesity and alcohol or tobacco use disorders. GLP-1RA combination therapies were associated with decreased risk for HCC and hepatic decompensations compared with monotherapies. GLP-1RAs were associated with a reduced risk of incident HCC and hepatic decompensation compared with other anti-diabetes medications in patients with T2DM. These findings provide supporting evidence for future studies to investigate the underlying mechanisms and their clinical use. Glucagon-like peptide-1 receptor agonists alone and in combination with other anti-diabetes medications were associated with a reduced risk of hepatocellular carcinoma incidence and hepatic decompensation events in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Introduction: Uncontrolled hypertension is the leading risk factor for global mortality. Most hypertensive patients can be controlled with standard medication combinations, but some may not respond adequately to ≥3 or even to ≥5 antihypertensive agents. Areas covered: In this review, we summarize the recent literature on difficult-to-treat hypertension identified by a Medline search, and we discuss the options for fourth line and subsequent therapy. Expert opinion: It is essential to confirm resistant hypertension with out-of-office blood pressure measurements and to consider lifestyle factors, adherence to medication and secondary causes of hypertension. When true resistant hypertension is confirmed and blood pressure is not controlled with an optimal triple combination, preferably as a fixed dose combination tablet, spironolactone is usually recommended as the fourth medication. Comorbid conditions should be treated as appropriate with sodium-glucose-cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, sacubitril-valsartan or finerenone. Renal denervation appears to be a useful addition to overcome some of the problems of medication adherence. The endothelin antagonist aprocitentan may be a final option in some countries. Of the drugs in development, the RNA based therapeutics that inhibit angiotensinogen synthesis appear to be some of the most promising. [ABSTRACT FROM AUTHOR]

Obesity is a significant predisposing factor for heart failure with preserved ejection fraction (HFpEF). Although a substantial proportion of individuals with HFpEF also have obesity, those with obesity are under-represented in clinical trials for heart failure. In turn, current guidelines provided limited recommendations for the medical management of this patient population. Both obesity and diabetes induce a pro-inflammatory state that can contribute to endothelial dysfunction and coronary microvascular impairment, finally resulting in HFpEF. Additionally, obesity leads to increased epicardial and chest wall adiposity, which enhances ventricular interdependence. This condition is further aggravated by plasma and blood volume expansion and excessive vasoconstriction, ultimately worsening HFpEF. Despite the well-documented benefits of GLP-1 receptor agonists in subjects with diabetes, obesity, or both, their role in obesity-related HFpEF remains unclear. In light of the recently published literature, this review aims to investigate the potential mechanisms and synthesize the available clinical evidence regarding the role of GLP-1 receptor agonists in patients with obesity-related HFpEF. [ABSTRACT FROM AUTHOR]

Abstract 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 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.

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

The incidence of diabetes is continuously increasing worldwide, resulting in a considerable socioeconomic burden. Glycemic control using traditional diabetes medications prevents microvascular complications; however, there is no objective evidence that it prevents macrovascular complications. In the 21st century, concerns have arisen that strict glycemic control and the diabetes drug rosiglitazone might increase mortality. This led the United States Food and Drug Administration to establish guidelines that require that cardiovascular outcome trials (CVOTs) with 3-point major adverse cardiovascular events (3-P MACE) as the primary endpoints be performed for new diabetes drugs. Since then, 20 CVOTs have been reported. Dipeptidyl peptidase 4 inhibitors do not increase the incidence of cardiovascular disease; however, saxagliptin increases the risk of heart failure. Sodium-glucose cotransporter inhibitors (SGLT2is) and glucagonlike peptide 1 receptor agonists (GLP-1RAs) not only have proven cardiovascular safety but also have shown results beyond expectations by reducing the incidence of cardiovascular diseases. Additionally, SGLT2is have been reported to markedly prevent heart failure and kidney disease. The reduction in 3-P MACE by GLP-1RAs was observed only with long-acting agents; long-acting GLP-1RAs also markedly reduced renal endpoints. However, no preventive effect against heart failure was observed with GLP-1RAs. The preventive effects of both drug types against cardiovascular and kidney diseases appear to be independent of glycemic control. In conclusion, based on CVOT results, it is necessary to actively prescribe SGLT2is and GLP-1RAs to prevent cardiovascular disease in patients with diabetes, regardless of glycemic control.