Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule.

Glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic ß cells. We herein investigated the role of GLP-1R on T lymphocytes during immune response. Our data showed that a subset of T lymphocytes expresses GLP-1R, which is upregulated during alloimmune response, similarly to PD-1. When mice received islet or cardiac allotransplantation, an expansion of GLP-1Rpos T cells occurred in the spleen and was found to infiltrate the graft. Additional single-cell RNA sequencing (scRNA-seq) analysis conducted on GLP-1Rpos and GLP-1Rneg CD3+ T cells unveiled the existence of molecular and functional dissimilarities between both subpopulations, as the GLP-1Rpos are mainly composed of exhausted CD8 T cells. GLP-1R acts as a T cell-negative costimulatory molecule, and GLP-1R signaling prolongs allograft survival, mitigates alloimmune response, and reduces T lymphocyte graft infiltration. Notably, GLP-1R antagonism triggered anti-tumor immunity when tested in a preclinical mouse model of colorectal cancer.

[18F]FB(ePEG12)12-exendin-4 noninvasive imaging of insulinoma negative for insulin immunostaining on specimen from endoscopic ultrasonography-guided fine needle aspiration: a case report with review of literature.

Insulinomas are the most common functional pancreatic neuroendocrine neoplasm; when treatment is delayed, they induce hyperinsulinemic hypoglycemia, which is life-threatening. As surgical resection is the only curative treatment for insulinoma, preoperative localization is crucial; however, localization based on conventional imaging modalities such as computed tomography (CT) and magnetic resonance imaging is often inconclusive. Somatostatin receptor-targeted imaging is another option for detecting pancreatic neuroendocrine neoplasms but has low sensitivity and is not specific for insulinoma. The clinical application of other localizing approaches such as selective arterial calcium stimulation and endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) is limited by their being invasive and/or technically complex. Moreover, an EUS-FNA specimen of an insulinoma may be negative on insulin immunostaining. Thus, a noninvasive and clinically practical insulinoma-specific diagnostic tool to discriminate insulinomas with high accuracy is anticipated. Glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged in the effort to fulfill this need. We recently developed the novel fluorine-18-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4) for positron emission tomography (PET) imaging and reported its clinical benefit in a case of insulinoma in the pancreatic tail. We report here a case of insulinoma in the pancreatic head in which an EUS-FNA specimen was negative on insulin immunostaining while precise preoperative localization and conclusive evidence for curative enucleation was provided by 18F-exendin-4 PET/CT (Japan Registry of Clinical Trials; jRCTs051200156).

The effect of SGLT2 inhibitors and GLP1 receptor agonists on arterial stiffness: A meta-analysis of randomized controlled trials.

BACKGROUND: Pulse wave velocity (PWV) and augmentation index (AIx) are indices used to assess arterial stiffness. We evaluated the effect of sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) on arterial stiffness indices. METHODS: We searched PubMed (up to January 2024) for RCTs assessing the effect of SGLT2i or GLP1-RA on arterial stiffness with reporting outcomes PWV and AIx. Effect sizes of the included studies were expressed as weighted mean difference (WMD) and 95 % confidence interval. Subgroup analyses were performed based on comparator (placebo vs. active comparator), design (RCT vs. crossover), population (diabetic vs. all) and blindness (yes vs. no). RESULTS: A total of 19 studies (SGLT2i, 12 studies; GLP1-RA, 5 studies; SGLT2i/GLP1-RA combination, 2 studies) assessing 1212 participants were included. We did not find any statistically significant association between GLP1-RA or SGLT2i and PWV or AIx. None of the subgroup analyses showed any statistically significant result. CONCLUSION: No evidence of a favorable change in arterial stiffness indices (PWV, AIx) was found following the administration of SGLT2i or GLP1-RA.

Tirzepatide ameliorates eating behaviors regardless of prior exposure to glucagon-like peptide receptor agonists in Japanese patients with type 2 diabetes mellitus.

AIMS: To investigate effects of tirzepatide, a dual receptor agonist for glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), on eating behaviors. METHODS: Eating behaviors were evaluated by using a validated questionnaire survey in 33 Japanese patients with type 2 diabetes mellitus (T2DM) (mean age: 51.8 years) who were treated with tirzepatide (2.5 mg/week for 4 weeks and then 5.0 mg/week) for 6 months (M). RESULTS: Treatment with tirzepatide significantly decreased median hemoglobin A1c (HbA1c) (baseline/3 M/6 M: 7.3 %/6.0 %/5.8 %), mean body weight (BW) (baseline/3 M/6 M: 87.7 kg/82.0 kg/79.6 kg) and mean relative score of eating behaviors (baseline/3 M/6 M: 57.0/50.7/45.9). In the GLP-1 receptor agonist (GLP-1RA) naïve group (n = 20, men/women: 13/7), HbA1c and BW were continuously decreased up to 6 M. Changes in eating behaviors were mainly observed in the first 3 M. In the GLP-1RA non-naïve group (n = 13, men/women: 8/5), reductions in HbA1c and BW were predominant in the first 3 M, and changes in eating behaviors were observed up to 6 M. There were no significant correlations of changes in scores of eating behaviors with changes in glycemic control or those in BW. CONCLUSIONS: Tirzepatide ameliorates eating behaviors as well as glycemic management and obesity in Japanese patients with T2DM, and the patterns of improvement are partially dependent on prior exposure to GLP-1RAs.

Fluid transitions.

Water is critical for survival and thirst is a powerful way of ensuring that fluid levels remain in balance. Overconsumption, however, can have deleterious effects, therefore optimization requires a need to balance the drive for water with the satiation of that water drive. This review will highlight our current understanding of how thirst is both generated and quenched, with particular focus on the roles of angiotensin II, glucagon like-peptide 1, and estradiol in turning on and off the thirst drive. Our understanding of the roles these bioregulators play has benefited from modern behavioral analyses, which have improved the time resolution of intake measures, allowing for attention to the details of the patterns within a bout of intake. This has led to behavioral interpretation in ways that are helpful in understanding the many controls of water intake and has expanded our understanding beyond the dichotomy that something which increases water intake is simply a "stimulator" while something that decreases water intake is simply a "satiety" factor. Synthesizing the available information, we describe a framework in which thirst is driven directly by perturbations in fluid intake and indirectly modified by several bioregulators. This allows us to better highlight areas that are in need of additional attention to form a more comprehensive understanding of how the system transitions between states of thirst and satiety.

GLP1-GIP receptor co-agonists: a promising evolution in the treatment of type 2 diabetes.

Type 2 diabetes represents a growing challenge for global public health. Its prevalence is increasing worldwide, and, like obesity, it affects progressively younger populations compared to the past, with potentially greater impact on chronic complications. Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge. Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. In this context, the aim of the present document is to summarize, in the form of a narrative literature review, the currently available data on the main mechanisms of action of GIP/GLP-1 co-agonists and the clinical effects of tirzepatide evaluated in various clinical trials.

GLP-1 increases heart rate by a direct action on the sinus node.

AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear. METHODS AND RESULTS: We employed a large animal model, the female landrace pig, and used multiple in-vivo and ex-vivo approaches including pharmacological challenges, electrophysiology and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate. In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta or combined alpha-beta blockade), ganglionic blockade (hexamethonium) nor inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1. GLP-1 administration to isolated perfused pig hearts also increased heart rate, which was abolished by GLP-1 receptor blockade. Electrophysiological characterization of GLP-1 effects in vivo and in isolated perfused hearts localized electrical modulation to the atria and conduction system. In isolated sinus nodes, GLP-1 administration shortened action potential cycle length of pacemaker cells and shifted the site of earliest activation. The effect was independent of HCN blockade. Collectively, these data support a direct effect of GLP-1 on GLP-1 receptors within the heart. Consistently, single nucleus RNA sequencing (snRNAseq) showed GLP-1 receptor expression in porcine pacemaker cells. Quantitative phosphoproteomics analyses of sinus node samples revealed that GLP-1 administration leads to phosphorylation changes of calcium cycling proteins of the sarcoplasmic reticulum, known to regulate heart rate. CONCLUSION: GLP-1 has direct chronotropic effects on the heart mediated by GLP-1 receptors in pacemaker cells of the sinus node, inducing changes in action potential morphology and the leading pacemaker site through a calcium signaling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pace making. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in GLP-1 RA recipients.

GLP-1 receptor agonists for weight reduction in people living with obesity but without diabetes: a living benefit-harm modelling study.

Background: The benefit of Glucagon-like Peptide-1 (GLP-1) receptor agonists (RAs) in weight reduction against potential harms remains unclear. This study aimed at evaluating the benefit-harm balance of initiating GLP-1 RAs versus placebo for weight loss in people living with overweight and obesity but without diabetes. Methods: We performed benefit-harm balance modelling, which will be updated as new evidence emerges. We searched for randomised controlled trials (RCTs) in PubMed, controlled trials registry, drug approval and regulatory documents, and outcome preference weights as of April 10, 2024. We synthesize data using pairwise meta-analysis to estimate the effect of GLP-1 RAs to inform the benefit-harm balance modelling. We predicted the absolute effects of the positive and negative outcomes over 1 and 2 years of treatment using exponential models. We applied preference weights to the outcomes, ranging from 0 for least concerning to 1.0 for most concerning. We then calculated whether the benefit of achieving 5% and 10% weight loss outweighed the harms on a common scale. The analyses accounted for the statistical uncertainties of treatment effects, preference weights, and outcome risks. Findings: We included 8 RCTs involving 8847 participants. The pooled average age was 46.7 years, with the majority being women (74%) and people living with obesity (96%). Of 1000 persons treated with GLP-1 RAs for 2 years, 375 (95% confidence interval 352 to 399) achieved a 10% weight loss, and 318 (296 to 339) achieved a 5% weight loss compared to those treated with placebo. Several harm outcomes were more frequent in the GLP-1 RA group, including 41 abdominal pain events per 1000 persons over 2 years (19 to 69), cholelithiasis (8, 1 to 21), constipation (118, 78 to 164), diarrhoea (100, 42 to 173), alopecia (57, 10 to 176), hypoglycaemia (17, 1 to 68), injection site reactions (4, -3 to 19), and vomiting (110, 80 to 145) among others. Achieving a 10% weight loss with GLP-1 RA therapy outweighed the cumulative harms, with a net benefit probability of 0.97 at year 1 and 0.91 at year 2. The absolute net benefit was equivalent to 104 (100 to 112) per 1000 persons achieving a 10% weight loss over 2 years without experiencing any worrisome harm. A 5% weight loss did not show a net benefit, with probabilities of 0.13 and 0.01 at year 1 and year 2, respectively. However, these benefits were sensitive to preference weights, suggesting that even a 5% weight loss could be net beneficial for individuals with less concern about harm outcomes. The net benefit for a 10% weight loss was highest for semaglutide, followed by liraglutide and tirzepatide, with 2-year probabilities of 0.96, 0.72, and 0.60, respectively. Interpretation: The benefit of GLP-1 RAs exceeded the harms for weight loss in the first 2 years of treatment, yet the net benefit was dependent on individual' treatment goals (10% or 5% weight loss) and willingness to accept harms in pursuit of weight loss. This implies that treatment decisions have to be personalized to individuals to optimize benefits and reduce harms and overuse of treatments. Due to varying evidence, especially regarding harm outcomes across studies, it is necessary to continuously update and monitor the benefit-harm balance of GLP-1 RAs. Funding: SNSF and LOOP Zurich.

GLP-1 RA for cardiometabolic risk reduction in obesity - How do we best describe benefit and value?

How do we assess the overall benefit and value of GLP1-RAs? Current clinical trials often focus narrowly on individual atherosclerotic cardiovascular endpoints like MACE, potentially missing broader GLP-1 RA benefits across multiple comorbidities. Herein, we set out a framework for expanding outcome analyses in large trials that we believe will provide a more holistic understanding of GLP-1 RA benefits across the cardio-kidney-metabolic (CKM) spectrum, guiding patient care, guidelines, and insurance coverage decisions.

A Real-World Study of the Effectiveness and Safety of Semaglutide for Weight Loss.

Introduction Recent randomized controlled trials (RCTs) have shown the great efficacy of semaglutide in achieving significant weight loss in overweight and obese adults. However, real-world data about its effectiveness are still limited. This study evaluated the effectiveness and adverse events of semaglutide for weight management in a real-life setting, excluding patients with diabetes mellitus (DM). Methods This is a retrospective chart review of 40 overweight or obese individuals with a median age of 47 years, weight of 111.7 kg, and body mass index (BMI) of 39.7 kg/m2 who were prescribed semaglutide for weight management. Results After three months of semaglutide administration, the median weight reduction was 7.4 kg (6.6% of the baseline weight), with 28 (70%) and eight patients (20%) achieving greater than 5% (5.6 kg) and 10% (11.2 kg) weight loss, respectively. Among 25 patients with six-month data, 22 (88%), 17 (68%), and eight (32%) patients exceeded 5% (5.6 kg), 10% (11.2 kg), and 15% (16.8 kg) weight loss, respectively. The maintenance semaglutide dose was 1 mg in 16 cases and 2 mg in nine cases, leading to a similar weight loss of 13.6% (14.9 kg) and 12.8% (14 kg), respectively. Relatively low response rates were observed in males, with seven responders out of 12 (58.4%) compared to 24 out of 28 (85.8%) in females (P value = 0.057), and in five out of nine (55.6%) among those with a history of psychiatric disease. The rate of adverse events was 26 out of 40 patients (65%), mostly mild to moderate and of short duration, leading to discontinuation in only a single case (2.5%). Conclusion This retrospective study demonstrated the significant effectiveness of semaglutide for weight loss, even at lower than approved maintenance doses, combined with a good safety profile. Therefore, semaglutide may dramatically change the landscape of obesity treatment.

Glucagon-like peptide-1 receptor agonists rescued diabetic vascular endothelial damage through suppression of aberrant STING signaling.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) protect against diabetic cardiovascular diseases and nephropathy. However, their activity in diabetic retinopathy (DR) remains unclear. Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications, suggesting their advantage in DR treatment. By single-cell RNA-sequencing analysis and immunostaining, we observed a high expression of GLP-1R in retinal endothelial cells, which was down-regulated under diabetic conditions. Treatment of GLP-1 RAs significantly restored the receptor expression, resulting in an improvement in retinal degeneration, vascular tortuosity, avascular vessels, and vascular integrity in diabetic mice. GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs. Additionally, the treatment attenuated STING signaling activation in retinal endothelial cells, which is typically activated by leaked mitochondrial DNA. Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes. Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling. This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.

Outcomes of concomitant antiobesity medication use with endoscopic sleeve gastroplasty in clinical US settings.

Background: To evaluate the weight loss outcomes of the large US cohort of patients undergoing endoscopic sleeve gastroplasty (ESG) with or without concomitant anti-obesity (AOM) use. Methods: We performed a retrospective analysis of adult patients who underwent ESG from seven different sites, from January 1, 2020 to November 30, 2022. Percent total body weight loss (%TBWL) and %excess weight loss (%EWL) were calculated based on baseline weight at the procedure. Medication use was considered if the subject received a prescribed AOM during the study period. SPSS (version 29.0) was used for statistical analyses. Results: A total of 1506 patients were included (1359 (90.2 %) no AOM use and 147 (9.8 %) AOM use). Patients who were on an active AOM at the time of the procedure had a significantly lower TBWL% as compared to patients not on AOMs at 6 months. At the 24-month visit, patients who were prescribed AOMs after the 12-month visit had a significantly higher TBWL% and EWL% as compared to patients who were on active AOM at the time of the procedure. There was no significant difference between classes of medications at any time point, however, patients on a GLP-1RA had a trend towards improved weight loss at 18 and 24 months. Conclusion: In this large, real-world cohort of patients from the United States, data signal that with the use of pharmacotherapy at the appropriate time, patients can achieve optimal results.

Virtual Screening of GLP-1-Secreting Peptides from Pea Protein Hydrolysates via Peptide Transporter 1 (PepT1) Activation-Based Molecular Docking.

Dietary proteins regulate glucose homeostasis via intestinal protein sensing-induced glucagon-like peptide 1 (GLP-1) secretion. However, the reported GLP-1-secreting peptides derived from dietary proteins are few, and studies regarding GLP-1-secreting peptide identification by traditional separation and purification methods are laborious. Herein, we have rapidly virtual-screened two GLP-1 secreting peptides from pea protein hydrolysates (PPHs) by peptidomic analysis and molecular docking with peptide transporter 1 (PepT1). PPH-stimulated GLP-1 secretion decreased after adding the PepT1 antagonist 4-aminobenzoic acid (4-AMBA), indicating that PepT1 activation was involved in PPH-induced GLP-1 secretion in NCI-H716 cells. Subsequently, 307 tripeptides in PPHs were obtained through peptidomic analysis. Among them, two GLP-1-secreting peptides, FLR and LRW, were identified via PepT1 activation-based molecular docking. FLR and LRW (1 mg/mL) increased GLP-1 levels to 170.20% ± 27.83% and 272.37% ± 45.96%, respectively (p < 0.05). More importantly, molecular docking implied that the interactions between peptides and the active center of PepT1 (especially Glu595, Asn329, and Asn171 in the N-pocket and Arg27 in the C-pocket) were crucial for peptide activity in stimulating GLP-1 secretion. Our study suggested that the combination of peptidomics and PepT1 activation-based molecular docking is a promising approach for identification of GLP-1-secreting peptides.

Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis.

Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms.

Combined sodium-glucose-transporters inhibitors and glucagon-like-peptide receptor agonist compared with monotherapy improves long-term survival: A Real-World Registry.

BACKGROUND: The benefits of new glucose-lowering agents on cardiovascular disease have been demonstrated in randomized clinical trials. However, more evidence is required to assess the additive value of a combined therapy based on sodium-glucose transporter inhibitors (SGLT2i) and glucagon-like peptide receptor agonists (GLP1ra) in a real-world population. METHODS: A non-concurrent prospective study was conducted using integrated electronic medical records from primary care and hospitals obtained through 'Big data' technologies in a healthy area in Galicia. The study involved patients who were given SGLT2i, GLP1ra, or both treatments between January 2018 and June 2022 and were categorized as either mono or combined therapy (SGLT2i, GLP1ra, or both). The cumulative risk for different events: hospitalization and/or mortality for a) coronary artery disease, b) heart failure, c) cerebrovascular accident, and all-cause mortality were represented by Kaplan Meier curves and multivariate Cox regression analysis to obtain the hazard rate (HR) and (95% confidence interval (CI)). Validation was performed in a subpopulation with a propensity score matching. RESULTS: The patients (15,549) who were included were 68 (12) years old, with 41% of them being females and 46% experiencing obesity. The median (interquartile range) of follow-up was 19 (8-33) months. The Kaplan-Meier analysis determined that the cumulative risk for coronary artery disease and cerebrovascular accident events was similar among the 3 different therapy groups. However, the combined therapy vs. SGLT2i reduced the risk of, heart failure events (HR: 0.69 [95% CI; 0.56-0.87]) or all-cause mortality (HR: 0.68 [95% CI;0.54-0.86]). Multivariate Cox regression analysis, after matching with a propensity score, confirmed the benefits of combined therapy regarding SGLT2i or GLP1ra monotherapy. CONCLUSION: Compared to SGLT2i or GLP1ra alone, combined therapy SGLT2i + GLP1ra reduces heart failure risk and all-cause mortality in a real-world population.

Real-World Clinical Experience of Oral Semaglutide in a Secondary Diabetes Clinic in the UK: A Retrospective Observational Study.

INTRODUCTION: Oral semaglutide improves cardiovascular risk factors in people with type 2 diabetes (T2D) in clinical trials, though real-world evidence is limited. We aimed to determine the real-world impact of oral semaglutide on routinely collected clinical data in our practice. METHODS: People with T2D initiated on oral semaglutide in secondary care diabetes clinics at two hospital sites in Wales (United Kingdom) were included. Data were collected on reasons for oral semaglutide initiation and changes in bodyweight, blood pressure, glycemic control, and lipid profiles over follow-up at 3-6 months, and at 6-12 months. Data were collected to determine the safety of oral semaglutide. RESULTS: Seventy-six patients were included, with a median age 59.3 [51.4-67.6] years, and 38 (50.0%) patients were female. The most common reasons for oral semaglutide were need for weight loss and improved glycemia (69.8%), and improved glycemia alone (25.0%). Oral semaglutide associated with significantly reduced bodyweight (- 3.3 kg), body mass index (BMI) (- 0.9 kg/m2), glycated hemoglobin (HbA1c) (- 11 mmol/mol), and total cholesterol (- 0.4 mmol/l) by 3-6 months follow-up. At 6-12 months, there was a significant reduction in systolic blood pressure (- 7.0 mmHg), in addition to sustained reductions in other metabolic parameters. By 12 months, 18 (23.6%) patients had discontinued the drug, largely resulting from gastrointestinal disturbance, but there were no serious events in this cohort. CONCLUSIONS: Oral semaglutide was effective in improving cardiovascular risk factors in this real-world population living with T2D, and no serious events were identified related to oral semaglutide in this patient group.

L-carnitine and Ginkgo biloba Supplementation In Vivo Ameliorates HCD-Induced Steatohepatitis and Dyslipidemia by Regulating Hepatic Metabolism.

Treatment strategies for steatohepatitis are of special interest given the high prevalence of obesity and fatty liver disease worldwide. This study aimed to investigate the potential therapeutic mechanism of L-carnitine (LC) and Ginkgo biloba leaf extract (GB) supplementation in ameliorating the adverse effects of hyperlipidemia and hepatosteatosis induced by a high-cholesterol diet (HCD) in an animal model. The study involved 50 rats divided into five groups, including a control group, a group receiving only an HCD, and three groups receiving an HCD along with either LC (300 mg LC/kg bw), GB (100 mg GB/kg bw), or both. After eight weeks, various parameters related to lipid and glucose metabolism, antioxidant capacity, histopathology, immune reactivity, and liver ultrastructure were measured. LC + GB supplementation reduced serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, glucose, insulin, HOMA-IR, alanine transaminase, and aspartate transaminase levels and increased high-density lipoprotein cholesterol levels compared with those in the HCD group. Additionally, treatment with both supplements improved antioxidant ability and reduced lipid peroxidation. The histological examination confirmed that the combination therapy reduced liver steatosis and fibrosis while also improving the appearance of cell organelles in the ultrastructural hepatocytes. Finally, the immunohistochemical analysis indicated that cotreatment with LC + GB upregulated the immune expression of GLP-1 and ß-Cat in liver sections that were similar to those of the control animals. Mono-treatment with LC or GB alone substantially but not completely protected the liver tissue, while the combined use of LC and GB may be more effective in treating liver damage caused by high cholesterol than either supplement alone by regulating hepatic oxidative stress and the protein expression of GLP-1 and ß-Cat.

Effects of Glucagon-like Peptide-1 Receptor Agonists on Upper Endoscopy in Diabetic and Non-Diabetic Patients.

BACKGROUND AND AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) promote weight loss by suppressing appetite, enhancing satiety, regulating glucose metabolism and delaying gastric motility. We sought to determine whether GLP-1 RA use could impact sedated medical procedures like esophagogastroduodenoscopy (EGD). METHODS: We conducted a retrospective study on 35,183 patients who underwent EGD between 2019 and 2023, 922 of which were using a GLP-1-RA. Data were collected regarding demographics, diabetes status, retained gastric contents during EGD (RGC), incidence of aborted EGD, and necessity for repeat EGD. RESULTS: GLP-1 RA use was associated with a fourfold increase in the retention of gastric contents (p<0.0001), fourfold higher rates of aborted EGD (p<0.0001), and twice the likelihood of requiring repeat EGD (p=0.0001), even after stratifying for presence of diabetes. CONCLUSIONS: GLP-1 RA use can lead to delayed gastric emptying, affecting EGD adequacy regardless of the presence of diabetes, and may warrant dose adjustment to improve safety and efficacy of these procedures.

Treatment intensification following glucagon-like peptide-1 receptor agonist in type 2 diabetes: Comparative effectiveness analyses between free vs. fixed combination of GLP-1 RA and basal insulin. RESTORE-G real-world study.

BACKGROUND AND AIMS: Add-on of basal insulin (BI) to intensify the ongoing therapy with glucagon-like peptide 1 receptor agonist (GLP-1 RA) is recommended, but it is unclear if free or fixed combination of BI and GLP-1 RA produce similar outcomes. A retrospective comparative effectiveness analysis of the add-on of glargine 300 U/mL (Gla-300) to ongoing GLP-1 RA vs. switch to fixed ratio combination of degludec and liraglutide (iDegLira) was performed. METHODS AND RESULTS: Real-world data collected in electronic medical records by 32 Italian diabetes clinics. Propensity score (PS) adjustment was applied to assess changes in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), body weight, and BI dose after 6 months from Gla-300 or iDegLira initiation. Compared to iDegLira group (N = 260), Gla-300+GLP-1 RA group (N = 255) had older age and higher levels of HbA1c (9.1 vs. 8.9%). After 6 months, statistically significant greater FBG improvement [estimated mean difference and 95% confidence intervals: -24.05 mg/dl (-37.04; -11.06; p = 0.0003) and BI dose increase [+0.03 U/kg (95%CI 0.00; 0.06); p = 0.009] were found in the free vs. fixed combination group, although low doses of BI (0.2 U/kg) were reached in both groups. Trends of larger HbA1c and body weight reductions with the free combination were also found, without reaching the statistical significance. CONCLUSION: Although inertia in insulin initiation and titration was documented in both groups, higher benefit on FBG control was obtained with free vs. fixed combination, likely due to a better titration of BI and GLP-1 RA.

A comprehensive meta-analysis on the association of SGLT2is and GLP-1RAs with vascular diseases, digestive diseases and fractures.

AIM: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) are two new classes of antidiabetic agents. We aimed to evaluate the association between these two drug classes and risk of various vascular diseases, digestive diseases and fractures. METHODS: Large randomized trials of SGLT2is and GLP-1RAs were included. Outcomes of interest were the various serious adverse events related to vascular diseases, digestive diseases and fractures. We performed meta-analyses using synthesize risk ratio (RR) and 95% confidence interval (CI) as effect size. RESULTS: We included 27 large trials. SGLT2is had significant association with less hypertension (RR 0.70, 95% CI 0.54-0.91), hypertensive crisis (RR 0.63, 95% CI 0.47-0.84), varicose vein (RR 0.34, 95% CI 0.13-0.92), and vomiting (RR 0.55, 95% CI 0.31-0.97); but more spinal compression fracture (RR 1.73, 95% CI 1.02-2.92) and tibia fracture. GLP-1RAs had significant association with more deep vein thrombosis (RR 1.92, 95% CI 1.23-3.00), pancreatitis (RR 1.54, 95% CI 1.07-2.22), and cholecystitis acute (RR 1.51, 95% CI 1.08-2.09); but less rib fracture (RR 0.59, 95% CI 0.35-0.97). Sensitivity analyses suggested that our findings were robust. CONCLUSIONS: SGLT2is may have protective effects against specific vascular and digestive diseases, whereas they may increase the incidence of site-specific fractures (e.g., spinal compression fracture). GLP-1RAs may have protective effects against site-specific fractures (i.e., rib fracture), whereas they may increase the incidence of specific vascular and digestive diseases. These findings may help to make a choice between SGLT2is and GLP-1RAs in clinical practice.