Long-acting Glucagon-like Peptide-1 Receptor Agonist Research Articles

Designing and computational analyzing of chimeric long-lasting GLP-1 receptor agonists for type 2 diabetes

Glucagon-like peptide-1 (GLP-1) is an intestinally derived incretin that plays a vital role in engineering the biological circuit involved in treating type 2 diabetes. Exceedingly short half-life (1–2 min) of GLP-1 limits its therapeutic applicability, and the implication of its new variants is under question. Since albumin-binding DARPin as a mimetic molecule has been reported to increase the serum half-life of therapeutic compounds, the interaction of new variants of GLP-1 in fusion with DARPin needs to be examined against the GLP-1 receptor. This study was aimed to design stable and functional fusion proteins consisting of new protease-resistant GLP-1 mutants (mGLP1) genetically fused to DARPin as a critical step toward developing long-acting GLP-1 receptor agonists. The stability and solubility of the engineered fusion proteins were analyzed, and their secondary and tertiary structures were predicted and satisfactorily validated. Molecular dynamics simulation studies revealed that the predicted structures of engineered fusion proteins remained stable throughout the simulation. The relative binding affinity of the engineered fusion proteins' complex with human serum albumin and the GLP-1 receptor individually was assessed using molecular docking analyses. It revealed a higher affinity compared to the interaction of the individual GLP-1 and HSA-binding DARPin with the GLP-1 receptor and human serum albumin, respectively. The present study suggests that engineered fusion proteins can be used as a potential molecule in the treatment of type 2 diabetes, and this study provides insight into further experimental use of mimetic complexes as alternative molecules to be evaluated as new bio-breaks in the engineering of biological circuits in the treatment of type 2 diabetes.

Predictors of efficacy of Sodium-GLucose Transporter-2 inhibitors and Glucagon-Like Peptide 1 receptor agonists: Aretrospective cohort study.

The aim of the present study was to verify predictors of HbA1c reduction with Sodium-GLucose Transporter-2 (SGLT2) inhibitors and Glucagon-Like Peptide 1 (GLP1) receptor agonists in routine clinical practice. A retrospective cohort study was performed, enrolling patients with type 2 diabetes aged ≥18years who received a prescription of an SGLT2 inhibitor or a long-acting GLP1 receptor agonist with at least 6months of persistence in therapy. Therapeutic success was defined as HbA1c reduction >10mmol/mol or attainment of the recommended HbA1c target. Out of 236 patients receiving SGLT2 inhibitors, 148 were categorised as successes: successes had a mean lower age and higher estimated Glomerular Filtration Rate than failures, but only age retained statistical significance at multivariate analysis (Odds Ratio with 95% confidence interval: 0.94 [0.91-0.98], p=0.006). In the GLP1 receptor agonists cohort (N=214) there were 146 successes, showing a significantly shorter duration of diabetes even after adjusting for age, and baseline HbA1c (HR 0.96 [0.91-0.99], p=0.02). The present study is a preliminary exploration of factors associated with HbA1c response to SGLT2 inhibitors and GLP1 receptor agonists. Differences in predictors of HbA1c changes across different classes of drugs could be useful in identifying the most suitable drug in individual patients. SGLT2 inhibitors seem to be associated with a greater reduction of HbA1c in younger subjects, and GLP1 agonists in those with a shorter duration of diabetes.

Obesity: a gender-view.

There is a growing awareness of the importance of understanding gender differences in obesity. The aim of this short review was to revise the current evidence on anthropometric characteristics and nutritional and pharmacological aspects of obesity from a gender perspective. A literature search within PubMed was performed. Selected publications related to obesity and gender differences were reviewed. The prevalence of obesity among men is higher than in women, but women have a higher percentage of body fat content compared to men, and gender appears to be an important factor in the manifestation of central (android) or peripheral (gynoid) obesity. In addition, while in most clinical trials, women are still underrepresented, in clinical registration trials of anti-obesity drugs, women are commonly up-represented and gender-specific analysis is uncommon. Considering that adipose tissue is one of the factors affecting the volume of distribution of many drugs, mainly lipophilic drugs, gender differences might be expected in the pharmacokinetics and pharmacodynamics of anti-obesity drugs. Indeed, although Liraglutide 3mg, a long-acting glucagon-like peptide-1 receptor agonist, and naltrexone/bupropion display lipophilic properties, currently, a gender-dose adjustment for both these drugs administration is not recommended. In addition, despite that predicted responders to treatment offer substantial opportunities for efficient use, especially of expensive new therapies, such as anti-obesity drugs, data on gender differences to identify early responders to both these have not yet been investigated. Finally, bariatric surgery gender disparity reflects healthcare practices. Weight loss similar, but differing effects: women need more correction and face psychology challenges; men have worse physiology and fewer comorbidity improvements. Gender differences exist in obesity prevalence and phenotype, body fat distribution, drug efficacy, clinical trial representation, and different secondary effects of bariatric surgery. Gender is an important variable in obesity analysis.

Exendin-4 promotes retinal ganglion cell survival and function by inhibiting calcium channels in experimental diabetes

Progressive damage of retinal ganglion cells (RGCs) is observed in early diabetic retinopathy. Intracellular Ca2+ overload mediated by Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) is involved in neurodegeneration, whereas glucagon-like peptide-1 (GLP-1) provides neuroprotection. However, whether GLP-1 plays a neuroprotective role in diabetic retinas by modulating VGCCs remains unknown. We found that eye drops of exendin-4, a long-acting GLP-1 receptor (GLP-1R) agonist, prevented the increase of L-type Ca2+ current (ILCa) densities of RGCs induced by 4-week hyperglycemia and promoted RGC survival by suppressing L-type VGCC (L-VGCC) activity in streptozotocin-induced diabetic rats. Moreover, exendin-4-induced suppression of ILCa in RGCs may be mediated by a GLP-1R/Gs/cAMP-PKA/ryanodine/Ca2+/calmodulin/calcineurin/PP1 signaling pathway. Furthermore, exendin-4 functionally improved the light-evoked spiking ability of diabetic RGCs. These results suggest that GLP-1R activation enhances cAMP to PP1 signaling and that PP1 inactivates L-VGCCs by dephosphorylating them, thereby reducing Ca2+ influx, which could protect RGCs against excitotoxic Ca2+ overload.

Comparative efficacy and safety of glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes: A network meta-analysis.

This study aimed to evaluate the clinical efficacy and safety of 4 weekly formulations of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on glycemic control, including glycemic control, by using a network meta-analysis (NMA). PubMed, EMBASE, and Cochrane Library Central Register of Controlled Trials were searched from inception until June 10, 2022. Randomized clinical trials (RCTs) enrolling participants with diabetes mellitus type 2 and a follow-up of at least 12 weeks were included, for which 4 eligible GLP-1RAs Exenatide, Dulaglutide, Semaglutide, Loxenatide were compared with either each other or placebo. The primary outcome is the change of hemoglobin A1c level. Secondary outcomes including additional glycemic control indicators and adverse events (AE). Frequentist random-effect NMA were conducted for effect comparison. This meta-analysis was registered on PROSPERO, CRD42022342241. The NMA synthesized evidence from 12 studies covering 6213 patients and 10 GLP-1RA regimens. A pairwise comparison of glycosylated hemoglobin type A1C (HbA1c) lowering effects showed that once-weekly GLP-1 receptor agonists were significantly better than placebo, and their glucose-lowering intensity was Semaglutide 2.0mg, Semaglutide 1.0mg, Dulaglutide 4.5mg, and Semaglutide 0.5mg, Dulaglutide 3.0mg, PEX168 200ug, Dulaglutide 1.5mg, PEX168 100ug and Dulaglutide 0.75mg. The GLP-1RA regimen has a comparable safety profile for hypoglycemia. And with the exception of PEX168, all other long-acting GLP-1RA drugs had lower rates of diarrhea, nausea and vomiting than placebo. Regimens of GLP-1RAs had differential glycemic control. The efficacy and safety of Semaglutide 2.0mg in comprehensively lowering blood sugar showed the best performance.

1479-P: Targeted Exome Sequencing for Long-Term Efficacy and Weight Loss of Dulaglutide in Type 2 Diabetes

Introduction: There are individual differences in glucose lowering effect and weight reduction of dulaglutide, long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. It is expected that genetic variations in the mechanism of action of drugs are involved in treatment response to drugs. This study aims to investigate genetic variants associated with long-term efficacy and weight reduction of dulaglutide using targeted next-generation sequencing. Methods: We recruited 77 patients those who were treated with dulaglutide at least one year after switching from DPP-4 inhibitors (±basal insulin) due to uncontrolled type 2 diabetes (HbA1c ≥8.0%) at Korean VHS medical center between September 2018 and October 2019, and followed up until March 2021. The responder was defined by ≥1.0% HbA1c reduction at 24 weeks and achievement of HbA1c ≤7.5% at 52 weeks. We designed targeted exome panel based on the mechanism of drug action, and candidate genetic variants included known GLP-1 response related genes (n=10), gastric emptying related genes (n=18), pancreatic insulin secretion related genes (n=25). At the same time, we also performed whole exome sequencing. Results: During follow-up period of median 2.5±1.3 years, HbA1c was 9.7±1.3% at baseline and reduced to 8.2±1.5% at 6 months, and maintained thereafter up to 4 years. Glycemic response was associated with GNB3, SPARC, and COL4A1 genes. Weight loss (n=13) was more frequently observed in patients with minor G alleles of COL4A1 gene (OR 2.516, 95% CI 1.013, 6.249, p=0.047). Glycemic effectiveness of dulaglutide therapy is associated with genetic variants (OR 2.106, 95% CI 1.358, 3.265, p=0.001) as well as baseline HbA1c (OR 1.682, 95% CI 1.067, 2.650, p=0.025). Conclusion: The glucose lowering effect of dulaglutide, which exempts some patients from insulin therapy, has been associated with GNB3, SPARC, and COL4A1 variants. Polymorphisms in COL4A1 gene was associated with weight loss, although further studies are needed for validation. Disclosure Y.Kim: None. J.Seo: None. Funding VHS Medical Center (VHSMC20026)

#5826 NEPHROPROTECTIVE EFFECTS OF SEMAGLUTIDE IN A MOUSE MODEL OF HYPERTENSION-ACCELERATED DIABETIC KIDNEY DISEASE

Abstract Background and Aims Obesity, hyperglycemia and hypertension are critical risk factors for development of diabetic kidney disease (DKD). Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular and renal outcomes in type 2 diabetes patients. Here, we characterized the effect of long-acting GLP-1R agonist semaglutide alone and in combination with an ACE inhibitor in a model of hypertension-accelerated, advanced DKD facilitated by adeno-associated virus-mediated renin overexpression (ReninAAV) in uninephrectomized (UNx) female db/db mice. Method Seven weeks after ReninAAV administration and six weeks post-UNx, db/db UNx-ReninAAV mice were administered (q.d.) vehicle, semaglutide (30 nmol/kg, s.c.) or semaglutide (30 nmol/kg, s.c.) + lisinopril (30 mg/kg, p.o.) for 11 weeks. Endpoints included tail-cuff blood pressure evaluation at week 1 and 10, plasma/urine biochemistry, kidney histopathology as well as RNA sequencing. Results Semaglutide robustly reduced hyperglycemia, hypertension and albuminuria concurrent with notable improvements in glomerulosclerosis severity, urine/renal kidney injury molecule-1 (KIM-1) levels. Furthermore, semaglutide suppressed gene expression markers of extracellular matrix modelling and immune system activation. Co-administration of lisinopril further ameliorated hypertension, glomerulosclerosis as well as markers of fibrogenesis and inflammation. Conclusion Semaglutide improves disease hallmarks in the db/db UNx-ReninAAV mouse model of advanced DKD. Renal outcomes were further improved by combined antihypertensive standard-of-care. These data display the translatability of the db/db UNx-ReninAAV mouse model of DKD.

The Effects of NLY01, a Novel Glucagon-Like Peptide-1 Receptor Agonist, on Cuprizone-Induced Demyelination and Remyelination: Challenges and Future Perspectives.

Recent evidence suggests that the glucagon-like peptide-1 receptor (GLP-1R) agonists have neuroprotective activities in the CNS in animal models of Parkinson's disease, Alzheimer's disease, and multiple sclerosis (MS). This study aimed to investigate whether a novel long-acting GLP-1R agonist, NLY01, could limit demyelination or improve remyelination as occurs in MS using the cuprizone (CPZ) mouse model. Herein, we assessed the expression of GLP-1R on oligodendrocytes in vitro and found that mature oligodendrocytes (Olig2+PDGFRa-) express GLP-1R. We further confirmed this observation in the brain by immunohistochemistry and found that Olig2+CC1+ cells express GLP-1R. We next administered NLY01 twice per week to C57B6 mice while on CPZ chow diet and found that NLY01 significantly reduced demyelination with greater weight loss than vehicle-treated controls. Because GLP-1R agonists are known to have anorexigenic effect, we then administered CPZ by oral gavage and treated the micewith NLY01 or vehicle to ensure the dose consistency of CPZ ingestion among mice. Using this modified approach, NLY01 was no longer effective in reducing demyelinationofthe corpus callosum (CC). We next sought to examine the effects of NLY01 treatment on remyelination after CPZ intoxication and during the recovery period using an adoptive transfer-CPZ (AT-CPZ) model. We found no significant differences between the NLY01 and vehicle groups in the amount of myelin or the number of mature oligodendrocytes in the CC. In summary, despite the promising anti-inflammatory and neuroprotective effects of GLP-1R agonists that have been previously described, our experiments provided no evidence to support a beneficial effect of NLY01 on limiting demyelination or enhancing remyelination. This information may be useful in selecting proper outcome measures in clinical trials of this promising class of drugs in MS.

Antipsychotic-induced weight gain: exploring the role of psychiatrists in managing patients' physical health - challenges, current options and direction for future care.

Antipsychotics and severe mental illness (SMI) are associated with weight gain, and obesity increases the risks of cardiometabolic disease and premature death. These present management and liability issues for psychiatrists. Physical healthcare for people with SMI is poor, and this may partly be owing to training limitations and lack of proactiveness by psychiatrists. Ethically and legally, psychiatrists have a duty to avoid unnecessary harm and to maintain an acceptable standard of care. This would apply particularly to patients receiving compulsory treatment for their SMI owing to their vulnerability. Discrepancy between psychiatric and non-psychiatric approaches to pharmacological treatment creates ambiguity, and weight gain could demotivate antipsychotic adherence. This article explores how the Mental Health Act could be used to address these issues, and the ethical considerations, and proposes how long-acting glucagon-like peptide-1 receptor agonists could be introduced into existing psychiatric practice as a treatment option for antipsychotic-induced weight gain and obesity in SMI.

GLP-1 receptor agonist, liraglutide, protects podocytes from apoptosis in diabetic nephropathy by promoting white fat browning

Glucagon like peptide-1 receptor agonists (GLP-1RAs) belong to the class of incretin drugs. Incretin is a hormone secreted into blood by intestinal cells after food stimulation that induces insulin secretion. Liraglutide is a long-acting GLP-1RA that can reduce blood pressure, blood lipids, and inflammation. Previous studies showed that liraglutide can promote white fat browning and improve renal outcomes in patients with type 2 diabetes mellitus. However, no studies have linked white fat browning to kidney damage. The objective of this study was to investigate the effects of liraglutide-induced white fat browning on podocyte apoptosis in diabetic nephropathy. We also aimed to determine whether podocytes express glucagon like peptide-1 receptor (GLP-1R) and if liraglutide directly affects podocytes via GLP-1R. We assessed fat and renal function in db/db and wild-type mice and the effects of adipocyte conditioned medium on cultured podocytes. Liraglutide (400 mg/kg/d) was subcutaneously injected for 8 weeks. Liraglutide promoted white fat browning in vivo. During adipogenic differentiation of 3T3-L1 cells in vitro, liraglutide also upregulated expression of peroxisome proliferator-activated receptor γ coactivator-1 alpha (PGC1α) and uncoupling protein 1 (UCP1), which can induce white fat browning in vitro. Furthermore, we found that supernatant from 3T3-L1 cells stimulated by liraglutide reduced podocyte apoptosis. The inhibitory effect of liraglutide on apoptosis was eliminated by exogenous TNF-α. Finally, podocytes express GLP-1R. In vivo and in vitro studies showed that the apoptosis of podocytes in diabetic nephropathy may be related to the effect of liraglutide on promoting white lipid browning. Similarly, liraglutide may directly affect podocytes via GLP-1R.

Special Report: Potential Strategies for Addressing GLP-1 and Dual GLP-1/GIP Receptor Agonist Shortages.

Unexpected drug shortages of the long-acting glucagon-like peptide-1 (GLP-1) receptor agonists dulaglutide and semaglutide and the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide emerged in late 2022 and have persisted through the first quarter of 2023 (1). The drug shortage has not affected product doses equally; some doses are more widely available than others (2). For the purposes of this article, we will consider the dual GLP-1/GIP receptor agonist tirzepatide to be included when referring to GLP-1 receptor agonist product shortages. These shortages predominately occurred because of an unexpected increase in demand for GLP-1 receptor agonists without adequate adjustment in production (3). The inadequate supply has created new access barriers for patients previously using or wishing to initiate these products for glycemic management, weight loss, and/or cardiovascular risk reduction. Thus, strategies to mitigate this disruption to patient care are needed.

Relationship between perioperative semaglutide use and residual gastric content: A retrospective analysis of patients undergoing elective upper endoscopy

Study objectiveSemaglutide is a long-acting glucagon-like peptide-1 receptor agonist used for management of type 2 diabetes and/or obesity. To test the hypothesis that perioperative semaglutide use is associated with delayed gastric emptying and increased residual gastric content (RGC) despite adequate preoperative fasting, we compared the RGC of patients who had and had not taken semaglutide prior to elective esophagogastroduodenoscopy. The primary outcome was the presence of increased RGC. DesignSingle-center retrospective electronic chart review. SettingTertiary hospital. PatientsPatients undergoing esophagogastroduodenoscopy under deep sedation/general anesthesia between July/2021–March/2022. InterventionsPatients were divided into two (SG = semaglutide, NSG = non-semaglutide) groups, according to whether they had received semaglutide within 30 days prior to the esophagogastroduodenoscopy. MeasurementsIncreased RGC was defined as any amount of solid content, or > 0.8 mL/Kg (measured from the aspiration/suction canister) of fluid content. Main resultsOf the 886 esophagogastroduodenoscopies performed, 404 (33 in the SG and 371 in the NSG) were included in the final analysis. Increased RGC was observed in 27 (6.7%) patients, being 8 (24.2%) in the SG and 19 (5.1%) in the NSG (p < 0.001). Semaglutide use [5.15 (95%CI 1.92–12.92)] and the presence of preoperative digestive symptoms (nausea/vomiting, dyspepsia, abdominal distension) [3.56 (95%CI 2.2–5.78)] were associated with increased RGC in the propensity weighted analysis. Conversely, a protective [0.25 (95%CI 0.16–0.39)] effect against increased RGC was observed in patients undergoing esophagogastroduodenoscopy combined with colonoscopy. In the SG, the mean time of preoperative semaglutide interruption in patients with and without increased RGC was 10.5 ± 5.5 and 10.2 ± 5.6 days, respectively (p = 0.54). There was no relationship between semaglutide use and the amount/volume of RGC found on esophagogastroduodenoscopy (p = 0.99). Only one case (in the SG) of pulmonary aspiration was reported. ConclusionsSemaglutide was associated with increased RGC in patients undergoing elective esophagogastroduodenoscopy. Digestive symptoms prior to esophagogastroduodenoscopy were also predictive of increased RGC.

Glucagon-Like Peptide-1 Receptor Agonist Protects Against Diabetic Cardiomyopathy by Modulating microRNA-29b-3p/SLMAP.

Our aims were to investigate the pathogenesis of diabetic cardiomyopathy (DCM) and to explore the protective effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) on DCM. After 12 weeks of treatment with exenatide-loaded microspheres, a long-acting GLP-1RA, in DCM mice, cardiac structure and function were evaluated by plasma B-type natriuretic peptide (BNP), echocardiography, H&E, oil red and Sirius staining. The expression of glucagon-like peptide-1 receptor in mouse heart tissue was determined by immunofluorescence staining. The label-free proteomic analysis of cardiac proteins was conducted among control, DCM and DM+GLP-1RA groups. Then, quantitative real-time PCR, Western blotting and dual-luciferase reporter assay were performed to verify the regulation of target protein by the upstream microRNA (miRNA). GLP-1RA treatment obviously improved serum BNP, myocardial fibrosis, lipid deposition of the myocardium and echocardiography parameters in DCM mice. Sarcolemmal membrane-associated protein (SLMAP) was one of 61 differentially expressed cardiac proteins found in three groups by proteomic analysis. Up-regulation of microRNA-29b-3p (miR-29b-3p) and down-regulation of SLMAP were found in the ventricular myocardium of GLP-1RA-treated DCM mice. SLMAP was a target of miR-29b-3p, while GLP-1RA regulated SLMAP expression through miR-29b-3p. Furthermore, inhibition of glucagon-like peptide-1 receptor (GLP-1R) in cardiomyocytes reversed the effects of GLP-1RA on miR-29b/SLMAP. SLMAP may play roles in the pathogenesis of DCM and may be a target of GLP-1RA in protecting against DCM. After binding to myocardial GLP-1R, GLP-1RA can regulate the expression of myocardial SLMAP through miR-29b-3p.

GLP-1 Receptor Agonists Induce Growth Hormone Secretion in Healthy Volunteers.

Growth hormone (GH) is an essential regulator of growth, body composition and fuel metabolism and, consequently, GH secretion is under the feedback control of numerous nutritional and endocrine mediators. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to exert pleiotropic effects, including stimulation of the activity of the hypothalamic-pituitary-adrenal axis. As GLP-1RAs exert multiple metabolic effects, we hypothesised that they may also affect the secretion of GH and examined the effect of a short-acting and a long-acting GLP-1 RA on GH secretion. This is a post hoc analysis of data from clinical trials. Two separate single-group open-label clinical trials were carried out in the ambulatory care setting with a duration of 1 and 21days, respectively. Healthy adult male and female volunteers with no chronic illnesses or use of daily medicines were recruited for the study. The two interventions were: study 1, single dose of 10µg exenatide administered subcutaneously (s.c.); study 2, 0.6mg liraglutide administered s.c. once daily for 21days. Administration of a single dose of exenatide (study 1) caused a clear increase in GH levels, peaking between 60 and 120min post-administration. There was also a small but statistically significant decrease in luteinising hormone and testosterone levels 120min after exenatide dosing. Administration of the long-acting GLP-1RA liraglutide daily for 21 days (study 2) elicited an increase in GH levels with no change in insulin-like growth factor-1 (IGF-1) concentrations after 3weeks of treatment. The results show that the administration of GLP-1RAs may elicit an increase in growth hormone levels. GLP-1 signalling may be a novel mechanism of regulation of GH secretion. This finding needs to be replicated in the placebo-controlled trial. NCT02089256 and NCT03160261.

Evaluating the Efficacy and Safety of Long-Acting GLP-1 Receptor Agonists in T1DM Patients

(1) Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) are a class of therapeutic agents that mimic the endogenous incretin hormone GLP-1. While this class of agents is not approved for Type 1 Diabetes (T1DM) due to concern of increased diabetic ketoacidosis (DKA) risk, long-acting GLP-1 medications are being commonly prescribed off label for T1DM in clinical practice. Several studies addressed the efficacy and safety of short-acting GLP-1 agonists therapy in patients with T1DM, but the data on long-acting agents are lacking. In our study, we aim to fill in this gap and help healthcare providers in their clinical decision making on the use of these agents for T1DM patients. (2) Methods: We conducted a retrospective chart review of T1DM patients on a long-acting GLP-1 for at least six months. Our retrospective chart review included information starting two years prior to starting GLP-1, and six or more months after starting GLP-1. Parameters collected included HbA1c, 14-day Continuous Glucose Monitor (CGM) and blood glucose (BG) data, and metabolic data (weight, systolic and diastolic blood pressure, and cholesterol levels). Statistical analysis was conducted using paired t-tests on R and Excel with α of 0.05. (3) Results: Our cohort consisted of 54 participants with T1DM on a long-acting GLP-1 (semaglutide, dulaglutide, exenatide extended-release [ER], albiglutide). Mean GLP-1 treatment duration was 23.85 ± 15.46 months. HbA1c values decreased significantly by an average of 0.71% percentage points (%-points, p = 0.002) comparing pre-therapy vs. on GLP-1 treatment. Similarly, for pre-therapy vs. on GLP-1 treatment values, CGM results were significant for increased time in range by 12.15%-points (p = 0.0009) showing a decreased average time in hyperglycemia (BG &gt; 180 mg/dL) by a mean difference of 11.97%-points (p = 0.006), decreased 14-day mean BG by 19 mg/dl (p = 0.01), decreased 14-day BG standard deviation by 8.45 mg/dl (p = 0.01), decreased incidence of DKA hospitalization, and a decrease in weight by 3.16 kg (p = 0.007). (4) Conclusions: As more data emerges on cardiovascular and renal benefits of long acting GLP-1 in type 2 diabetes, there have been no reported outcomes in T1DM. Our study is the first to demonstrate glycemic and metabolic benefits of this class of medication as an adjunct therapy to insulin in T1DM, and safety of its use over an average of 1.5–2 years’ time. This study represents real life experience and the data warrants confirmation by additional prospective studies.

The GLP-1 receptor agonist exenatide ameliorates neuroinflammation, locomotor activity, and anxiety-like behavior in mice with diet-induced obesity through the modulation of microglial M2 polarization and downregulation of SR-A4.

Obesity is associated with multiple comorbidities, such as metabolic abnormalities and cognitive dysfunction. Moreover, accumulating evidence indicates that neurodegenerative disorders are associated with chronic neuroinflammation. GLP-1 receptor agonists (RAs) have been extensively studied as a treatment for type 2 diabetes. Emerging evidence has demonstrated a protective effect of GLP-1 RAs on neurodegenerative disease, which is independent of its glucose-lowering effects. In this study, we aimed to examine the effects of a long-acting GLP-1 RA, exenatide, on high-fat diet (HFD)-induced neuroinflammation and related brain function impairment. First, mice treated with exenatide exhibited significantly reduced HFD-increased body weight and blood glucose. In an open field test, exenatide treatment ameliorated the reduction in local motor activity and anxiety in HFD-fed mice. Moreover, HFD induced astrogliosis, microgliosis, and upregulation of IL-1β, IL-6 and TNF-α in hippocampus and cortex. Exenatide treatment reduced HFD-induced astrogliosis and IL-1β and TNF-α expressions. Moreover, exenatide increased phosphor-ERK and M2-type microglia marker arginase-1 expression in the hippocampus and cortex. In addition, we found that scavenger receptor-A4 protein expression was induced by HFD and was subsequently inhibited by exenatide. SR-A4 knockout reversed the locomotor activity impairment but not the anxiety behavior caused by HFD consumption. SR-A4 knockout also reduced HFD-induced neuroinflammation, as shown by the reduced expression of GFAP and IBA-1 compared with that in wild-type control mice. These results demonstrate that exenatide decreases HFD-increased neuroinflammation and promotes anti-inflammatory M2 differentiation. The inhibition of SR-A4 by exenatide exerts anti-inflammatory activity.

Metabolic remodeling of glycerophospholipids acts as a signature of dulaglutide and liraglutide treatment in recent-onset type 2 diabetes mellitus.

As metabolic remodeling is a pathological characteristic in type 2 diabetes (T2D), we investigate the roles of newly developed long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as dulaglutide and liraglutide on metabolic remodeling in patients with recent-onset T2D. We recruited 52 cases of T2D and 28 control cases in this study. In the patient with T2D, 39 cases received treatment with dulaglutide and 13 cases received treatment with liraglutide. Using untargeted metabolomics analysis with broad-spectrum LC-MS, we tracked serum metabolic changes of the patients from the beginning to the end of follow-up (12th week). We identified 198 metabolites that were differentially expressed in the patients with T2D, compared to the control group, in which 23 metabolites were significantly associated with fasting plasma glucose. Compared to pre-treatment, a total of 46 and 45 differentially regulated metabolites were identified after treatments with dulaglutide and liraglutide, respectively, in which the most differentially regulated metabolites belong to glycerophospholipids. Furthermore, a longitudinal integration analysis concurrent with diabetes case-control status revealed that metabolic pathways, such as the insulin resistance pathway and type 2 diabetes mellitus, were enriched after dulaglutide and liraglutide treatments. Proteins such as GLP-1R, GNAS, and GCG were speculated as potential targets of dulaglutide and liraglutide. In total, a metabolic change in lipids existed in the early stage of T2D was ameliorated after the treatments of GLP-1RAs. In addition to similar effects on improving glycemic control, remodeling of glycerophospholipid metabolism was identified as a signature of dulaglutide and liraglutide treatments.

Liraglutide Effectiveness in Type 2 Diabetes: Insights from a Real-World Cohort of Portuguese Patients.

Liraglutide is a long-acting glucagon-like peptide-1 receptor agonist prescribed to diabetic patients for glycaemic control. To understand the impact of liraglutide in the real-world setting, this study analysed its effects in a Portuguese cohort of Type 2 diabetes patients. This was an observational, multicentric, and retrospective study that included 191 liraglutide-treated patients with at least 12 months of treatment. Patients' data were collected and analysed during a 24-month follow-up period. Overall, liraglutide treatment effectively reduced HbA1c levels from 8.3% to around 7.5%, after 6, 12, and 24 months (p &lt; 0.001). In fact, 38.2%, 37.2%, and 44.8% of patients at 6, 12, and 24 months, respectively, experienced an HbA1c reduction of at least 1%. Moreover, a persistent reduction in anthropometric features was also observed, with 44.0%, 47.6%, and 54.4% of patients achieving a weight reduction of at least 3% at 6, 12, and 24 months, respectively. Finally, significant improvements were observed in the HDL-c and LDL-c levels. Our results demonstrate that liraglutide effectively promoted the reduction of HbA1c values during routine clinical practice, which was sustained throughout the study. In addition, there were significant improvements in anthropometric parameters and other cardiovascular risk factors.

ODP259 Evaluating the Efficacy and Safety of Long-Acting GLP-1 Receptor Agonist in T1DM Patients

Abstract Introduction GLP-1 receptor agonist is a medication class that mimics the endogenous incretin hormone GLP-1. Short-acting GLP-1 agents were studied as adjunct therapies in type 1 diabetes (T1DM) but not approved due to concern of increased diabetic ketoacidosis (DKA) risk. Long-acting GLP-1 medications are still commonly prescribed for T1DM patients. One study has assessed the impact of a long-acting GLP-1 in 11 T1DM patients. No hospitalizations were observed, and time in range was not reported. [1] Our study aims to evaluate the efficacy and safety of long-acting GLP-1 medications in a larger cohort of T1DM patients. Methodology We conducted a retrospective chart review of T1DM patients taking a long-acting GLP-1 for at least three months. ICD-10 code E10. Type 1 diabetes mellitus was used to search our institution's Electronic Health Record system (EPIC). Primary parameters collected included A1C and glycemic trends. Data analysis was done by averaging values over a two-year period before and after starting the medication. Results We identified 27 participants with T1DM (mean age 42yrs, mean T1DM duration 18.1yrs) on a long-acting GLP-1 (semaglutide 70.4%, dulaglutide 33.3%, long-acting exenatide 3.7%, albiglutide 3.7%). Mean therapy duration was 24.28±19. 01mo. A1C values decreased significantly from7.61±1. 08% to 7.16±0.73% (p=0. 015, N=25). Per CGM data, average time in range (TIR) increased significantly from48.82±22.35% to64.70±16.58% (p=0. 0002, N=15), average time in hyperglycemia decreased from42.39±23.32% to 31.58±16.65% (p=0. 019, N=14) and 14-day blood mean glucose decreased from 190.40±38.42 mg/dl to 167. 06±25.86 mg/dl (p=0. 001, N=17). There were no statistically significant differences in time in hypoglycemia and incidence of DKA. Hyperglycemic and hypoglycemic episodes were defined per patients’ individualized CGM settings (most commonly Blood Glucose levels&amp;gt;180 and &amp;lt;70 respectively). Patients’ weight decreased non-significantly from182. 00±50.92 lbs to 170.88±51.37 lbs (p=0.128, N=8). There were no ER visits or hospitalizations for DKA while on GLP-1 therapy. Conclusion There is an urgent need for strategies to improve glycemic control and reduce morbidity and mortality in T1DM. Long-acting GLP-1s are a promising adjunct to insulin. Our study is the first to demonstrate significant A1C reduction and TIR increase without increased hypoglycemia and DKA risk in 27 T1DM patients on long-acting GLP-1s. Longer prospective studies are warranted. Presentation: No date and time listed

Four-month treatment with long-acting glucagon-like peptide-1 receptor agonists (GLP-1) or sodium-glucose co-trasporter-2 inhibitors (SGLT-2i) improves vascular function in type 2 diabetes mellitus

Abstract Background/Introduction Patients with type 2 diabetes mellitus (T2DM) and ischemic stroke present impaired markers of vascular and endothelial function. Glucagon-like peptide-1 receptor agonists (GLP-1) and sodium-glucose contrasporter-2 inhibitors (SGLT-2) are novel antidiabetic agents reducing the risk of cardiovascular complications. Purpose The aim of the study is to investigate the effect of treatment with GLP-1 or SGLT2 on arterial stiffness and endothelial glycocalyx in patients with T2DM and ischemic stroke. Methods We recruited in total 81 patients with T2DM and ischemic stroke who received dulaglutide (n=27), dapagliflozin (n=27) or insulin (n=27). We measured at baseline and at four months post-treatment the: a) Carotid-femoral pulse wave velocity (PWV-Complior; ALAM Medical), b) Augmentation index (Aix), c) Central systolic blood pressure (cSBP), and d) Perfused boundary region (PBR) of the sublingual arterial microvessels(marker of endothelial glycocalyx thickness), e) Left ventricular global longitudinal strain (GLS) using speckle-tracking echocardiography. Results At baseline, patients among the three groups had similar age, sex, HbA1c and markers of endothelial and cardiovascular function (p&amp;gt;0.05). Dapagliflozin and dulaglutide showed a greater reduction of PBR, PWV and central SBP than insulin, despite a similar HbA1c reduction (p&amp;lt;0.05). After four months treatment, patients on dapagliflozin and on dulaglutide displayed a greater reduction of PWV (−10% and −8% vs −1%), of cSBP (−9% and −8% vs +1%), of Aix (−65% and −13% vs −3%) and of GLS (+11% and +7% vs +5%) compared to patients on insulin (p&amp;lt;0.05 for all comparisons) (Table 1). PBR values were improved only in patients who received dulaglutide (−4% vs dapagliflozin: −2% vs insulin +1%). Conclusions Dulaglutide and dapagliflozin improve cardiovascular function, but only dulaglutide improves endothelial glycocalyx in patients with T2DM and ischemic stroke after four months treatment. Funding Acknowledgement Type of funding sources: None.