Dietary salt promotes cognition impairment through GLP-1R/mTOR/p70S6K signaling pathway.

Dietary salt has been associated with cognitive impairment in mice, possibly related to damaged synapses and tau hyperphosphorylation. However, the mechanism underlying how dietary salt causes cognitive dysfunction remains unclear. In our study, either a high-salt (8%) or normal diet (0.5%) was used to feed C57BL/6 mice for three months, and N2a cells were cultured in normal medium, NaCl medium (80 mM), or NaCl (80 mM) + Liraglutide (200 nM) medium for 48 h. Cognitive function in mice was assessed using the Morris water maze and shuttle box test, while anxiety was evaluated by the open field test (OPT). Western blotting (WB), immunofluorescence, and immunohistochemistry were utilized to assess the level of Glucagon-like Peptide-1 receptor (GLP-1R) and mTOR/p70S6K pathway. Electron microscope and western blotting were used to evaluate synapse function and tau phosphorylation. Our findings revealed that a high salt diet (HSD) reduced the level of synaptophysin (SYP) and postsynaptic density 95 (PSD95), resulting in significant synaptic damage. Additionally, hyperphosphorylation of tau at different sites was detected. The C57BL/6 mice showed significant impairment in learning and memory function compared to the control group, but HSD did not cause anxiety in the mice. In addition, the level of GLP-1R and autophagy flux decreased in the HSD group, while the level of mTOR/p70S6K was upregulated. Furthermore, liraglutide reversed the autophagy inhibition of N2a treated with NaCl. In summary, our study demonstrates that dietary salt inhibits the GLP-1R/mTOR/p70S6K pathway to inhibit autophagy and induces synaptic dysfunction and tau hyperphosphorylation, eventually impairing cognitive dysfunction.

Liraglutide prevents cellular senescence in human retinal endothelial cells (HRECs) mediated by SIRT1: an implication in diabetes retinopathy.

Diabetes mellitus (DM) is a chronic metabolic disorder affecting millions of people worldwide, characterized by dysregulated glucose homeostasis and hyperglycemia. Diabetic retinopathy (DR) is one of the serious multisystemic complications. Aging is an important risk factor for DR. Endothelial sirtuin 1 (SIRT1) plays an important role in regulating the pathophysiology of glucose metabolism, cellular senescence, and aging. Liraglutide, an analog of Glucagon-like peptide 1 (GLP-1), has been widely used in the treatment of DM. However, the effects of Liraglutide on DR are less reported. Here, we investigated whether treatment with Liraglutide has beneficial effects on high glucose (HG)-induced injury in human retinal microvascular endothelial cells (HRECs). First, we found that exposure to HG reduced the expression of glucagon-like peptide 1 receptor 1 (GLP-1R). Additionally, Liraglutide ameliorated HG-induced increase in the expression of vascular endothelial growth factor-A (VEGF-A) and interleukin 6 (IL-6). Importantly, Liraglutide ameliorated cellular senescence and increased telomerase activity in HG-challenged HRECs. Liraglutide also reduced the levels of p53 and p21. Mechanistically, Liraglutide restored the expression of SIRT1 against HG. In contrast, the knockdown of SIRT1 abolished the protective effects of Liraglutide in cellular senescence of HRECs. Our findings suggest that Liraglutide might possess a benefit on DR mediated by SIRT1.

Comparing the effects of empagliflozin and liraglutide on lipid metabolism and intestinal microflora in diabetic mice.

Background and Objectives: Recent studies have shown that the imbalance of intestinal flora is related to the occurrence and progression of diabetic nephropathy (DN) and can affect lipid metabolism. Sodium-dependent glucose transporters 2 (SGLT2) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist are commonly used hypoglycemic drugs and have excellent renal safety. The purpose of this study was to compare the protective effects of empagliflozin and liraglutide on kidneys, lipid metabolism, and intestinal microbiota in diabetic mice. Methods: We established a mouse model of type two diabetes by feeding rats a high-fat diet (HFD) followed by an intraperitoneal injection of STZ. The mice were randomly divided into groups: normal control (NC), diabetic model (DM), liraglutide treatment (LirT), empagliflozin treatment (EmpT), and liraglutide combined with empagliflozin treatment (Emp&LirT) groups. Blood glucose, lipids, creatinine, and uric acid, as well as urinary nitrogen and albumin levels were measured. The renal tissues were subjected to HE, PAS and Masson's staining. These parameters were used to evaluate renal function and histopathological changes in mice. Mice feces were also collected for 16sRNA sequencing to analyze the composition of the intestinal flora. Results: All the indexes related to renal function were significantly improved after treatment with drugs. With respect to lipid metabolism, both drugs significantly decreased the serum triglyceride levels in diabetic mice, but the effect of liraglutide on reducing serum cholesterol was better than that of empagliflozin. However, empagliflozin had a better effect on the reduction of low-density lipoproteins (LDL). The two drugs had different effects on intestinal flora. At the phylum level, empagliflozin significantly reduced the ratio of Firmicutes to Bacteroidota, but no effect was seen with liraglutide. At the genus level, both of them decreased the number of Helicobacter and increased the number of Lactobacillus. Empagliflozin also significantly increased the abundance of Muribaculaceae, Muribaculum, Olsenella, and Odoribacter, while liraglutide significantly increased that of Ruminococcus. Conclusion: Liraglutide and empagliflozin were both able to improve diabetes-related renal injury. However, the ability of empagliflozin to reduce LDL was better compared to liraglutide. In addition, their effects on the intestine bacterial flora were significantly different.

Effect of liraglutide on cardiac function in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials.

BACKGROUND: Liraglutide widely utilized in type 2 diabetes treatment, has elicited conflicting findings regarding its impact on cardiac function in patients with this condition. Therefore, The objective of this study was to conduct a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of liraglutide on cardiac function in patients diagnosed with type 2 diabetes. METHODS: We identified double-blind randomized trials assessing the effects of liraglutide compared to placebo on cardiac function in patients with type 2 diabetes. Data were synthesized with the fixed-effect models to generate standard mean differences (SMDs) with 95% confidence intervals (CIs) of each outcome for liraglutide versus placebo. The risk of bias would be assessed according to the Cochrane Risk of Bias Tool, while meta-analysis would be conducted using Revman 5.3.0 software. The evidence was graded based on the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: The meta-analysis encompassed 5 RCTs including 220 participants. Results revealed that liraglutide exhibited significant enhancements in left ventricular ejection fraction [SMD = -0.38, 95%CI(-0.70, -0.06), P = .02], cardiac index [SMD = -1.05, 95%CI(-1.52, -0.59), P < .0001], stroke volume [SMD = -0.67, 95%CI(-1.02, -0.32), P = .0002] and early diastolic filling velocity/late atrial filling velocity ratio [SMD = -0.52, 95%CI(-0.82, -0.22), P = .0006]. However, no statistically significant impact on cardiac output [SMD = -0.20, 95%CI(-0.53, 0.14), P = .26], early diastolic filling velocity/early diastolic annular velocity (E/Ea) ratio [SMD = -0.34, 95%CI(-0.75, 0.06), P = .10] and early diastolic filling velocity/early diastolic mitral annular velocity ratio [SMD = 0.21, 95%CI(-0.15, 0.56), P = .25] was observed. The Grading of Recommendations Assessment, Development and Evaluation evidence quality ratings indicated that all the outcome measures included in this study were evaluated as having low and very low quality. CONCLUSION: The available evidence suggested that liraglutide may exert a favorable impact on cardiac function in patients with type 2 diabetes. Consequently, the utilization of liraglutide as a preventive measure against heart failure incidents in individuals with type 2 diabetes represents a promising strategy. However, robust evidence support requires the conduct of large-scale, multicenter high-quality RCTs.

[Current State of Pharmacotherapy in Obesity].

The prevalence of obesity with various complications is increasing rapidly in Korea. Although lifestyle modification is fundamental in obesity treatment, more effective treatment tools are required. Many advances in obesity treatment have been reported recently, including lifestyle modifications and pharmacological, endoscopic, and surgical treatments. Drugs with proven long-term efficacy and safety are preferred because management for obesity treatment is a long-term process. Currently, four medications are available for long-term use in Korea: Orlistat, Naltrexone/bupuropion NR, Phentermine/topiramate capsule, and Liraglutide. Recently, semaglutide and tirzepatide have been attracting attention because of their effectiveness and convenience, but they are not yet available in Korea. In addition, there are limitations such as the yo-yo effect when discontinuing the drug, long-term safety, and cost. Patients and medical staff must be aware of the advantages and side effects of each medication to ensure the successful treatment of obesity.

Comparison of the Efficacy of Anti-Obesity Medications in Real-World Practice.

Purpose: Anti-obesity medications (AOMs), along with lifestyle interventions, are effective means of inducing and maintaining weight loss in patients with obesity. Although the efficacy of AOMs has been reported, there have been no direct comparisons of these drugs. Therefore, in the present study, we aimed to compare the efficacy of all the AOMs available in Korea in a real-world setting. Patients and Methods: The body weight and composition of 205 adults treated with phentermine, phentermine/topiramate, liraglutide, naltrexone/bupropion, lorcaserin, or orlistat for at least 6 months were analyzed at 2 month intervals. The prevalence of the achievement of a ≥5% weight loss and the changes in body composition were compared between participants using each AOM at each visit. Results: A total of 132 (64.4%) participants achieved ≥5% weight loss within 6 months (prevalence of ≥5% weight loss after 6 months: phentermine, 87.2%; phentermine/topiramate, 67.7%; liraglutide, 58.1%; naltrexone/bupropion, 35.3%; lorcaserin, 75%; orlistat, 50%). At each visit, after adjustment for age, sex, and baseline body weight, phentermine use was associated with a significantly higher prevalence of ≥5% weight loss than the use of the other AOMs, except for liraglutide. There were significant differences in the body weight, body mass index and body fat mass among the AOM groups by visit (P for interaction <0.05), but not in their waist circumference, skeletal muscle mass, percentage body fat, or visceral fat area. Conclusion: All the AOMs were effective at inducing and maintaining weight loss, in the absence of significant changes in muscle mass, over a 6 month period, and the short-term use of phentermine and the long-term use of phentermine/topiramate or liraglutide would be practical choices for the treatment of obesity. However, further, large-scale studies are necessary to confirm these findings.

Liraglutide improved the reproductive function of obese mice by upregulating the testicular AC3/cAMP/PKA pathway.

BACKGROUND: The incidence of male reproductive dysfunction is increasing annually, and many studies have shown that obesity can cause severe harm to male reproductive function. The mechanism of male reproductive dysfunction caused by obesity is unclear, and there is no ideal treatment. Identification of effective therapeutic drugs and elucidation of the molecular mechanism involved in male reproductive health are meaningful. In this study, we investigated the effects of the GLP-1 receptor agonist liraglutide on sex hormones, semen quality, and testicular AC3/cAMP/PKA levels in high-fat-diet-induced obese mice. METHODS: Obese mice and their lean littermates were treated with liraglutide or saline for 12 weeks. Body weight was measured weekly. Fasting blood glucose (FBG) was measured using a blood glucose test strip. The serum levels of insulin (INS), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), free testosterone (F-TESTO), estradiol (E2), and sex hormone binding globulin (SHBG) were detected using ELISA. The sperm morphology and sperm count were observed after Pap staining. The mRNA and protein expression levels of testicular GLP-1R and AC3 were measured by RT-qPCR and Western blot, respectively. Testicular cAMP levels and PKA activity were detected using ELISA. RESULTS: Liraglutide treatment can decrease body weight, FBG, INS, HOMA-IR, E2 and SHBG levels; increase LH, FSH, T, and F-TESTO levels; increase sperm count; decrease the sperm abnormality rate; and increase GLP-1R and AC3 expression levels and cAMP levels and PKA activity in testicular tissue. CONCLUSIONS: Liraglutide can improve the sex hormone levels and semen quality of obese male mice. In addition to its weight loss effect, liraglutide can improve the reproductive function of obese male mice, which may also be related to the upregulation of AC3/cAMP/PKA pathway in the testis. This work lays the groundwork for future clinical studies.

The GLP-1R as a model for understanding and exploiting biased agonism in next-generation medicines.

The glucagon-like peptide 1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that emerged as a pharmacologic target in cardiometabolic disease, including diabetes and obesity, over 30 years ago. The subsequent widespread clinical use of GLP-1R agonists, including exenatide, liraglutide, and semaglutide, has made the GLP-1R a preeminent model for understanding basic GPCR biology, including the emergent field of biased agonism. Recent data demonstrate that the dual GLP-1R/glucose dependent insulinotropic polypeptide receptor (GIPR) agonist tirzepatide exhibits a biased signaling profile characterized by preferential Gαs activation over ß-arrestin recruitment, which appears to contribute to its insulinotropic and body-weight reducing effects in preclinical models. This constitutes a major finding in which nuanced, mechanistic receptor signaling dynamics in vitro mediate real-world clinical differentiation within a drug class. Because of the striking bench-top-to-bed side relevance of this biased signaling phenomenon, we have undertaken a review of the emerging data detailing biased agonism at the GLP-1R. In this review, we introduce the core concept of biased agonism followed by a detailed consideration of the key mechanisms, including ligand-mediated bias, receptor-mediated bias, and systems/cell-type bias. Current industry programs are largely, if not entirely, focused on developing biased ligands, and so we have dedicated a section of the review to a brief meta-analysis of compounds reported to drive biased signaling, with a consideration of the structural determinants of receptor-ligand interactions. In this work, we aim to assess the current knowledge regarding signaling bias at the GLP-1R and how these ideas might be leveraged in future optimization.

Effects of Liraglutide, Empagliflozin and Their Combination on Left Atrial Strain and Arterial Function.

Background and Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are cardioprotective drugs. We investigated their effects on left atrial function, a major determinant of cardiac diastolic dysfunction in type 2 diabetes mellitus. We also explored the association of changes in arterial stiffness with those of the LA strain after treatment. Materials and Methods: A total of 200 patients (59.5 ± 9.1 year old, 151 male) with type 2 diabetes mellitus treated with metformin were randomized to insulin (n = 50 served as controls), liraglutide (n = 50), empagliflozin (n = 50) or their combination (liraglutide + empagliflozin) (n = 50). We measured at baseline and 6 months post-treatment: (a) left atrial and global left ventricular longitudinal strain by speckle tracking echocardiography; (b) pulse wave velocity (PWV) and central systolic blood pressure. Results: At baseline, there was a correlation of the LA reservoir strain with PWV (r = -0.209, p = 0.008), central SBP (r = -0.151, p = 0.030), EF (r = 0.214, p = 0.004) and GLS (r = -0.279, p = 0.009). The LA reservoir change 6 months post-treatment was correlated with the PWV change in all groups (r = -0.242, p = 0.028). The LA reservoir change 6 months post-treatment was correlated with the GLS change in all groups (r = -0.322, p = 0.004). Six months after intervention, patients treated with liraglutide, empagliflozin and their combination improved the left atrial reservoir strain (GLP1RA 30.7 ± 9.3 vs. 33.9 ± 9.7%, p = 0.011, SGLT2i 30 ± 8.3 vs. 32.3 ± 7.3%, p = 0.04, GLP1&SGLT2i 29.1 ± 8.7 vs. 31.3 ± 8.2, p = 0.007) compared to those treated with insulin (33 ± 8.3% vs. 32.8 ± 7.4, p = 0.829). Also, patients treated with liraglutide and the combination liraglutide and empagliflozin had improved left atrial conduction strain (p < 0.05). Empagliflozin or the combination liraglutide and empagliflozin showed a greater decrease of PWV and central and brachial systolic blood pressure than insulin or GLP-1RA. (p < 0.05). Conclusions: Impaired aortic elastic properties are associated with a decreased LA strain in type 2 diabetics. Treatment with liraglutide, empagliflozin and their combination for 6 months showed a greater improvement of left atrial function compared to insulin treatment in parallel with the improvement of arterial and myocardial functions.

An oncolytic vaccinia virus encoding hyaluronidase reshapes the extracellular matrix to enhance cancer chemotherapy and immunotherapy.

BACKGROUND: The redundant extracellular matrix (ECM) within tumor microenvironment (TME) such as hyaluronic acid (HA) often impairs intratumoral dissemination of antitumor drugs. Oncolytic viruses (OVs) are being studied extensively for cancer therapy either alone or in conjunction with chemotherapy and immunotherapy. Here, we designed a novel recombinant vaccinia virus encoding a soluble version of hyaluronidase Hyal1 (OVV-Hyal1) to degrade the HA and investigated its antitumor effects in combination with chemo drugs, polypeptide, immune cells, and antibodies. METHODS: We constructed a recombinant oncolytic vaccinia virus encoding the hyaluronidase, and investigated its function in remodeling the ECM of the TME, the antitumor efficacy both in vitro and in several murine solid tumors either alone, or in combination with chemo drugs including doxorubicin and gemcitabine, with polypeptide liraglutide, with immune therapeutics such as PD-L1/PD-1 blockade, CD47 antibody, and with CAR-T cells. RESULTS: Compared with control OVV, intratumoral injection of OVV-Hyal1 showed superior antitumor efficacies in a series of mouse subcutaneous tumor models. Moreover, HA degradation by OVV-Hyal1 resulted in increased intratumoral dissemination of chemo drugs, infiltration of T cells, NK cells, macrophages, and activation of CD8+ T cells. When OVV-Hyal1 was combined with some antitumor therapeutics, for example, doxorubicin, gemcitabine, liraglutide, anti-PD-1, anti-CD47 blockade, or CAR-T cells, more profound therapeutic outcomes were obtained. CONCLUSIONS: OVV-Hyal1 effectively degrades HA to reshape the TME, therefore overcoming some major hurdles in current cancer therapy, such as limited OVs spread, unfavored dissemination of chemo drugs, polypeptides, antibodies, and insufficient infiltration of effector immune cells. OVV-Hyal1 holds the promise to improve the antitumor outcomes of current cancer therapeutics.

Effect of Liraglutide combined with Jinlida granules on glycolipid metabolism and islet function of type 2 diabetes mellitus.

To investigate whether Liraglutide combined with Jinlida granules affects glycolipid metabolism and islet function in the treatment of type 2 diabetes mellitus (T2DM), a control group and an observation group were established with 90 T2DM patients. The control group was given Jinlida treatment and the observation group was given liraglutide combined treatment for 12 weeks. The clinical efficacy, glycolipid metabolism, bone metabolism, islet function, and endothelial function. The curative effect of the observation group was better than that of the control group. After treatment, FBG, 2hPG, HbAlc, TC, TG, and LDL-C in the observation group were lower and HDL-C was higher than those in the control group (P < 0.05). After treatment, the observation group showed higher bone mineral density, osteocalcin, FINS, and HOMA-ß and lower HOMA-IR than the control group (P < 0.05). After treatment, endothelin-1 level in the observation group was lower than that in the control group, and the NO level was higher (P < 0.05). No significant difference was found in the incidence of adverse reactions between the two groups (P > 0.05). Liraglutide combined with Jinlida in T2DM can improve glucose, lipid, and bone metabolism, promote the recovery of islet function, and enhance vascular endothelial function.

Protecting cardiomyocytes from hypoxia-reoxygenation injury, empaglifozin and liraglutide alone or in combination?

OBJECTIVES: Empagliflozin, a sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, are commonly recognized for their cardiovascular benefits in individuals with type 2 diabetes (T2D). In prior studies, we have demonstrated that both drugs, alone or in combination, were able to protect cardiomyocytes from injury induced by diabetes. Mechanistic investigations also suggested that the cardioprotective effect may be independent of diabetes In this study, we utilized a hypoxia-reoxygenation (H/R) model to investigate the cardiovascular benefits of SGLT2 inhibitor empagliflozin and GLP-1 receptor (GLP-1R) agonist liraglutide, both alone and in combination, in the absence of T2D. Our hypothesis was that empagliflozin and liraglutide, either individually or in combination, would demonstrate cardioprotective properties against H/R-induced injury, with an additive and/or synergistic effect anticipated from combination therapy. METHODS: In this study, the cardiac muscle cell line, HL-1 cells, were treated with vehicle, empagliflozin, liraglutide, or a combination of the two drugs. The cells were then subjected to a hypoxia-reoxygenation (H/R) protocol, consisting of 1 h of hypoxia followed by 24 h of reoxygenation. The effects of the treatments on cytotoxicity, oxidative stress, endothelial nitric oxide synthase (eNOS) activity, phospho-protein kinase C (PKC) beta and phospho-eNOS (Thr495) expression were subsequently evaluated at the end of the treatments. RESULTS: We found that H/R increased cytotoxicity and reduces eNOS activity, empagliflozin, liraglutide or combination treatment attenuated some or all of these effects with the combination therapy showing the greatest improvement. CONCLUSIONS: Empagliflozin, liraglutide or combination of these two have cardioprotective effect regardless of diabetes. Cardioprotective effects of SGLT2 inhibitor and GLP-1R agonist is additive and synergistic.

Coordinated ASBT and EGFR Mechanisms for Optimized Liraglutide Nanoformulation Absorption in the GI Tract.

Background: For maintenance therapy in type 2 diabetes, glucagon-like peptide-1 agonist (GLP-1A), which exhibits low cardiovascular risk and high efficacy, is a promising peptide therapeutic. However, developing an oral GLP-1A presents challenges due to the analog's poor cellular permeability and gastrointestinal (GI) stability. Methods: To mitigate such limitations, an oral nanoformulation of liraglutide (LG) was designed and achieved by combining LG with bile acid derivatives using the nanoprecipitation method. This strategy allowed the bile acid moieties to localize at the nanoparticle surface, enhancing the binding affinity for apical sodium-dependent bile acid transporter (ASBT) and improving GI stability. The in vitro characteristics, cellular permeability, and absorption mechanisms of the LG nanoformulation (LG/TD-NF) were thoroughly investigated. Furthermore, the in vivo oral absorption in rats and the glucose-lowering effects in a diabetic (db/db) mouse model were evaluated. Results: The LG/TD-NF produced neutral nanoparticles with a diameter of 58.7 ± 4.3 nm and a zeta potential of 4.9 ± 0.4 mV. Notably, when exposed to simulated gastric fluid, 65.7 ± 3.6% of the LG/TD-NF remained stable over 120 min, while free LG was fully degraded. Relative to unformulated LG, the Caco-2 cellular permeability of the nanoformulation improved, measuring 10.9 ± 2.1 (× 10-6 cm/s). The absorption mechanism prominently featured endocytosis simultaneously mediated by both ASBT and epidermal growth factor receptor (EGFR). The oral bioavailability of the LG/TD-NF was determined to be 3.62% at a dosage of 10 mg/kg, which is 45.3 times greater than that of free LG. In a diabetes model, LG/TD-NF at 10 mg/kg/day exhibited commendable glucose sensitivity and reduced HbA1c levels by 4.13% within 28 days, similar to that of subcutaneously administered LG at a dosage of 0.1 mg/kg/day. Conclusion: The oral LG/TD-NF promotes ASBT/EGFR-mediated transcytosis and assures cellular permeability within the GI tract. This method holds promise for the development of oral GLP-1A peptides as an alternative to injections, potentially enhancing patient adherence to maintenance therapy.

A Review and Meta-Analysis of the Safety and Efficacy of Using Glucagon-like Peptide-1 Receptor Agonists.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to reduce glucose levels in patients with type 2 diabetes mellitus since 2005. This meta-analysis discusses the mechanisms and potential benefits of several GLP-1 RAs. In particular, this meta-analysis focuses on the safety and associations with weight loss, glucose reduction, cardiovascular outcomes, heart failure, and renal outcomes of GLP-1 RAs to determine their benefits for patients with different conditions. In terms of glycemic control and weight loss, semaglutide was statistically superior to other GLP-1 RAs. In terms of cardiovascular outcomes, 14 mg of semaglutide taken orally once daily and 1.8 mg of liraglutide injected once daily reduced the incidence of cardiovascular death, whereas other GLP-1 RAs did not provide similar benefits. Moreover, semaglutide was associated with superior outcomes for heart failure and cardiovascular death in non-diabetic obesity patients, whereas liraglutide worsened heart failure outcomes in diabetic patients with a reduced ejection fraction. Additionally, semaglutide, dulaglutide, and liraglutide were beneficial in terms of composite renal outcomes: These GLP-1 RAs were significantly associated with less new or persistent macroalbuminuria, but not with improved eGFR deterioration or reduced requirement for renal replacement therapy. However, GLP-1 RAs may benefit patients with type 2 diabetes mellitus or obesity.

Liraglutide for Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease: The STARDUST Randomized Clinical Trial.

Importance: Peripheral artery disease (PAD) in diabetes may lead to diabetic foot ulcer and lower-extremities amputation. Glucagon-like peptide 1 receptor agonists have proven cardiovascular benefits in trials of people with type 2 diabetes at high cardiovascular risk. Objective: To examine the effect of liraglutide on peripheral perfusion measured as peripheral transcutaneous oxygen pressure (TcPo2) in individuals with type 2 diabetes and PAD. Design, Setting, and Participants: This open-label randomized clinical trial was conducted between February 1, 2021, and June 30, 2022, with a final follow-up on December 30, 2022, at University of Campania "Luigi Vanvitelli," Naples, Italy. Fifty-five individuals with type 2 diabetes, PAD, and TcPo2 between 30 and 49 mm Hg were included. Interventions: Patients were randomized to receive 1.8 mg of subcutaneous liraglutide or conventional treatment of cardiovascular risk factors (control group) for 6 months. Main Outcomes and Measures: Coprimary outcomes were the change from baseline of peripheral perfusion between groups and the comparison of the proportion of individuals who reached 10% increase of TcPo2 from baseline in each group. Results: Fifty-five participants (mean [SD] age, 67.5 [8.5] years; 43 [78%] male) were randomized (27 to the liraglutide group and 28 to the control group) and analyzed. Participants had a median (IQR) hemoglobin A1c level of 6.9% (6.5%-7.8%) and a mean (SD) TcPo2 of 40.3 (5.7) mm Hg. Transcutaneous Po2 increased over time in both groups, with significant differences favoring the liraglutide group after 6 months (estimated treatment difference, 11.2 mm Hg; 95% CI, 8.0-14.5 mm Hg; P < .001). The 10% increase of TcPo2 occurred in 24 participants (89%) in the liraglutide group and 13 (46%) in the control group (relative risk, 1.91; 95% CI, 1.26-2.90; P < .001). Compared with the control group, individuals in the liraglutide group had a significant reduction of C-reactive protein (-0.4 mg/dL; 95% CI, -0.7 to -0.07 mg/dL; P = .02), urinary albumin to creatinine ratio (-119.4 mg/g; 95% CI, -195.0 to -43.8 mg/g; P = .003), and improvement of 6-minute walking distance (25.1 m; 95% CI, 21.8-28.3 m; P < .001). Conclusions and Relevance: In this randomized clinical trial of people with type 2 diabetes and PAD, liraglutide increased peripheral perfusion detected by TcPo2 measurement during 6 months of treatment. These results support the use of liraglutide to prevent the clinical progression of PAD in individuals with type 2 diabetes. Trial Registration: ClinicalTrials.gov Identifier: NCT04881110.

Characterizing the D-Amino Acid Position in Peptide Epimers by Using Higher-Energy Collisional Dissociation Tandem Mass Spectrometry: A Case Study of Liraglutide.

D-amino acid-containing peptides (DAACPs) occur in biological and artificial environments. Since the importance of DAACPs has been recognized, various mass spectrometry-based analytical approaches have been developed. However, the capability of higher-energy collisional dissociation (HCD) fragmentation to characterize DAACP sites has not been evaluated. In this study, we compared the normalized spectra intensity under different conditions of HCD and used liraglutide along with its DAACPs as examples. Our results indicated that the difference in the intensity of y ions between DAACPs and all-L liraglutide could not only distinguish them but also localize the sites of D-amino acids in the DAACPs. Our data demonstrate the potential of using HCD for the site characterization of DAACPs, which may have great impact in biological studies and peptide drug development.

Uncovering the potential molecular mechanism of liraglutide to alleviate the effects of high glucose on myoblasts based on high-throughput transcriptome sequencing technique.

BACKGROUND: Myoblasts play an important role in muscle growth and repair, but the high glucose environment severely affects their function. The purpose of this study is to explore the potential molecular mechanism of liraglutide in alleviating the effects of high glucose environments on myoblasts. METHODS: MTT, western blot, and ELISA methods were used to investigate the role of liraglutide on C2C12 myoblasts induced by high glucose. The high-throughput transcriptome sequencing technique was used to sequence C2C12 myoblasts from different treated groups. The DESeq2 package was used to identify differentially expressed-mRNAs (DE-mRNAs). Then, functional annotations and alternative splicing (AS) were performed. The Cytoscape-CytoHubba plug-in was used to identify multicentric DE-mRNAs. RESULTS: The MTT assay results showed that liraglutide can alleviate the decrease of myoblasts viability caused by high glucose. Western blot and ELISA tests showed that liraglutide can promote the expression of AMPKα and inhibit the expression of MAFbx, MuRF1 and 3-MH in myoblasts. A total of 15 multicentric DE-mRNAs were identified based on the Cytoscape-CytoHubba plug-in. Among them, Top2a had A3SS type AS. Functional annotation identifies multiple signaling pathways such as metabolic pathways, cytokine-cytokine receptor interaction, cAMP signaling pathway and cell cycle. CONCLUSION: Liraglutide can alleviate the decrease of cell viability and degradation of muscle protein caused by high glucose, and improves cell metabolism and mitochondrial activity. The molecular mechanism of liraglutide to alleviate the effect of high glucose on myoblasts is complex. This study provides a theoretical basis for the clinical effectiveness of liraglutide in the treatment of skeletal muscle lesions in diabetes.

Liraglutide for the treatment of obesity among patients with hidradenitis suppurativaLiraglutida en el tratamiento de la obesidad en pacientes con hidradenitis supurativa / Liraglutide for the treatment of obesity among patients with hidradenitis suppurativa Liraglutida en el tratamiento de la obesidad en pacientes con hidradenitis supurativa

Background and aims: Hidradenitis suppurativa (HS) is associated with obesity. Weight loss is frequently reflected in an amelioration in the severity of the lesions. Case reports have suggested that liraglutide might improve not only weight but also skin. We aimed to study the effects of liraglutide 3mg in patients with obesity and HS on metabolic and dermatological parameters. Methods: 14 patients started treatment with liraglutide for 3 months. Severity of the lesions was evaluated using the Hurley Staging System and quality of life with the DLQI (Dermatology Quality Index). Results: There was a significant reduction in BMI (39.3±6.2 vs 35.6±5.8; p=0.002), waist circumference (121.3±19.2 vs 110.6±18.1cm; p=0.01), CRP (4.5±2.2 vs 3±2.1mg/L; p=0.04), homocysteine (16.2±2.9 vs 13.3±3μmol/L; p=0.005) and plasma cortisol (15.9±4.8 vs 12.6±4.5μg/dL; p=0.007). Hurley (2.6±0.5 vs 1.1±0.3; p=0.002) and DLQI (12.3±2.8 vs 9.7±6.9; p=0.04) improved significantly. In multiple regression analysis, weight loss did not correlate with any inflammatory parameter or Hurley. Conclusions: Liraglutide 3mg is effective and safe among patients with HS and obesity. Long-term studies are mandatory to assess the effects of liraglutide on skin lesions and inflammatory markers among subjects with HS beyond weight loss.(AU)

Antecedentes y objetivos: La hidradenitis supurativa (HS) se asocia a la obesidad. La pérdida de peso frecuentemente comporta una mejora en la gravedad de las lesiones. Casos aislados han sugerido que la liraglutida podría mejorar no solo el peso sino también la piel. Nuestro objetivo fue estudiar los efectos de liraglutida 3mg en pacientes con obesidad y HS sobre los parámetros metabólicos y dermatológicos. Métodos: Catorce pacientes iniciaron tratamiento con liraglutida durante 3meses. La gravedad de las lesiones se evaluó mediante la Escala de Hurley y la calidad de vida con el Dermatology Quality Index (DLQI). Resultados: Hubo una reducción significativa en el IMC (39,3±6,2 vs 35,6±5,8; p=0,002), la circunferencia de cintura (121,3±19,2 vs 110,6±18,1cm; p=0,01), la PCR (4,5±2,2 vs 3±2,1mg/l; p=0,04), la homocisteína (16,2±2,9 vs 13,3±3μmol/l; p=0,005) y el cortisol plasmático (15,9±4,8 vs 12,6±4,5μg/dl; p=0,007). El Hurley (2,6±0,5 vs 1,1±0,3; p=0,002) y la DLQI (12,3±2,8 vs 9,7±6,9; p=0,04) mejoraron significativamente. En el análisis de regresión múltiple, la pérdida de peso no se correlacionó con ningún parámetro inflamatorio ni con el Hurley. Conclusiones: Liraglutida 3mg es eficaz y segura en pacientes con HS y obesidad. Serán necesarios estudios a largo plazo para evaluar los efectos de la liraglutida sobre las lesiones cutáneas y los marcadores inflamatorios en la HS más allá de la pérdida de peso.(AU)

Treatment of obesity with medications binding the glucagon-like peptide 1 receptor: what is the current state of play?

INTRODUCTION: Obesity, marked by abnormal fat accumulation, poses significant health risks, necessitating effective therapeutic interventions. The focus of this review is to elucidate the importance of glucagon-like peptide 1 (GLP-1) receptor-binding medications in addressing obesity-related health deteriorations. AREAS COVERED: Exploring the mechanisms, efficacy, and safety profiles, this review comprehensively assesses medications selectively or non-selectively binding the GLP-1 receptor for obesity treatment. A meticulous analysis of phase 2 and phase 3 data positions retatrutide, CagriSema, survudotide, tirzepatide, semaglutide, and liraglutide in order of effectiveness. While showcasing their efficacy and safety, the review acknowledges the ongoing phase 3 studies, highlighting the need for further exploration of contraindications, dosage, and potential adverse effects to inform personalized treatment decisions. EXPERT OPINION: The ongoing anticipation of long-term benefits, particularly sustained weight loss and cardiovascular outcomes, underscores the significance of future treatment algorithms for addressing the disease of obesity.

Glucagon-Like Peptide-1 Receptor Agonist Cases Reported to United States Poison Centers, 2017-2022.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of medications for management of diabetes and obesity. The objective of this study is to characterize the epidemiology of GLP-1RA cases reported to US poison centers. METHODS: We analyzed cases involving a GLP-1RA reported to the National Poison Data System during 2017-2022. RESULTS: There were 5,713 single-substance exposure cases reported to US poison centers involving a GLP-1RA. Most cases were among females (71.3%) and attributable to therapeutic errors (79.9%). More than one-fifth (22.4%) of cases were evaluated in a healthcare facility, including 0.9% admitted to a critical care unit and 4.1% admitted to a non-critical care unit. Serious medical outcomes were described in 6.2% of cases, including one fatality. The rate of cases per one million US population increased from 1.16 in 2017 to 3.49 in 2021, followed by a rapid increase of 80.9% to 6.32 in 2022. Trends for rates of serious medical outcomes and admissions to a healthcare facility showed similar patterns with 129.9% and 95.8% increases, respectively, from 2021 to 2022. CONCLUSIONS: Most GLP-1RA cases reported to US poison centers were associated with no or minimal effects and did not require referral for medical treatment; however, a notable minority of individuals experienced a serious medical outcome or healthcare facility admission. The rate of reported cases increased during the study period, including an 80.9% increase from 2021 to 2022. Opportunities exist to improve provider and patient awareness of the adverse effects of these medications.