Glucagon-like Peptide-1 Receptor Agonist Liraglutide Research Articles

The microbial metabolite agmatine acts as an FXR agonist to promote polycystic ovary syndrome in female mice.

Polycystic ovary syndrome (PCOS), an endocrine disorder afflicting 6-20% of women of reproductive age globally, has been linked to alterations in the gut microbiome. We previously showed that in PCOS, elevation of Bacteroides vulgatus in the gut microbiome was associated with altered bile acid metabolism. Here we show that B. vulgatus also induces a PCOS-like phenotype in female mice via an alternate mechanism independent of bile acids. We find that B. vulgatus contributes to PCOS-like symptoms through its metabolite agmatine, which is derived from arginine by arginine decarboxylase. Mechanistically, agmatine activates the farnesoid X receptor (FXR) pathway to subsequently inhibit glucagon-like peptide-1 (GLP-1) secretion by L cells, which leads to insulin resistance and ovarian dysfunction. Critically, the GLP-1 receptor agonist liraglutide and the arginine decarboxylase inhibitor difluoromethylarginine ameliorate ovarian dysfunction in a PCOS-like mouse model. These findings reveal that agmatine-FXR-GLP-1 signalling contributes to ovarian dysfunction, presenting a potential therapeutic target for PCOS management.

Obesity pharmacotherapy in older adults: a narrative review of evidence.

The prevalence of obesity in older adults (people aged >60 years) is increasing in line with the demographic shift in global populations. Despite knowledge of obesity-related complications in younger adults (increased risk of type 2 diabetes, liver and cardiovascular disease and malignancy), these considerations may be outweighed, in older adults, by concerns regarding weight-loss induced reduction in skeletal muscle and bone mass, and the awareness of the 'obesity paradox'. Obesity in the elderly contributes to various obesity-related complications from cardiometabolic disease and cancer, to functional decline, worsening cognition, and quality of life, that will have already suffered an age-related decline. Lifestyle interventions remain the cornerstone of obesity management in older adults, with emphasis on resistance training for muscle strength and bone mineral density preservation. However, in older adults with obesity refractory to lifestyle strategies, pharmacotherapy, using anti-obesity medicines (AOMs), can be a useful adjunct. Recent evidence suggests that intentional weight loss in older adults with overweight and obesity is effective and safe, hence a diminishing reluctance to use AOMs in this more vulnerable population. Despite nine AOMs being currently approved for the treatment of obesity, limited clinical trial evidence in older adults predominantly focuses on incretin therapy with glucagon-like peptide-1 receptor agonists (liraglutide, semaglutide, and tirzepatide). AOMs enhance weight loss and reduce cardiometabolic events, while maintaining muscle mass. Future randomised controlled trials should specifically evaluate the effectiveness of novel AOMs for long-term weight management in older adults with obesity, carefully considering the impact on body composition and functional ability, as well as health economics.

Liraglutide protects against microvascular dysfunction and sepsis-mediated inflammation and organ injury

Introduction: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection characterized by increased systemic inflammation and microvascular injury. Recently, commonly used diabetes and obesity medications, glucagon-like peptide-1 (GLP-1) receptor agonists, have demonstrated unexpected anti-inflammatory effects. We tested GLP-1 receptor agonist liraglutide in a clinically relevant two-hit murine model of polymicrobial abdominal sepsis and hyperoxia and microvascular endothelial injury in vitro, hypothesizing that GLP-1 receptor agonists exert protective effects during sepsis, limiting microvascular permeability, inflammation, organ injury and death. Methods: Sepsis was induced in male and female mice by intraperitoneal (IP) injection of cecal contents (CS;1.8 mg/g body weight) collected from euthanized donor mice. Mice were also exposed to hyperoxia (FiO2 90-96%) for 24 hours. Six and 18 hours after CS injection, mice were administered saline or liraglutide (0.1 mg/kg). At 12 hours, mice were given fluids and antibiotics. At 24 hours, mice were euthanized for plasma and bronchoalveolar lavage (BAL; right lung) collection. Plasma cytokines, organ injury markers, and BAL immune cells and protein were measured. The left lung was tied off and excised to measure wet-to-dry lung weight ratios. Additionally, for in vitro studies, primary human lung microvascular endothelial cells (HLMVECs) were treated with saline or liraglutide for 24 hours prior to saline (control) or LPS (100 ng/mL). HLMVEC barrier dysfunction was quantified using express permeability testing (XPerT) assay or Electric Cell-Substrate Impedance Sensing (ECIS) to measure transendothelial electrical resistance (TER). Results: In murine sepsis, illness severity scores and lung injury were improved in mice pretreated with liraglutide (N=12). Plasma blood urea nitrogen (BUN; P=0.0581), alanine transaminase (ALT; P=0.0311) and aspartate aminotransferase (AST; P=0.0263), and cytokines IL-1β (P=0.0078), IL-6 (P=0.0038), and TNF-α (P=0.0183) in plasma were reduced in mice treated with liraglutide. In HLMVECs, liraglutide (1.5 nM) significantly reduced LPS-induced barrier dysfunction measured by XPerT assay (P=0.0030) and ECIS (P=0.0075). Conclusion: Liraglutide reduces illness severity, inflammation, and organ injury in a two-hit model of sepsis-induced ALI. Liraglutide has direct effects in the microvascular endothelium, limiting LPS-mediated barrier dysfunction. These findings support a protective role for GLP-1 receptor agonism in sepsis, mediated through the microvasculature. HL150783, AG075341, HL158906. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

GLP-1 receptor agonist improves metabolic disease in a pre-clinical model of lipodystrophy.

Individuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed. Here we performed the first detailed investigation of the effects of a glucagon like peptide-1 receptor (GLP-1R) agonist in lipoatrophic diabetes, using mice with generalised lipodystrophy. Lipodystrophic insulin resistant and glucose intolerant seipin knockout mice were treated with the GLP-1R agonist liraglutide either acutely preceding analyses of insulin and glucose tolerance or chronically prior to metabolic phenotyping and ex vivo studies. Acute liraglutide treatment significantly improved insulin, glucose and pyruvate tolerance. Once daily injection of seipin knockout mice with liraglutide for 14 days led to significant improvements in hepatomegaly associated with steatosis and reduced markers of liver fibrosis. Moreover, liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. GLP-1R agonist liraglutide significantly improved lipoatrophic diabetes and hepatic steatosis in mice with generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition.

Liraglutide and not lifestyle intervention reduces soluble CD163 after comparable weight loss in obese participants with prediabetes or type 2 diabetes mellitus

BackgroundThe GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus.MethodPlasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase‐associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or liraglutide treatment (n = 20), and in healthy subjects (n = 13).ResultsAt baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group.ConclusionWeight loss following treatment with liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with liraglutide.

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

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. Obese mice and their lean littermates were treated with liraglutide or saline for 12weeks. 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. 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. 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.

Formulary Management of Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists


 Health Canada has approved 4 sodium-glucose cotransporter-2 (SGLT2) inhibitors (ertugliflozin, dapagliflozin, canagliflozin, and empagliflozin) and 5 glucagon-like peptide-1 (GLP-1) receptor agonists (semaglutide, liraglutide, dulaglutide, lixisenatide, and exenatide), with 5 fixed-dose combination products (SGLT2 inhibitors: dapagliflozin-metformin, canagliflozin-metformin, and empagliflozin-metformin; GLP-1 receptor agonists: liraglutide–insulin degludec and lixisenatide–insulin glargine).
 Data protection has ended for all SGLT2 inhibitors in Canada as well as their fixed-dose combinations. Eleven dapagliflozin generics are currently available, and there are several canagliflozin and empagliflozin generics under review at Health Canada. Patent protection has not expired for GLP-1 receptor agonists.
 There is heterogeneity in public drug program reimbursement criteria for each SGLT2 inhibitor and GLP-1 receptor agonist ranging from restricted to unrestricted benefit.
 This Environmental Scan highlights that as SGLT2 inhibitors and GLP-1 receptor agonists have matured, additional indications (heart failure, chronic kidney disease, weight management) have been added to their initial Health Canada–approved indication (type 2 diabetes mellitus). SGLT2 inhibitors are beginning to lose their exclusivity status and are experiencing generic competition.

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

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. 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. 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. 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.

The impact of GLP-1 receptor agonist liraglutide on blood pressure profile, hydration, natriuresis in diabetic patients with severely impaired kidney function

Chronic treatment with GLP-1R agonists may moderately lower blood pressure due to increased natriuresis and RAAS inhibition. Short-term effect of these drugs on blood pressure may be opposite and its mechanism remains unclear. We investigated the effect of a single dose of liraglutide on diurnal blood pressure profile, natriuresis, hydration and serum concentration of renin, aldosterone and atrial natriuretic peptide (ANP) in diabetic kidney disease (DKD). 17 patients with eGFR < 30 ml/min/1.73 m2 and 17 with > 60 ml/min/1.73 m2 received in a random order a single subcutaneous dose 1.2 mg liraglutide and placebo with subsequent 24 h blood pressure and natriuresis monitoring. Before and after each medication thoracic fluid index and plasma renin, aldosterone and ANP were also assessed. The blood pressure load in the daytime and nighttime were significantly increased after liraglutide compared to placebo in patients with eGFR < 30 ml/min/1.73 m2. In patients with eGFR > 60 ml/min/1.73 m2 the changes of arterial pressure were comparable, while the morning surge was significantly reduced after liraglutide compared to placebo. After liraglutide 24 h urine sodium excretion increased in both groups vs. placebo (p < 0.001), the effect was greatest in subjects with eGFR > 60 ml/min/1.73 m2. Plasma ANP increased after liraglutide in both groups, most in patients with eGFR < 30 ml/min/1.73 m2 group. Plasma aldosterone (p = 0.013) and thoracic fluid index (p = 0.01) decreased after liraglutide compared to placebo (p = 0.013 and p + 0.01, respectively. Plasma renin concentration remained unchanged. In severe chronic kidney disease liraglutide induces a transient increase of blood pressure due to reduced natriuresis. The natriuretic effect of liraglutide in DKD may be related to increased ANP and decreased aldosterone secretion.

Differential Effects of Type 2 Diabetes Treatment Regimens on Diabetes Distress and Depressive Symptoms in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

We evaluated whether adding basal insulin to metformin in adults with early type 2 diabetes mellitus (T2DM) would increase emotional distress relative to other treatments. The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) of adults with T2DM of <10 years' duration, HbA1c 6.8-8.5%, and taking metformin monotherapy randomly assigned participants to add insulin glargine U-100, sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or the dipeptidyl peptidase 4 inhibitor sitagliptin. The Emotional Distress Substudy enrolled 1,739 GRADE participants (mean [SD] age 58.0 [10.2] years, 32% female, 56% non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic) and assessed diabetes distress and depressive symptoms every 6 months. Analyses examined differences at 1 year and over the 3-year follow-up. Across treatments, diabetes distress (-0.24, P < 0.0001) and depressive symptoms (-0.67, P < 0.0001) decreased over 1 year. Diabetes distress was lower at 1 year for the glargine group than for the other groups combined (-0.10, P = 0.002). Diabetes distress was also lower for liraglutide than for glimepiride or sitagliptin (-0.10, P = 0.008). Over the 3-year follow-up, there were no significant group differences in total diabetes distress; interpersonal diabetes distress remained lower for those assigned to liraglutide. No significant differences were observed for depressive symptoms. Contrary to expectations, this randomized trial found no evidence for a deleterious effect of basal insulin on emotional distress. Glargine lowered diabetes distress modestly at 1 year rather than increasing it. Liraglutide also reduced diabetes distress at 1 year. Results can inform treatment decisions for adults with early T2DM.

The Key Role of Liraglutide in Preventing Autophagy of Vascular Smooth Muscle Cells in High Glucose Conditions

The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (LIRA) is a potential hypoglycemic drug with anti-atherosclerosis (AS) effects. Autophagy in the vascular smooth muscle cells (VSMCs) facilitates AS. However, the role of autophagy in the anti-AS mechanism of LIRA remains unclear. To examine the role and mechanisms of autophagy in LIRA’s improvement of the biological characteristics of VSMCs in high glucose conditions. Experimental animal study. VSMCs isolated from the thoracic aorta of male SD rats were subjected to a high glucose (HG) condition (25 mM) in Dulbecco’s Modified Eagle’s Medium with or without LIRA, the GLP-1 receptor antagonist exendin9-39 (Exe9-39), a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), and autophagy inhibitors (3-methyladenine [3-MA] and bafilomycin A1 [Baf A1]). Acridine orange staining, western blotting, transmission electron microscopy, and mCherry-GFP-LC3 transfection were performed to evaluate the autophagy flux. Additionally, VSMC migration, calcification, proliferation, and apoptosis in HG conditions were observed. Addition of LIRA alone or in combination with autophagy inhibitors significantly downregulated Beclin, increased the LC3-II/LC3-I ratio, and upregulated p62 in VSMCs in HG conditions. Furthermore, autophagolysosome formation was markedly curbed after treatment with LIRA and/or autophagy inhibitors. Inhibition of autophagy by LIRA and/or the autophagy inhibitors attenuated VSMC phenotype conversion, proliferation, migration, and calcification and promoted VSMC apoptosis in HG conditions. This protective role of LIRA was augmented by LY294002, but inhibited by Exe9-39. LIRA plays a significant role in the improvement of the biological features of VSMCs in HG conditions.

Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have emerged as promising therapeutic agents with potent anti-inflammatory properties and diverse clinical implications. This in-depth review article explores the mechanisms behind the anti-inflammatory actions of GLP-1RAs and assesses their prospective applicability in a wide range of disease scenarios. The current review establishes the significance of comprehending the anti-inflammatory role of GLP-1RAs and identifies pertinent research gaps. A concise overview of inflammation and its clinical consequences underscores the critical need for effective anti-inflammatory interventions. Subsequently, the article elucidates the intricate mechanisms through which GLP-1RAs modulate immune cell signaling and regulate the nuclear factor-kappa B (NF-κB) pathway. Detailed discussions encompass their impact on inflammatory responses, cytokine production, and attenuation of oxidative stress. The exposition is substantiated by a collection of pertinent examples and an extensive array of references from both preclinical and clinical investigations. The historical trajectory of GLP-1RA drugs, including exenatide, lixisenatide, liraglutide, and semaglutide, is traced to delineate their development as therapeutic agents. Moreover, the review emphasizes the therapeutic potential of GLP-1RAs in specific disease contexts like type 2 diabetes, a neurodegenerative disorder, and inflammatory bowel disease (IBD), shedding light on their anti-inflammatory effects through rigorous examination of preclinical and clinical studies. The article also provides an outlook on future perspectives for GLP-1RAs, encompassing the domains of diabetes, neurodegenerative diseases, and IBD. In conclusion, GLP-1RAs exhibit substantial anti-inflammatory effects, rendering them promising therapeutic agents with broad clinical implications. They are very useful in a wide variety of diseases because they regulate immunological responses, block NF-κB activation, and decrease production of pro-inflammatory cytokines. Ongoing research endeavors aim to optimize their therapeutic use, delineate patient-specific treatment paradigms, and explore novel therapeutic applications. GLP-1RAs represent a significant breakthrough in anti-inflammatory therapy, offering novel treatment options, and improved patient outcomes.

The association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicidality: reports to the Food and Drug Administration Adverse Event Reporting System (FAERS)

ABSTRACT Introduction Recently, the European Medicines Agency (EMA) received reports of suicidal thoughts and self-injury associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and semaglutide. Research design and methods Herein, we sought to evaluate suicidality associated with all GLP-1 RAs relative to other glucose-lowering agents currently approved by the United States Food and Drug Administration (FDA). Reports of suicidal ideation, “depression/suicidal”, suicidal behavior, suicidal attempts, and completed suicide associated with GLP-1 RA exposure reported to the FDA between 2005 and October 2023 were obtained from the FDA Adverse Event Reporting System (FAERS). We present data using the reporting odds ratio (ROR). The ROR was considered significant when the lower limit of the 95% confidence interval (CI) was greater than 1.0. Results Disproportionate reporting of suicidal ideation and “depression/suicidal” was observed with semaglutide and liraglutide. Disproportionate reporting of suicidal behavior, suicide attempts, and completed suicide was not observed for any of the FDA-approved GLP-1 RAs. Conclusions Using the Bradford Hill criteria, however, and taking into consideration confounders, no causal link between GLP-1 RAs and suicidality exists.

GLP-1 receptor agonist liraglutide inhibits the proliferation and migration of thyroid cancer cells.

This research was done to find out how liraglutide affected the growth and movement of two human thyroid cancer cell lines overexpressing GLP-1 receptor (migration of medullary thyroid cancer TT/GLP-1R and papillary thyroid carcinoma TCP-1/GLP-1R). Flow cytometer and cAMP assays were used to identify the expression and activation of GLP-1R in two stable cell lines. Counting Kit-8 for Cells was applied to examine the proliferative ability of cells in two stable cell lines after treatment with different concentrations of liraglutide at indicated time points. To track the capacity for cell migration, the Transwell test was utilized. We found that liralutide-activated GLP-1R could significantly reduce the growth and metastasis of two kinds of thyroid tumor cells, and the inhibitory effect was dose- and time- dependent. The phosphorylatios of Akt, S6K1, and 70SK declined after receiving liraglutide therapy In our previous studies, we found that the GLP-1 receptor agonist Liraglutide inhibited the proliferation and migration of thyroid cancer cells through the PI3K/Akt/mTOR pathway. This finding provides a theoretical basis for the treatment of diabetes mellitus complicated with medullary thyroid cancer, and is relatively safe.

GLP1 receptor agonists exhibit antioxidant and anti-inflammatory properties in human heart tissue via the canonical GLP1 receptor expression through a AMPK-mediated pathway

Abstract Background Clinical research has demonstrated that glucagon-like peptide-1 receptor (GLP1R) agonists (GLP1RA) can decrease the occurrence of major cardiovascular events in diabetic patients, regardless of their glycemic control. However, a significant challenge in understanding the positive effects of GLP1RA has been the lack of knowledge regarding the specific cellular types that express GLP1R. Despite the established cardiovascular benefits of GLP1RA, previous studies have been unable to confirm the expression of GLP1R in the heart. Aim The study aimed to investigate the expression and function of GLP1R in heart tissue. Methods We collected human cardiac tissue samples from 30 patients who underwent left ventricle (LV) biopsies (n=21) or right atrial (RA) appendage closure (n=9) at a university hospital. Gene expression levels were assessed using RT-qPCR, protein levels by Western blot analysis, in situ tissue localization of proteins by immunofluorescence (IF) staining, and the level of oxidative stress using dihydroethidium. Results LV biopsies and RA appendages showed a substantial heterogeneity in GLP1R mRNA levels. GLP1R mRNA levels exhibited a positive correlation with IL1B, IL6, TNFα, CCL2, CD68, ACE1, AT1R, and VCAM1 mRNA levels, but a negative correlation with NOS3 mRNA levels. High GLP1R expression in both RA appendages and LV biopsies was associated with increased oxidative stress levels, which were mitigated by the antioxidant N-acetylcysteine (NAC), NADPH oxidase inhibitor (VAS-2870), ACE inhibitor (perindoprilat), AT1R antagonist (losartan), TNF-α receptor neutralizing antibody (infliximab) and by GLP1R agonists (liraglutide and semaglutide) with inhibitory effects amounting to about 50-60 %. Exendin, a GLP1R antagonist reversed the effect of liraglutide and semaglutide which accounted for a receptor-mediated antioxidant effect. H-89, a PKA inhibitor equally reversed liraglutide and semaglutide effect on ROS generation suggesting a canonical GLP1R mediated effect involving the AMPK pathway. Conclusion These findings indicate that human cardiac GLP1R expression levels are correlated to low-grade inflammation and endothelial dysfunction. Increased expression levels of GLP1R were associated with higher levels of oxidative stress sensitive to GLP1RA in a canonical GLP1R AMPK-mediated manner. Therefore, the cardiovascular beneficial effects of GLP1RA might be attributable to their antioxidant and anti-inflammatory properties, specifically within the cardiac system.

Abstract 12365: Liraglutide Improves Myocardial Stress Perfusion and Energetics in Patients With Type 2 Diabetes- A Randomised, Single Centre, Open Label, Cross-Over Drug Trial

Background: Insulin secretion and insulin resistance in Type 2 diabetes (T2D) are amenable to pharmacological intervention. In a single center, open-label, randomized, cross-over drug trial we compared two glycaemic control strategies using Glucagon-like peptide-1 receptor agonists liraglutide and peroxisome proliferator activated receptor-gamma agonist-pioglitazone to see the effect on myocardial perfusion, energetics and function. Methods: Forty-one eligible patients with T2D and no known prior CV disease were randomized in a 1:1 ratio to the study drugs for a 16-week treatment period followed by an 8-week washout and a further 16-week treatment period for the second drug. Participants underwent rest and dobutamine stress 31 phosphorus magnetic resonance spectroscopy followed by CMR scans. The CMR protocol consisted of rest and dobutamine stress cine imaging, perfusion imaging and late gadolinium enhanced imaging immediately before and after each treatment arm. Results: Liraglutide therapy resulted in significant reductions in the body mass index. Pioglitazone led to a significant increment in LV mass. Liraglutide therapy resulted in increased rest and dobutamine stress energetics, global stress myocardial blood flow and myocardial perfusion reserve. With pioglitazone treatment, an isolated increase in the E/A was observed. Conclusions: In this study we showed for the first time that four months treatment with GLP-1RA (liraglutide) results in significant improvements in myocardial perfusion and energetics, while the insulin sensitiser pioglitazone shows no effect in modulation of these parameters.

Glucagon-like peptide-1 receptor activation stimulates PKA-mediated phosphorylation of Raptor and this contributes to the weight loss effect of liraglutide.

The canonical target of the glucagon-like peptide-1 receptor (GLP-1R), Protein Kinase A (PKA), has been shown to stimulate mechanistic Target of Rapamycin Complex 1 (mTORC1) by phosphorylating the mTOR-regulating protein Raptor at Ser791 following β-adrenergic stimulation. The objective of these studies is to test whether GLP-1R agonists similarly stimulate mTORC1 via PKA phosphorylation of Raptor at Ser791 and whether this contributes to the weight loss effect of the therapeutic GLP-1R agonist liraglutide. We measured phosphorylation of the mTORC1 signaling target ribosomal protein S6 in Chinese Hamster Ovary cells expressing GLP-1R (CHO-Glp1r) treated with liraglutide in combination with PKA inhibitors. We also assessed liraglutide-mediated phosphorylation of the PKA substrate RRXS*/T* motif in CHO-Glp1r cells expressing Myc-tagged wild-type (WT) Raptor or a PKA-resistant (Ser791Ala) Raptor mutant. Finally, we measured the body weight response to liraglutide in WT mice and mice with a targeted knock-in of PKA-resistant Ser791Ala Raptor. Liraglutide increased phosphorylation of S6 and the PKA motif in WT Raptor in a PKA-dependent manner but failed to stimulate phosphorylation of the PKA motif in Ser791Ala Raptor in CHO-Glp1r cells. Lean Ser791Ala Raptor knock-in mice were resistant to liraglutide-induced weight loss but not setmelanotide-induced (melanocortin-4 receptor-dependent) weight loss. Diet-induced obese Ser791Ala Raptor knock-in mice were not resistant to liraglutide-induced weight loss; however, there was weight-dependent variation such that there was a tendency for obese Ser791Ala Raptor knock-in mice of lower relative body weight to be resistant to liraglutide-induced weight loss compared to weight-matched controls. Together, these findings suggest that PKA-mediated phosphorylation of Raptor at Ser791 contributes to liraglutide-induced weight loss.

Endocannabinoid-related molecules predict the metabolic efficacy of GLP-1 receptor agonism in humans with obesity.

N-acylethanolamines (NAEs) include endocannabinoid (EC) and EC-related molecules that impact the anti-obesity and anti-diabetic efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RA) in animal studies. However, the clinical relevance of these findings remains to be determined. Here, we tested whether GLP-1RA treatment affects circulating NAE levels and whether NAEs may predict the efficacy of GLP-1RA treatment in humans with obesity undergoing weight loss maintenance. We profiled plasma levels of NAEs in participants with obesity undergoing weight loss maintenance with (n = 23)/or without (n = 20) treatment with the GLP-1RA liraglutide. NAE levels were measured at three different time points: before the start of the study, at the end of the diet-induced weight loss, and after 52-weeks treatment. Linear regression analyses were used to investigate whether pharmacological responses could be predicted by NAEs levels. Liraglutide treatment reduced plasma concentrations of the NAE and oleoyl-ethanolamide (OEA), without altering arachidonoyl-ethanolamide (AEA) levels and palmitoyl-ethanolamide (PEA) levels. High pre-treatment levels of OEA were predictive of superior compound-mediated effects on fasting insulin and triglyceride levels. High pre-treatment PEA and AEA levels were also predictive of superior Liraglutide-mediated effects on triglyceride levels. Our data suggests that specific NAEs such as OEA and AEA are promising biomarkers of GLP-1RA metabolic efficacy in humans with obesity during weight loss maintenance. Plasma profiling of EC-related molecules may be a promising strategy to tailor GLP-1R-based therapies to individual needs in obesity and diabetes management.

Glucagon-like Peptide-1 Receptor Pathway Attenuates Platelet Activation in Aspirin-Exacerbated Respiratory Disease.

Platelets are key contributors to allergic asthma and aspirin-exacerbated respiratory disease (AERD), an asthma phenotype involving platelet activation and IL-33-dependent mast cell activation. Human platelets express the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R agonists decrease lung IL-33 release and airway hyperresponsiveness in mouse asthma models. We hypothesized that GLP-1R agonists reduce platelet activation and downstream platelet-mediated airway inflammation in AERD. GLP-1R expression on murine platelets was assessed using flow cytometry. We tested the effect of the GLP-1R agonist liraglutide on lysine-aspirin (Lys-ASA)-induced changes in airway resistance, and platelet-derived mediator release in a murine AERD model. We conducted a prospective cohort study comparing the effect of pretreatment with liraglutide or vehicle on thromboxane receptor agonist-induced invitro activation of platelets from patients with AERD and nonasthmatic controls. GLP-1R expression was higher on murine platelets than on leukocytes. A single dose of liraglutide inhibited Lys-ASA-induced increases in airway resistance and decreased markers of platelet activation and recruitment to the lung in AERD-like mice. Liraglutide attenuated thromboxane receptor agonist-induced activation as measured by CXCL7 release in plasma from patients with AERD and CD62P expression in platelets from both patients with AERD (n = 31) and nonasthmatic, healthy controls (n = 11). Liraglutide, a Food and Drug Administration-approved GLP-1R agonist for treatment of type 2 diabetes and obesity, attenuates invivo platelet activation in an AERD murine model and invitro activation in human platelets in patients with and without AERD. These data advance the GLP-1R axis as a new target for platelet-mediated inflammation warranting further study in asthma.

IDegLira for type 2 diabetes: a systematic review and meta-analysis.

IDegLira is a novel fixed-ratio soluble combination of insulin degludec and the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide approved for type 2 diabetes (T2D) patients. Individual trials have assessed the clinical profile of IDegLira vs different comparators. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of IDegLira for T2D. PubMed, Embase, Cochrane Library and ClinicalTrials.gov were searched from inception to August 15, 2023. The primary outcomes included change from baseline in haemoglobin A1c (HbA1c) and body weight. Risk ratios (RR), mean differences (MD), and 95% confidence intervals (CI) were calculated to evaluate the outcomes. This meta-analysis identified 1044 citations, and included 13 eligible trials, enroling 7773 patients. Compared with the control groups, IDegLira was optimal in change in HbA1c, percentage of patients achieving HbA1c < 7%, percentage of patients achieving HbA1c < 6.5%, HbA1c < 7.0% without weight gain and without severe or blood glucose (BG)-confirmed hypoglycaemia episodes, HbA1c < 6.5% without weight gain and without severe or BG-confirmed hypoglycaemia episodes, change in fasting plasma glucose, change in self-measured plasma glucose, change in systolic pressure, and total daily insulin dose. No difference was found between the IDegLira and control groups in terms of change in body weight, change in diastolic pressure, severe or BG-confirmed symptomatic hypoglycaemia, nocturnal severe or BG-confirmed symptomatic hypoglycaemia, adverse events or serious adverse events. In patients with T2D, IDegLira improved glycaemic control whilst balancing out risk for hypoglycaemia and gastrointestinal side effects.