Glucagon-like Peptide-1 Analogue Research Articles

Effect of combined GLP-1 analogue and bupropion/naltrexone on weight loss: a retrospective cohort study

Effect of combined GLP-1 analogue and bupropion/naltrexone on weight loss: a retrospective cohort study

Glucagon-like peptide-1 analogs activate AMP kinase leading to reversal of the Warburg metabolic switch in breast cancer cells.

Breast cancer (BC) is associated with type 2 diabetes mellitus (T2DM) and obesity. Glucagon-like peptide (GLP)-1 regulates post-prandial insulin secretion, satiety, and gastric emptying. Several GLP-1 analogs have been FDA-approved for the treatment of T2DM and obesity. Moreover, GLP-1 regulates various metabolic activities across different tissues by activating metabolic signaling pathways like adenosine monophosphate (AMP) activated protein kinase (AMPK), and AKT. Rewiring metabolic pathways is a recognized hallmark of cancer, regulated by several cancer-related pathways, including AKT and AMPK. As GLP-1 regulates AKT and AMPK, we hypothesized that it alters BC cells' metabolism, thus inhibiting proliferation. The effect of the GLP-1 analogs exendin-4 (Ex4) and liraglutide on viability, AMPK signaling and metabolism of BC cell lines were assessed. Viability of BC cells was evaluated using colony formation and MTT/XTT assays. Activation of AMPK and related signaling effects were evaluated using western blot. Metabolism effects were measured for glucose, lactate and ATP. Exendin-4 and liraglutide activated AMPK in a cAMP-dependent manner. Blocking Ex4-induced activation of AMPK by inhibition of AMPK restored cell viability. Interestingly, Ex4 and liraglutide reduced the levels of glycolytic metabolites and decreased ATP production, suggesting that GLP-1 analogs impair glycolysis. Notably, inhibiting AMPK reversed the decline in ATP levels, highlighting the role of AMPK in this process. These results establish a novel signaling pathway for GLP-1 in BC cells through cAMP and AMPK modulation affecting proliferation and metabolism. This study suggests that GLP-1 analogs should be considered for diabetic patients with BC.

Effects of glucagon-like peptide-1 analogs on prolactin: a randomized, double-blind, placebo-controlled crossover trial

Effects of glucagon-like peptide-1 analogs on prolactin: a randomized, double-blind, placebo-controlled crossover trial

Cost-effectiveness of semaglutide 2.4 mg in chronic weight management in Portugal

BackgroundObesity and overweight are a significant public health concern. Subcutaneous semaglutide 2.4 mg injection is a glucagon-like peptide-1 (GLP-1) analogue approved by the European Medicines Agency as an adjunct to a reduced calorie diet and increased physical activity (diet and exercise, D&E) for the treatment obesity and overweight in the presence of at least one weight related comorbidity. This study aimed to assess the cost-effectiveness of semaglutide 2.4 mg in combination with D&E compared to D&E alone for the Portuguese setting.MethodsAnalysis were conducted using the Core Obesity Model (COM) version 18, a Markov state transition cohort model, to predict the health outcomes and costs of weight related complications based on changes in surrogate endpoints. Efficacy and safety data were sourced from the STEP trials (Body Mass Index, systolic blood pressure and glycemic status) from a cohort of adults aged on average 48 years with obesity (BMI ≥ 30 kg/m2) and ≥ 1 obesity-related comorbidities, over a time horizon of 40 years. Costs were estimated from the perspective of the Portuguese National Health Service. Sensitivity analyses were conducted to test the robustness of results across a range of assumptions.ResultsOn a patient level, Semaglutide 2.4 mg in addition to D&E compared to D&E alone, improved QALYs by 0.098 and yielded higher costs by 1,325 EUR over a 40-year time horizon, with an ICER of 13,459 EUR per QALY gained and 100% probability of cost-effectiveness at the given WTP. Semaglutide 2.4 mg remained cost-effective across all different scenarios and sensitivity analysis at a WTP of 20,000 EUR per QALY. Among the subpopulations examined, Semaglutide 2.4 mg yielded ICERs of 18,459 EUR for patients with BMI ≥ 30 kg/m2 and of 22,657 EUR for patients with BMI ≥ 35 kg/m2.ConclusionsSemaglutide 2.4 mg was cost-effective compared to D&E alone for patients with obesity (BMI ≥ 30 kg/m2) and weight related comorbidities in Portugal, over a 40-year time horizon.

Peptides Are Cardioprotective Drugs of the Future: The Receptor and Signaling Mechanisms of the Cardioprotective Effect of Glucagon-like Peptide-1 Receptor Agonists.

The high mortality rate among patients with acute myocardial infarction (AMI) is one of the main problems of modern cardiology. It is quite obvious that there is an urgent need to create more effective drugs for the treatment of AMI than those currently used in the clinic. Such drugs could be enzyme-resistant peptide analogs of glucagon-like peptide-1 (GLP-1). GLP-1 receptor (GLP1R) agonists can prevent ischemia/reperfusion (I/R) cardiac injury. In addition, chronic administration of GLP1R agonists can alleviate the development of adverse cardiac remodeling in myocardial infarction, hypertension, and diabetes mellitus. GLP1R agonists can protect the heart against oxidative stress and reduce proinflammatory cytokine (IL-1β, TNF-α, IL-6, and MCP-1) expression in the myocardium. GLP1R stimulation inhibits apoptosis, necroptosis, pyroptosis, and ferroptosis of cardiomyocytes. The activation of the GLP1R augments autophagy and mitophagy in the myocardium. GLP1R agonists downregulate reactive species generation through the activation of Epac and the GLP1R/PI3K/Akt/survivin pathway. The GLP1R, kinases (PKCε, PKA, Akt, AMPK, PI3K, ERK1/2, mTOR, GSK-3β, PKG, MEK1/2, and MKK3), enzymes (HO-1 and eNOS), transcription factors (STAT3, CREB, Nrf2, and FoxO3), KATP channel opening, and MPT pore closing are involved in the cardioprotective effect of GLP1R agonists.

Effects ofsemaglutide-loaded lipid nanocapsules on metabolic dysfunction-associated steatotic liverdisease.

Metabolic dysfunction-associated steatotic liver disease(MASLD) is a highly prevalent chronic liver disease that can progress to end-stage conditions with life-threatening complications, but no pharmacologic therapy has been approved. Drug delivery systems such as lipid nanocapsules (LNC) are very versatile platforms that areeasy to produce and can induce the secretion of the native glucagon-like peptide 1 (GLP-1) when orally administered. GLP-1 analogs are currently being studied in clinical trials in the context of MASLD. Our nanosystem provides with increased levels of the native GLP-1 and increased plasmatic absorption of the encapsulated GLP-1 analog (semaglutide). Our goal was touse our strategy to demonstrate a better outcome and a greater impact on the metabolic syndrome associated with MASLD and on liver disease progression with our strategy compared with the oral marketed version of semaglutide, Rybelsus®. Therefore, we studied the effect of our nanocarriers on a dietary mouse model of MASLD, the Western diet model, during a daily chronic treatment of 4weeks. Overall, the results showed a positive impact of semaglutide-loaded lipid nanocapsules towards the normalization of glucose homeostasis and insulin resistance. In the liver, there were no significant changes in lipid accumulation, but an improvement in markers related to inflammation was observed. Overall, our strategy had a positive trend on the metabolic syndrome and atreducing inflammation, mitigating the progression of the disease. Oral administration of the nanosystem was more efficient at preventing the progression of the disease to more severe states when compared to the administration ofRybelsus®, as a suspension.

Glucagon-like Peptide-1 analogues and delipidation of coronary atheroma in statin-treated type 2 diabetic patients with coronary artery disease: The prespecified sub-analysis of the OPTIMAL randomized clinical trial

Background and aimsRandomized clinical trials have demonstrated the ability of glucagon-like peptide-1 analogues (GLP-1RAs) to reduce atherosclerotic cardiovascular disease events in patients with type 2 diabetes (T2D). How GLP-1RAs modulate diabetic atherosclerosis remains to be determined yet. MethodsThe OPTIMAL study was a prospective randomized controlled study to compare the efficacy of 48-week continuous glucose monitoring- and HbA1c-guided glycemic control on near infrared spectroscopty (NIRS)/intravascular ultrasound (IVUS)-derived plaque measures in 94 statin-treated patients with T2D (jRCT1052180152, UMIN000036721). Of these, 78 patients with evaluable serial NIRS/IVUS images were analyzed to compare plaque measures between those treated with (n = 16) and without GLP-1RAs (n = 72). ResultsAll patients received a statin, and on-treatment LDL-C levels were similar between the groups (66.9 ± 11.6 vs. 68.1 ± 23.2 mg/dL, p = 0.84). Patients receiving GLP-1RAs demonstrated a greater reduction of HbA1c [-1.0 (-1.4 to −0.5) vs. −0.4 (-0.6 to −0.2)%, p = 0.02] and were less likely to demonstrate a glucose level >180 mg/dL [-7.5 (-14.9 to −0.1) vs. 1.1 (-2.0 - 4.2)%, p = 0.04], accompanied by a significant decrease in remnant cholesterol levels [-3.8 (-6.3 to −1.3) vs. −0.1 (-0.8 - 1.1)mg/dL, p = 0.008]. On NIRS/IVUS imaging analysis, the change in percent atheroma volume did not differ between the groups (−0.9 ± 0.25 vs. −0.2 ± 0.2%, p = 0.23). However, GLP-1RA treated patients demonstrated a greater frequency of maxLCBI4mm regression (85.6 ± 0.1 vs. 42.0 ± 0.6%, p = 0.01). Multivariate analysis demonstrated that the GLP-1RA use was independently associated with maxLCBI4mm regression (odds ratio = 4.41, 95%CI = 1.19–16.30, p = 0.02). ConclusionsIn statin-treated patients with T2D and CAD, GLP-1RAs produced favourable changes in lipidic plaque materials, consistent with its stabilization.

Comparing major and mild cognitive impairment risks in older type-2 diabetic patients: a Danish register-based study on dipeptidyl peptidase-4 inhibitors vs. glucagon-like peptide-1 analogues.

The prevalence of major and mild cognitive impairment (CI) in type-2 diabetes older patients is 15-25% and 30-60%, respectively, thus affecting quality of life and health outcomes. There is, therefore, the need of head-to-head studies aiming at identifying the optimal treatment for individuals with type-2 diabetes at increased risk of mild and major CI. This study focuses on the risk of developing mild and major CI in Danish patients treated with dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 analogues (GLP-1a) using administrative and healthcare registers. An active comparator design with a 3-year follow-up period was used. The main outcome was the hospital admission with a diagnosis of mild CI or major CI. Multivariate Cox Regression analysis was performed using the high-dimensional propensity score to obtain adjusted Hazard Ratio (HR) estimates. Inverse probability of treatment weighting (IPTW) and marginal structured model were used to calculate risk differences while accounting for the variations of confounders throughout the follow-up period. Our results show a significant higher risk of major CI between DPP-4i and GLP-1a in unadjusted [HR (95% CI) = 3.13 (2.45-4.00), p < 0.001] and adjusted analyses [HR (95% CI) = 1.58 (1.22-2.06), p = 0.001]. No statistically significant differences were observed for mild CI. IPTW resulted stable throughout the follow-up period. Marginal structure modeling (β (95% CI) = 0.022 (0.020-0.024), p < 0.001) resulted in a higher risk of major CI for DPP-4i when compared to GLP-1a. DPP-4i was associated with an increased risk of developing major CI when compared to GLP-1a among older individuals with type-2 diabetes.

Engineering of a Biologically Active Glycosylated Glucagon-Like Peptide-1 Analogue.

Glucagon-like peptide receptor (GLP-1R) agonists (e.g., semaglutide, liraglutide, etc.) are efficient treatment options for people with type 2 diabetes and obesity. The manufacturing method to produce semaglutide, a blockbuster GLP-1 drug on the market, involves multistep synthesis. The large peptide has a hydrophobic fatty acid side chain that makes it sparingly soluble, and its handling, purification, and large-scale production difficult. The growing demand for semaglutide that the manufacturer is not capable of addressing immediately triggered a worldwide shortage. Thus, we have developed a potential alternative analogue to semaglutide by replacing the hydrophobic fatty acid with a hydrophilic human complex-type biantennary oligosaccharide. Our novel glycoGLP-1 analogue was isolated in an ∼10-fold higher yield compared with semaglutide. Importantly, our glycoGLP-1 analogue possessed a similar GLP-1R activation potency to semaglutide and was biologically active in vivo in reducing glucose levels to a similar degree as semaglutide.

Changes in food preferences and ingestive behaviors after glucagon-like peptide-1 analog treatment: techniques and opportunities.

Glucagon-like peptide-1 (GLP-1) analogs are approved for the treatment of obesity in adults and adolescents. Reports have emerged that the weight loss effect of these medications may be related to changes in food preferences and ingestive behaviors following the treatment. Understanding the mechanisms which impact ingestive behavior could expand opportunities to develop more refined and personalized treatment options for obesity. Recent studies investigating the relationship between GLP-1 analogs and ingestive behaviors were retrieved from PubMed using the search terms: "obesity," "food preference," "taste," "ingestive behavior," "weight loss medication," "anti-obesity medication," "GLP-1 analog," "tirzepatide," "liraglutide," "semaglutide." Measurement tools were studied to compare variables used to assess food intake behavior. The main outcomes from each study were analyzed to evaluate the current standing and future directions of appetitive, ingestive, and consummatory behaviors and their association with GLP-1 analogs. Thus far, studies have primarily explored the weight loss phase and report decreased short-term appetite and food intake upon treatment. However, research during the weight maintenance phase and objective measurements of food intake are notably sparse. Additionally, verbal reports have been primarily used to examine food intake, which can be susceptible to subjectivity. Elucidating the relationship between GLP-1 analogs and ingestive behavior could reveal additional parameters which contribute to their anti-obesity effects. To better understand these mechanisms, it is imperative to consider objective measurements of food intake in future studies. Several measurement tools have been adapted to measure variables of food behavior in humans, and each must be carefully considered with their strengths and limitations to develop optimal investigations.

From liver to hormones: The endocrine consequences of cirrhosis.

Hepatocrinology explores the intricate relationship between liver function and the endocrine system. Chronic liver diseases such as liver cirrhosis can cause endocrine disorders due to toxin accumulation and protein synthesis disruption. Despite its importance, assessing endocrine issues in cirrhotic patients is frequently neglected. This article provides a comprehensive review of the epidemiology, pathophysiology, diagnosis, and treatment of endocrine disturbances in liver cirrhosis. The review was conducted using the PubMed/Medline, EMBASE, and Scielo databases, encompassing 172 articles. Liver cirrhosis is associated with endocrine disturbances, including diabetes, hypoglycemia, sarcopenia, thyroid dysfunction, hypogonadotropic hypogonadism, bone disease, adrenal insufficiency, growth hormone dysfunction, and secondary hyperaldosteronism. The optimal tools for diagnosing diabetes and detecting hypoglycemia are the oral glucose tolerance test and continuous glucose monitoring system, respectively. Sarcopenia can be assessed through imaging and functional tests, while other endocrine disorders are evaluated using hormonal assays and imaging studies. Treatment options include metformin, glucagon-like peptide-1 analogs, sodium-glucose co-transporter-2 inhibitors, and insulin, which are effective and safe for diabetes control. Established standards are followed for managing hypoglycemia, and hormone replacement therapy is often necessary for other endocrine dysfunctions. Liver transplantation can address some of these problems.

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.

New insights into nanomedicines for oral delivery of glucagon-like peptide-1 analogs.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that arises when the body cannot respond fully to insulin, leading to impaired glucose tolerance. Currently, the treatment embraces non-pharmacological actions (e.g., diet and exercise) co-associated with the administration of antidiabetic drugs. Metformin is the first-line treatment for T2DM; nevertheless, alternative therapeutic strategies involving glucagon-like peptide-1 (GLP-1) analogs have been explored for managing the disease. GLP-1 analogs trigger insulin secretion and suppress glucagon release in a glucose-dependent manner thereby, reducing the risk of hyperglycemia. Additionally, GLP-1 analogs have an extended plasma half-life compared to the endogenous peptide due to their high resistance to degradation by dipeptidyl peptidase-4. However, GLP-1 analogs are mainly administered via subcutaneous route, which can be inconvenient for the patients. Even considering an oral delivery approach, GLP-1 analogs are exposed to the harsh conditions of the gastrointestinal tract (GIT) and the intestinal barriers (mucus and epithelium). Hereupon, there is an unmet need to develop non-invasive oral transmucosal drug delivery strategies, such as the incorporation of GLP-1 analogs into nanoplatforms, to overcome the GIT barriers. Nanotechnology has the potential to shield antidiabetic peptides against the acidic pH and enzymatic activity of the stomach. In addition, the nanoparticles can be coated and/or surface-conjugated with mucodiffusive polymers and target intestinal ligands to improve their transport through the intestinal mucus and epithelium. This review focuses on the main hurdles associated with the oral administration of GLP-1 and GLP-1 analogs, and the nanosystems developed to improve the oral bioavailability of the antidiabetic peptides. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Home-based Intervention with Semaglutide Treatment of Neuroleptic-Related Prediabetes (HISTORI): protocol describing a prospective, randomised, placebo controlled and double-blinded multicentre trial

IntroductionSubjects with schizophrenia have a 2–3 fold higher mortality rate than the general population and a reduced life expectancy of 10–20 years. Approximately one-third of this excess mortality has been...

Semaglutide attenuates doxorubicin-induced cardiotoxicity by ameliorating BNIP3-Mediated mitochondrial dysfunction

AimsDoxorubicin is a powerful chemotherapeutic agent for cancer, whose use is limited due to its potential cardiotoxicity. Semaglutide (SEMA), a novel analog of glucagon-like peptide-1 (GLP-1), has received widespread attention for the treatment of diabetes. However, increasing evidence has highlighted its potential therapeutic benefits on cardiac function. Therefore, the objective of this study was to examine the efficacy of semaglutide in ameliorating doxorubicin-induced cardiotoxicity. Methods and resultsDoxorubicin-induced cardiotoxicity is an established model to study cardiac function. Cardiac function was studied by transthoracic echocardiography and invasive hemodynamic monitoring. The results showed that semaglutide significantly ameliorated doxorubicin-induced cardiac dysfunction. RNA sequencing suggested that Bnip3 is the candidate gene that impaired the protective effect of semaglutide in doxorubicin-induced cardiotoxicity. To determine the role of BNIP3 on the effect of semaglutide in doxorubicin-induced cardiotoxicity, BNIP3 with adeno-associated virus serotype 9 (AAV9) expressing cardiac troponin T (cTnT) promoter was injected into tail vein of C57/BL6J mice to overexpress BNIP3, specifically in the heart. Overexpression of BNIP3 prevented the improvement in cardiac function caused by semaglutide. In vitro experiments showed that semaglutide, via PI3K/AKT pathway, reduced BNIP3 expression in the mitochondria, improving mitochondrial function. ConclusionSemaglutide ameliorates doxorubicin-induced mitochondrial and cardiac dysfunction via PI3K/AKT pathway, by reducing BNIP3 expression in mitochondria. The improvement in mitochondrial function reduces doxorubicin-mediated cardiac injury and improves cardiac function. Therefore, semaglutide is a potential therapy to reduce doxorubicin-induced acute cardiotoxicity.

The Uricosuric Effect of SGLT2 Inhibitors Is Maintained in the Long Term in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus.

(1) Background: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) increase uric acid excretion. The intensity of uricosuria is linked to glycosuria. (2) Methods: We aim to analyze the effect of SGLT2 inhibitors on urinary fractional excretion (FE) of uric acid and glucose in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in a single-center retrospective study with patients with T2DM and CKD who started on treatment with SGLT2is. Patients on renal replacement therapy or with glucagon-like peptide-1 (GLP1) analogs were excluded. Subgroup analysis was performed according to the estimated glomerular filtration rate (eGFR), the SGLT2i molecule, the main comorbidities, and concomitant treatment. As a secondary objective, the study analyzed the effect of SGLT2 inhibitors on uricemia levels. (3) Results: Seventy-three patients were analyzed, with a mean follow-up of 1.2 years. Uric acid and glucose FE significantly increased after the initiation of SGLT2is. This increase remained stable during the follow-up without differences among eGFR groups. No significant reduction in uricemia was observed. However, a trend towards a decrease was observed. (4) Conclusion: The use of SGLT2is in patients with CKD and T2DM is associated with an increase in uric acid FE, which maintains stability irrespective of glomerular filtration loss at least during 24 months of follow-up.

GLP-1 analogs: a comparison of new anti diabetic medications - presenting benefits and risks

Introduction and purpose: Diabetes has emerged as a global lifestyle disease, with an alarming rise in cases, particularly of type 2 diabetes. In Poland, over 3 million people are diagnosed, and an estimated 4 million cases are expected by 2030. Effective treatment involves a multifaceted approach, including dietary intervention, physical activity, and pharmacological options. Incretins, such as glucagon-like peptide-1 (GLP-1), play a pivotal role in carbohydrate metabolism regulation, and GLP-1 analogs have become essential in managing type 2 diabetes. This paper explores the development and mechanisms of GLP-1 analogs, detailing their impact on insulin secretion, gastric emptying, and weight reduction.&#x0D; Description of the state knowledge: Various GLP-1 receptor agonists, including exenatide, liraglutide, dulaglutide, semaglutide, and the novel tirzepatide, are discussed. These drugs exhibit diverse pharmacokinetics, modes of administration, and effects on glucose metabolism and weight. Despite their efficacy, there is a concerning trend of off-label use, particularly for obesity treatment, leading to shortages for patients with valid prescriptions. This misuse is fueled by para-advertising on social media platforms, contributing to a surge in prescriptions and reimbursement costs. To address this, guidelines for GLP-1 analog use in obesity treatment are proposed, emphasizing the need for a stable drug supply and normalizing drug availability.&#x0D; Summary: In 2023, concerns intensified with reports of counterfeit GLP-1 analogs, prompting regulatory interventions. The paper concludes by underscoring the critical role GLP-1 analogs play in diabetes and obesity treatment, while emphasizing the importance of responsible prescription practices, guidelines adherence, and regulatory vigilance to ensure patient safety and mitigate the risks associated with misuse and counterfeit drugs.

Feasibility study of Glucagon-like peptide-1 analogues for the optimization of Outcomes in obese patients undergoing AbLation for Atrial Fibrillation (GOAL-AF) protocol

BackgroundCatheter ablation for atrial fibrillation is recommended for symptomatic patients after failed medical therapy. Ablation has a higher failure rate in obese patients, and both the prevalence of atrial fibrillation and obesity are increasingly globally. The outcome of ablation can be improved if obese patients can achieve goal-oriented weight reduction prior to ablation. Conventional weight loss strategies, however, can be difficult to access and can delay ablation, thereby risking a lower chance of maintaining sinus rhythm. Effective weight-loss medications, such as the glucagon-like peptide inhibitor-1 drugs, offer the potential for incremental impact on weight loss over a shorter period of time as a bridging therapy. The aim of this study is to assess the feasibility of using liraglutide, a glucagon-like peptide inhibitor-1, in producing weight loss in obese patients before catheter ablation.MethodsThe study is an open-label, uncontrolled, prospective single-centre feasibility study of daily liraglutide injections in the treatment of obese patients for at least 13 weeks before and 52 weeks after AF ablation. Adult patients with symptomatic AF whose body mass index ≥ 30 will be recruited from those planning to undergo ablation. Feasibility will be determined based on the recruitment rate, adherence to the medication, and the amount of weight loss achieved over the study period. Exploratory outcomes include changes in atrial structure, function, and fibrosis with weight loss evaluated by cardiac magnetic resonance imaging, electroanatomic mapping, and patient-reported outcome measure.DiscussionThis study will allow us to determine whether the use of liraglutide in obese patients with atrial fibrillation undergoing ablation is feasible with adequate recruitment. The additional information on adherence and average weight loss over the study period will inform the design of a future definitive randomized controlled trial.Trial registrationClinicalTrials.gov (NCT05221229). Registered on 2 February 2022.Trial fundingMetchley Park Medical Society and University of Birmingham Starter Fellowship, British Heart Foundation Accelerator Grant, Abbott Investigator-Initiated Study Grant.

A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings

Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R). AMG 133 (maridebart cafraglutide) is a bispecific molecule engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. In a phase 1, randomized, double-blind, placebo-controlled clinical study in participants with obesity (NCT04478708), AMG 133 had an acceptable safety and tolerability profile along with pronounced dose-dependent weight loss. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133.

Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice.

Glucagon-like peptide 1 (GLP-1) analogues have been commercialized for the management of type 2 diabetes. Recent studies have underscored GLP-1's role as a modulator of alcohol-related behavior. However, the role of the GLP-1 analogue liraglutide on alcohol-withdrawal responses have not been fully elucidated. Liraglutide binds to the G-protein-coupled receptor and activates an adenylyl cyclase and the associated classic growth factor signaling pathway, which acts growth factor-like and neuroprotective properties. The underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on the emotion and memory ability of alcohol-withdrawal mice, and synaptic morphology in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the relapse-like drinking of alcohol-withdrawal mice. The alcohol-withdrawal group was reintroduced to a 20% v/v alcohol and water through the two-bottle choice for four consecutive days, a period referred to as alcohol re-drinking. Male C57BL/6J mice were exposed to a regimen of 20% alcohol and water for a duration of 6 weeks. This regimen established the two-bottle choice model of alcohol exposure. Learning capabilities, memory proficiency, and anxiety-like behavior were evaluated using the Morris water maze, open field, and elevated plus maze paradigms. Furthermore, synaptic morphology and the levels of synaptic transport-related proteins were assessed via Golgi staining and Western Blot analysis after a two-week alcohol deprivation period. Alcohol re-drinking of alcohol-withdrawal mice was also evaluated using a two-bottle choice paradigm. Our findings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) in the alcohol group and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01) of alcohol-withdrawal mice. Alcohol consumption led to a reduction in dendritic spine density in the mPFC and HP, which was restored to normal levels by liraglutide (p < 0.001). Furthermore, liraglutide was found to augment the levels of synaptic transport-related proteins in mice subjected to alcohol withdrawal (p < 0.01). The study findings corroborate that liraglutide has the potential to mitigate alcohol consumption and ameliorate the memory impairments and anxiety induced by alcohol withdrawal. The therapeutic efficacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions and thus prevented relapse-like drinking in alcohol-withdrawal mice.