Glucagon-like Peptide-1 Receptor Research Articles

Glucagon-Like Peptide-1 Receptor Agonists and Liver Outcomes in Patients With MASLD and Type 2 Diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated long-term liver benefits in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D). However, no direct comparison between these therapies has been conducted. This study aimed to compare major adverse liver outcomes (MALOs) between GLP-1 RAs and SGLT2is in patients with MASLD and T2D. Using the TriNetX Research Network, a multinational and multi-institutional database, we identified adults with MASLD and T2D who received their first prescription for either a GLP-1 RA or an SGLT2i between January 2010 and June 2023. We conducted a propensity score-matched (PSM) cohort study comparing new users of GLP-1 RAs and SGLT2is. The primary outcome was the risk of MALOs, a composite endpoint consisting of decompensated cirrhosis events, hepatocellular carcinoma, and liver transplantation. Secondary outcomes included all-cause mortality and individual components of the primary outcome. This study included 15,176 pairs of patients treated with either a GLP-1 RA or a SGLT2i. The adjusted hazard ratio (HR) for MALO associated with GLP-1 RAs relative to SGLT2is was 0.84 (95% confidence interval [CI]: 0.73-0.97; incidence rate: 88.9 versus 105.3 events per 10,000 person-years), primarily driven by reduction in decompensated cirrhosis events (adjusted HR: 0.83, 95% CI: 0.71-0.96). GLP-1 RAs were associated with lower all-cause mortality (adjusted HR: 0.84, 95% CI: 0.75-0.94). GLP-1 RAs are associated with better long-term liver outcomes compared to SGLT2is in patients with MASLD and T2D.

Lifestyle and Pharmacologic Approaches to Prevention of MASLD-related HCC.

Hepatocellular carcinoma (HCC) is a major concern for public health. Fatty liver disease, related to alcohol misuse or metabolic syndrome, has become the leading cause of chronic liver disease and HCC. The strong association between type 2 diabetes mellitus and HCC can be partly attributed to the development of metabolic dysfunction associated steatotic liver disease (MASLD). There is a strong interest in strategies that may mitigate HCC risk and reduce HCC incidence in this growing population of at-risk individuals. In this review, we describe the pathogenesis of HCC in patients with MASLD and discuss potential emerging pharmacological and lifestyle interventions for MASLD-related HCC. HCC risk has been observed to be lower with healthy lifestyle behaviors, such as healthy dietary patterns, e.g., high consumption of vegetables, whole grains, fish, and poultry, yogurt, and olive oil, and low consumption of red and processed meats and dietary sugar) and increased physical activity. Selecting an appropriate anti-diabetic therapy for individuals with liver disease and diabetes may also decrease the occurrence of HCC. Metformin, PPAR activators, sodium-glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RA), aspirin, and statins have all shown promise to reduce the risk of HCC, although guidelines do not recommend their use for the sole purpose of chemoprevention at this time given a dearth of data defining their risk-benefit ratio.

AMPK-Mediated Multi-Organ Protective Effects of GLP-1 Receptor Agonists

Review AMPK-Mediated Multi-Organ Protective Effects of GLP-1 Receptor Agonists Xin Wang 1 and Linxi Wang 2,* 1 Emergency Department, Fujian Medical University Union Hospital, Fuzhou 350001, China 2 Department of Endocrinology and Metabolism, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou 350001, China * Correspondence: dr.linxi.wang@foxmail.com Received: 11 October 2024; Revised: 23 October 2024; Accepted: 20 December 2024; Published: 9 January 2025 Abstract: AMP-activated protein kinase (AMPK) is a key enzyme broadly involved in regulating cellular metabolism, often called an “energy sensor”. Activated AMPK promotes ATP production and storage within cells, primarily by inhibiting ATP-consuming anabolic processes (such as protein, lipid, and ribosomal synthesis) and initiating ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis) to maintain energy homeostasis. AMPK regulates metabolic processes in various peripheral tissues, including glucose and lipid metabolism, cholesterol metabolism, and fatty acid and protein metabolism in pancreatic β-cells, the cardiovascular system, liver, kidneys, skeletal muscles, and the central nervous system. As an antidiabetic drug, the multi-organ protective effects of Glucagon-like peptide-1 receptor agonists (GLP-1RA) are increasingly being recognized. This paper reviews the mechanisms by which GLP-1RA confers organ protection via the AMPK signaling pathway.

Real-world retrospective study in elderly patients aged 65 years and older with type 2 diabetes mellitus treated with daily oral semaglutide (SEMA-elderly).

This real-world, retrospective cohort study aimed to assess the efficacy, safety and tolerability of oral semaglutide-the first GLP-1 receptor agonist available in oral form-in patients aged 65 years and older with type 2 diabetes mellitus (T2DM). The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline (V1) to six months (V3). Secondary endpoints included change in body weight, proportion of patients achieving HbA1c <7%, proportion of patients achieving both an HbA1c reduction of ≥1% and a body weight reduction of ≥5%. Exploratory endpoints were also assessed, including evaluations at three months (V2). One hundred and one patients (mean age 74.7 ± 6.1 years) started oral semaglutide treatment. Mean HbA1c decreased significantly from V1 to V3 (change: -0.44%, p < 0.001), with reductions already evident at V2. The proportion of patients achieving an HbA1c ≤7% increased from 36.6% at V1 to 61.7% at V3. At V3, 9.6% of patients achieved an HbA1c reduction of ≥1% and a weight loss of ≥5%. Body weight decreased from a baseline mean of 76.8-73.7 kg at V3 (p < 0.001). Body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and systolic blood pressure decreased significantly from V1 to V3, with changes already evident at V2. Eleven patients (10.9%) reported adverse events. Seven patients (6.9%) discontinued treatment. Oral semaglutide effectively improves glycaemic control and weight management in elderly patients with T2DM while improving lipid and cardiovascular parameters and proving to be safe and well tolerated.

A Comprehensive Analysis of Diabetic Complications and Advances in Management Strategies.

Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), is a pervasive chronic disease that affects millions of people worldwide. It predisposes individuals to a range of severe microvascular and macrovascular complications, which drastically impact the patient's quality of life and increase mortality rates owing to various comorbidities. This extensive review explores the intricate pathophysiology underlying diabetic complications, focusing on key mechanisms, such as atherosclerosis, insulin resistance, chronic inflammation, and endothelial dysfunction. It also highlights recent therapeutic advancements, including the introduction of SGLT2 inhibitors and GLP-1 receptor agonists, which provide benefits beyond glycemic control and offer cardiovascular and renal protection. Furthermore, the future position of SGLT2 inhibitors and GLP-1 receptor agonists in terms of the prevention of diabetes and macrovascular diseases will be discussed. Considering the differences in insulin secretion capacity between Western and Asian patients, including Japanese patients, we propose a treatment strategy for high-quality diabetes in Japan.

Glucagon-Like Peptide-1 Receptor Agonists in the Peri-Operative Period

Glucagon-Like Peptide-1 Receptor Agonists in the Peri-Operative Period

Impact of Preoperative Glucagon-Like Peptide-1 Receptor Agonist on Outcomes Following Major Surgery.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) are increasingly being used for the management of diabetes mellitus and obesity. We sought to define the impact of preoperative GLP-1RA use on outcomes following major surgical procedures. Patients who underwent a major surgical procedure between 2013 and 2021 were identified using the IBM MarketScan database. Patients who took GLP-1RA within a year before surgery were categorized as "exposed." After propensity score matching (PSM), multivariable regression analysis was used to define the association of GLP-1RA exposure with postoperative complications. Among 138,980 patients (coronary artery bypass graft: n=39,516, 28.4%; pneumonectomy: n=4,881, 3.5%; abdominal aortic aneurysm repair: 4,459, 3.3%; pancreatectomy: n=15,873, 11.4%; and colectomy: n=74,251, 53.4%), most individuals were male (n=80,871, 58.2%) with a median age of 58 (IQR 53-61) years. 2944 (2.2%) individuals had GLP-1RA exposure before surgery. Overall incidence of complications was 36.5% (n=50,724); complications included sepsis (n=6,385, 4.6%), surgical site infections (n=7,431, 5.3%), thromboembolism (n=3,609, 2.6%), pneumonia (n=4,783, 3.4%), renal (n=9,017, 6.5%), or cardiopulmonary failure (n=26,661, 19.2%). On unmatched analysis, patients on GLP-1RA had a higher risk of complications (no GLP-1RA: 36.3% vs. GLP-1RA: 44.5% p<0.001); however, after PSM to account for measured confounders, GLP-1RA exposure was not associated with the odds of surgical complications (OR 0.99 95% CI 0.91-1.08; p>0.05). Among patients using GLP-1RA during the 2 weeks before surgery (n=522, 17.7%), there was no association of GLP-1RA with risk of complications (nonrecent GLP-1RA: 44.7% vs. recent GLP-1RA: 44.1%; p=0.992). GLP-1RA use was not associated with an increased risk of complications following major surgical procedures.

Exploring Predictors of Treatment Response to GLP-1 Receptor Agonists for Smoking Cessation.

Understanding predictors of smoking cessation medication efficacy facilitates the ability to enhance treatment effectiveness. In our pilot trial, exenatide, a glucagon-like peptide-1 receptor agonist, adjunct to nicotine patch improved smoking abstinence compared to nicotine patch alone. This secondary analysis explores potential baseline characteristics associated with differential treatment response to exenatide. The parent trial randomized (1:1) 84 smokers with prediabetes and/or overweight to once-weekly placebo or exenatide, 2mg, subcutaneously. All participants received nicotine patch (21mg) and brief smoking cessation counseling, with biologically confirmed 7-day point prevalence abstinence at week 6 (end-of-treatment) deemed the primary outcome. Bayesian generalized linear modeling explored differential response to treatment as a function of baseline patient characteristics, including demographic, psychosocial, clinical, smoking related, and genetic factors. Posterior probability (PP)≥75% that an effect exists was taken as a minimum threshold of evidence in favor of model effects. Exenatide showed stronger benefit versus placebo in participants that smoked >20 cigarettes per day (PP=81.7%) and in those without prediabetes (PP=76.0%) or obesity (PP=94.4%). Exenatide's efficacy was observed only in individuals with no/minimal depression symptoms but not in those with symptoms (PP=91.2%). Finally, exenatide was more efficacious than placebo only in those with the CHRNA rs16969968 GG genotype (PP=88.6%). The effect of exenatide on abstinence may be moderated by the number of cigarettes smoked daily, metabolic, psychological, and genetic factors. Larger prospective investigations are needed to confirm and extend these findings. Understanding predictors of smoking cessation medication efficacy enhances the ability to improve treatment effectiveness. In our pilot trial, extended-release exenatide, a GLP-1 receptor agonist, adjunct to nicotine patch, improved smoking abstinence in smokers with prediabetes and/or overweight. The current post-hoc analysis found that the effect of exenatide on smoking abstinence may be moderated by the number of cigarettes smoked daily, metabolic, psychological, and genetic factors. Larger investigations are needed to confirm and extend these findings.

Cardiovascular risk associated with glucagon-like peptide-1 receptor agonists versus other conventional glucose-lowering drugs in patients with type-2 diabetes: protocol for a nationwide observational comparative study in routine care

IntroductionSeveral cardiovascular outcome trials have been conducted to assess the cardiovascular safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP1-RAs) on cardiorenal outcomes in patients with type-2 diabetes (T2D). However,...

Elective peri-operative management of adults taking glucagon-like peptide-1 receptor agonists, glucose-dependent insulinotropic peptide agonists and sodium-glucose cotransporter-2 inhibitors: a multidisciplinary consensus statement: A consensus statement from the Association of Anaesthetists, Association of BritishClinical Diabetologists, British Obesity and Metabolic Surgery Society, Centrefor Perioperative Care, Joint British Diabetes Societies for Inpatient Care, RoyalCollege of Anaesthetists, Society for Obesity and Bariatric Anaesthesia and

Glucagon-like peptide-1 receptor agonists, dual glucose-dependent insulinotropic peptide receptor agonists and sodium-glucose cotransporter-2 inhibitors are used increasingly in patients receiving peri-operative care. These drugs may be associated with risks of peri-operative pulmonary aspiration or euglycaemic ketoacidosis. We produced a consensus statement for the peri-operative management of adults taking these drugs. This multidisciplinary consensus statement included surgeons, anaesthetists, physicians, pharmacists and people with lived experience relevant to these guidelines. Following the directed literature review, a three-round modified Delphi process was conducted to generate and ratify recommendations. Patients taking glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic peptide receptor agonists should: continue these drugs before surgery; have full risk assessment and stratification; and receive peri-operative techniques that may mitigate risk of pulmonary aspiration before, during and after sedation or general anaesthesia. Patients taking sodium-glucose cotransporter-2 inhibitors should omit them the day before and the day of a procedure. All patients should have risks and mitigation strategies discussed with a shared decision-making approach. Until more evidence becomes available, this pragmatic, multidisciplinary consensus statement aims to support shared decision-making and improve safety for patients taking glucagon-like peptide-1 receptor agonists, dual glucose-dependent insulinotropic peptide receptor agonists and sodium-glucose cotransporter-2 inhibitors during the peri-operative period.

The role of GLP-1 receptor agonists in the management of obesity: risks and opportunities for the Australian health care system.

The role of GLP-1 receptor agonists in the management of obesity: risks and opportunities for the Australian health care system.

Prognostic impact of glucagon-like peptide-1 receptor (GLP1R) expression on cancer survival and its implications for GLP-1R agonist therapy: an integrative analysis across multiple tumor types.

Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exenatide (Byetta, Bydureon), liraglutide (Victoza, Saxenda), albiglutide (Tanzeum), dulaglutide (Trulicity), lixisenatide (Lyxumia, Adlyxin), semaglutide (Ozempic, Rybelsus, Wegovy), and tirzepatide (Mounjaro, Zepbound), are widely used for the treatment of type 2 diabetes mellitus (T2DM) and obesity. While these agents are well known for their metabolic benefits, there is growing interest in their potential effects on cancer biology. However, the role of GLP-1R agonists in cancer remains complex and not fully understood, particularly across different tumor types. This study aimed to evaluate the prognostic significance of GLP1R expression on overall survival across various cancer types. Using a comprehensive analysis of gene expression data and survival outcomes a large cohorts of different tumor types, we employed Cox proportional hazards survival analyses, coupled with false discovery rate determinations, to explore correlations between GLP1R expression and survival. The integrated database included thousands of cancer specimens with available overall survival time and event data from numerous independent cohorts, providing a robust platform for survival analysis. Our findings reveal that increased GLP1R expression is associated with improved overall survival in cancers such as bladder cancer, breast cancer, esophageal adenocarcinoma, renal clear cell carcinoma, and thyroid carcinoma. Conversely, higher GLP1R expression is linked to poorer survival outcomes in cervical squamous cell carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Additionally, GLP1R expression showed no significant impact on overall survival in cancers such as esophageal squamous cell carcinoma, colon cancer, head-neck squamous cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, ovarian cancer, and pancreatic cancer. In conclusion, GLP1R expression levels serve as an important biomarker with potential prognostic significance across multiple cancers, demonstrating both protective and adverse associations depending on the tumor type. These findings highlight the complex role of GLP-1R agonists in cancer risk and survival, suggesting that the therapeutic use of these agents should be carefully tailored to the individual patient's cancer risk profile.

Thyroid Cancer Risk with GLP-1 Receptor Agonists: Evidence, Knowledge Gaps, and the Path Forward.

Thyroid Cancer Risk with GLP-1 Receptor Agonists: Evidence, Knowledge Gaps, and the Path Forward.

Physician Perceptions of the Safety and Efficacy of GLP-1 Receptor Agonists: Underestimation of Cardiovascular Risk Reduction and Discrepancies with Clinical Evidence

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists (GIP/GLP-1 RAs) are emerging as effective treatments for obesity and cardiometabolic disease. This study evaluated physician perceptions of the safety and efficacy of semaglutide and tirzepatide through a questionnaire administered to 165 attending physicians specializing in internal or family medicine, with 122 responses received. Physicians reported an average patient weight loss of 9.22%, significantly lower than the 14.9% and 18.5% reported in the STEP and SURMOUNT trials, respectively. Estimated side effect rates (32.62%) were markedly lower than trial-reported rates (89.7% and 80.5%), while estimated discontinuation rates (8.59%) exceeded trial data. Cardiovascular benefits were perceived by 48.4% of physicians in diabetic patients, consistent with random guessing, and by only 39.3% in nondiabetic patients, significantly below random guessing expectations. These results highlight discrepancies between physician perceptions and clinical evidence, suggesting gaps in understanding regarding these agents’ efficacy and safety profiles. Addressing these gaps could enhance physician knowledge, patient adherence, and clinical outcomes.

Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes

Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes

Combination Therapy with SGLT2 Inhibitors and GLP-1 Receptor Agonists for Diabetic Kidney Disease.

Combination Therapy with SGLT2 Inhibitors and GLP-1 Receptor Agonists for Diabetic Kidney Disease.

Annals Video Summary - Efficacy and Safety of GLP-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes

Annals Video Summary - Efficacy and Safety of GLP-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes

Emirates consensus recommendations on cardiovascular risk management in type 2 diabetes

BackgroundThe combination of cardiovascular disease and diabetes is a highly prevalent condition in the United Arab Emirates. Development and dissemination of evidence-based regional recommendations for optimal screening, treatment and referrals of people with diabetes and high cardiovascular risk is an important priority.Consensus panelAn expert panel of diabetologists, endocrinologists and cardiologists from the Emirates Cardiac Society and Emirates Diabetes and Endocrine Society as well as different entities in the UAE, discussed and reviewed evidence and also a consensus report from the American Diabetes Association to formulate contextualized recommendations that could be applied for optimal management of cardiovascular risk in people with diabetes in the UAE.Consensus findingsThe combination of heart failure and other cardiovascular risks is a highly prevalent finding among people with diabetes in the United Arab Emirates. The causal inter-relationships between diabetes and heart failure are multifactorial and regular assessments of symptoms and steps for mitigation of risk factors are an important priority. The universal definition and classification of heart failure provides a useful framework for recommending optimal screening, treatment, and referral strategies to diabetic individuals at various stages of the cardiovascular continuum. Routine measurement (at least yearly) of natriuretic peptides and high-sensitivity troponins can help identify patients requiring cardiac imaging referrals. However, recommending routine measurements of natriuretic peptides and/or high-sensitivity troponins to all diabetic individuals must balance clinical judgment and cost implications. While SGLT2i must be an important part of the standard of care, insulin, GLP1 receptor agonists and/or metformin can be useful for additional glycemic control.ConclusionThe consensus panel hopes that the recommendations presented herein can offer guidance for optimal screening, treatment and referral of people with a concomitance of diabetes and high cardiovascular risk in the United Arab Emirates.

Antidepressants and Weight Gain: An Update on the Evidence and Clinical Implications.

To highlight recent research on antidepressant use and weight change and explore best clinical practices for reducing weight gain and obesity risk in individuals with depression. Research on antidepressant use and weight gain suggests that genetic and biological factors including metabolizer phenotypes and inflammation can help to predict an individual's threshold for weight change among specific agents. For individuals with increased susceptibility to metabolic complications, medications including bupropion, fluoxetine, and newer agents (e.g., gepirone) have shown to be efficacious in improving depressive symptoms while concurrently reducing metabolic risks. Additional areas of focus following antidepressant related weight gain include switching to a weight neutral drug alternative, integrated behavioral interventions, and/or pharmacotherapy including GLP-1 receptor agonists (e.g., metformin, liraglutide). Individuals experiencing depression are at heightened risk of metabolic disorders and weight gain, which may be further exacerbated by antidepressant treatment. The increased support of weight neutral antidepressant agents in addition to innovative lifestyle interventions, breakthroughs in drug mechanisms, anti-obesity medications and overall familiarity with the side effects of each antidepressant class will help clinicians make appropriate decisions when treating patients with depression.

Evaluating the causal effect of using glucagon-like peptide-1 receptor agonists on the risk of autoimmune diseases.

To investigate the causal association of using glucagon-like peptide-1 receptor (GLP1R) agonists with autoimmune diseases. The available cis-eQTLs for drugs target genes (GLP1R) were used as genetic variants for exposure to GLP1R agonists. Type 2 diabetes was used as positive control. Mendelian randomizations (MR) were performed to explore the association of genetically-proxied GLP1R agonists with 11 autoimmune diseases from large-scale consortia. Replicating the findings in the FinnGen study and then pooled with meta-analysis. Finally, we performed MR analysis to examine whether GLP1R agonists affect 731 immune cell phenotypes to clarify the potential mechanism. We observed supportive evidence to support the association of GLP1R agonists with reduced the risk of hypothyroidism (OR [95%]=0.89 [0.82-0.95], P<0.001), but increased risk of ulcerative colitis (OR [95%]=1.48 [1.27-1.71], P<0.001), type 1 diabetes (OR [95%]=1.34 [1.21-1.50], P<0.001), systemic lupus erythematosus (OR [95%]=1.61 [1.29-2.02], P<0.001) and sarcoidosis (OR [95%]=1.38 [1.08-1.75], P=0.008). There was no supporting evidence to verify the association of GLP1R expression with asthma, Crohn's disease, multiple sclerosis and myasthenia gravis (P>0.05). In addition, we found that GLP1R agonists was positively associated with 221 immune cell phenotypes (P<0.05, OR > 1), and negatively associated with 317 immune cell phenotypes (P<0.05, OR<1). GLP1R agonists are causally associated with various autoimmune diseases potentially through the modulation of 731 immune cell phenotypes.