Glucagon-like Peptide-1 Receptor Agonists Research Articles

Comparison of cardiovascular outcomes in patients with diabetes treated with tirzepatide versus semaglutide: a multi-institutional analysis

Abstract Introduction Glucagon-like-peptide-1 (GLP-1) receptor agonists have been demonstrated to have cardiovascular benefits in patients with diabetes. Two of the most prescribed medications in this class are tirzepatide and semaglutide. Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, while semaglutide is a selective GLP-1 receptor agonist. Tirzepatide and semaglutide have previously been directly compared to assess efficacy in glycemic control as the primary endpoint. However, there is limited data directly comparing cardiovascular outcomes between the two medications in patients with diabetes. This retrospective cohort study compares the incidence of major adverse cardiovascular events (MACE) in patients with diabetes treated with tirzepatide or semaglutide. Purpose The purpose of this study is to identify differences in cardiovascular outcomes between patients with diabetes treated with tirzepatide as compared to semaglutide. Materials and Methods The TriNetX research network was used for this study. Two patient cohorts were generated using International Classification of Disease 10 (ICD-10) codes and medication codes in the TriNetX system. Both cohorts of patients had a history of diabetes (E08-E13) and no prior history of cerebral vascular accident (I63) or myocardial infarction (I21). One cohort received semaglutide and the other tirzepatide. Each cohort was prohibited from receiving the other agent. The cohorts were balanced for age, race, gender, and ethnicity by propensity score matching and the greedy nearest neighbor algorithm resulting in 36,212 patients in each arm. They were then evaluated for the 3-year outcomes of major adverse cardiovascular events (myocardial infarction, cerebral vascular accident, and death). Results Tirzepatide was associated with statistically significantly fewer MACE outcomes compared to semaglutide for each of the individual endpoints as well as the overall composite endpoint over the 3 year follow up period. Table 1. MACE events for semaglutide and tirzepatide. Table 2. Relative risks for semaglutide MACE endpoints compared to tirzepatide. Conclusions In this retrospective cohort study, tirzepatide was associated with a lower incidence of major adverse cardiovascular events compared to semaglutide in patients with diabetes. These findings suggest that tirzepatide offers superior cardiovascular protection for primary prevention compared to semaglutide and warrant further investigation in future studies and clinical trials.Table 1Table 2

Semaglutide modulates pro-inflammatory neutrophil phenotype induced by supraphysiological levels of the adipokine FABP4 in patients with cardiovascular disease

Abstract Background Increased adiposity is a risk factor for cardiovascular disease (CVD). Adipose tissue is an endocrine organ that releases proteins with pro-inflammatory effects. One of them is FABP4, which levels are increased after adipogenesis. Insulin resistance is linked to supraphysiological levels of this biomarker. Therapies to reduce body weight and improve insulin response, such as the GLP-1 receptor agonists, like semaglutide, have been shown to benefit patients with CVD and obesity, who have a high pro-inflammatory neutrophil profile. Purpose To study the FABP4 effects on neutrophils from patients with cardiovascular disease and cellular models and its possible modulation by semaglutide. Methods We included 11 patients undergoing open heart surgery. Neutrophils from blood were isolated by single-step centrifugation, counted, and same number were treated with FABP4 (100 ng/mL), semaglutide (1nM) or both. Finally, their phenotype was assessed using flow cytometry (FACS). The same treatment conditions were used on differentiated HL-60 cells (dHL-60) to test their phenotype and functionality based on a) oxidative burst capacity using dihydrorhodamine 123 and b) adhesion to coronary artery endothelial cells. At the end, neutrophils phenotype was tested on patients with obesity and diabetes under semaglutide treatment for 6 months, according to clinical practice. Neutrophils phenotype was determined by FACS and FABP4/C5a plasma levels by immunofluorescence assay. Results FABP4 reduced neutrophils’ CD88 (p=0.006) and CXCR2 (p=0.02) levels. This was also verified in dHL60 cells (p=0.01). In these cells, we were also able to observe a CD11b increment after FABP4 treatment (p=0.04), modulated by semaglutide (p=0.02). This phenotype increased the neutrophil-coronary adhesion (p=0.03). Their oxidative burst capacity was attenuated after semaglutide treatment. In addition, 32% of patients underwent semaglutide treatment reduced plasmatic FABP4 (p=0.03) levels and increased CD88 (p=0.01). We confirmed that CD88 modulation does not lead to a change in plasma C5a. Conclusions High FABP4 levels reduce CD88 of neutrophils from patients with cardiovascular disease and enhance their adhesion to coronary endothelial cells. Modulation of the FABP4 effects by semaglutide treatment might suggest a protective mechanism against adiposity/coronary endothelial inflammation.

Cardiovascular prevention with GLP1 agonists in high or very-high cardiovascular risk irrespective of diabetes

Abstract Introduction Patients with established cardiovascular disease have an increased risk of stroke and myocardial infarction, even in the absence of atrial fibrillation. Several trials have analyzed the effect of glucagon-like peptide-1 receptor (GLP1) agonists in patients with high cardiovascular risk and lately this effect has been studied even in the absence of diabetes. Methods A meta-analysis of randomized clinical trials (RCT) comparing GLP1 agonists with placebo was performed. The primary objective of the study was to analyze the composite endpoint of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke (MACE). As secondary objectives, cardiovascular death, non-fatal myocardial infarction and non-fatal stroke have been studied separately. The meta-analysis was performed using the inverse variance method, using the fixed effects model when there was no heterogeneity and the random effects model when heterogeneity is significant. In the case of significant heterogeneity in the primary objective, a stratified analysis with exposure time have been performed to explain this outcome. Results A sum of 9 randomized controlled trials were included where a GLP1 agonist such as albiglutide, dulaglutide, exenatide, liraglutide, lixinatide or semaglutide was compared with placebo. 77684 patients were incorporated, while 39497 were treated with a GLP1 agonist. The mean age was of 63.7 years (SD ± 1.97 years), 60080 (77.3%) suffered from diabetes and 60552 (77.9%) from cardiovascular disease. As showed in figure 1, the GLP1 agonists showed a reduction of 13% of the MACE (RR: 0.87, 95% CI 0.81-0.92; p<0.001). Heterogeneity could be explained by exposure time and concentration in the blood, considering that it disappears within each group when applying this condition. Treatment with GLP1 agonist also reduced cardiovascular death by 12% (RR: 0.88, 95% CI 0.82-0.94; p<0.001), non-fatal strokes by 14% (RR: 0.86, 95%CI 0.79-0.95; p<0.001) and non-fatal miocardial infarction by 13% (RR: 0.87, 95% CI 0.78-0.97; p<0.001). Conclusion Treatment with a GLP1 agonist reduced the incidence of the MACE by 13% and cardiovascular death by 12%, as well as it decreased the incidence of nonfatal stroke by 14% and of nonfatal myocardial infarction by 13% in different RCTs involving patients with high or very-high cardiovascular risk with or without diabetes.

Anti-inflammatory effect of semaglutide: updated systematic review and meta-analysis

Abstract Background Glucagon-like peptide-1 (GLP-1RA) receptor agonists possess multiple favourable metabolic, anti-inflammatory effects and their use is associated with marked body weight reduction. More importantly, this drug class has been shown to reduce cardiovascular events in patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk or with established cardiovascular disease. Accordingly, current guidelines recommend the use of GLP-1RA sas first-line antidiabetic therapies in patients at high cardiovascular risk. Semaglutide is a potent GLP-1RA used in the treatment of T2DM with proven cardiovascular benefits. It is currently available in formulations for oral and subcutaneous administration. The anti-inflammatory effect could be one of the mechanisms by which semaglutide reduces cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) and/or obesity. Determining the anti-inflammatory effect of semaglutide was the objective of this systematic review and meta-analysis. Methods This meta-analysis was performed according to the PRISMA guidelines. A literature search was performed to detect randomised clinical trials that have quantified the effect of semaglutide on C-reactive protein (CRP) levels compared to placebo or a control group (other glucose-lowering drugs). The primary outcome was CRP index (final CRP/basal CRP). A random-effects model was used. Results Overall, this meta-analysis shows that semaglutide therapy was associated with lower CRP index values compared to placebo (SMD -0.56; 95% CI -0.69 to -0.43, I2 92%) or when comparing semaglutide treatment versus a control group consisting of patients medicated with other glucose-lowering drugs (SMD -0.45; 95% CI -0.68 to -0.23, I 3 82%). The stratified analysis was performed by analysing only the trials that used a placebo group as comparator, When the trials were analysed according to the different dosing schemes (subcutaneous vs. oral), the results were not statistically significantly different (oral semaglutide group: SMD -0.33; 95% CI -0.75 to 0.08, I2 95%); semaglutide subcutaneous dose group: SMD -0.69; 95% CI -0.78 to -0.60, I2 74%); interaction p = 0.098. Furthermore, when the trials were analysed according to the included populations (patients with or without T2DM), the results were similar (patients with T2DM: SMD -0.32; 95% CI -0.51 to -0.14, I2 86%); patients without T2DM: SMD -0.82; 95% CI -0.90 to -0.74, I2 58%); interaction p = < 0.0001. Conclusion The present meta-analysis demonstrated that the use of semaglutide was associated with a reduction in inflammation irrespective of the population evaluated or the treatment regimen used. These findings would explain one of the mechanisms by which semaglutide reduces cardiovascular events.

Heart failure and renal outcomes in patient treated with GLP1 agonists

Abstract Introduction Glucagon-like peptide-1 receptor (GLP1) agonists are emerging as a primordial treatment for diabetes and to reduce cardiovascular burden, both of them factors that play an important role in the developing of renal chronic disease and heart failure, and vice versa. The debut of renal chronic disease and the manifestation of acute renal injury/failure can lead to the discontinuation of treatment, which in patients suffering from heart failure who tend to be polymedicated could end up in lessening their survival. Methods A metanalysis of randomized clinical trials (RCT) comparing GLP1 agonists with placebo was performed. The endpoint of the study was to analyze all-cause mortality, hospitalization or urgent medical visit for heart failure, a kidney outcome composite, which is slightly heterogenic depending on the RCT, and the manifestation of acute renal injury/failure as an adverse effect or that lead to the discontinuation of treatment. The meta-analysis was performed using the inverse variance method, using the fixed effects model when there was no heterogeneity and the random effects model when heterogeneity is significant. Results A sum of 9 randomized controlled trial were included where a GLP1 agonists such as albiglutide, dulaglutide, exenatide, liraglutide, lixinatide or semaglutide compared with placebo. 77684 patients were incorporated, while 39497 were treated with a GLP1 agonists. The mean age was of 63.7 years (SD ± 1.97 years), 60080 (77.3%) suffered from diabetes, 60552 (77.9%) from cardiovascular disease and 14367 from chronic heart failure (18.4%). The mean eGFR was 77.3 mL/min (SD ± 3.3 mL/min). As showed in the forest plots, treatment with GLP1 agonists reduced all-cause mortality by 12% (RR: 0.88, 95% CI 0.83-0.92; p<0.001), hospitalization or urgent medical visit for heart failure by 10% (RR: 0.90, 95% CI 0.83-0.98; p<0.001), the kidney composite outcome by 22% (RR: 0.78, 95% CI 0.70-0.87; p<0.001), while it showed no statistical reduction in acute renal injury/failure (RR: 0.89, 95% CI 0.79-1.01; p=0.069). Conclusion Treatment with a GLP1 agonists reduced the incidence of all-cause mortality by 12%. In addition, hospitalization or urgent medical visit for heart failure was decreased by 10%. In terms of renal asessment, the composite of kidney function was reduced by 22%, while the manifestation of acute renal injury/failure, though no statistical signification was accomplished, showed some evidence of beneficial effect but more RCTs are needed to prove it. Hence, GLP1 analogues appear as a possible new pillar of treatment for heart failure and renal disease in determined patients.

BMI shift and associated cardiometabolic risk factors in people with type 2 diabetes and obesity and/or overweight: a post hoc analysis from SURMOUNT-2

Abstract In SURMOUNT-2 (SM-2), treatment with once weekly GIP and GLP-1 receptor agonist tirzepatide (TZP) resulted in superior body weight reductions relative to placebo in people living with obesity and T2D. This post hoc analysis assessed whether participants with obesity (body mass index [BMI] ≥30 kg/m2) or overweight (BMI ≥27 kg/m2 with at least one weight-related comorbid condition) who shifted to a lower BMI category had improved cardiometabolic factors. Change in BMI category (<25 kg/m2, 25 to <30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2, and ≥40 kg/m2) from baseline to week 72 was assessed in participants from SM-2 treated with TZP 10 or 15 mg (N=623) or placebo (PBO)(N=315). BMI shifts were grouped into "improved" (shift to lower BMI category) or "non-improved" (stable or shift to a higher BMI category). Cardiometabolic parameters examined included waist circumference, fasting insulin, fasting glucose, HbA1c, blood pressure, and lipid profile. A mixed model with repeated measures was performed to estimate the mean change from baseline to week 72 for these parameters. In this post hoc analysis a total of 484 (52.1%) participants had improved BMI at week 72. For those whose BMI did not improve, most had stable BMI and only 11 (1.2%) had worsened BMI. Nine participants had no post-baseline BMI measurements and were excluded from analysis. Most participants demonstrated improved BMI with TZP treatment (N=418, 67%) vs PBO (N=66, 21%)(Table). Furthermore, 21% (N=129) of participants on TZP improved by ≥2 BMI categories compared to only 1 participant with PBO. Compared to those with non-improved BMI, participants with improved BMI demonstrated greater improvement in cardiometabolic risk factors, including decreases from baseline in waist circumference, fasting insulin, fasting glucose, HbA1c, systolic and diastolic blood pressure, triglycerides, and cholesterol (non-HDL-c, and LDL-c) and increases from baseline in HDL-c (Figure). Greater improvements to cardiometabolic risk factors were seen in participants on TZP vs PBO. Shifts to lower BMI categories were greater among TZP-treated people living with obesity or overweight and T2D in SM-2 and were associated with improved cardiometabolic risk factors, in this post hoc analysis. SURMOUNT-mortality and morbidity and cardiovascular outcome trials are ongoing to examine the impact of TZP treatment on CVD and mortality.

The Influence of GLP1 on Body Weight and Glycemic Management in Patients with Diabetes—A Scientometric Investigation and Visualization Study

Diabetes medications can affect weight and cardiovascular health. Some medications can aid in weight management, while others may lead to weight gain. Patients must be monitored and receive appropriate care to manage weight and prevent cardiovascular complications. Despite advancements in diabetes treatments that can influence weight and cardiovascular outcomes, ongoing research is necessary in this intricate field. Long-term effects, individual variations, and combination therapies are still subjects of uncertainty and ongoing investigation. The major objective of the research is to evaluate the impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on body weight in diabetic patients through a scientometric assessment. Methodology: Research data were gathered from the Web of Science Core Collection (WoSCC) database by searching for the keywords “Body Weight”, dulaglutide, and semaglutide, identifying 60 relevant articles in the field. While there are advantages in managing diseases in which the cardiovascular system is implicated, there are also clinical considerations for personalized medicine and shared decision-making. The scientometric analysis of the articles revealed important insights into how dulaglutide and semaglutide impact weight management and their potential benefits for managing cardiovascular diseases in individuals with diabetes. Conclusions: Semaglutide shows superior outcomes compared to other commercially available GLP-1RAs, particularly in improving blood sugar control, lowering body weight, and addressing other cardio-metabolic risk factors in individuals with type 2 diabetes (T2DM). The findings suggest that GLP-1 RAs have the potential to provide cardiovascular protection by influencing various physiological factors such as blood pressure, pulse rate, glycated hemoglobin (HbA1c) levels, and the urinary albumin-to-creatinine ratio (RAC). The development and validation of the 4GI model provides a sophisticated tool for evaluating the complex interactions involved in diabetes treatments, offering insights into the mechanisms of action of various medications.

Effect of Glucagon-like Peptide-1 Receptor Agonism on Aortic Valve Stenosis Risk: A Mendelian Randomization Analysis

Background: Aortic valve repair is currently the only effective treatment for calcific aortic valve stenosis (CAVS), as no pharmacological therapies exist to prevent or slow its progression. Recent promising results showed that glucagon-like peptide-1 (GLP-1) attenuates the calcification of aortic valve interstitial cells. Therefore, we conducted a two-sample Mendelian randomization analysis to investigate the effect of GLP-1 receptor agonism (GLP-1Ra) on the risk of CAVS. Methods: The inverse variance weighted (IVW) method was used to obtain the primary causal inference, and several sensitivity analyses, including MR-Egger, were performed to assess the robustness of the results. Results: Based on the IVW estimates, the GLP-1Ra showed a neutral effect on the risk of CAVS (odds ratio [OR] per 1 mmol/mol decrease in glycated hemoglobin = 0.87, 95% CI = [0.69, 1.11], p = 0.259; I2 = 4.5%, Cohran’s Q = 2.09, heterogeneity p = 0.35; F statistic = 16.8). A non-significant effect was also derived by the sensitivity analyses. No evidence of horizontal pleiotropy was identified. Conclusions: GLP-1Ra was not significantly associated with the risk of CAVS. Furthermore, pragmatically designed studies are required to evaluate the effect of GLP-1Ra on the clinical course of CAVS in different patient subgroups.

SGLT2i and GLP1RA effects in patients followed in a hospital diabetology consultation

ABSTRACT Background We aimed to investigate the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) in patients with type 2 diabetes mellitus (T2DM) in clinical practice. Research design and methods A total of 340 patients were included. Data on age, gender, antidiabetic medications, and bioanalytical parameters were collected at baseline and one year later. Were analyzed estimated glomerular filtration rate (eGFR), blood sodium and potassium levels, blood pressure, weight, cardiovascular risk, and glycated hemoglobin (HbA1c). Results Patients treated with SGLT2i exhibited a significant improvement in eGFR at the endpoint compared to baseline (p = 0.006). Both treatment groups experienced reductions in systolic blood pressure at the endpoint; especially patients treated with SGLT2i (p = 0.0002). GLP1RA treatment resulted in a statistically significant weight reduction from baseline to endpoint (p < 0.0001), with a higher percentage of patients achieving ≥ 5% weight loss compared to the non-GLP1RA group (33.6% vs. 19.8%). Both SGLT2i and GLP1RA treatments significantly reduced cardiovascular risk scores (p = 0.004 and p = 0.002, respectively). Additionally, both treatments were associated with a significant reduction in HbA1c levels at the endpoint (p = 0.010 and p = 0.002, respectively). Conclusions Our findings suggest that SGLT2i and GLP1RA offer beneficial effects in patients with T2DM.

Current Perspectives in Pre- and Diabetic Peripheral Neuropathy Diagnosis and Management: An Expert Statement for the Gulf Region.

Peripheral neuropathy (PN) significantly impacts the quality of life, causing substantial morbidity and increased mortality, as well as escalating healthcare costs. While PN can have various causes, the most common form, diabetic peripheral neuropathy, poses considerable risks for potential complications. Diabetic peripheral neuropathy (DPN) affects over 50% of people with prediabetes and diabetes. Despite its prevalence, a global gap in diagnosis and management exists, exacerbated by the COVID-19 pandemic. This expert consensus was formulated through a comprehensive evaluation by a panel of experts, informed by a focused literature review, aiming to establish a clinically robust approach to diagnosing and managing pre- and diabetic PN with the early utilization of neurotropic B vitamins. This document offers a consensus perspective on the existing challenges in diagnosing and managing PN, focusing on DPN. The expert panel proposes measures to address this underdiagnosed burden, highlighting the importance of early intervention through innovative screening methods, integrated care approaches, and therapeutic strategies. The document advocates for increased awareness, targeted campaigns, and proactive care strategies to bridge gaps in the patient care of individuals with diabetes, emphasizing the importance of early detection and timely management to improve overall health outcomes. Specific recommendations include incorporating simplified questionnaires and innovative screening methods into routine care, prioritizing neurotropic B vitaminsupplementation, optimizing glucagon-like peptide1 (GLP-1) receptor agonist treatments, and adopting a holistic approach to neuropathy management. The consensus underscores the urgent need to address the underdiagnosis and undertreatment of PN, offering practical measures to enhance early detection and improve health outcomes for individuals with DPN.

Effects of glucagon-like peptide-1 receptor agonists on cardiovascular outcomes in high-risk type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to provide cardiovascular benefits in patients with type 2 diabetes mellitus (T2DM). However, their cardiovascular protective efficacy in high-risk T2DM patients, particularly those with a history of cardiovascular events or severe chronic kidney disease, remains uncertain.MethodsA comprehensive search was conducted in PubMed, Embase, Web of Science, and The Cochrane Library to identify randomized controlled trials (RCTs) that evaluated the effects of GLP-1 RAs on cardiovascular outcomes in high-risk patients with T2DM. A random-effects model was used to calculate pooled hazard ratios (HRs) for cardiovascular outcomes. Subgroup analyses and GRADE assessment were also performed.ResultsNine RCTs involving 63,613 patients were included. GLP-1 RAs significantly reduced the risk of the primary composite outcome (HR: 0.86, 95% CI: 0.80–0.92), cardiovascular death (HR: 0.85, 95% CI: 0.78–0.93), all-cause death (HR: 0.87, 95% CI: 0.82–0.93), myocardial infarction (HR: 0.90, 95% CI: 0.82–0.98), stroke (HR: 0.85, 95% CI: 0.77–0.95), and heart failure (HF) hospitalization (HR: 0.90, 95% CI: 0.83–0.97). No significant difference in unstable angina (UA) hospitalization was observed (HR: 1.04, 95% CI: 0.95–1.15). Subgroup analyses indicated greater benefits with combination therapy, particularly in patients with chronic kidney disease. The quality of evidence was rated as “High” for six outcomes and “Moderate” for UA hospitalization.ConclusionsGLP-1 RAs significantly reduce cardiovascular risk in high-risk T2DM patients, especially with combination therapy and in those with chronic kidney disease. However, further research is needed to confirm their long-term effects.

Incretin hormones: Revolutionizing the treatment landscape for kidney and liver diseases in type 2 diabetes and obesity.

Several ongoing trials are evaluating incretin-based therapies, including GLP-1 receptor agonists, for their effects on CKD and MASLD. These studies will offer insights into their potential for metabolic diseases in people with type 2 diabetes and obesity.

The diabetes cardiovascular outcomes trials and racial and ethnic minority enrollment: impact, barriers, and potential solutions

Type 2 diabetes (T2D) affects millions of individuals worldwide and is a well-documented risk factor for cardiovascular (CV) disease and chronic kidney disease, both of which are leading causes of mortality. Racial and ethnic minority groups in the US, including but not limited to Hispanic/Latino, non-Hispanic Black, and Southeast Asian individuals, are disproportionately burdened by both T2D and its adverse outcomes. In recent years, there have been numerous cardiovascular outcomes trials (CVOTs) on novel antidiabetic therapies, including the dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors. CVOTs’s initial aim was to demonstrate the cardiovascular safety of these drugs. Unexpected CV and kidney protective effects were found, specifically among the GLP-1 RAs and the SGLT2 inhibitors. These benefits informed the new paradigm of the management of patients with T2D. However, some experts argued that the lack of racial and ethnic minority group representation in these trials represented a challenge. While the downstream effects of this lack of representation must be further elucidated, it is clear and recognized that efforts need to be made to include a more representative sample in future CVOTs, specifically including individuals from those groups most burdened by T2D and its complications, if clinicians are to have an accurate picture of the benefits and potential pitfalls of utilizing these drugs in a real-world setting. In this comprehensive review, we briefly summarize the significant findings from the CVOTs, report the lack of representation of Hispanic/Latino, non-Hispanic Black, and Southeast Asian individuals in the CVOTs, investigate the barriers to recruiting racial and ethnic minority groups into clinical trials, and suggest potential solutions to overcome these obstacles at the patient-, provider-, and sponsor/system-level in future trials.

Effect of the glucagon-like peptide-1 receptor agonists on diabetic peripheral neuropathy: A meta-analysis.

Previous researches found that glucagon-like peptide 1 receptor agonists (GLP-1RA) offer benefits beyond their anti-diabetic properties, including weight loss and cardiovascular disease prevention. However, the effects of GLP-1RA on diabetic peripheral neuropathy (DPN) remain unclear. This meta-analysis aims to assess the potential benefits of GLP-1RA treatment in DPN patients by evaluating peripheral neural function. Following the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a meta-analysis of the clinical trials investigating the impact of GLP-1RA treatment on peripheral neural function in patients with DPN. Outcomes were measured using electrophysiological tests, including nerve conduction velocity (NCV) and action potential amplitude. Our meta-analysis included six studies with 271 participants. Following GLP-1RA treatment, NCV significantly improved compared to the control group (MD 1.74; 95% CI 1.16 to 2.33; p < 0.001) and before treatment (MD 2.16; 95% CI 1.04 to 3.27; p < 0.001). Despite the improvement in NCV, blood glucose levels did not change significantly (MD -0.20 95% CI -0.87 to 0.46, p = 0.55) indicating that GLP-1RA enhances NCV through mechanisms other than glucose lowering. Nonetheless, as a result of the limited population studied, further research is needed to strengthen the reliability of these findings.

Use of Glucagon-Like Peptide-1 Receptor Agonists Does Not Increase the Risk of Cancer in Patients with Type 2 Diabetes Mellitus.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for the treatment of type 2 diabetes mellitus (T2DM) given their extra-pancreatic effects. However, there are concerns about carcinogenesis in the pancreas and thyroid gland. We aimed to evaluate the site-specific incidence of cancer in patients with T2DM-treated GLP-1 RAs using a nationwide cohort. This study included data obtained from the Korean National Health Insurance Service (between 2004 and 2021). The primary outcome was newly diagnosed cancer, and the median follow-up duration for all participants was 8 years. After propensity score matching, 7,827 participants were analyzed; 2,609 individuals each were included in the GLP-1 RA, diabetes mellitus (DM) control, and non-DM control groups. The incidence rate ratio (IRR) of subsequent cancer in patients with T2DM was 1.73, which was higher than that of individuals without DM, and it increased in both men and women. Analysis of patients with T2DM showed no increased cancer risk associated with the use of GLP-1 RA, and similar results were observed in both men and women. The IRRs of pancreatic cancer (0.74), thyroid cancer (1.32), and medullary thyroid cancer (0.34) did not significantly increase in the GLP-1 RA group compared with those in the DM control group. There was a 73% higher risk of cancer in patients with T2DM compared with the general population. However, among patients with T2DM, there was no association between the use of GLP-1 RAs and new-onset cancers, including pancreatic and medullary thyroid cancers.

Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US.

Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. However, real-world evidence for its ability to protect against Alzheimer's disease (AD) is lacking. We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First-ever diagnosis of AD occurred within a 3-year follow-up period and was examined using Cox proportional hazards and Kaplan-Meier survival analyses. Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups. These findings support further studies to assess semaglutide's potential in preventing AD. Semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in T2DM patients compared to other antidiabetic medications, including other GLP-1RAs. Semaglutide was associated with significantly lower AD-related medication prescriptions. Similar reductions were seen across obesity status, gender, and age groups. Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM. These findings support further clinical trials to assess semaglutide's potential in delaying or preventing AD.

GLP-1 Receptor Agonist and SGLT2 Inhibitor Prescribing in People With Type 1 Diabetes

This pooled cross-sectional study explores prescribing rates for glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors among US patients with type 1 diabetes.

A Scoping Review of GLP-1 Receptor Agonists: Are They Associated with Increased Gastric Contents, Regurgitation, and Aspiration Events?

Background: The increased popularity and ubiquitous use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of diabetes, heart failure, and obesity has led to significant concern for increased risk for perioperative aspiration, given their effects on delayed gastric emptying. This concern is highlighted by many major societies that have published varying guidance on the perioperative management of these medications, given limited data. We conducted a scoping review of the available literature regarding the aspiration risk and aspiration/regurgitant events related to GLP-1 RAs. Methods: A librarian-assisted search was performed using five electronic medical databases (PubMed, Embase, and Web of Science Platform Databases, including Web of Science Core Collection, KCI Korean Journal Database, MEDLINE, and Preprint Citation Index) from inception through March 2024 for articles that reported endoscopic, ultrasound, and nasogastric evaluation for increased residual gastric volume retained food contents, as well as incidences of regurgitation and aspiration events. Two reviewers independently screened titles, abstracts, and full text of articles to determine eligibility. Data extraction was performed using customized fields established a priori within a systematic review software system. Results: Of the 3712 citations identified, 24 studies met eligibility criteria. Studies included four prospective, six retrospective, five case series, and nine case reports. The GLP-1 RAs reported in the studies included semaglutide, liraglutide, lixisenatide, dulaglutide, tirzepatide, and exenatide. All studies, except one case report, reported patients with confounding factors for retained gastric contents and aspiration, such as a history of diabetes, cirrhosis, hypothyroidism, psychiatric disorders, gastric reflux, Barrett’s esophagus, Parkinson’s disease, dysphagia, obstructive sleep apnea, gastric polyps, prior abdominal surgeries, autoimmune diseases, pain, ASA physical status classification, procedural factors (i.e., thyroid surgery associated with risk for nausea, ketamine associated with nausea and secretions), and/or medications associated with delayed gastric emptying (opioids, anticholinergics, antidepressants, beta-blockers, calcium channel blockers, DPP-IV inhibitors, and antacids). Of the eight studies (three prospective and five retrospective) that evaluated residual contents in both GLP-1 users and non-users, seven studies (n = 7/8) reported a significant increase in residual gastric contents in GLP-1 users compared to non-users (19–56% vs. 5–20%). In the three retrospective studies that evaluated for aspiration events, there was no significant difference in aspiration events, with one study reporting aspiration rates of 4.8 cases per 10,000 in GLP-1 RA users compared to 4.6 cases per 10,000 in nonusers and the remaining two studies reporting one aspiration event in the GLP-1 RA user group and none in the non-user group. In one study that evaluated for regurgitation or reflux by esophageal manometry and pH, there was no significant difference in reflux episodes but a reduction in gastric acidity in the GLP-1 RA user group compared to the non-user group. Conclusions: There is significant variability in the findings reported in the studies, and most of these studies include confounding factors that may influence the association between GLP-1 RAs and an increased risk of aspiration and related events. While GLP-1 RAs do increase residual gastric contents in line with their mechanism of action, the currently available data do not suggest a significant increase in aspiration and regurgitation events associated with their use and the withholding of GLP-1 RAs to reduce aspiration and regurgitation events, as is currently recommended by many major societal guidelines. Large randomized controlled trials (RCTs) may be helpful in further elucidating the impact of GLP-1 RAs on perioperative aspiration risk.

Glucagon-like peptide-1 receptor agonists before upper gastrointestinal endoscopy and risk of pulmonary aspiration or discontinuation of procedure: cohort study

ObjectiveTo assess whether use of glucagon-like peptide-1 (GLP-1) receptor agonists before upper gastrointestinal endoscopy is associated with increased risk of pulmonary aspiration or discontinuation of the procedure compared with sodium-glucose...

GLP-1 Receptor Agonists Confer No Increased Rates of IBD Exacerbation Among Patients With IBD.

In patients with inflammatory bowel disease (IBD), multimorbidity with obesity and type 2 diabetes is common and increasing. Glucagon-like peptide 1 (GLP-1) receptor agonists are increasingly being prescribed for patients with IBD, yet their impact on patients with IBD is largely unknown. We aimed to assess the impact of GLP-1 receptor agonists on the course of IBD. We identified all IBD patients prescribed GLP-1 receptor agonists at a large academic healthcare network between 2009 and 2023. We analyzed demographics and IBD characteristics in the year pre- and post-GLP-1 receptor agonist prescription and matched them to non-IBD controls. Our primary outcome was IBD exacerbation in the year following GLP-1 receptor agonist initiation, measured as a composite of IBD-related hospitalization, corticosteroid prescription, medication escalation or changes, or IBD-related surgery. Secondary outcomes included change in metabolic risk factors. Overall, 224 patients met inclusion criteria. At GLP-1 receptor agonist initiation, the median age was 54 years, 63% were female, 77% were White, and median BMI was 33.2kg/m2. Compared to the 12-month period prior to GLP-1 receptor agonist initiation, in the 12 months post-GLP-1 receptor agonist initiation, there was no change in rates of IBD exacerbation, IBD-related hospitalization, steroids prescription, medication escalation or changes, or IBD-related surgery. There was a significant decrease in BMI in the year following GLP-1 receptor agonist initiation (median BMI 33.5 vs 31.6kg/m2, P < .01), with rates of decrease comparable to non-IBD matched controls. In patients with IBD, GLP-1 receptor agonists are effective for weight loss and associated with few episodes of disease exacerbation.