The relationship between the use of GLP-1 receptor agonists and the incidence of respiratory illness: a meta-analysis of randomized controlled trials.

AIM: We aimed to assess the association between the use of Glucagon-like peptide-1 receptor agonists and the risk of 12 respiratory diseases in patients with type 2 diabetes, obesity, or overweight. METHOD: The PubMed (MEDLINE), EMBASE, Cochrane Library, and ClinicalTrials.gov databases were searched from the establishment of the database to December 24, 2022. Dichotomous outcomes were analyzed using RR and 95% CI calculated from fixed-effects models. RESULTS: Twenty-eight RCTs were ultimately included for analysis, involving a total of 77,485 participants. Compared to controls, patients with GLP-1RAs have a 14% lower risk of respiratory disease (RR 0.86, 95% CI 0.81-0.93 p < 0.0001), with Semaglutid (RR 0.82, 95% CI 0.68-0.97, p = 0.02), Liraglutide (RR 0.86. 95% CI 0.75-0.98, p = 0.03), Dulaglutide (RR 0.82, 95% CI 0.70-0.96, p = 0.02), Albiglutide (RR 0.93,95% CI 0.79-1.10, p = 0.40), Exenatide (RR 0.93, 95% CI 0.74-1.18, p = 0.55), Lixisenatide (RR 0.83, 95% CI 0.62-1.12, p = 0.22), and Efpeglenatide (RR 0.76, 95% CI 0.46-1.24, p = 0.27). Semaglutide, Liraglutide and Dulaglutide reduce the risk of respiratory diseases by 18%, 14% and 18%, respectively.Trial duration, control type, and indication were not associated with the impact of GLP-1 receptor agonists on overall respiratory disease. Among secondary outcomes, the risk of Pulmonary edema (RR 0.66, 95% CI 0.44-0.98, p = 0.04), and Bronchitis (RR 0.86, 95% CI 0.74-1.00, p = 0.04) was reduced. CONCLUSION: In conclusion, GLP-1RAs were linked to a lower risk of overall respiratory diseases, especially Pulmonary edema and Bronchitis. In the future, physicians should pay attention to the relationship between GLP-1 RA and the risk of respiratory diseases and evaluate the efficacy of GLP-1RAs in the primary and secondary prevention of respiratory diseases. Trial registration CRD42023396138.

Effect of sacubitril/valsartan and ACEI/ARB on glycaemia and the development of diabetes: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Sacubitril/valsartan and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) therapies were reported to affect glycaemic control and the development of diabetes mellitus (DM), but the findings are inconsistent. We examined the evidence for the effects of sacubitril/valsartan and ACEI/ARB in DM by conducting a meta-analysis. METHODS: The Cochrane Central Register of Controlled Trials (The Cochrane Library), Embase, PubMed, and ClinicalTrials.gov were searched for data from randomised clinical trials (RCTs) that evaluated the efficacy of sacubitril/valsartan and ACEI/ARB in patients, as of May 25, 2022. Patients were grouped by their disease background at baseline. The main outcomes were the number of new-onset DM and hypoglycaemia, elevated glycaemia, inadequate DM control, diabetes treatment, and diabetic complications, from baseline to the end of the trials. The risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (ROB 2). The quality of the evidence was evaluated according to the Recommendations for Assessment, Development, and Evaluation guidelines. The meta-analysis of the incidence of various outcomes was conducted using fixed or random effects models. The results are expressed as binary risk, 95% confidence interval (CI), and relative risk (RR). The Mantel-Haenszel method and Z test were used to determine the overall results and determine the significance of the RR. RESULTS: This study included 31 RCTs and 86,809 subjects. Compared with placebo, sacubitril/valsartan treatment significantly reduced the risk of new-onset DM among all patients (RR = 0.78, 95% CI: 0.64-0.95), patients with heart failure (HF) (RR = 0.24, 95% CI: 0.12-0.48), HF with reduced ejection fraction (HFrEF) (RR = 0.24, 95% CI: 0.12-0.50), and HF with preserved ejection fraction (HFpEF) (RR = 0.54, 95% CI 0.34-0.85). In contrast, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among all patients (RR = 1.91, 95% CI: 1.05-3.47), patients with not all-DM (defined as part of the study population having DM at baseline) (RR = 5.71, 95% CI: 2.02-16.21), and patients with HFpEF (RR = 7.06, 95% CI: 2.10-23.76). Compared with ACEI/ARB, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among patients with HF (RR 1.85, 95% CI 1.12-3.06, p = 0.02) and HFpEF (RR 3.59, 95% CI 1.51-8.55, p = 0.004). Compared with placebo, ACEI/ARB treatment did significantly reduce the risk of new-onset DM among all patients (RR 0.85, 95% CI 0.77-0.93, p = 0.0007) and patients with not all-HF (defined as part of the study population having HF at baseline) (RR 0.87, 95% CI 0.82-0.93, p<0.0001) and HFpEF (RR 0.60, 95% CI 0.44-0.83, p = 0.002), diabetes complications among patients with non-HF (/not all-DM) (RR 0.87, 95% CI 0.76-0.99, p = 0.04), and subsequent diabetes treatment among patients with new-onset DM (RR 0.70, 95% CI 0.58-0.84, p = 0.0002) and significantly increased the risk of hypoglycaemia among patients with not all-DM (RR 2.06, 95% CI 1.172-3.61, p = 0.01). CONCLUSIONS: The results of our study, especially in reducing glycaemia and new-onset DM, revealed that sacubitril/valsartan had a positive effect on the control of glycaemia and the development of DM. ACEI/ARB also had a beneficial effect but the effect was weaker than that of sacubitril/valsartan. The above effects varied across diseases but the evidence was strongest in patients with HF. TRIAL REGISTRATION: CRD42022336311.

Risk of stroke and retinopathy during GLP-1 receptor agonist cardiovascular outcome trials: An eight RCTs meta-analysis.

Purpose: To explore the risk of stroke (including ischemic and hemorrhagic stroke) in type 2 diabetes mellitus treated with glucagon-like peptide 1 receptor agonist (GLP-1RA) medication according to data from the Cardiovascular Outcome Trials(CVOT). Methods: Randomized controlled trials (RCT) on GLP-1RA therapy and cardiovascular outcomes in type 2 diabetics published in full-text journal databases such as Medline (via PubMed), Embase, Clinical Trials.gov, and the Cochrane Library from establishment to May 1, 2022 were searched. We assess the quality of individual studies by using the Cochrane risk of bias algorithm. RevMan 5.4.1 software was use for calculating meta- analysis. Results: A total of 60,081 randomized participants were included in the data of these 8 GLP-1RA cardiovascular outcomes trials. Pooled analysis reported statistically significant effect on total stroke risk[RR=0.83, 95%CI(0.73, 0.95), p=0.005], and its subtypes such as ischemic Stroke [RR=0.83, 95%CI(0.73, 0.95), p=0.008] from treatment with GLP-1RA versus placebo, and have no significant effect on the risk of hemorrhagic stroke[RR=0.83, 95%CI(0.57, 1.20), p=0.31] and retinopathy [RR=1.54, 95%CI(0.74, 3.23), p=0.25]. Conclusion: GLP-1RA significantly reduces the risk of ischemic stroke in type 2 diabetics with cardiovascular risk factors.

Effects of different types of radiation therapy on cardiac-specific death in patients with thyroid malignancy.

Radiation therapy (RT) is one of the common and widely used treatment method for thyroid tumors. Considering that the thyroid is located close to the heart, the radiation generated during the treatment of thyroid tumors may have an adverse greater impact on the heart. This study is to explore the influencing factors, especially additional effects of RT, on cardiac-specific death among patients with malignant thyroid tumors. Collecting information from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database using SEER*Stat. Patients with malignant thyroid tumors were searched, whether receiving RT or not. Ultimately, 201, 346 eligible patients were included. Propensity Score Matching (PSM) was used to minimize bias of baseline characteristics by adjusting for confounding factors. COX (proportional hazards) and fine-gray (competing risk) model regression analysis were used to explore the effects of various influencing factors on cardiac-specific death. The present analysis showed that, compared with non-RT, RT based upon radioactive implants and beam radiation were associated with lower risk of cardiac-specific death in patients with thyroid malignancy, beam radiation therapy may had a similar effect. Besides, the remaining RT methods did not significantly increase the risk of cardiac-specific death. In addition, Asian or Pacific Islander ethnicity, female sex, marital status, combined summary stage (localized, regional, and distant), high-income, and later year of diagnosis were associated with lower risk of cardiac-specific death. While older age of diagnosis, African ethnicity, non-Hispanic ancestry, and derived AJCC stage (IV) were risk factors for cardiac-specific death. These results help to identify the factors influencing cardiac-specific death among patients with thyroid malignancies. Furthermore, it may helps to improve the clinical application of RT without too much concern about adverse cardiac effects.

Effect of radiotherapy on cardiac-specific death in patients with non-malignant tumors of central nervous system and related clinical features.

Importance: Cardiac-specific death from radiation caused by radiation therapy (RT) in patients with malignant tumors has received extensive attention, however, little is known regarding the potential cardiotoxic effects of RT in patients with non-malignant tumors. Objectives and methods: In this study, we used the SEER data to explore the incidence of post-radiation cardiovascular complications in patients with non-malignant tumors of central nervous system (CNS), and identify the influencing factors of cardiac-specific death. Results: Ultimately 233, 306 patients were included (97.8% of patients had brain tumors and 2.2% had spinal cord tumors). For patients with non-malignant tumors of CNS, RT {yes (odds ratio [OR] 0.851, 95% confidence interval [CI] 0.774-0.936, p = 0.001, before propensity score matching (PSM); OR 0.792, 95% CI 0.702-0.894, p < 0.001, after PSM) vs. no} was associated with lower risk of cardiac-specific death, other clinical features affecting cardiac death similar to those in patients with non-malignant tumors of CNS receiving RT. For patients with non-malignant tumors of CNS receiving RT, female, married status, Hispanic ethnicity, surgery, and tumor site (brain exclude nerve and endocrine, nervous system) were associated with lower risks of cardiac-specific death, while earlier year of diagnosis, older age of diagnosis, Black, larger tumor and bilateral tumor were risk factors for cardiac-specific death. Conclusions: Our study shows the influencing factors for cardiac-specific death in patients with non-malignant tumors of CNS, and found RT is associated with lower risk of cardiac-specific death. These results can facilitate the identification of patients with non-malignant tumors of CNS who can benefit from RT while avoiding cardiovascular events. In addition, this study helps to enhance the clinical use of RT in these populations, especially in patients who may have impaired cardiac function due to CNS tumors.

HADH may be the target molecule of early vascular endothelial impairment in T2DM.

Background: Type 2 diabetes mellitus (T2DM) will significantly increase the risk of atherosclerosis (AS). Vascular endothelial cell dysfunction (VECD) is the foundation of AS. Early identification and intervention of VECD caused by T2DM can help us effectively delay or even suppress the occurrence of AS. Methods: We downloaded the gene expression profiles from the Gene Expression Omnibus (GEO). The differential expression genes (DEGs) were identified in R software and weighted gene co-expression network analysis (WGCNA) was performed to further screen the target genes. In addition, we used the receiver operating characteristic curve (ROC curve) to verify the diagnostic efficiency of target genes. Finally, target genes were validated by quantitative polymerase chain reaction (qPCR). Results: Four target genes (CLUH, COG4, HADH, and MPZL2) were discovered in early vascular endothelial impairment caused by T2DM through differential expression analysis and WGCNA. The ROC curve of target genes showed that HADH had the best diagnostic efficacy in VECD and AS. qPCR showed that the mRNA level expression of HADH and MPZL2 were decreased in human coronary artery endothelial cells (HCAECs) treated with high glucose and palmitic acid. Conclusion: HADH may be the target gene in early VECD caused by T2DM.

Effects of GLP-1 receptor agonists on arrhythmias and its subtypes in patients with type 2 diabetes: A systematic review and meta-analysis.

Purpose: An update of a systematic review and meta-analysis of the risk of arrhythmias and their subtypes in type 2 diabetic patients receiving glucagon-like peptide 1 receptor agonist (GLP-1RA) medication according to data from the Cardiovascular Outcome Trial(CVOT). Methods: Randomized controlled trials (RCT) on GLP-1RA therapy and cardiovascular outcomes in type 2 diabetes mellitus patients published in full-text journal databases such as MEDLINE (via PubMed), Embase, Clinical Trials.gov, and the Cochrane Library from establishment to March 1, 2022 were searched. We assessed the quality of individual studies by the Cochrane risk-of-bias algorithm. RevMan 5.4.1 software was use for calculating meta-analysis. Results: A total of 60,081 randomized participants were included in the data of these 8 GLP-1RA cardiovascular outcomes trials. Pooled analysis reported no significant effect on total arrhythmia [RR=0.96, 95% CI (0.96, 1.05), p =0.36], and its subtypes such as atrial fibrillation [RR=0.96, 95% CI (0.86, 1.07), p =0.43], atrial flutter [RR= 0.82, 95% CI (0.57, 1.19), p =0.30], atrial tachycardia [RR=0.64, 95% CI (0.20, 2.01), p =0.44)], sinoatrial node dysfunction [RR=0.74, 95% CI (0.44, 1.25), p =0.26], ventricular preterm systole [RR=1.42, 95% CI (0.62, 3.26), p =0.41], second degree AV block [RR=0.96, 95% CI (0.53, 1.72), p =0.88], complete AV block [RR=0.75, 95% CI (0.49, 1.17), p =0.21], ventricular fibrillation [RR=1.00, 95% CI (0.50, 2.02), p =1.00], ventricular tachycardia [RR=1.37, 95% CI (0.91, 2.08), p =0.13] from treatment with GLP-1RA versus placebo. However, the risk of hypoglycemia was reduced by about 30% [RR=0.70, 95% CI (0.57, 0.87), p=0.001] and the risk of pneumonia by about 25% [RR=0.85, 95% CI (0.75, 0.97), p=0.01], both statistically significant differences. Conclusion: In type 2 diabetic patients, treatment with GLP-1RA has no significant effect on the risk of major arrhythmias but significantly reduces the risk of hypoglycemia and pneumonia.

Bioinformatics Analysis Identifies Potential Ferroptosis Key Gene in Type 2 Diabetic Islet Dysfunction.

Background: Islet ß cells dysfunction (IBCD) is a cortical component in pathogenesis of type 2 diabetic mellitus (T2DM). However, the relationship of ferroptosis and IBCD remains unknown. This study was aimed to screen potential ferroptosis key genes to reveal latent physiological and pathological process of IBCD in T2DM. Methods: Firstly, T2DM key genes were screened by combining with differentially expressed genes (DEGs) analysis and WGCNA. Then, ferroptosis-related genes (FRGs) in IBCD of T2DM were identified by taking the intersection between T2DM key genes and FRGs. Finally, T2DM-FRGs were validated in another T2DM dataset as well as islet single-cell RNA sequencing dataset and the miRNA regulated T2DM-FRG was predicted by using four miRNA databases. Results: 89 T2DM key genes were identified between DEGs and WGCNA. Then, 3 T2DM-FRGs were screened by taking the intersection of T2DM key genes and FRGs, namely ITGA6, MGST1 and ENO2. At last, MGST1 were validated as the T2DM-FRG in another T2DM islet issues dataset and islet single-cell RNA sequencing dataset. Conclusion: MGST1 may be the potential ferroptosis key gene of IBCD in T2DM.

Effect of Sacubitril/Valsartan on Reducing the Risk of Arrhythmia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background and Objective: Relevant data of PARADIGM-HF reveals sacubitril/valsartan (SV) therapy led to a greater reduction in the risks of arrhythmia, and sudden cardiac death than angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor inhibitor (ARB) therapy in HFrEF, however, inconsistent results were reported in subsequent studies. Here, we conduct a meta-analysis of related randomized controlled trials (RCTs) to evaluate the protective effect of SV on reducing the risk of arrhythmias. Methods and Results: RCTs focused on the difference in therapeutic outcomes between SV and ACEI/ARB were searched from PUBMED, EMBASE, ClinicalTrials.gov, and Cochrane Library. The results were extracted from each individual study, expressed as binary risk, 95% confidence interval (CI) and relative risk (RR). Sixteen RCTs including 22, 563 patients met the study criteria. Compared with ACEI/ARB therapy, SV therapy did significantly reduce in the risks of severe arrhythmias among patients with heart failure with reduced ejection fraction (HFrEF) (RR 0.83, 95% CI 0.73-0.95, p = 0.006), ventricular tachycardia (VT) among patients with HFrEF (RR 0.69, 95% CI 0.51-0.92, p = 0.01), cardiac arrest among patients with heart failure (HF) (RR 0.52, 95% CI 0.37-0.73, p = 0.0002), cardiac arrest among patients with HFrEF (RR 0.49, 95% CI 0.32-0.76, p = 0.001), cardiac arrest or ventricular fibrillation (VF) among patients with HF (RR 0.63, 95% CI 0.48-0.83, p = 0.001), and cardiac arrest or VF among patients with HFrEF (RR 0.65, 95% CI 0.47-0.89, p = 0.008), but reduced the risks of arrhythmias (RR 0.87, 95% CI 0.74-1.01, p = 0.07), atrial arrhythmias (RR 0.98, 95% CI 0.83-1.16, p = 0.85), and atrial fibrillation (RR 0.98, 95% CI 0.82-1.17, p = 0.82) among all patients with no significant between-group difference. The merged result was robust after sensitivity analysis, and there was no publication bias. Conclusion: Our meta-analysis provides evidence that, compared with ACEI/ARB, SV can additionally reduce the risks of most arrhythmias, just the significant differences are revealed in reducing the risks of VT, severe arrhythmias, and cardiac arrest in patients with HFrEF. Besides, the positive effect of SV on VF according to statistical result of combining VF with cardiac arrest in patients with HFrEF is credibility.

Preliminary evidence for the presence of multiple forms of cell death in diabetes cardiomyopathy.

Diabetic mellitus (DM) is a common degenerative chronic metabolic disease often accompanied by severe cardiovascular complications (DCCs) as major causes of death in diabetic patients with diabetic cardiomyopathy (DCM) as the most common DCC. The metabolic disturbance in DCM generates the conditions/substrates and inducers/triggers and activates the signaling molecules and death executioners leading to cardiomyocyte death which accelerates the development of DCM and the degeneration of DCM to heart failure. Various forms of programmed active cell death including apoptosis, pyroptosis, autophagic cell death, autosis, necroptosis, ferroptosis and entosis have been identified and characterized in many types of cardiac disease. Evidence has also been obtained for the presence of multiple forms of cell death in DCM. Most importantly, published animal experiments have demonstrated that suppression of cardiomyocyte death of any forms yields tremendous protective effects on DCM. Herein, we provide the most updated data on the subject of cell death in DCM, critical analysis of published results focusing on the pathophysiological roles of cell death, and pertinent perspectives of future studies.