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The Lancet Regional Health. Western... Jun 2024Type 2 diabetes (T2DM) remains a challenge to treat despite the expansion of various therapeutic classes. Visepegenatide (PB-119) is a once a week, subcutaneous,...
Efficacy and safety of visepegenatide, a long-acting weekly GLP-1 receptor agonist as monotherapy in type 2 diabetes mellitus: a randomised, double-blind, parallel, placebo-controlled phase 3 trial.
BACKGROUND
Type 2 diabetes (T2DM) remains a challenge to treat despite the expansion of various therapeutic classes. Visepegenatide (PB-119) is a once a week, subcutaneous, glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection without the requirement of dose titration that has shown glycaemic control and safety profile in two phase 2 studies conducted in China and the United States, respectively. The aim of this study was to evaluate the efficacy and safety of visepegenatide as a monotherapy in treatment-naïve patients with T2DM.
METHODS
This was a multicentre, double-blind, parallel, placebo-controlled, phase 3 trial conducted in 30 centres in China. Adult participants (aged 18-75 years) with T2DM, glycated haemoglobin (HbA1c) of 7.5%-11.0% [58.47-96.73 mmol/mol], body mass index (BMI) of 18-40 kg/m, and who had been treated with diet and exercise alone for at least 8 weeks before the screening visit were eligible for enrolment. After a 4-week placebo injection run-in period, participants with HbA1c of 7.0%-10.5% [53.0-91.3 mmol/mol] and fasting plasma glucose (FPG) < 15 mmol/L were randomised in a ratio of 1:1 to receive visepegenatide (150 μg) or placebo subcutaneous injections once a week for 24 weeks. The treatment was extended to another 28 weeks during which all participants received visepegenatide. The primary outcome was a change in HbA1c from baseline to week 24. This study was registered with ClinicalTrials.gov, as NCT04504370.
FINDINGS
Between November 2, 2020, and November 2, 2022, we randomly assigned 273 adult participants to the visepegenatide (n = 137) and placebo (n = 136) groups. In total, 257 (94.12%) participants, 131 (95.6%) on visepegenatide, and 126 (92.6%) on placebo, completed the double-blinded treatment period. At baseline, the mean (SD) HbA1c was 8.47% (0.81) [69.07 [8.81] mmol/mol], which rapidly decreased to 7.63% (0.80) [59.94 [8.70] mmol/mol] with visepegenatide by week 4 of treatment, and the change from baseline was significantly greater than that in the placebo group (-0.82% [-0.90 to -0.74]; [-8.99 [-9.89 to -8.10] mmol/mol] -0.30% [-0.41 to -0.19]; [-3.30 [-4.50 to -2.09] mmol/mol]). At week 24, when evaluating the effects of treatment with treatment policy estimand, the least square mean (LSM change in HbA1c from baseline was -1.36 (95% confidence interval [CI] -1.52 to -1.20) [-14.84 [-16.60 to -13.08] mmol/mol] in the visepegenatide group -0.63 (-0.79 to -0.46) [-6.84 [-8.61 to -5.07] mmol/mol] in the placebo group. The reduction in HbA1c was significantly greater with visepegenatide than placebo (LSM difference -0.73, 95% CI -0.96 to -0.50; p < 0.001). When evaluating the treatment estimand with hypothetic policy, the LSM change in HbA1c from baseline in the visepegenatide group (-1.37 [-1.53 to -1.20]) [-14.95 [-16.76 to -13.14] mmol/mol] was significantly greater than the placebo group (-0.63 [-0.81 to -0.45]) [6.90 (-8.89 to -4.90) mmol/mol]. The LSM difference was (-0.74, 95% CI -0.98 to -0.49; [-8.00 [-10.50 to -5.50] mmol/mol]; p < 0.001]. A significantly greater proportion of the visepegenatide group achieved a target HbA1c level of <7% (<53 mmol/mol) than the placebo (50.4% 14.2%; p < 0.05) and stringent HbA1c level of ≤6.5% (≤48 mmol/mol) (26.7% 7.9%), respectively. There was also a significantly greater improvement in FPG, 2-h postprandial glucose, homeostasis model assessment (HOMA) of beta cell function, post-prandial insulin, fasting, and post-prandial C-peptide level (p < 0.05) with visepegenatide treatment. The number (3 [2.2%]) of participants who received rescue therapy in the visepegenatide group was remarkably lower compared with those (17 [12.5%]) in the placebo group (p < 0.05). During the extended treatment period, visepegenatide consistently maintained the efficacy till week 52 confirmed by all the above endpoints. The reduction in HbA1c at week 52 was -1.39% (-1.58 to -1.19) [-15.14 [-17.28 to -13.01] mmol/mol], which was even greater than that at week 24. There was also a significant improvement in HOMA-insulin resistance (p = 0.004) at week 52 compared with the baseline value. For the placebo→visepegenatide group, which received visepegenatide in the extended treatment period, a notable decrease in HbA1c at week 52 compared to baseline was observed. The change from baseline in HbA1c was -1.49% (-1.68 to -1.30) [-16.27 [-18.37 to -14.16] mmol/mol]. The outcome was in the same direction as the visepegenatide group from the double-blind treatment period. Comprehensive benefits of visepegenatide including weight loss, improvement in lipid profile, and reduction in blood pressure have been demonstrated in this study. Visepegenatide reduced the body weight in a BMI-dependent manner that was prominent in BMI ˃32 kg/m with a mean (SD) reduction of -4.77 (13.94) kg at week 52 (p < 0.05). Incidences of gastrointestinal adverse events were less common than other weekly GLP-1 RA in the market, and most of the adverse events were mild and moderate in nature, occurring in the first weeks of the treatment, and were transient. No serious hypoglycaemia or grade 2 hypoglycaemia (blood glucose: ≤3 mmol/L) was reported during the study.
INTERPRETATION
As a monotherapy, visepegenatide provided rapid without the risk of hypoglycaemia, significant, and sustainable glycaemic control by improving islet β-cell function and insulin resistance. Treatment with visepegenatide induced early treatment response in reducing HbA1c and maintaining glycaemic control for 52 weeks. Meanwhile, visepegenatide provided a comprehensive benefit in body weight loss, lipids, and blood pressure reduction. Visepegenatide had a better safety profile than other weekly GLP-1 RA in participants with T2DM even without the requirement of dose titration. Visepegenatide would provide an optimal treatment approach with its high benefit and low-risk balance.
FUNDING
PegBio Co., Ltd.
PubMed: 38948164
DOI: 10.1016/j.lanwpc.2024.101101 -
Frontiers in Network Physiology 2024Algorithms for the detection of COVID-19 illness from wearable sensor devices tend to implicitly treat the disease as causing a stereotyped (and therefore recognizable)...
Algorithms for the detection of COVID-19 illness from wearable sensor devices tend to implicitly treat the disease as causing a stereotyped (and therefore recognizable) deviation from healthy physiology. In contrast, a substantial diversity of bodily responses to SARS-CoV-2 infection have been reported in the clinical milieu. This raises the question of how to characterize the diversity of illness manifestations, and whether such characterization could reveal meaningful relationships across different illness manifestations. Here, we present a framework motivated by information theory to generate quantified maps of illness presentation, which we term "manifestations," as resolved by continuous physiological data from a wearable device (Oura Ring). We test this framework on five physiological data streams (heart rate, heart rate variability, respiratory rate, metabolic activity, and sleep temperature) assessed at the time of reported illness onset in a previously reported COVID-19-positive cohort (N = 73). We find that the number of distinct manifestations are few in this cohort, compared to the space of all possible manifestations. In addition, manifestation frequency correlates with the rough number of symptoms reported by a given individual, over a several-day period prior to their imputed onset of illness. These findings suggest that information-theoretic approaches can be used to sort COVID-19 illness manifestations into types with real-world value. This proof of concept supports the use of information-theoretic approaches to map illness manifestations from continuous physiological data. Such approaches could likely inform algorithm design and real-time treatment decisions if developed on large, diverse samples.
PubMed: 38948084
DOI: 10.3389/fnetp.2024.1211413 -
Theranostics 2024Current treatments for ocular angiogenesis primarily focus on blocking the activity of vascular endothelial growth factor (VEGF), but unfavorable side effects and...
Current treatments for ocular angiogenesis primarily focus on blocking the activity of vascular endothelial growth factor (VEGF), but unfavorable side effects and unsatisfactory efficacy remain issues. The identification of novel targets for anti-angiogenic treatment is still needed. We investigated the role of tsRNA-1599 in ocular angiogenesis using endothelial cells, a streptozotocin (STZ)-induced diabetic model, a laser-induced choroidal neovascularization model, and an oxygen-induced retinopathy model. CCK-8 assays, EdU assays, transwell assays, and matrigel assays were performed to assess the role of tsRNA-1599 in endothelial cells. Retinal digestion assays, Isolectin B4 (IB4) staining, and choroidal sprouting assays were conducted to evaluate the role of tsRNA-1599 in ocular angiogenesis. Transcriptomic analysis, metabolic analysis, RNA pull-down assays, and mass spectrometry were utilized to elucidate the mechanism underlying angiogenic effects mediated by tsRNA-1599. tsRNA-1599 expression was up-regulated in experimental ocular angiogenesis models and endothelial cells in response to angiogenic stress. Silencing of tsRNA-1599 suppressed angiogenic effects in endothelial cells and inhibited pathological ocular angiogenesis . Mechanistically, tsRNA-1599 exhibited little effect on VEGF signaling but could cause reduced glycolysis and NAD/NADH production in endothelial cells by regulating the expression of HK2 gene through interacting with YBX1, thus affecting endothelial effects. Targeting glycolytic reprogramming of endothelial cells by a tRNA-derived small RNA represents an exploitable therapeutic approach for ocular neovascular diseases.
PubMed: 38948065
DOI: 10.7150/thno.96946 -
World Journal of Clinical Pediatrics Jun 2024This editorial discusses a case-control study by Ibrahim published in the recent issue of the . Childhood bronchial asthma is a chronic inflammatory respiratory...
This editorial discusses a case-control study by Ibrahim published in the recent issue of the . Childhood bronchial asthma is a chronic inflammatory respiratory disease. It was found that an increase in oxidative stress leads to a decrease in antioxidants causing oxidative damage to mitochondrial respiratory chain complexes resulting in the inflammation of the airway, hypersecretion of mucus causing a cascade of clinical manifestations ranging from recurrent episodes of coughing, wheezing, and breathlessness to shortness of breath. Since oxidative stress mediates the inflammatory response in asthma, the supplementation of anti-oxidants can be one strategy to manage this disease. Zinc is one such antioxidant that has attracted much attention about asthma and airway inflammation. Zinc is a crucial trace element for human metabolism that helps to regulate gene expression, enzyme activity, and protein structure. Apart from zinc, free serum ferritin levels are also elevated in case of inflammation. Several previous studies found that ferritin levels may also help determine the pathology of disease and predict prognosis in addition to tracking disease activity. However, this study's results were different from the findings of the previous studies and the zinc levels did not show a significant difference between asthmatic children and non-asthmatic children but ferritin levels were significantly high in asthmatic children as compared to the controls. Hence, the possible role of the biochemical nutritional assessment including zinc and ferritin as biomarkers for asthma severity should be assessed in the future.
PubMed: 38947994
DOI: 10.5409/wjcp.v13.i2.91699 -
World Journal of Clinical Pediatrics Jun 2024Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and repetitive behaviors. Metabolomic profiling has...
BACKGROUND
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and repetitive behaviors. Metabolomic profiling has emerged as a valuable tool for understanding the underlying metabolic dysregulations associated with ASD.
AIM
To comprehensively explore metabolomic changes in children with ASD, integrating findings from various research articles, reviews, systematic reviews, meta-analyses, case reports, editorials, and a book chapter.
METHODS
A systematic search was conducted in electronic databases, including PubMed, PubMed Central, Cochrane Library, Embase, Web of Science, CINAHL, Scopus, LISA, and NLM catalog up until January 2024. Inclusion criteria encompassed research articles (83), review articles (145), meta-analyses (6), systematic reviews (6), case reports (2), editorials (2), and a book chapter (1) related to metabolomic changes in children with ASD. Exclusion criteria were applied to ensure the relevance and quality of included studies.
RESULTS
The systematic review identified specific metabolites and metabolic pathways showing consistent differences in children with ASD compared to typically developing individuals. These metabolic biomarkers may serve as objective measures to support clinical assessments, improve diagnostic accuracy, and inform personalized treatment approaches. Metabolomic profiling also offers insights into the metabolic alterations associated with comorbid conditions commonly observed in individuals with ASD.
CONCLUSION
Integration of metabolomic changes in children with ASD holds promise for enhancing diagnostic accuracy, guiding personalized treatment approaches, monitoring treatment response, and improving outcomes. Further research is needed to validate findings, establish standardized protocols, and overcome technical challenges in metabolomic analysis. By advancing our understanding of metabolic dysregulations in ASD, clinicians can improve the lives of affected individuals and their families.
PubMed: 38947988
DOI: 10.5409/wjcp.v13.i2.92737 -
Journal of Extracellular Biology Jul 2024Neuroinflammation is initiated through microglial activation and cytokine release which can be induced through lipopolysaccharide treatment (LPS) leading to a...
Neuroinflammation is initiated through microglial activation and cytokine release which can be induced through lipopolysaccharide treatment (LPS) leading to a transcriptional cascade culminating in the differential expression of target proteins. These differentially expressed proteins can then be packaged into extracellular vesicles (EVs), a form of cellular communication, further propagating the neuroinflammatory response over long distances. Despite this, the EV proteome in the brain, following LPS treatment, has not been investigated. Brain tissue and brain derived EVs (BDEVs) isolated from the cortex of LPS-treated mice underwent thorough characterisation to meet the minimal information for studies of extracellular vesicles guidelines before undergoing mass spectrometry analysis to identify the differentially expressed proteins. Fourteen differentially expressed proteins were identified in the LPS brain tissue samples compared to the controls and 57 were identified in the BDEVs isolated from the LPS treated mice compared to the controls. This included proteins associated with the initiation of the inflammatory response, epigenetic regulation, and metabolism. These results allude to a potential link between small EV cargo and early inflammatory signalling.
PubMed: 38947878
DOI: 10.1002/jex2.165 -
Cureus May 2024Advanced glycation end products (AGEs) accumulate in the brain, leading to neurodegenerative conditions such as Alzheimer's disease (AD). The pathophysiology of AD is... (Review)
Review
Advanced glycation end products (AGEs) accumulate in the brain, leading to neurodegenerative conditions such as Alzheimer's disease (AD). The pathophysiology of AD is influenced by receptors for AGEs and toll-like receptor 4 (TLR4). Protein glycation results in irreversible AGEs through a complicated series of reactions involving the formation of Schiff's base, the Amadori reaction, followed by the Maillard reaction, which causes abnormal brain glucose metabolism, oxidative stress, malfunctioning mitochondria, plaque deposition, and neuronal death. Amyloid plaque and other stimuli activate macrophages, which are crucial immune cells in AD development, triggering the production of inflammatory molecules and contributing to the disease's pathogenesis. The risk of AD is doubled by risk factors for atherosclerosis, dementia, advanced age, and type 2 diabetic mellitus (DM). As individuals age, the prevalence of neurological illnesses such as AD increases due to a decrease in glyoxalase levels and an increase in AGE accumulation. Insulin's role in proteostasis influences hallmarks of AD-like tau phosphorylation and amyloid β peptide clearance, affecting lipid metabolism, inflammation, vasoreactivity, and vascular function. The high-mobility group box 1 (HMGB1) protein, a key initiator and activator of a neuroinflammatory response, has been linked to the development of neurodegenerative diseases such as AD. The TLR4 inhibitor was found to improve memory and learning impairment and decrease Aβ build-up. Therapeutic research into anti-glycation agents, receptor for advanced glycation end products (RAGE) inhibitors, and AGE breakers offers hope for intervention strategies. Dietary and lifestyle modifications can also slow AD progression. Newer therapeutic approaches targeting AGE-related pathways are needed.
PubMed: 38947632
DOI: 10.7759/cureus.61373 -
IScience Jun 2024A diet lacking dietary fibers promotes the expansion of gut microbiota members that can degrade host glycans, such as those on mucins. The microbial foraging on mucin...
A diet lacking dietary fibers promotes the expansion of gut microbiota members that can degrade host glycans, such as those on mucins. The microbial foraging on mucin has been associated with disruptions of the gut-protective mucus layer and colonic inflammation. Yet, it remains unclear how the co-utilization of mucin and dietary fibers affects the microbiota composition and metabolic activity. Here, we used 14 dietary fibers and porcine colonic and gastric mucins to study the dynamics of mucin and dietary fiber utilization by the human fecal microbiota . Combining metaproteome and metabolites analyses revealed the central role of the genus in the utilization of complex fibers together with mucin while was the main utilizer of sole porcine colonic mucin but not gastric mucin. This study gives a broad overview of the colonic environment in response to dietary and host glycan availability.
PubMed: 38947523
DOI: 10.1016/j.isci.2024.110093 -
IScience Jun 2024The constrained energy model posits that the increased total daily energy expenditure (TDEE) in response to exercise is often less than the energy cost of the exercise...
The constrained energy model posits that the increased total daily energy expenditure (TDEE) in response to exercise is often less than the energy cost of the exercise prescribed. The mechanisms behind this phenomenon, coined "exercise-related energy compensation" (ExEC), are poorly understood, and it is unknown if ExEC is coupled with metabolic adaptation. Using a randomized controlled 24-week exercise intervention, individuals who demonstrated ExEC were identified. Changes to all components of TDEE and metabolic adaptation were assessed using doubly labeled water over 14 days and room calorimetry over 24-h 48% of individuals exhibited ExEC (-308 ± 158 kcals/day). There were no statistically significant differences in sex, age, or BMI between ExEC and non-ExEC. ExEC was associated with baseline TDEE (r = -0.50, = 0.006). There were no statistically significant differences in metabolic adaptations for 24 h, sleep, or resting expenditures. These findings reveal that ExEC occurs independent of metabolic adaptation in sedentary components of EE.
PubMed: 38947494
DOI: 10.1016/j.isci.2024.109842 -
Journal of Cancer 2024TMEM132A is a transmembrane protein that regulates gastric cancer cell malignancy and overall survival in bladder cancer patients. However, while some studies have...
TMEM132A is a transmembrane protein that regulates gastric cancer cell malignancy and overall survival in bladder cancer patients. However, while some studies have investigated the involvement of TMEM132A in specific cancers, further systematic studies are required to elucidate its specific mechanisms of action in different cancer types. We investigated the pan-cancer role of TMEM132A using several databases. We analyzed TMEM132A expression and its correlation with clinical survival, immune checkpoints, tumor stemness score, prognostic value, immunomodulators, genomic profiles, immunological characteristics, immunotherapy and functional enrichment. First, it was observed that TMEM132A expression levels were higher in the majority of tumors compared to non-tumor tissues. In addition, high TMEM132A expression may have a higher prognostic value in some cancers. Furthermore, TMEM132A was significantly associated with immune checkpoints, immunomodulators, prognosis, immunomodulatory genes, tumor stemness score, cell function status and immune infiltration in most tumors. Further analysis of TMEM132A-related gene enrichment, mutation sites and types, RNA modification and genomic heterogeneity showed that the major mutations of TMEM132A were missense mutations and that TMEM132A plays a very important role in UCEC, LUAD and LIHC. Finally, these results suggest that high TMEM132A expression may be associated with a better response to specific immunotherapies. : This comprehensive study uncovers an important function for TMEM132A in different types of cancer. It also has the potential to identify TMEM132A as a potential biomarker for predicting treatment response. This may help us to better understand how TMEM132A plays a role in cancer and provide valuable insights for developing personalised treatments.
PubMed: 38947398
DOI: 10.7150/jca.96396