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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 -
Plastic and Reconstructive Surgery.... Mar 2024This study presents a case of thumb replantation performed despite several risk factors: age, comorbidities, and trauma mechanism are major adverse prognostic factors...
BACKGROUND
This study presents a case of thumb replantation performed despite several risk factors: age, comorbidities, and trauma mechanism are major adverse prognostic factors directly impacting thumb replantation. Most of the literature backs up this claim that a thumb that works, even partially, is a better outcome for the patient than amputation.
METHODS
We performed thumb replantation on a 94-year-old patient with type 2 diabetes mellitus who arrived at the emergency department with a thumb avulsion due to a dog bite. The intraoperative indocyanine green fluorescence angiography method aided us in carrying out the operation.
RESULTS
We successfully used indocyanine green angiography intraoperatively to guide surgical debridement and evaluate the efficacy of anastomosis and reperfusion of the replanted segment during surgery. Two months after the operation, the patient had regained satisfactory hand function.
CONCLUSIONS
Although indocyanine green angiography is not a technology created for revascularization procedures, it is instrumental in assessing vascular function and predicting a successful outcome. Given its undeniable potential, more research is needed on the possibility of widespread use in hand surgery and its indications.
PubMed: 38948159
DOI: 10.1097/GOX.0000000000005670 -
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.
Topics: Animals; Glycolysis; Mice; Endothelial Cells; Choroidal Neovascularization; Humans; Y-Box-Binding Protein 1; Angiogenesis Inhibitors; Hexokinase; Diabetes Mellitus, Experimental; Mice, Inbred C57BL; Male; Disease Models, Animal; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Diabetic Retinopathy; Human Umbilical Vein Endothelial Cells; RNA, Small Untranslated
PubMed: 38948065
DOI: 10.7150/thno.96946 -
International Journal of Hypertension 2024Cardiovascular risk factors such as obesity, type 2 diabetes, hypertension, smoking, and dyslipidemia enfold heart disease morbimortality. Diagonal earlobe crease has...
Traditional Cardiovascular Risk Factors Associated with Diagonal Earlobe Crease (Frank Sign) in Mexican Adults: Aging, Obesity, Arterial Hypertension, and Being Male Are the Most Important.
INTRODUCTION
Cardiovascular risk factors such as obesity, type 2 diabetes, hypertension, smoking, and dyslipidemia enfold heart disease morbimortality. Diagonal earlobe crease has been proposed as a prognostic marker of extension and severity of illness in patients with acute coronary syndrome. But its usefulness remains unclear in patients with or without coronary disease.
METHODS
A case-control study was carried out on a total of 805 patients with and without cardiovascular risk factors or acute coronary syndrome. Univariate and multivariate binary logistic regression analyses were used to determine the probability of having diagonal earlobe crease with the presence of cardiovascular risk factors and acute coronary syndrome. Data were summarized as odds ratio with 95% confidence intervals and values.
RESULTS
An unadjusted (univariate) analysis showed that being male, being older than 55 years, obesity, type 2 diabetes mellitus, arterial hypertension, smoking, and dyslipidemia, as well as having acute coronary syndrome, were associated with the presence of diagonal earlobe crease. The multivariate analysis showed that men (OR 1.6, 95% IC 1.1-2.4, =0.007), being over 55 years old (OR 4.8, 95% IC 3.2-7.2, < 0.001), being obese (OR 2.1, 95% IC 1.4-3.1, < 0.001), having arterial hypertension (1.5, 95% IC 1.1-2.3, =0.025), or suffering from acute coronary syndrome (OR 5.3, 95% IC 2.5-11.1, < 0.001), were independent factors associated with diagonal earlobe crease. The rest of cardiovascular risk factors were not relevant in the multivariate model.
CONCLUSIONS
In Mexican adults, having an acute coronary syndrome is not the only factor associated with diagonal earlobe crease but also being a man, older than 55 years, having high blood pressure and obesity. Diagonal earlobe crease may simply be caused by changes in the skin and connective tissues of the ears because of the aging process, obesity, and/or being male. These factors, by themselves, enfold cardiovascular risk due to well-known pathophysiological causes.
PubMed: 38948003
DOI: 10.1155/2024/5598134 -
World Journal of Clinical Pediatrics Jun 2024Over the past 20 years, the incidence and prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents have increased, particularly in racial and ethnic... (Review)
Review
Over the past 20 years, the incidence and prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents have increased, particularly in racial and ethnic minorities. Despite the rise in T2DM in children and adolescents, the pathophysiology and progression of disease in this population are not clearly understood. Youth-onset T2DM has a more adverse clinical course than is seen in those who develop T2DM in adulthood or those with T1DM. Furthermore, the available therapeutic options are more limited for children and adolescents with T2DM compared to adult patients, mostly due to the challenges of implementing clinical trials. A better understanding of the mechanisms underlying the de-velopment and aggressive disease phenotype of T2DM in youth is important to finding effective prevention and management strategies. This review highlights the key evidence about T2DM in children and adolescents and its current burden and challenges both in clinical care and research activities.
PubMed: 38947996
DOI: 10.5409/wjcp.v13.i2.91587 -
World Journal of Clinical Pediatrics Jun 2024Prediabetes in children and adolescents is on the rise which has drawn significant attention over the past decade. It is an early warning sign of the underlying...
Prediabetes in children and adolescents is on the rise which has drawn significant attention over the past decade. It is an early warning sign of the underlying pathophysiological changes which in due course of time might compound into type II diabetes mellitus. The incidence of prediabetes in adolescents ranges from 4%-23% which is alarmingly high and requires active intervention from the system. We have discussed early identification of high-risk patients, prompt screening and active intervention to manage this growing problem.
PubMed: 38947990
DOI: 10.5409/wjcp.v13.i2.92127 -
Frontiers in Oncology 2024Type 2 diabetes mellitus (T2DM) was associated with digestive system tumors. We analyzed publicly available data from GWAS studies using Mendelian randomization methods...
INTRODUCTION
Type 2 diabetes mellitus (T2DM) was associated with digestive system tumors. We analyzed publicly available data from GWAS studies using Mendelian randomization methods to clarify its causal relationship and mechanisms. Five common digestive system tumors and four diabetes-related phenotypes were included.
METHODS
Inverse variance weighted method was the main analytical method. Meta-analysis was used to summarize results of multiple data sources. Horizontal pleiotropy was tested using Egger-intercept method and validated by MRPRESSO method. Heterogeneity and sensitivity analysis were conducted by Cochran's Q test and leave-one-out method, respectively.
RESULTS
T2DM is associated with a reduced risk of esophageal (OR: 0.77, 95% CI: 0.71 to 0.83, P< 0.001), gastric (OR: 0.87, 95% CI: 0.84 to 0.90, P< 0.001) and colorectal cancer (OR: 0.88, 95% CI: 0.85 to 0.91, P< 0.001) and hepatocellular carcinoma (OR: 0.92, 95% CI: 0.86 to 0.97, P = 0.005) and an increased risk of pancreatic cancer (OR: 1.92, 95% CI: 1.47 to 2.50, P< 0.001) in East Asian population. T2DM causes decreased fasting insulin levels (OR = 0.966, 95% CI: 0.95 to 0.98, P< 0.001) and increased glycated hemoglobin levels (OR=1.41, 95% CI: 1.39 to 1.44, P<0.001). Elevated fasting insulin levels increase the risk of esophageal cancer (OR = 10.35, 95% CI: 1.10 to 97.25, P = 0.041), while increased glycated hemoglobin levels increase pancreatic cancer risk (OR=2.33, 95% CI: 1.37 to 3.97, P=0.002) but decrease gastric cancer risk (OR=0.801, 95% CI: 0.65 to 0.99, P=0.044).
CONCLUSION
T2DM is associated with a reduced risk of esophageal, gastric and colorectal cancer and hepatocellular carcinoma in East Asian populations. The causal relationships between T2DM with esophageal and gastric cancer are partially mediated by decreased fasting insulin and increased glycated hemoglobin levels, respectively. T2DM indirectly increases the risk of pancreatic cancer by increasing glycated hemoglobin levels.
PubMed: 38947888
DOI: 10.3389/fonc.2024.1327154 -
Cureus May 2024Diabetic autonomic neuropathy (DAN) is a prevalent yet often overlooked complication of diabetes mellitus (DM), impacting multiple organs and substantially elevating the...
Evaluating Yoga-Based Intervention Versus the American Diabetes Association Exercise Regimen in Conjunction With Standard Care for Autonomic Neuropathy in Diabetes Mellitus: An Exploratory Clinical Trial.
INTRODUCTION
Diabetic autonomic neuropathy (DAN) is a prevalent yet often overlooked complication of diabetes mellitus (DM), impacting multiple organs and substantially elevating the risk of morbidity and mortality. This study aimed to assess the effectiveness of yoga-based intervention (YBI) compared to the American Diabetes Association exercise regimen (ADA Ex. Regime) and standard care for treating autonomic neuropathy in type 2 DM.
METHODS
This open-label exploratory clinical trial featured two parallel study arms: Group A (Intervention), which received YBI alongside standard care, and Group B, which adhered to the ADA Ex. Regime in conjunction with standard care. A total of 80 participants aged 35-60, diagnosed with type 2 DM and autonomic neuropathy, were equally allocated to both groups. Data collection included nerve conduction velocity (NCV) tests, autonomic function tests (AFTs), as well as evaluations of depression and quality of life.
RESULTS
YBI demonstrated a drop in parasympathetic tone compared to the ADA Ex. Regime. Following a six-month intervention, the sympathetic activity indicator (SD2) exhibited a significantly lower value in the YBI group than in the ADA Ex. Regime group, indicating a positive effect (p < 0.05), while the ADA Ex. Regime showed more improvement in certain areas of NCV (e.g., left and right peroneal NCV, right and left peroneal F-latency), notable differences were observed in alkaline phosphatase levels, depression scores, and WHO-5 wellness, all reaching statistical significance at p < 0.05.
CONCLUSIONS
The study findings observed that a 24-week YBI significantly reduced in symptoms of diabetic neuropathy and stress. Although the ADA Ex. Regime demonstrated greater improvement in specific aspects of NCV compared to YBI, YBI outperformed the ADA Ex. Regime in enhancing WHO-5 wellness and reducing depression symptoms.
PubMed: 38947647
DOI: 10.7759/cureus.61329 -
Cureus May 2024Gastrointestinal (GI) endoscopies are essential for detecting and treating various digestive tract problems. While typically safe, these treatments can entail the risk...
Gastrointestinal (GI) endoscopies are essential for detecting and treating various digestive tract problems. While typically safe, these treatments can entail the risk of severe adverse events (SAEs), especially in individuals with a low body mass index (BMI). The current study aimed to evaluate whether post-endoscopy SAEs are more common in patients with low BMI and find risk factors for serious adverse outcomes in Saudi Arabian patients from Khamis Mushait, Aseer region, Saudi Arabia. The data of 398 adult patients with abdominal endoscopies between April and November 2023 were analyzed. Patients were divided into two groups: low BMI (BMI ≤ 18.5) and control (18.5 ≤ BMI ≤ 30). They were matched for age, gender, comorbidities, endoscopy type, and other pertinent characteristics. Low-BMI patients (Group I, n = 108) were substantially younger and had lower levels of albumin and total protein than the control group (Group II, n = 209). Comorbidities varied between groups, with diabetes mellitus more prevalent in Group II and inflammatory bowel disease (IBD) more commonplace in Group I. Treatment options also differed, with Group I receiving more biological treatments, steroids, and feeding tubes. Endoscopic procedures and indications were comparable among groups, with no significant variations in post-endoscopy complications. The endoscopy results varied from gastritis to colon malignancy, with no SAEs recorded in either group. Unlike earlier findings, this study found no higher incidence of SAEs in low-BMI individuals having abdominal endoscopy. This might be because of the restricted guidelines of different medical authorities, including clear informed consent that illustrates any risks, benefits, alternatives, sedation plan, and potential diagnostic or therapeutic interventions. Also, professional endoscopists and consultants who ensure adequate visualization of the GI mucosa, using mucosal cleansing and insufflation as necessary, should avoid any risk of abdominal hemorrhage. These findings highlight the significance of personalized risk assessment and pre-procedural optimization, including nutritional assistance, in this patient population. More prospective research with larger sample sizes is needed to validate these findings and create targeted techniques for improving outcomes in individuals with a low BMI having endoscopic operations.
PubMed: 38947624
DOI: 10.7759/cureus.61276 -
Cureus May 2024Background Hypertension significantly contributes to the severity, prolonged hospitalization, the need for intensive care, and mortality of COVID-19 patients. However,...
Background Hypertension significantly contributes to the severity, prolonged hospitalization, the need for intensive care, and mortality of COVID-19 patients. However, the data is still evolving. This study investigated the predictors of severity among hypertensive COVID-19 patients. Methodology This cohort study included 333 hospitalized hypertensive COVID-19 patients at the Indus Hospital, Karachi, Pakistan, from April 2021 to October 2021. The study evaluated the clinical features, antihypertensive therapy, and predictors of severity. A multivariable binary logistic regression model was used to determine severity predictors using IBM SPSS Statistics for Windows, Version 27.0 (Released 2020; IBM Corp., Armonk, NY, USA). Results The majority of hypertensive COVID-19 patients were females (54.7%), aged <65 years (55.8%), and coexisted with diabetes mellitus (56.5%). The independent predictors of severity were male (aOR 2.65, 95% CI, 1.08-6.51; p < 0.033), fever (aOR 3.52, 95% CI, 1.24-9.92; p = 0.017), shortness of breath (aOR 4.49, 95% CI, 1.73-11.63; p = 0.002), oxygen saturation (<90%) (aOR 87.39, 95% CI, 19.15-398.75; p < 0.001), and D-dimer (>0.5 mcg/ml) (aOR 3.03, 95% CI, 1.19-7.71; p = 0.020). Conclusions Our study concluded that males with fever before admission, shortness of breath, lower oxygen saturation, and elevated D-dimer are the predictors of severity among hypertensive COVID-19 patients.
PubMed: 38947593
DOI: 10.7759/cureus.61356