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Frontiers in Endocrinology 2024Lu-oxodotreotide peptide receptor therapy (LuPRRT) is an efficient treatment for midgut neuroendocrine tumors (NETs) of variable radiological response. Several clinical,...
BACKGROUND
Lu-oxodotreotide peptide receptor therapy (LuPRRT) is an efficient treatment for midgut neuroendocrine tumors (NETs) of variable radiological response. Several clinical, biological, and imaging parameters may be used to establish a relative disease prognosis but none is able to predict early efficacy or toxicities. We investigated expression levels for mRNA and miRNA involved in radiosensitivity and tumor progression searching for correlations related to patient outcome during LuPRRT therapy.
METHODS
Thirty-five patients received LuPRRT for G1/G2 midgut NETs between May 2019 and September 2021. Peripheral blood samples were collected prior to irradiation, before and 48 h after the second and the fourth LuPRRT, and at 6-month follow-up. Multiple regression analyses and Pearson correlations were performed to identify the miRNA/mRNA signature that will best predict response to LuPRRT.
RESULTS
Focusing on four mRNAs and three miRNAs, we identified a miRNA/mRNA signature enabling the early identification of responders to LuPRRT with significant reduced miRNA/mRNA expression after the first LuPRRT administration for patients with progressive disease at 1 year ( < 0.001). The relevance of this signature was reinforced by studying its evolution up to 6 months post-LuPRRT. Moreover, nadir absolute lymphocyte count within the first 2 months after the first LuPRRT administration was significantly related to low miRNA/mRNA expression level ( < 0.05) for patients with progressive disease.
CONCLUSION
We present a pilot study exploring a miRNA/mRNA signature that correlates with early hematologic toxicity and therapeutic response 12 months following LuPRRT. This signature will be tested prospectively in a larger series of patients.
Topics: Humans; Neuroendocrine Tumors; Male; Female; MicroRNAs; Middle Aged; Intestinal Neoplasms; RNA, Messenger; Aged; Follow-Up Studies; Adult; Prognosis; Biomarkers, Tumor; Somatostatin; Receptors, Peptide; Radiopharmaceuticals; Lutetium; Radioisotopes
PubMed: 38948517
DOI: 10.3389/fendo.2024.1385079 -
Frontiers in Pharmacology 2024Heart failure and cognitive impairment emerge as public health problems that need to be addressed due to the aging global population. The conditions that often coexist... (Review)
Review
Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, anti-diabetic drugs in heart failure and cognitive impairment: potential mechanisms of the protective effects.
Heart failure and cognitive impairment emerge as public health problems that need to be addressed due to the aging global population. The conditions that often coexist are strongly related to advancing age and multimorbidity. Epidemiological evidence indicates that cardiovascular disease and neurodegenerative processes shares similar aspects, in term of prevalence, age distribution, and mortality. Type 2 diabetes increasingly represents a risk factor associated not only to cardiometabolic pathologies but also to neurological conditions. The pathophysiological features of type 2 diabetes and its metabolic complications (hyperglycemia, hyperinsulinemia, and insulin resistance) play a crucial role in the development and progression of both heart failure and cognitive dysfunction. This connection has opened to a potential new strategy, in which new classes of anti-diabetic medications, such as glucagon-like peptide-1 receptor (GLP-1R) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, are able to reduce the overall risk of cardiovascular events and neuronal damage, showing additional protective effects beyond glycemic control. The pleiotropic effects of GLP-1R agonists and SGLT2 inhibitors have been extensively investigated. They exert direct and indirect cardioprotective and neuroprotective actions, by reducing inflammation, oxidative stress, ions overload, and restoring insulin signaling. Nonetheless, the specificity of pathways and their contribution has not been fully elucidated, and this underlines the urgency for more comprehensive research.
PubMed: 38948473
DOI: 10.3389/fphar.2024.1422740 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024Kisspeptin, a protein encoded by the gene, functions as an essential factor in suppressing tumor growth. The intricate orchestration of cellular processes such as...
OBJECTIVE
Kisspeptin, a protein encoded by the gene, functions as an essential factor in suppressing tumor growth. The intricate orchestration of cellular processes such as proliferation and differentiation is governed by the Notch1/Akt/Foxo1 signaling pathway, which assumes a central role in maintaining cellular homeostasis. In the specific context of this investigation, the focal point lies in a meticulous exploration of the intricate mechanisms underlying the regulatory effect of kisspeptin on the process of endometrial decidualization. This investigation delves into the interplay between kisspeptin and the Notch1/Akt/Foxo1 signaling pathway, aiming to elucidate its significance in the pathophysiology of recurrent spontaneous abortion (RSA).
METHODS
We enrolled a cohort comprising 45 individuals diagnosed with RSA, who were admitted to the outpatient clinic of the Reproductive Center at the Second Affiliated Hospital of Soochow University between June 2020 and December 2020. On the other hand, an additional group of 50 women undergoing elective abortion at the outpatient clinic of the Family Planning Department during the same timeframe was also included. To comprehensively assess the molecular landscape, Western blot and RT-qPCR were performed to analyze the expression levels of kisspeptin (and its gene ), IGFBP1 (an established marker of decidualization), Notch1, Akt, and Foxo1 within the decidua. Human endometrial stromal cells (hESC) were given targeted interventions, including treatment with siRNA to disrupt or exposure to kisspeptin10 (the bioactive fragment of kisspeptin), and were subsequently designated as the siKP group or the KP10 group, respectively. A control group comprised hESC was transfected with blank siRNA, and cell proliferation was meticulously evaluated with CCK8 assay. Following induction for decidualization across the three experimental groups, immunofluorescence assay was performed to identify differences in Notch1 expression and decidualization morphology between the siKP and the KP10 groups. Furthermore, RT-qPCR and Western blot were performed to gauge the expression levels of IGFBP1, Notch1, Akt, and Foxo1 across the three cell groups. Subsequently, decidualization was induced in hESC by adding inhibitors targeting Notch1, Akt, and Foxo1. The expression profiles of the aforementioned proteins and genes in the four groups were then examined, with hESC induced for decidualization without adding inhibitors serving as the normal control group. To establish murine models of normal pregnancy (NP) and RSA, CBA/J×BALB/c and CBA/J×DBA/2 mice were used. The mice were respectively labeled as the NP model and RSA model. The experimental groups received intraperitoneal injections of kisspeptin10 and kisspeptin234 (acting as a blocker) and were designated as RSA-KP10 and NP-KP234 groups. On the other hand, the control groups received intraperitoneal injections of normal saline (NS) and were referred to as RSA-NS and NP-NS groups. Each group comprised 6 mice, and uterine tissues from embryos at 9.5 days of gestation were meticulously collected for observation of embryo absorption and examination of the expression of the aforementioned proteins and genes.
RESULTS
The analysis revealed that the expression levels of kisspeptin, IGFBP1, Notch1, Akt, and Foxo1 were significantly lower in patients diagnosed with RSA compared to those in women with NP (<0.01 for kisspeptin and <0.05 for IGFBP1, Notch1, Akt, and Foxo1). After the introduction of kisspeptin10 to hESC, there was an observed enhancement in decidualization capability. Subsequently, the expression levels of Notch1, Akt, and Foxo1 showed an increase, but they decreased after interference with . Through immunofluorescence analysis, it was observed that proliferative hESC displayed a slender morphology, but they transitioned to a rounder and larger morphology post-decidualization. Concurrently, the expression of Notch1 increased, suggesting enhanced decidualization upon the administration of kisspeptin10, but the expression decreased after interference with . Further experimentation involved treating hESC with inhibitors specific to Notch1, Akt, and Foxo1 separately, revealing a regulatory sequence of Notch1/Akt/Foxo1 (<0.05). In comparison to the NS group, NP mice administered with kisspeptin234 exhibited increased fetal absorption rates (<0.001) and decreased expression of IGFBP1, Notch1, Akt, and Foxo1 (<0.05). Conversely, RSA mice administered with kisspeptin10 demonstrated decreased fetal absorption rates (<0.001) and increased expression levels of the aforementioned molecules (<0.05).
CONCLUSION
It is suggested that kisspeptin might exert its regulatory influence on the process of decidualization through the modulation of the Notch1/Akt/Foxo1 signaling cascade. A down-regulation of the expression levels of kisspeptin could result in suboptimal decidualization, which in turn might contribute to the development or progression of RSA.
Topics: Female; Forkhead Box Protein O1; Humans; Proto-Oncogene Proteins c-akt; Endometrium; Signal Transduction; Decidua; Pregnancy; Receptor, Notch1; Abortion, Habitual; Kisspeptins; Adult; Insulin-Like Growth Factor Binding Protein 1; Cell Proliferation
PubMed: 38948287
DOI: 10.12182/20240560206 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024As a member of the tumor necrosis factor receptor family, osteoprotegerin (OPG) is highly expressed in adults in the lung, heart, kidney, liver, spleen, thymus,... (Review)
Review
As a member of the tumor necrosis factor receptor family, osteoprotegerin (OPG) is highly expressed in adults in the lung, heart, kidney, liver, spleen, thymus, prostate, ovary, small intestines, thyroid gland, lymph nodes, trachea, adrenal gland, the testis, and bone marrow. Together with the receptor activator of nuclear factor-κB (RANK) and the receptor activator of nuclear factor-κB ligand (RANKL), it forms the RANK/RANKL/OPG pathway, which plays an important role in the molecular mechanism of the development of various diseases. MicroRNAs (miRNAs) are a class of endogenous non-coding RNAs performing regulatory functions in eukaryotes, with a size of about 20-25 nucleotides. miRNA genes are transcribed into primary transcripts by RNA polymerase, bind to RNA-induced silencing complexes, identify target mRNAs through complementary base pairing, with a single miRNA being capable of targeting hundreds of mRNAs, and influence the expression of many genes through pathways involved in functional interactions. In recent years, a large number of studies have been done to explore the mechanism of action of miRNA in diseases through miRNA isolation, miRNA quantification, miRNA spectrum analysis, miRNA target detection, and regulation of miRNA levels, and other technologies. It was found that miRNA can play a key role in the pathogenesis of osteoporosis, rheumatoid arthritis, and other diseases by targeting OPG. The purpose of this review is to explore the interaction between miRNA and OPG in various diseases, and to propose new ideas for studying the mechanism of action of OPG in diseases.
Topics: Osteoprotegerin; Humans; MicroRNAs; Receptor Activator of Nuclear Factor-kappa B; RANK Ligand; Neoplasms; Animals; Signal Transduction; Arthritis, Rheumatoid
PubMed: 38948285
DOI: 10.12182/20240560607 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024To investigate the roles of histone H3K27me3 methylation and its regulatory enzymes JMJD3 and EZH2 in the differentiation of Th17 cells in ankylosing spondylitis (AS),...
OBJECTIVE
To investigate the roles of histone H3K27me3 methylation and its regulatory enzymes JMJD3 and EZH2 in the differentiation of Th17 cells in ankylosing spondylitis (AS), to unveil their potential involvement in the pathogenesis of AS, and to provide new strategies and targets for the clinical treatment of AS by analyzing the methylation state of H3K27me3 and its interactions with Th17-related factors.
METHODS
A total of 84 AS patients (42 active AS patiens and 42 patients in the stable phase of AS) were enrolled for the study, while 84 healthy volunteers were enrolled as the controls. Blood samples were collected. Peripheral blood mononuclear cells were isolated. ELISA assay was performed to examine Th17 cells and the relevant cytokines IL-21, IL-22, and IL-17. The mRNA expressions of , , and were analyzed by RT-PCR, the protein expressions of RORc, JAK2/STAT3 pathway protein, H3K27me3 and the relevant protease (EZH2 and JMJD3) were determined by Western blot. Correlation between H3K27me3, EZH2 and JMJD3 and the key signaling pathway molecules of Th cell differentiation was analyzed by Pearson correlation analysis.
RESULTS
The mRNA expressions of , , and were significantly higher in the active phase group than those in the stable phase group ( <0.05). The relative grayscale values of H3K27me3 and EZH2 in the active phase group were lower than those of the stable phase group, which were lower than those of the control group, with the differences being statistically significant ( <0.05). The relative grayscale values of JMJD3, RORc, JAK2, pJAK2, STAT3, and pSTAT3 proteins were significantly higher in the active phase group than those in the stable phase group, which were higher than those in the control group (all <0.05). The proportion of Th17 and the expression level of inflammatory factors in the active period group were higher than those in the other two groups (P<0.05). H3K27me3 was negatively correlated with RORc, JAK2, STAT3, and IL-17, JMJD3 was positvely correlated with JAK2, STAT3, and IL-17, and EZH2 was negatively correlated with JAK2, STAT3, and IL-17 (all <0.05).
CONCLUSION
The low expression of H3K27me3 in AS is influenced by the gene loci JMJD3 and EZH2, which can regulate the differentiation of Th17 cells and thus play a role in the pathogenesis and progression of AS.
Topics: Humans; Spondylitis, Ankylosing; Th17 Cells; Jumonji Domain-Containing Histone Demethylases; Cell Differentiation; Histones; STAT3 Transcription Factor; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Interleukin-17; Nuclear Receptor Subfamily 1, Group F, Member 3; Janus Kinase 2; Methylation; Interleukins; Interleukin-22; Male; Female; Adult
PubMed: 38948276
DOI: 10.12182/20240560605 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024To investigate the effect of Sanshentongmai (SSTM) mixture on the regulation of oxidative damage to rat cardiomyocytes (H9C2) through microRNA-146a and its mechanism.
OBJECTIVE
To investigate the effect of Sanshentongmai (SSTM) mixture on the regulation of oxidative damage to rat cardiomyocytes (H9C2) through microRNA-146a and its mechanism.
METHODS
H9C2 were cultured , HO was used as an oxidant to create an oxidative damage model in H9C2 cells. SSTM intervention was administered to the H9C2 cells. Then, the changes in HO-induced oxidative damage in H9C2 cells and the expression of microRNA-146a were observed to explore the protective effect of SSTM on H9C2 and its mechanism. H9C2 cells cultured were divided into 3 groups, including a control group, a model group of HO-induced oxidative damage (referred to hereafter as the model group), and a group given HO modeling plus SSTM intervention at 500 μg/L for 72 h (referred to hereafter as the treatment group). The cell viability was measured by CCK8 assay. In addition, the levels of N-terminal pro-brain natriuretic peptide (Nt-proBNP), nitric oxide (NO), high-sensitivity C-reactive protein (Hs-CRP), and angiotensin were determined by enzyme-linked immunosorbent assay (ELISA). The expression level of microRNA-146a was determined by real-time PCR (RT-PCR).
RESULT
H9C2 cells were pretreated with SSTM at mass concentrations ranging from 200 to 1500 μg/L. Then, CCK8 assay was performed to measure cell viability and the findings showed that the improvement in cell proliferation reached its peak when the mass concentration of SSTM was 500 μg/L, which was subsequently used as the intervention concentration. ELISA was performed to measure the indicators related to heart failure, including Nt-proBNP, NO, Hs-CRP, and angiotensin Ⅱ. Compared with those of the control group, the expressions of Nt-proBNP and angiotensin Ⅱ in the treatment group were up-regulated (<0.05), while the expression of NO was down-regulated (<0.05). There was no significant difference in the expression of Hs-CRP between the treatment group and the control group. These findings indicate that SSTM could effectively ameliorate oxidative damage in H9C2 rat cardiomyocytes. Finally, according to the RT-PCR findings for the expression of microRNA-146a in each group, HO treatment at 15 μmol/L could significantly reduce the expression of microRNA-146a, and the expression of microRNA-146a in the treatment group was nearly doubled compared with that in the model group. There was no significant difference between the treatment group and the control group.
CONCLUSION
SSTM can significantly resist the HO-induced oxidative damage of H9C2 cells and may play a myocardial protective role by upregulating microRNA-146a.
Topics: Myocytes, Cardiac; Animals; MicroRNAs; Rats; Oxidative Stress; Hydrogen Peroxide; Drugs, Chinese Herbal; Up-Regulation; Cell Survival; Cell Line; Drug Combinations
PubMed: 38948270
DOI: 10.12182/20240560601 -
PeerJ 2024Fibroblast growth factor 21 (FGF21) is a key hormone factor that regulates glucose and lipid homeostasis. Exercise may regulate its effects and affect disease states.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Fibroblast growth factor 21 (FGF21) is a key hormone factor that regulates glucose and lipid homeostasis. Exercise may regulate its effects and affect disease states. Therefore, we sought to determine how exercise affects FGF21 concentrations in adults.
METHODS
The review was registered in the International Prospective Systematic Review (PROSPERO, CRD42023471163). The Cochrane Library, PubMed, and Web of Science databases were searched for studies through July 2023. Studies that assessed the effects of exercise training on FGF21 concentration in adults were included. The random effect model, data with standardized mean difference (SMD), and 95% confidence intervals (CI) were used to evaluate the pooled effect size of exercise training on FGF21. The risk of heterogeneity and bias were evaluated. A total of 12 studies involving 401 participants were included.
RESULTS
The total effect size was 0.3 (95% CI [-0.3-0.89], = 0.33) when comparing participants who exercised to those who were sedentary. However, subgroup analysis indicated that concurrent exercise and a duration ≥10 weeks significantly decreased FGF21 concentrations with an effect size of -0.38 (95% CI [-0.74--0.01], < 0.05) and -0.38 (95% CI [-0.63--0.13], < 0.01), respectively.
CONCLUSION
Concurrent exercise and longer duration may be more efficient way to decrease FGF21 concentrations in adults with metabolic disorder.
Topics: Fibroblast Growth Factors; Humans; Exercise; Adult
PubMed: 38948228
DOI: 10.7717/peerj.17615 -
PeerJ 2024Ischemic stroke (IS) is a disease with a high mortality and disability rate worldwide, and its incidence is increasing per year. Angiogenesis after IS improves blood...
β-asarone induces viability and angiogenesis and suppresses apoptosis of human vascular endothelial cells after ischemic stroke by upregulating vascular endothelial growth factor A.
Ischemic stroke (IS) is a disease with a high mortality and disability rate worldwide, and its incidence is increasing per year. Angiogenesis after IS improves blood supply to ischemic areas, accelerating neurological recovery. β-asarone has been reported to exhibit a significant protective effect against hypoxia injury. The ability of β-asarone to improve IS injury by inducing angiogenesis has not been distinctly clarified. The experimental rats were induced with middle cerebral artery occlusion (MCAO), and oxygen-glucose deprivation (OGD) model cells were constructed using human microvascular endothelial cell line (HMEC-1) cells. Cerebral infarction and pathological damage were first determined triphenyl tetrazolium chloride (TTC) and hematoxylin and eosin (H&E) staining. Then, cell viability, apoptosis, and angiogenesis were assessed by utilizing cell counting kit-8 (CCK-8), flow cytometry, spheroid-based angiogenesis, and tube formation assays in OGD HMEC-1 cells. Besides, angiogenesis and other related proteins were identified with western blot. The study confirms that β-asarone, like nimodipine, can ameliorate cerebral infarction and pathological damage. β-asarone can also upregulate vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) and induce phosphorylation of p38. Besides, the study proves that β-asarone can protect against IS injury by increasing the expression of VEGFA. experiments affirmed that β-asarone can induce viability and suppress apoptosis in OGD-mediated HMEC-1 cells and promote angiogenesis of OGD HMEC-1 cells by upregulating VEGFA. This establishes the potential for β-asarone to be a latent drug for IS therapy.
Topics: Allylbenzene Derivatives; Anisoles; Apoptosis; Ischemic Stroke; Humans; Vascular Endothelial Growth Factor A; Cell Survival; Animals; Up-Regulation; Rats; Endothelial Cells; Male; Cell Line; Rats, Sprague-Dawley; Neovascularization, Physiologic; Angiogenesis
PubMed: 38948219
DOI: 10.7717/peerj.17534 -
PeerJ 2024The integration of diagnostic methods holds promise for advancing the surveillance of malaria transmission in both endemic and non-endemic regions. Serological assays...
BACKGROUND
The integration of diagnostic methods holds promise for advancing the surveillance of malaria transmission in both endemic and non-endemic regions. Serological assays emerge as valuable tools to identify and delimit malaria transmission, serving as a complementary method to rapid diagnostic tests (RDT) and thick smear microscopy. Here, we evaluate the potential of antibodies directed against peptides encompassing the entire amino acid sequence of the MSP-1 Sal-I strain as viable serological biomarkers for exposure.
METHODS
We screened peptides encompassing the complete amino acid sequence of the Merozoite Surface Protein 1 (MSP-1) Sal-I strain as potential biomarkers for exposure. Here, immunodominant peptides specifically recognized by antibodies from individuals infected with were identified using the SPOT-synthesis technique followed by immunoblotting. Two 15-mer peptides were selected based on their higher and specific reactivity in immunoblotting assays. Subsequently, peptides p70 and p314 were synthesized in soluble form using SPPS (Solid Phase Peptide Synthesis) and tested by ELISA (IgG, and subclasses).
RESULTS
This study unveils the presence of IgG antibodies against the peptide p314 in most -infected individuals from the Brazilian Amazon region. B-cell epitope prediction further supports the utilization of p314 as a potential biomarker for evaluating malaria transmission, strengthened by its amino acid sequence being part of a conserved block of MSP-1. Indeed, compared to patients infected with and uninfected individuals never exposed to malaria, -infected patients have a notably higher recognition of p314 by IgG1 and IgG3.
Topics: Humans; Malaria, Vivax; Merozoite Surface Protein 1; Plasmodium vivax; Biomarkers; Antibodies, Protozoan; Immunoglobulin G; Adult; Female; Male; Middle Aged; Peptides; Enzyme-Linked Immunosorbent Assay; Young Adult; Adolescent; Amino Acid Sequence
PubMed: 38948214
DOI: 10.7717/peerj.17632 -
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