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AIMS: To investigate the impact of various clinical factors associated with Graves' disease on the success rate of radioiodine (RAI) therapy for Graves' disease within 3 years, and to determine the optimal range of iodine dosage per unit volume that yields the highest cure rate for Graves' disease within 1 year. MATERIALS AND METHODS: This retrospective study included patients diagnosed with Graves' disease who underwent RAI therapy at the Second Affiliated Hospital of Anhui Medical University between October 2012 and October 2022. The cumulative success rate was analysed using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were employed to evaluate factors associated with successful treatment of Graves' disease. Outcomes were categorized as either success or failure for all patients. RESULTS: Overall, 1994 patients were enrolled in this study, including 594 (29.8%) male and 1399 (70.2%) female patients. The success and failure groups comprised 1645 (82.4%) and 349 patients (17.6%), respectively, after a 3-year follow-up period. Multivariate regression analysis demonstrated that sex, antithyroid drug (ATD) use before RAI therapy, age, thyroid receptor antibody (TRAb) levels, iodine dose, thyroid mass, and early ATD use before RAI therapy were independent influencing factors for Graves' disease cure. CONCLUSIONS: We found that female patients and those with TRAbs ≥31.83 IU/L and thyroid mass ≥ 73.42 g had a lower cure rate. Therefore, thyroid size, disease severity, and duration of disease should be comprehensively considered when making treatment decisions and iodine dose selection in clinical practice.
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AIM: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. METHODS: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. RESULTS: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. CONCLUSIONS: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.
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Glicemia , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Hemoglobinas Glicadas , Hipoglicemiantes , Metformina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Masculino , Pessoa de Meia-Idade , Feminino , Método Duplo-Cego , Metformina/administração & dosagem , Metformina/uso terapêutico , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Idoso , Adulto , Resultado do TratamentoRESUMO
BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM. METHODS: Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded. RESULTS: After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group. CONCLUSIONS: In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM. TRIAL REGISTRATION: ClinicalTrail.gov NCT05782192.
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Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas , Glicemia , Hipoglicemiantes/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Resultado do TratamentoRESUMO
AIM: To assess the efficacy and safety of a dipeptidyl peptidase-4 (DPP-4) inhibitor combined respectively with three oral antihyperglycaemic agents in Chinese patients with newly diagnosed type 2 diabetes mellitus (T2DM) with high levels of glycated haemoglobin (HbA1c). MATERIALS AND METHODS: Between 30 December 2014 and 1 November 2017, a 24-week, multicentre, parallel-controlled study was performed on drug-naive T2DM patients. In total, 648 patients with 8.0% ≤ HbA1c ≤ 11.0%, aged 18-80 years and body mass index (BMI) 19-40 kg/m2 were randomly assigned 1:1:1 to receive saxagliptin (Saxa) combined with metformin (Met), acarbose (Aca) or gliclazide (Gli) modified release (MR) tablets (Saxa + Met, Saxa + Aca and Saxa + Gli). The primary outcome was the absolute change in HbA1c from baseline; secondary outcome was the percentage of patients achieving HbA1c <7.0% and ≤6.5%. RESULTS: Each treatment arm contained 216 patients; overall, 583 completed the 24-week trial. At 24 weeks, the mean (95% confidence interval) change in HbA1c from baseline in Saxa + Met, Saxa + Aca and Saxa + Gli were, respectively: -2.9% [-3.1, -2.8]; -2.6% [-2.8, -2.5]; and -2.8% [-2.9, -2.6] (overall p = .04, Saxa + Aca vs. Saxa + Met, p = .010, Saxa + Gli vs. Saxa + Met, p = 0.18). At 24 weeks, 84.9%, 74.7% and 80.3% of participants were at HbA1c <7.0% (overall p = .05); and 72.6%, 59.8% and 63.3% were HbA1c ≤6.5% (overall p = 0.10). The rates of minor or symptomatic hypoglycaemia were very low. CONCLUSIONS: Initial treatment with a DPP-4 inhibitor combined with Metform, alpha-glycosidase inhibitor or sulphonylurea was safe and effective for patients with newly diagnosed T2DM and high HbA1c. DPP-4 inhibitor combined with Met showed the best efficacy for this population.
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Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Humanos , China/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hemoglobinas Glicadas , Hipoglicemiantes/uso terapêuticoRESUMO
BACKGROUND: Red cell distribution width (RDW) is a predicter of infections, cancer and diabetes. However, the relationship between RDW and ß-cell function and insulin resistance remains unclear in patients with type 2 diabetes mellitus (T2DM). The aim of the study was to explore the relationship between RDW and ß-cell function in patients with T2DM. METHODS: A total of 559 T2DM patients were enrolled in this cross-sectional study. Patients were divided into three groups according to RDW tertiles. Clinical and biochemical characteristics such as age, duration of diabetes, blood pressure, RDW, glycosylated hemoglobin A1c (HbA1c), C-peptide and lipid profiles were collected. Homeostasis model assessment of insulin resistance (HOMA2IR) and homeostasis model assessment of ß-cell function (HOMA2%B) were assessed using homeostasis model assessment (HOMA) based on fasting blood glucose (FBG) and fasting C-peptide index (FCPI). Correlations and multiple linear regressions were performed to explore the association between RDW and islet function indexes in total population and in different gender subgroups. RESULTS: The HOMA2%B gradually increased according to RDW tertiles (lowest, second, highest RDW tertiles; 47.1(32.9-75.4), 54.05(34.1-81), and 57.9(38.65-95.4), respectively; P = 0.036). Correlation analysis indicated that there were significant correlations between RDW and age, diabetes duration, diastolic blood pressure (DBP), triglycerides (TG), aspartate transaminase (AST), FBG, HbA1c and HOMA2%B in all subjects. In male subjects, RDW correlated positively with age, high-density lipoprotein cholesterol (HDL) and AST, and it correlated negatively with body mass index (BMI), DBP and TG. In female subjects, RDW correlated positively with age, duration, serum creatinine (Cr), FCPI and HOMA2%B, and it correlated negatively with alanine transaminase (ALT), FBG and HbA1c. Multiple linear regressions indicated that RDW was significantly correlated with HOMA2%B and HbA1c in the total population in both unadjusted and adjusted analysis. This finding could be reproduced in the subgroup of men for HOMA2%B only and in women for HbA1c only. CONCLUSIONS: RDW is associated with ß-cell function assessed by HOMA2%B after adjusting for covariates in male T2DM patients.
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Biomarcadores/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Eritrócitos/patologia , Hemoglobinas Glicadas/análise , Resistência à Insulina , Células Secretoras de Insulina/patologia , Adulto , Idoso , Glicemia/análise , China/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Eritrócitos/metabolismo , Feminino , Seguimentos , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are inflammatory markers used for prediction of chronic complications of diabetes. Lower extremity arterial disease (LEAD) is one of chronic complications of type 2 diabetes mellitus (T2DM). The correlation between NLR, PLR, and lower extremity vascular lesions was investigated in subjects with T2DM to determine the best predictive marker for LEAD. METHODS: Three hundred thirty-five patients with T2DM (199 males and 136 females; age 54.12 ± 14.07 years) were enrolled. Blood differential counts and anklebrachial index (ABI) were assessed. Patients were divided into the LEAD group (ABI ≤ 0.9, n = 236) and non-LEAD group (ABI > 0.9, n = 99), and NLR and PLR were compared between the two groups. The independent risk factors for LEAD were analyzed using a logistic regression model. Receiver operating characteristic (ROC) curve analysis was used to assess the optimal cutoff values of PLR and NLR for prediction of LEAD. RESULTS: NLR and PLR in the LEAD group were significantly increased compared to non-LEAD group patients. Univariate analyses identified that NLR was positively correlated with age, glycosylated hemoglobin (HbA1c), triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and 2-hours postprandial glucose levels. PLR was positively correlated with age, duration of T2DM, HbA1c, TG, TC, and LDL, but negatively correlated with diastolic blood pressure and fasting C-peptide levels. Binary logistic regression analysis identified that age, total number of white blood cells, PLR, and TC were significant and independent factors of diabetic LEAD. Moreover, ROC curve analysis showed that NLR and PLR were both predictive markers of LEAD in diabetes, and that the area under the PLR curve was larger than NLR. CONCLUSIONS: NLR and PLR are positively correlated with LEAD in diabetes. PLR was superior to NLR as a predictor of LEAD in diabetes.
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Diabetes Mellitus Tipo 2/imunologia , Pé Diabético/imunologia , Adulto , Idoso , China/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Pé Diabético/diagnóstico , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
OBJECTIVE: To explore whether palmitate-induced apoptosis of osteoblastic MC3T3-E1 cell is mediated by an activation of nuclear factor-kappa B (NF-κB). METHODS: Cell viability was assessed with methyl thiazolyl tetrazolium (MTT) assay and cell apoptosis by Hochest 33258 staining. Palmitate was added at different timepoints and dosages.Western blot was used to evaluate the expression levels of IκBα, p-NF-κB p65 and NF-κB p65 protein. RESULTS: Palmitate led to a dose- and time-dependent decreases in cell viability and increase in cell apoptosis. Cell viability dropped to 54% and cleaved caspase-3 increased 3.1-fold in cells treated with 500 µmol/L palmitate compared to control. The level of p-NF-κB p65 protein markedly increased at 60 min post-stimulation and reached a 2.96-fold increase of baseline level at 120 min (P < 0.05) . The IκBα level markedly declined at 60 min post-stimulation and decreased by 57% at 120 min (P < 0.05) . Compared to the group with palmitate treatment alone, pyrrolidine dithiocarbamic acid (10/20 µmol/L) significantly inhibited the palmitate-induced increase of p-NF-κB p65 (1.39 ± 0.12, 1.25 ± 0.10 vs 1.76 ± 0.14, both P < 0.05) , restored the palmitate-induced decrease of caspase-3 (2.24 ± 0.28 vs 1.29 ± 0.27, P < 0.05) and inhibited the palmitate-induced increase of cleaved caspase-3 (0.63 ± 0.01 vs 1.13 ± 0.10, P < 0.05) . CONCLUSION: Palmitate induces apoptosis of MC3T3-E1 cell by an activation of NF-κB.
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Apoptose/efeitos dos fármacos , NF-kappa B/metabolismo , Palmitatos/farmacologia , Células 3T3 , Animais , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Background: Previous studies have shown that the prevalence of sarcopenia in patients with type 2 diabetes mellitus (T2DM) has increased significantly over the years. However, the risk factors for the association of sarcopenia in patients with T2DM are unknown. Therefore, we attempted to investigate the risk factors through measurement and analysis of the patients' data from April 2020 to April 2022. Methods: A total of 334 hospitalized patients with T2DM were divided into sarcopenia group (n=101) and non-sarcopenia group (n=233). Clinical factors were compared between the two groups and also between the two genders. Receiver operating characteristic curve (ROC) was used to analyze the ROC diagnostic ability of related factors in sarcopenia. Results: (1) Among the 334 patients, the overall prevalence of sarcopenia was 30.2%; 41.3% in men and 20.1% in women. (2) The multifactorial logistic regression analysis showed that gender (specifically for men; OR=4.997, 95% CI: 2.611-9.564), low body mass index (BMI) (OR=1.525, 95% CI: 1.353-1.718), lower 25(OH)D levels (OR=1.076, 95% CI:1.036-1.117), and lower IGF-1 (OR=1.013, 95% CI:1.006-1.020) were independent risk factors (P < 0.05). (3) ROC curve analysis results showed that BMI, 25 (OH) D, IGF-1, and testosterone (for men) had predictive significance for sarcopenia with T2DM (P < 0.05). However, the AUC of 25 (OH) D, IGF-1 and testosterone (for men) were all <0.7, while the AUC of BMI and the combined factors were all >0.7, has great predictive significance. Conclusion: The prevalence of sarcopenia in hospitalized patients with T2DM is higher in men than in women. Low BMI and lower serum levels of 25 (OH) D and IGF-1 are risk factors of sarcopenia in patients with T2DM. Low BMI, 25(OH)D, IGF-1, and testosterone (for men) all contributed to the prediction of sarcopenia, among which BMI and combined factors were more significant.
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Objective: To develop and validate an artificial intelligence diagnostic model based on fundus images for predicting Carotid Intima-Media Thickness (CIMT) in individuals with Type 2 Diabetes Mellitus (T2DM). Methods: In total, 1236 patients with T2DM who had both retinal fundus images and CIMT ultrasound records within a single hospital stay were enrolled. Data were divided into normal and thickened groups and sent to eight deep learning models: convolutional neural networks of the eight models were all based on ResNet or ResNeXt. Their encoder and decoder modes are different, including the standard mode, the Parallel learning mode, and the Siamese mode. Except for the six unimodal networks, two multimodal networks based on ResNeXt under the Parallel learning mode or the Siamese mode were embedded with ages. Performance of eight models were compared via the confusion matrix, precision, recall, specificity, F1 value, and ROC curve, and recall was regarded as the main indicator. Besides, Grad-CAM was used to visualize the decisions made by Siamese ResNeXt network, which is the best performance. Results: Performance of various models demonstrated the following points: 1) the RexNeXt showed a notable improvement over the ResNet; 2) the structural Siamese networks, which extracted features parallelly and independently, exhibited slight performance enhancements compared to the traditional networks. Notably, the Siamese networks resulted in significant improvements; 3) the performance of classification declined if the age factor was embedded in the network. Taken together, the Siamese ResNeXt unimodal model performed best for its superior efficacy and robustness. This model achieved a recall rate of 88.0% and an AUC value of 90.88% in the validation subset. Additionally, heatmaps calculated by the Grad-CAM algorithm presented concentrated and orderly mappings around the optic disc vascular area in normal CIMT groups and dispersed, irregular patterns in thickened CIMT groups. Conclusion: We provided a Siamese ResNeXt neural network for predicting the carotid intimal thickness of patients with T2DM from fundus images and confirmed the correlation between fundus microvascular lesions and CIMT.
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Inteligência Artificial , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Espessura Intima-Media Carotídea , Redes Neurais de Computação , AlgoritmosRESUMO
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder that is linked to metabolic syndrome, mitochondrial dysfunction and impaired autophagy. Polydatin (PD), a natural polyphenol from Polygonum cuspidatum, exhibits various pharmacological effects and protects against NAFLD. The aim of this study was to reveal the molecular mechanisms and therapeutic potential of PD for NAFLD, with a focus on the role of mitochondrial autophagy mediated by sirtuin 3 (SIRT3), fork-head box O3 (FOXO3) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), and by PTEN-induced putative kinase 1 (PINK1) and parkin (PRKN). We combined network pharmacology analysis, animal models and cell culture experiments to show that PD could regulate the mitochondrial autophagy pathway by modulating several key genes related to mitochondrial function, and ameliorate the liver function, histopathology and mitochondrial biogenesis of NAFLD mice and hepatocytes by activating the SIRT3-FOXO3-BNIP3 axis and the PINK1-PRKN-dependent mechanism of mitochondrial autophagy. We also identified the core targets of PD, including SIRT3, FOXO3A, CASP3, PARKIN, EGFR, STAT3, MMP9 and PINK, and confirmed that silencing SIRT3 could significantly attenuate the beneficial effect of PD. This study provided novel theoretical and experimental support for PD as a promising candidate for NAFLD treatment, and also suggested new avenues and methods for investigating the role of mitochondrial autophagy in the pathogenesis and intervention of NAFLD.
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Proteína Forkhead Box O3 , Glucosídeos , Camundongos Endogâmicos C57BL , Mitocôndrias , Hepatopatia Gordurosa não Alcoólica , Proteínas Quinases , Sirtuína 3 , Estilbenos , Ubiquitina-Proteína Ligases , Animais , Proteína Forkhead Box O3/metabolismo , Sirtuína 3/metabolismo , Sirtuína 3/genética , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Glucosídeos/química , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteínas Quinases/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Humanos , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Autofagia/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Proteínas de MembranaRESUMO
Purpose: To investigate the relationship between HbA1c variability and vibrating perception threshold (VPT) in middle-aged and elderly patients with type 2 diabetes mellitus (T2DM). Patients and Methods: A total of 367 middle-aged and elderly patients with T2DM were enrolled. All patients were categorized into the control and vibration sensation deficiency group (VSD) based on VPT. Clinical data were collected. The coefficient of variation of glycated hemoglobin A1c (HbA1c-CV) and the mean glycated hemoglobin A1c(HbA1c-Mean) are considered as indexes of HbA1c variability. Multivariate logistic regression analysis, the generalized linear model and ROC curve correlation analysis were used to analyze the correlation of various factors and VPT. Results: The multivariate logistic regression analysis revealed that age, systolic blood pressure (SBP), and HbA1c-CV were identified as risk factors for vibration sensation deficiency in middle-aged and elderly patients with T2DM, while estimated glomerular filtration rate (eGFR), triiodothyronine (T3), and alanine aminotransferase (ALT) were considered as protective factors. In the unadjusted generalized linear model, a significant association was observed between HbA1c-CV and VPT values. After adjusting for age, diabetic duration, SBP, homeostatic model assessment for beta-cell function (HOMA-ß), ALT, eGFR, T3, 24-hour urinary protein excretion levels, and HbA1c-Mean, HbA1c-CV remained significantly correlated with VPT values on both sides. (left side, B=2.560, 95% CI 1.298~3.823; P<0.001; right side, B=2.608, 95% CI 1.498~3.718, P<0.001). The area under the curve (AUC) for HbA1c-CV and VSD prevalence was 0.723, with a sensitivity of 79.85%, specificity of 56.22%. Conclusion: The risk of developing VSD increases proportionally with higher HbA1c-CV levels in middle-aged and elderly patients with T2DM. Reaching and maintaining blood glucose stability is essential to the mitigation of diabetes peripheral neuropathy occurrence.
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Importance: Many patients with diabetic peripheral neuropathic pain (DPNP) experience inadequate relief, despite best available medical treatments. There are no approved and effective therapies for patients with DPNP in China. Objective: To evaluate the efficacy and safety of capsules containing γ-aminobutyric acid (GABA) analogue HSK16149 in the treatment of Chinese patients with DPNP. Design, Setting, and Participants: This phase 2 to 3 adaptive randomized clinical trial was multicenter, double blind, and placebo and pregabalin controlled. The trial started on December 10, 2020, and concluded on July 8, 2022. In stage 1, various doses of HSK16149 were evaluated to determine safety and efficacy for stage 2. The second stage then validated the efficacy and safety of the recommended dose. Intervention: In stage 1, enrolled patients (n = 363) were randomized 1:1:1:1:1:1 to 4 HSK16149 doses (40, 80, 120, or 160 mg/d), pregabalin (300 mg/d), or placebo. In stage 2, patients (n = 362) were randomized 1:1:1 to receive HSK16149, 40 or 80 mg/d, or placebo. The final efficacy and safety analysis pooled data from patients receiving the same treatment. Main Outcomes and Measures: The primary efficacy end point in stage 1 was the change from baseline in average daily pain score (ADPS) at week 5. The primary efficacy end point in stage 2 was the change from baseline in ADPS at week 13. When the final statistical analysis was performed, the P values calculated from the independent data of each phase were combined using the weighted inverse normal method to make statistical inferences. Results: Of 725 randomized patients in the full-analysis set (393 men [54.2%]; mean [SD] age, 58.80 [9.53] years; 700 [96.6%] of Han Chinese ethnicity), 177 received placebo; 178, HSK16149, 40 mg/d; 179, HSK16149, 80 mg/d; 66, HSK16149, 120 mg/d; 63, HSK16149, 160 mg/d; and 62, pregabalin, 300 mg/d. A total of 644 patients (88.8%) completed the study. The 40- and 80-mg/d doses of HSK16149 were recommended in stage 2. At week 13, the ADPS mean (SD) change from baseline was -2.24 (1.55) for the 40-mg/d and -2.16 (1.79) for 80-mg/d groups and -1.23 (1.68) for the placebo group, showing statistical significance for both HSK16149 doses vs placebo (both P < .001). In a safety set (n = 726), 545 patients (75.1%) had adverse events, which were generally mild to moderate, with dizziness and somnolence being the most common. Conclusions and Relevance: Forty- and eighty-mg/d doses of HSK16149 were recommended for treating patients with DPNP in China. The efficacy of HSK16149 capsules was superior to placebo in all groups for relieving DPNP and appeared well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT04647773.
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Neuropatias Diabéticas , Pregabalina , Ácido gama-Aminobutírico , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neuropatias Diabéticas/tratamento farmacológico , Método Duplo-Cego , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/uso terapêutico , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/efeitos adversos , China , Pregabalina/uso terapêutico , Idoso , Adulto , Analgésicos/uso terapêutico , Resultado do Tratamento , Medição da Dor , População do Leste AsiáticoRESUMO
Purpose: To explore the relationship between long-term glycemic variability and anxiety and depression in patients with type 2 diabetes. Participants and Methods: A cohort comprising 214 individuals diagnosed with type 2 diabetes participated in this study. Comprehensive demographic and laboratory information was gathered for them. The evaluation of anxiety relied on the 7-item Generalized Anxiety Disorder Scale (GAD-7), while depression was assessed utilizing the 9-item Health Questionnaire (PHQ-9). Based on the presence or absence of anxiety and depression, participants were categorized into either the mood disorder or control groups. Subsequently, univariate and stepwise multiple binary logistic regression analyses were conducted to investigate the potential correlations between factors and the presence of anxiety and depression. Results: The prevalence of anxiety disorders is 23%, and depression is 32%. The prevalence of smoking, diabetic autonomic neuropathy, stroke, and osteoporosis in the mood disorder group was significantly higher than that in the control group (P < 0.05), the glycated hemoglobin A1c variability score (HVS), mean hemoglobin A1c value, total cholesterol, urinary albumin/creatinine and systemic immune-inflammatory index (SII) were significantly higher in the control group (P < 0.05). The level of high-density lipoprotein in the mood disorder group was significantly lower than the control group (P < 0.05). In stepwise multiple binary logistic regression analyses, the main factors associated with anxiety were depression (P < 0.001, OR=117.581) and gender (P < 0.001, OR=9.466), and the main factors related to depression included anxiety (P < 0.001, OR=49.424), smoking (P=0.042, OR=2.728), HVS (P=0.004, OR=8.664), and SII (P=0.014, OR=1.002). Conclusion: Persistent fluctuations in blood glucose levels have been linked to anxiety and depression. Consequently, maintaining an optimal level of glycemic control and minimizing fluctuations becomes imperative in the comprehensive management of diabetes.
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Sepsis is a dangerous condition with a high mortality rate. In addition to promoting insulin secretion in a glucose-dependent manner, glucagon-like peptide-1 (GLP-1) also exhibits anti-inflammatory properties. Dulaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA). In this study, we investigated the effects and mechanism of action of dulaglutide (Dul) in lipopolysaccharide (LPS) induced lung injury in mice with sepsis. In mice with LPS (15 mg/kg, ip, qd)-induced acute lung injury, the administration of dulaglutide (0.6 mg/kg, ip, qd) improved weight loss, reduced lung injury, reversed the increase in IL-1ß, TNF-α, IL-6, CXCL1, CCL2 and CXCL2 expression in the lung, and reduced the infiltration of neutrophils and macrophages in the lung tissues. The decline in caspase-3, cleaved caspase-3, caspase-8, and Bcl-2/Bax expression and the increase in the number of TUNEL positive cells in the lung were reversed, suggesting that GLP-1RA could play a protective role in the lung by inhibiting inflammation and apoptosis. In addition, GLP-1RA could reduce the expression of P-STAT3 and NLRP3, suggesting that P-STAT3 and NLRP3 may be potential targets against lung injury in sepsis. Collectively, our data demonstrated that GLP-1RA exerts a protective effect against sepsis-induced lung injury through mechanisms related to the inhibition of inflammation, apoptosis, and STAT3 signaling.
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Lesão Pulmonar Aguda , Sepse , Camundongos , Animais , Caspase 3 , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Lipopolissacarídeos/farmacologia , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/induzido quimicamente , Apoptose , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Sepse/complicações , Sepse/tratamento farmacológicoRESUMO
BACKGROUND: Currently, the lack of comparative studies between weekly and daily formulations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for glucose excursion is worth investigation. AIM: To investigate the effects of weekly and daily formulations of GLP-1RA on glucose excursion and inflammation in overweight and obese patients with type 2 diabetes. METHODS: Seventy patients with type 2 diabetes mellitus who were treated at our hospital between January 2019 and January 2022 were enrolled in this retrospective analysis. All patients were treated with metformin. We evaluated changes in blood glucose levels and a series of important indicators in patients before and after treatment with either a weekly or daily preparation of GLP-1RA (group A; n = 33 and group B; n = 37). RESULTS: The degree of decrease in the levels of fasting blood glucose, mean blood glucose, mean amplitude of glycemic excursions, total cholesterol, triglycerides, tumor necrosis factor-α, interleukin-6, and high-sensitivity C-reactive protein after treatment in group A was higher than that in group B (P < 0.05), whereas the 2-h postprandial blood glucose levels decreased more so in group B than in group A (P < 0.001). However, there were no statistically significant differences in the levels of glycated hemoglobin, standard deviation of blood glucose, coefficient of variation, absolute mean of daily differences, percentage of time with 3.9 mmol/L < glucose < 10 mmol/L, and high- and low-density lipoproteins between the two groups (P > 0.05). The incidence of adverse reactions was significantly lower in group A than in group B (P < 0.05). CONCLUSION: The effect of the weekly preparation of GLP-1RA in controlling blood glucose levels in the patients, suppressing inflammation, and reducing adverse reactions was significantly higher than that of the daily preparations, which is worthy of clinical promotion.
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Objective: To investigate the current status of diabetes self-care behavior and the association between depression, self-efficacy and self-care in a sample of Chinese elderly type 2 diabetes mellitus (T2DM) patients. Methods: A cross-sectional study with a convenient sample including 240 elderly T2DM patients collected the data of demographic characteristics, diabetes self-care behavior, self-efficacy and depression status. The difference of self-care behavior in different sample characteristics was compared by independent t-test. The Personal correlation analysis was employed to examine the correlation of study variables. The method of bootstrap was used to analyze mediating role of depression. Results: Only 22.5% of patients reported better diabetes self-care behavior and depression partly mediated the association between self-efficacy and self-care behavior. The significant coefficient of path a (B = -0.052, p < 0.001) and path b (B = -0.423, p < 0.05) indicated negative associations of self-efficacy on depression, and depression on self-care behavior. The indirect effect (Path a × b) between self-efficacy and self-care behavior through depression was significant (B = 0.022, p < 0.05), the 95% bias-corrected bootstrap confidence interval was 0.004 to 0.006. Meanwhile, the mediating role of depression was not found significant among the participants reported 60-74 years old (B = 0.104, p < 0.001). But depression completely mediated this association among the participants reported 75-89 years old (B = 0.034, p > 0.05). Conclusion: The level of diabetes self-care behavior among the elderly T2DM patients in Dahu community of Anqing city was hardly optimistic. The self-efficacy focused intervention could be encouraged for community and clinicians to improve diabetes self-care behavior. Moreover, the prevalence of depression and T2DM is increasing in younger population. More work is needed to confirm these findings, especially conducting cohort studies on different populations.
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Background: The lymphocyte-to-high-density lipoprotein (HDL) ratio (LHR) is associated with both inflammation and immunity, and may have the potential to predict the prognosis of sepsis. Our study aimed to evaluate the relationship between LHR and sepsis-related mortality. Methods: We collected data from the Medical Information Mart for Intensive Care IV (MIMIC-IV, version 2.2) database by targeting patients who met the Sepsis-3 criteria and recorded the absolute values of lymphocytes and HDL after admission. We then used restricted cubic splines based on logistic regression to simulate the relationship between the LHR and 90-day mortality. Subsequently, the hazardous threshold was derived based on the mortality curve, and further evaluations were performed using different methods and data sources for hazardous threshold. Results: We ultimately included 1027 eligible patients from the MIMIC-IV database and described the nonlinear relationship between LHR and 90-day mortality. Based on the curve, an LHR of ≤ 0.6 indicated harmful threshold, and the odds ratio for mortality was 1.74 (P=0.001). The outperforming hazard was particularly marked in patients with chronic lung disease and remained consistent after adjusting for baseline data and validating multiple data sources. Conclusions: The LHR has prognostic value in patients with sepsis, and an LHR ≤ 0.6 is a deleterious load that increases mortality.
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Sepse , Humanos , Cuidados Críticos , Bases de Dados Factuais , Lipoproteínas HDL , LinfócitosRESUMO
Background: Type 2 diabetes mellitus increases the risk of sarcopenia, which is characterized by decreased muscle mass, strength, and function. However, there are no effective drugs to treat diabetic sarcopenia, and its underlying mechanism remains unknown. Here, we aimed to determine whether the GLP-1 receptor agonist (GLP-1RA) dulaglutide (Dul) affects the progression of diabetic sarcopenia. Methods: db/db mice were injected intraperitoneally with 0.6 mg/kg dulaglutide for 10 weeks. Mouse muscle tissues were then pathologically evaluated and stained with F4/80 or MPO to detect macrophages and neutrophils, respectively. In addition, inflammatory factors and FNDC5 in the muscle tissues were detected using qRT-PCR. Moreover, C2C12 cells were induced to enable their differentiation into skeletal muscle cells, and muscle factor levels were then detected. Furthermore, changes in muscle factor levels were detected at various glucose concentrations (11 mM, 22 mM, and 44 mM). Results: In vivo, dulaglutide alleviated muscle tissue injury; reduced levels of the inflammatory factors, IL-1ß, IL-6, CCL2, and CXCL1; and reversed the level of FNDC5 in the muscle tissues of db/db mice. In vitro, a C2C12 cell differentiation model was established through the observation of cell morphology and determination of myokine levels. Upon stimulation with high glucose, the differentiation of C2C12 cells was inhibited. Dulaglutide improved this inhibitory state by upregulating the levels of both FNDC5 mRNA and protein. Conclusions: Treatment with the GLP-1RA dulaglutide protects db/db mice against skeletal muscle injury by inhibiting inflammation and regulating the differentiation of myoblasts. High glucose inhibited the differentiation of C2C12 cells and decreased the mRNA and protein levels of myokines. Dulaglutide could reverse the differentiation state induced in C2C12 cells by high glucose.
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Objective: To investigate the correlation between long-term glycemic variability and cognitive function in middle-aged and elderly patients with type 2 diabetes mellitus (T2DM). Methods: This retrospective analysis includes 222 patients hospitalized at Second Affiliated Hospital of Anhui Medical University from June 2021 to June 2023. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). All patients were categorized into the MCI group and the non-MCI group based on their MoCA score. Long-term blood glucose fluctuations were measured using glycated hemoglobin A1c standard deviation (HbA1c-SD) and fasting plasma glucose standard deviation (FPG-SD). The study compared general clinical data, blood biochemical indicators, and glycemic variability indicators between the two groups. The differences between the groups were compared using t-test, Chi-Square Test, or Mann-Whitney U test. Kendall's correlation analysis, multivariate logistic regression analysis and ROC curve correlation analysis were further used to analyze the correlation and diagnostic power. Results: The differences in age, MoCA scores, MMSE scores, HOMA-ß, HbA1c-M, HbA1c-SD, FPG-M, FPG-SD, eGFR, Smoking, GLP-1RA and SGLT-2i usage were statistically significant between the two groups (P < 0.05). Kendall's correlation analysis showed that age, HbA1c-M, HbA1c-SD, FPG-M, and FPG-SD was negatively correlated with MoCA scores; meanwhile, the HOMA-ß, and eGFR was positively correlated with MoCA scores. Multiple logistic regression analysis revealed that HbA1c-SD, FPG-SD and Smoking were risk factors for cognitive dysfunction, while eGFR, GLP-1RA and SGLT-2i usage was a protective effect. The area under the curve (AUC) values for predicting MCI prevalence were 0.830 (95% CI [0.774-0.877], P < 0.001) for HbA1c-SD, 0.791 (95% CI [0.655-0.808], P < 0.001) for FPG-SD, and 0.698 (95% CI [0.633-0.757], P < 0.001) for eGFR. The optimal diagnostic values were 0.91, 1.32, and 74.81 ml/min/1.73 m2 for HbA1c-SD, FPG-SD, and eGFR, respectively. Conclusions: Cognitive function in middle-aged and elderly T2DM patients is influenced by long-term blood glucose variability, with poorer cognitive function observed in individuals with higher blood glucose variability. The impact of HbA1c-SD on MCI exhibited a greater magnitude compared to that of PFG-SD and smoking. Additionally, renal function, GLP-1RA and SGLT-2i usage exert positive effects on cognitive function.
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Diabetes Mellitus Tipo 2 , Idoso , Pessoa de Meia-Idade , Humanos , Diabetes Mellitus Tipo 2/complicações , Glicemia/análise , Estudos Retrospectivos , Hemoglobinas Glicadas , CogniçãoRESUMO
Objectives: This study assessed the efficacy, safety, pharmacokinetics (PK), and immunogenicity profiles of a denosumab biosimilar (LY06006) in Chinese postmenopausal osteoporotic women with a high risk of fracture. Methods: In this multicenter, randomized, double-blind, placebo-controlled, phase 3 trial, 448 postmenopausal women aged 50-85 years with osteoporosis were enrolled at 49 centers in China and were randomly assigned (3:1) to receive 60 âmg of the denosumab biosimilar (LY06006) or placebo subcutaneously every 6 months for 1 year. Lumbar spine bone mineral density (BMD) change was the primary endpoint. Results: Of the 448 randomized patients, 409 (LY06006, n â= â311; placebo, n â= â98) completed the study. All 448 (100.0%) subjects were included in the intent-to-treat (ITT) trial, 427 (95.3%) were included in the full analysis set (FAS), 408 (91.1%) were included in the per protocol set (PPS), 446 (99.6%) were included in the safety set (SS), and 336 (75.0%) were included in the pharmacokinetics concentration set (PKCs). For the primary endpoint, a 4.71% (95% CI, 3.81%, 5.60%) treatment difference in percent change in lumbar spine BMD from baseline to month 12 was observed in the LY06006 group compared with the placebo group (P â< â0.0001). For the secondary endpoints, LY06006 was associated with increased lumbar spine BMD levels measured at month 6, BMD levels at the femoral neck, total hip, and trochanter measured at months 6 and 12 and reduced serum C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 âN-peptide (P1NP) levels at months 1, 6, and 12. Safety analysis was based on the safety analysis set (SS), and 264 (78.6%) subjects in the LY06006 group and 83 (75.5%) in the placebo group experienced adverse events (AEs). Most events were mild or moderate and not related to the study drugs. Conclusion: In postmenopausal women with a high risk of fracture, LY06006 increased the BMD and decreased bone resorption; thus, LY06006 might be an effective treatment for osteoporosis. LY06006 was generally safe and well tolerated without unexpected adverse reactions, similar to the reference drug Prolia®. The characteristics of effectiveness and safety were similar to those reported in previous studies. The translational potential of this article: In this multi-center, randomized, double-blind, placebo-controlled phase 3 study, LY06006 showed substantially efficacy to increase BMD and well tolerance without unexpected adverse reactions, which is comparable to the reference drug Prolia ®. The presented results are encouraging and can offer some valuable evidence for the clinical practice.