Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial.

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.

Analysis of Risk Factors for the Association of Sarcopenia in Patients with Type 2 Diabetes Mellitus.

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.

A Siamese ResNeXt network for predicting carotid intimal thickness of patients with T2DM from fundus images.

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.

Association of HbA1c Variability with Vibrating Perception Threshold in Middle-Aged and Elderly Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Study.

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.

Association of Long-Term HbA1c Variability with Anxiety and Depression in Patients with Type 2 Diabetes: A Cross-Sectional Retrospective Study.

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.

Correlation between long-term glycemic variability and cognitive function in middle-aged and elderly patients with type 2 diabetes mellitus: a retrospective study.

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.

Low lymphocyte to high-density lipoprotein ratio predicts mortality in sepsis patients.

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.

Fotagliptin monotherapy with alogliptin as an active comparator in patients with uncontrolled type 2 diabetes mellitus: a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial.

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.

Effects of glucagon-like peptide-1 receptor agonists on glucose excursion and inflammation in overweight or obese type 2 diabetic patients.

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.

Dulaglutide Protects Mice against Diabetic Sarcopenia-Mediated Muscle Injury by Inhibiting Inflammation and Regulating the Differentiation of Myoblasts.

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.

Mediating Role of Depression Between Diabetes Management Self-Efficacy and Diabetes Self-Care Behavior Among Elderly Type 2 Diabetes Mellitus Patients in China.

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.

Dulaglutide provides protection against sepsis-induced lung injury in mice by inhibiting inflammation and apoptosis.

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.

Denosumab biosimilar (LY06006) in Chinese postmenopausal osteoporotic women: A randomized, double-blind, placebo-controlled, multicenter phase III study.

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 â€‹mg 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€‹= â€‹311; placebo, n â€‹= â€‹98) 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€‹< â€‹0.0001). 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 â€‹N-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.

Saxagliptin combined with additional oral antihyperglycaemic agents in drug-naive diabetic patients with high glycosylated haemoglobin: A 24-week, multicentre, randomized, open-label, active parallel-controlled group clinical trial in China (SUCCESS).

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.

Risk Factors for Nonalcoholic Fatty Liver Disease in Postmenopausal Women with Type 2 Diabetes Mellitus and the Correlation with Bone Mineral Density at Different Locations.

Objective: To explore the risk factors for nonalcoholic fatty liver disease (NAFLD) in postmenopausal women with type 2 diabetes mellitus (T2DM) and the correlation with bone mineral density (BMD) in different areas of the body. Methods: A total of 434 postmenopausal women with T2DM were enrolled and categorized as 198 patients in the NAFLD group and 236 patients in the non-NAFLD group based on color Doppler ultrasound of the liver. The BMD of the lumbar spine, femoral neck, and total hip were measured by dual-energy X-ray absorptiometry. Results: In postmenopausal women with T2DM, the prevalence of NAFLD was 45.6%. The body mass index (BMI), systolic blood pressure (SBP), glycosylated hemoglobin (HbA1c), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), triacylglycerol (TG), uric acid (UA), and homeostatic model assessment for insulin resistance (HOMA-IR) C-peptide (CP) were significantly higher in the NAFLD group than in the non-NFALD group, and the duration of diabetes, and high-density lipoprotein cholesterol (HDL-C) were lower than in the non-NAFLD group (P < 0.05). Logistic regression analysis revealed that BMI (odds ratio [OR] = 1.303, 95% confidence interval [CI]: 1.152-1.346), HbA1c (OR = 1.263, 95% CI: 1.095-1.392), TG (OR = 1.263, 95% CI: 1.031-1.601), and SUA (OR = 1.005, 95% CI: 1.001-1.007) were correlated with NAFLD (P < 0.05). The BMD of the total hip and femoral neck in the NAFLD group was higher than in the non-NAFLD group (P < 0.05). Conclusion: Complicated NAFLD in postmenopausal women with T2DM is associated with weight gain, poor blood glucose control, abnormal lipid metabolism, and elevated UA levels. In addition, the NAFLD group had higher femoral neck and total hip BMD than the non-NAFLD group, suggesting NAFLD in postmenopausal women with T2DM may reduce the risk of osteoporosis.

SGLT-2 inhibitor intervention in diabetes mellitus patients can reduce the incidence of renal injury and adverse events.

OBJECTIVE: To explore the therapeutic value of sodium-dependent glucose transporters 2 (SGLT-2) inhibitor in type 2 diabetes mellitus (DM). METHODS: A total of 131 patients with type 2 DM admitted to our hospital from October 2017 to November 2019 were recruited as research objects, including 58 patients treated with insulin + metformin + acarbose as the control group (CG), and 73 patients treated with SGLT-2 inhibitor on the basis of control group as the study group (SG). The levels of blood glucose, serum creatinine (Scr), 24-hour urinary protein quantity, serum uric acid, and the incidence of adverse events were compared between the two groups. RESULTS: After treatment, fasting blood glucose (FPG), 2 hours postprandial blood glucose (2hPG), body mass index (BMI), hemoglobin A1c (HbA1c), type IV collagen (CIV), procollagen type III (PCIII), serum creatinine (Scr), 24-hour urinary protein quantity and blood uric acid (UA) decreased significantly (P > 0.05), and they were lower in SG than in CG (P < 0.05). Besides, the total effective rate of SG was 95.89%, which was notably higher than that of CG (84.48%, P < 0.05). The adverse reaction rate (ADR) of patients in SG was notably lower than that in CG (P < 0.05). CONCLUSION: SGLT-2 inhibitor can effectively control the blood glucose level of DM patients, and can reduce the incidence of renal injury and adverse events.

The relationship between red blood cell distribution and islet ß-cell function indexes in patients with type 2 diabetes.

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.

The role of serum and urinary biomarkers in the diagnosis of early diabetic nephropathy in patients with type 2 diabetes.

BACKGROUND: Previous studies have shown that a variety of biomarkers are closely related to the occurrence and development of early-stage diabetic nephropathy (DN) in patients. The aim of this study was to evaluate the role of multiple sera and urinary biomarkers in the diagnosis of early-stage DN in patients with type 2 diabetes. METHODS: We enrolled 287 patients with type 2 diabetes, who were classified into normoalbuminuria (n = 144), microalbuminuria (n = 94), or macroalbuminuria (n = 49) groups based on their urine albumin to creatinine ratios (UACR), along with 42 healthy controls. We assessed 13 biomarkers, including transferrin (Tf), immunoglobulin G (IgG), podocalyxin, neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-glucosaminidase, α-1-microglobulin, 8-hydroxy-deoxyguanosine, tumor necrosis factor-alpha (TNF-α), and interleukin-18 in urine samples, along with cystatin C, total bilirubin, and uric acid in sera samples, to evaluate their diagnostic roles. From the measurements, the blood neutrophil to lymphocyte ratio was also calculated. RESULTS: Urinary Tf, IgG, NGAL, and TNF-α were significantly related to the UACR. We calculated the area under the receiver operating characteristic curves (area under the curve) and found that urinary IgG (0.894), NGAL (0.875), Tf (0.861), TNF-α (0.763), and the combination of urinary Tf + IgG + TNF-α + NGAL (0.922) showed good diagnostic value for early-stage DN. CONCLUSIONS: Urinary Tf, IgG, NGAL, TNF-α, and the combination of all four biomarkers demonstrated excellent diagnostic value for early-stage DN in patients with type 2 diabetes.

Protective effects of liraglutide on glomerular podocytes in obese mice by inhibiting the inflammatory factor TNF-α-mediated NF-κB and MAPK pathway.

OBJECTIVE: To evaluate the protective effects of Glucagon-like peptide-1(GLP-1) receptor agonist (liraglutide) on glomerular podocytes of obese mice, and explore the possible underlying mechanism. METHODS: Twelve of the thirty-four healthy and clean male mice were randomly selected as the normal control group. The remaining twenty-two mice were included in the high-fat diet (HFD) feeding group. After twelve weeks of high-fat diet and normal diet, two mice each from the HFD feeding group and the normal control group were randomly selected and sacrificed to suggested that the modeling was successful in the HFD feeding group. Then, twenty mice were randomly divided into HFD + liraglutide group (liraglutide group, n = 10) and HFD group (n = 10). The morphology and the structure of glomerular podocytes were observed using electron microscopy. Podocyte foot process diameter, glomerular basement membrane thickness were measured. ELISA was performed to determine the serum tumor necrosis factor α (TNF-α) level. The expression levels of TNF-α protein and nuclear factor-kappa B (NF-κB) in kidney tissues, extracellularsignal regulating kinase(ERK), c-Jun N-terminal kinase (JNK) and p38MAPK in the mitogenactivated protein kinases(MAPK) pathway were detected by western blotting. RESULTS: HFD-feeding caused significant renal injury, podocyte pathological changes, podocyte foot process diameter and glomerular basement membrane thickness were significantly increased compared with the control group. Liraglutide injection significantly alleviated HFD-induced effects on renal functions and podocyte morphology, as 24 h urine protein, urinary albumin and podocyte histomorphology. Moreover, HFD-induced Inflammatory reaction were obviously attenuated by Liraglutide administration, so did the HFD-induced activation of TNF-α-mediated NF-κB and MAPK pathways. CONCLUSION: Liraglutide reduced urinary albumin excretion in obesity-related glomerulopathy model mice, and improved podocyte morphology and structural damage. The mechanism may be partly related to the inhibition of TNF-α-mediated NF-κB and MAPK pathways.

The relationship between serum uric acid within the normal range and ß-cell function in Chinese patients with type 2 diabetes: differences by body mass index and gender.

BACKGROUND: Elevated serum uric acid (SUA) has a positive correlation with insulin secretion and insulin resistance indexes. However, whether weight- and gender-specific differences regarding the relationship between SUA within the normal range and ß-cell function and insulin resistance exist is unknown in type 2 diabetes mellitus (T2DM) patients. METHODS: A total of 380 patients with type 2 diabetes were divided into two groups as overweight/obesity (n = 268) and normal weight (n = 112). Each group were again divided into low (LSUA) and high normal SUA (HSUA). The HbA1c, C-peptide, SUA, creatinine, and lipids profiles were measured. HOMA2IR and HOMA%2B were estimated using fasting glucose and C-peptide by homeostasis model assessment (HOMA). Pearson's correlations and multiple linear regression analyses were conducted to assess the associations between SUA levels and islet function indexes. RESULTS: In overweight/obesity subgroup, the levels of body mass index, fasting C-peptide (FCP), P2hCP, fasting CPI (FCPI), postprandial CPI (PPCPI), ΔC-peptide, HOMA2%B, and HOMA2IR were higher in HSUA group than in LSUA group. In contrast, the HbA1c, FBS, and P2hBS were lower in HSUA than in LSUA. In normal weight subgroup, there were no differences between the HSUA than LSUA group in terms of clinical characteristics. Pearson's correlations indicated that there were no significant correlations between SUA and insulin secretory capacity in normal weight group, but in overweight/obesity group, SUA had positive significant correlations with P2hCP, FCPI, PPCPI, ΔC-peptide, and HOMA2%B. In the female group, there were no significant correlations between SUA and insulin secretory capacity. However, in the male group, SUA had positive significant correlations with insulin secretory capacity include P2hCP, FCPI, PPCPI, ΔC-peptide, and HOMA2%B. Multiple linear regression showed that SUA was significantly associated with HOMA2%B, but not with HOMA2IR in overweight/obesity and male group. CONCLUSIONS: Our study shows that SUA levels within normal range were associated with ß-cell function in T2DM patients with overweight/obesity or male. This finding supports that the association between SUA within normal range and insulin secretion ability differs by weight and sex.