ROS-induced imbalance of the miR-34a-5p/SIRT1/p53 axis triggers chronic chondrocyte injury and inflammation.

Osteoarthritis is a chronic degenerative disease based on the degeneration and loss of articular cartilage. Inflammation and aging play an important role in the destruction of the extracellular matrix, in which microRNA (miRNA) is a key point, such as miRNA-34a-5p. Upregulation of miRNA-34a-5p was previously reported in a rat OA model, and its inhibition significantly suppressed interleukin (IL)-1ß-induced apoptosis in rat chondrocytes. However, Oxidative stress caused by reactive oxygen species (ROS) can exacerbate the progression of miRNA regulated OA by mediating inflammatory processes. Thus, oxidative stress effects induced via tert-butyl hydroperoxide (tBHP) in human chondrocytes were assessed in the current research by evaluating mitochondrial ROS production, mitochondrial cyclooxygenase (COX) activity, and cell apoptosis. We also analyzed the activities of antioxidant enzymes including glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD). Additionally, inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, and IL-24, which contribute to OA development, were detected by enzyme-linked immunosorbent assay (ELISA). The results of this study indicated that miR-34a-5p/silent information regulator 1 (SIRT1)/p53 axis was involved in the ROS-induced injury of human chondrocytes. Moreover, dual-luciferase assay revealed that SIRT1 expression was directly regulated by miR-34a-5p, indicating the presence of a positive feedback loop in the miR-34a-5p/SIRT1/p53 axis that plays an important role in cell survival. However, ROS disrupted the miR-34a-5p/SIRT1/p53 axis, leading to the development of OA, and articular injection of SIRT1 agonist, SRT1720, in a rat model of OA effectively ameliorated OA progression in a dose-dependent manner. Our study confirms that miRNA-34a-5p could participate in oxidative stress responses caused by ROS and further regulate the inflammatory process via the SIRT1/p53 signaling axis, ultimately affecting the onset of OA, thus providing a new treatment strategy for clinical treatment of OA.

Efficacy and Safety of Dulaglutide Monotherapy Compared to Glimepiride in Oral Antihyperglycemic Medication-Naïve Chinese patients with Type 2 Diabetes: A Post Hoc Analysis of AWARD-CHN1.

INTRODUCTION: Glucagon-like peptide (GLP)-1 receptor agonists are glucose-lowering agents associated with weight loss, cardiovascular benefits, and low hypoglycemic risk and are recommended by recent guidelines as first-line therapy for some patients with type 2 diabetes (T2D). This post hoc analysis of the AWARD-CHN1 study compared the efficacy and safety of once-weekly dulaglutide with glimepiride in oral antihyperglycemic medication (OAM)-naïve Chinese patients with T2D. METHODS: AWARD-CHN1 was a phase 3, double-blind study with 737 patients randomized 1:1:1 to once-weekly dulaglutide (1.5 or 0.75 mg) or glimepiride (1-3 mg/day). This is a post hoc analysis of AWARD-CHN1 based on mixed-model repeated measures using a modified intent-to-treat analysis set with only the OAM-naïve Chinese population. RESULTS: There were 264 OAM-naïve Chinese patients included in this analysis (dulaglutide 1.5 mg, n = 87; dulaglutide 0.75 mg, n = 90; glimepiride, n = 87). A greater glycated hemoglobin (HbA1c) reduction from baseline was observed with dulaglutide 1.5 mg and 0.75 mg compared to glimepiride (- 2.02% and - 1.84% vs - 1.37%, respectively; both P < 0.001). Significantly more patients in dulaglutide 1.5 mg and 0.75 mg groups achieved HbA1c targets < 7.0% compared to glimepiride (86.2% and 81.1% vs 65.5%; P = 0.002 and P = 0.026, respectively). Beta cell function was significantly increased for dulaglutide groups compared to glimepiride. Mean body weight was significantly reduced for dulaglutide 1.5 mg and 0.75 mg compared to glimepiride (- 1.40 kg and - 0.96 kg vs + 0.73 kg, respectively; both P < 0.001). Through 26 weeks, 7.9%, 4.2%, and 18.2% of patients reported hypoglycemia, and 40.4%, 23.2%, and 8.0% of patients reported at least one gastrointestinal treatment emergent adverse event, in dulaglutide 1.5 mg, 0.75 mg, and glimepiride groups, respectively. CONCLUSIONS: In this post hoc analysis, dulaglutide was effective in reducing both HbA1c and weight with favorable tolerability and safety profile, which is consistent with results seen in larger international dulaglutide monotherapy studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01644500.

Prognostic significance of preoperative skeletal muscle status in patients with gastric cancer after radical gastrectomy.

BACKGROUND AND OBJECTIVES: The association between skeletal muscle status and gastric cancer (GC) prognosis remains unclear. Here, we investigated the impact of the skeletal muscle index (SMI) on overall survival (OS) in GC patients after radical gastrectomy. METHODS AND STUDY DESIGN: We divided 178 patients into four groups: adult men, adult women, elderly men and elderly women. The SMI, calculated using CT images, of patients was graded using cutoff values of group-specific tertiles. Age, body mass index, SMI grade, Charlson comorbidity index, surgical method (total vs distal gastrectomy), tumor stage, and histological type and differentiation were included in Cox regression models to assess the primary outcome parameter of OS. A new prognostic score for 3- year OS was established by combining the SMI grade and tumor stage, and receiver operating characteristic (ROC) curve analyses were used to determine its predictive reliability. RESULTS: For groups with high, medium, and low SMI grades, the 3-year OS rates were 94.04, 79.08 and 59.09% and 86.09, 70.11 and 49.11% (p<0.001) in patients undergoing distal and total gastrectomy, respectively. In the multivariate analysis, low SMI (hazard ratio (HR) 1.82, 95% confidence interval (CI) 1.14-2.9), advanced stage (HR 2.89, 95% CI 1.43-5.83), and total gastrectomy (HR 1.69, 95% CI 0.95-3.01) were independent risk factors for OS (p<0.010). The areas under the ROC curves for the prognostic score were 0.77 (range 0.61-0.93) and 0.76 (range 0.65-0.86) in patients undergoing distal and total gastrectomy, respectively. CONCLUSIONS: The preoperative SMI was an independent prognostic factor for long-term survival in GC patients after radical gastrectomy.

Efficacy and Safety of Dulaglutide Versus Insulin Glargine in Chinese T2DM Patients: A Subgroup Analysis of a Randomized Trial (AWARD-CHN2).

INTRODUCTION: To evaluate efficacy and safety data of dulaglutide in Chinese patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with 1-2 oral antihyperglycemic medications (OAMs). METHODS: This is a subgroup analysis of a phase 3, open-label, randomized, parallel-arm, 52-week study in Chinese patients aged ≥ 18 years with T2DM who had inadequate glycemic control with OAMs (glycated hemoglobin [HbA1c] ≥ 7.0% and ≤ 11.0%). The primary endpoint was assessment of the noninferiority of dulaglutide 1.5 mg as measured by change in HbA1c, compared with insulin glargine (glargine), using a 0.4% noninferiority margin at week 26. RESULTS: A total of 607 patients from China were randomized 1:1:1 to once-weekly dulaglutide 1.5 or 0.75 mg or once-daily glargine. At week 26, the least squares mean (LSM) change from baseline in HbA1c was greater with dulaglutide 1.5 mg (- 1.67%) and dulaglutide 0.75 mg (- 1.31%) compared with glargine (- 1.11%). The LSM (95% confidence interval) for the difference of dulaglutide 1.5 mg and 0.75 mg vs glargine was - 0.56% (- 0.75 to - 0.37) and - 0.20% (- 0.39 to - 0.01), respectively. Both doses of dulaglutide were noninferior and superior to glargine at 26 weeks and 52 weeks (two-sided P value < 0.05). The mean body weight decreased (P < 0.001) and total hypoglycemia rates were lower (P < 0.05) in the dulaglutide groups compared with the glargine group. Gastrointestinal adverse events (AEs) were the most frequently reported AEs in dulaglutide groups. CONCLUSION: Both doses of dulaglutide are efficacious and tolerable in Chinese patients with T2DM who had inadequate glycemic control on OAMs. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01648582. FUNDING: Eli Lilly and Company.

Blood glucose profiles in East Asian and Caucasian injection-naive patients with type 2 diabetes inadequately controlled on oral medication: a pooled analysis.

AIM: The primary objective of this study was to compare blood glucose (BG) excursions between East Asian and Caucasian patients with type 2 diabetes mellitus (T2DM) who were injection-naive, had inadequate glycemic control with oral antihyperglycemic medications, and who required initiation with injectable therapy. METHODS: This retrospective pooled analysis included individual patient data from completed clinical trials (Insulin lispro injection/dulaglutide development programs, first patient visit ≥1997). All included patients were ≥18 years, were East Asian or Caucasian, and had data for self-monitored BG at baseline. The primary outcome, BG excursion at baseline (least-squares mean, standard error), was compared between patient groups using an analysis of covariance with race as the fixed effect. Independent covariates included baseline body weight, baseline HbA1c, age, and duration of T2DM. RESULTS: Caucasian (n = 6779) and East Asian (n = 1638) patients from 21 trials were included. BG excursions were significantly higher for East Asian than Caucasian patients at breakfast (4.03 [0.075] vs 2.59 [0.045] mmol/L), lunch (3.37 [0.080] vs 1.43 [0.049] mmol/L), and dinner (3.16 [0.080] vs 1.74 [0.047] mmol/L) (P < 0.001 adjusted analyses). Similar findings were observed for the unadjusted analyses. At each time point, postprandial BG was significantly higher for East Asian than Caucasian patients (with adjusted and unadjusted analyses). CONCLUSION: These findings suggest that BG excursion and postprandial BG are higher among East Asian patients with T2DM than Caucasian patients. In addition, these findings may help clinicians select appropriate treatments for East Asian patients with T2DM who require injection therapy.

Differential Treatment Response to Insulin Intensification Therapy: A Post Hoc Analysis of a Randomized Trial Comparing Premixed and Basal-Bolus Insulin Regimens.

INTRODUCTION: Identification of subgroups of patients that may benefit most from certain treatment is important because individual treatment response varies due to multiple contributing factors. The present study used the subgroup identification based on the differential effect search (SIDES) algorithm to identify subgroups with different treatment responses to insulin intensification therapies. METHODS: This was a post hoc analysis of a 24-week, multicenter, open-label, randomized, parallel study comparing prandial premixed therapy (PPT) to basal-bolus therapy (BBT). Patients with type 2 diabetes mellitus were randomized to PPT (insulin lispro mix 50/50 thrice daily with meals) or BBT (glargine at bedtime plus mealtime insulin lispro) insulin intensification therapies. The SIDES algorithm was used to identify the subgroups from at-goal patients [glycated hemoglobin (HbA1c) <7.0% (53.0 mmol/mol) at the end of 24 weeks; n = 182] who could have benefitted from insulin intensification therapies. RESULTS: Baseline characteristics of overall at-goal patients were comparable between PPT and BBT groups. The SIDES algorithm identified patients with race other than Caucasian (i.e., African-American, Asian, and Hispanic) and baseline fasting blood glucose (FBG) <8.89 mmol/L as a subgroup that could respond better to PPT relative to BBT than the overall at-goal patient population. In this identified subgroup population, the HbA1c mean (standard deviation) changes from baseline to endpoint in PPT and BBT groups were -2.27 (0.88)% versus -2.05 (0.75)%; p = 0.40, respectively; while in the overall at-goal patients, the HbA1c changes were -2.17 (0.79)% versus -2.34 (1.00)%; p = 0.19, respectively. CONCLUSIONS: The preliminary results showed that the subgroup of patients with race other than Caucasian and FBG <8.89 mmol/L may respond better to premixed intensification therapy. This result provides some preliminary information for further investigation in prospective studies. FUNDING: Eli Lilly and Company. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov ID number: NCT00110370.

The change points of HbA(1C) for detection of retinopathy in Chinese type 2 diabetic patients.

AIMS: To investigate the change points of HbA(1C) for detection of retinopathy in Chinese type 2 diabetic patients. METHODS: This cross-sectional investigation included 992 diagnosed type 2 diabetic patients, who received non-mydriatic digital fundus photography examination. Joinpoint regression software was adopted to identify the change points of HbA(1C) in association with retinopathy prevalence. RESULTS: The mean age of all patients was 59.1 ± 8.4 years and the duration of diabetes was 5.5 (95% CI: 5.2-5.9) years. The prevalence of retinopathy was 10.3% in total, and 4.1%, 7.4% and 19.6% in patients with different diabetes duration of ≤ 5 years, 5-10 years and >10 years, respectively. The change point of HbA(1C) was 6.5% (95%CI 5.8-7.5%), at which retinopathy prevalence began to rise sharply. Furthermore, in subjects with diabetes duration ≤ 5 years, 5-10 years and >10 years, the change points of HbA(1C) were 8.1% (95%CI 7.9-8.3%), 6.1% (95%CI 5.7-6.8%), 5.6% (95%CI 5.1-8.1%) for detection of retinopathy, respectively. CONCLUSION: The steepest increase in retinopathy prevalence occurred when HbA(1C) reached 6.5%. However, the duration of diabetes should be taken into concern, when using the change points of HbA(1C) for detection of retinopathy in diabetic patients.