Efficacy and Safety of GPR119 Agonist DS-8500a in Japanese Patients with Type 2 Diabetes: a Randomized,Double-Blind,Placebo-Controlled, 12-Week Study

Introduction

G protein-coupled receptor 119 (GPR119) is a promising target for the treatment of type 2 diabetes mellitus (T2DM), as both insulin and glucagon-like peptide-1 secretion can be promoted with a single drug. We compared the efficacy and safety of the GPR119 agonist DS-8500a with placebo and sitagliptin 50 mg in Japanese patients with T2DM.

Methods

This randomized, double-blind, parallel-group comparison study was conducted in Japan (trial registration NCT02628392, JapicCTI-153068). Eligible patients aged ≥ 20 years with T2DM and hemoglobin A1c (HbA1c) ≥ 7.0% and < 10.0% were randomized to receive placebo, DS-8500a (25, 50, or 75 mg), or sitagliptin 50 mg once daily for 12 weeks. The primary efficacy endpoint was change in HbA1c from baseline to week 12. Secondary endpoints included change in fasting plasma glucose (FPG), glucose AUC_0–3h during a meal tolerance test, 2-hour postprandial glucose (2hr-PPG), and changes in lipid parameters (total, low-density lipoprotein (LDL-) and high-density lipoprotein (HDL-) cholesterol, and triglycerides) at week 12. Safety endpoints included adverse events, hypoglycemia, and clinical/laboratory variables.

Results

DS-8500a demonstrated dose-dependent HbA1c lowering compared with placebo at week 12: change from baseline ? 0.23% (p = 0.0173), ? 0.37% (p = 0.0001), and ? 0.44% (p < 0.0001) in the 25-mg, 50-mg, and 75-mg groups, respectively. At 50- and 75-mg doses, DS-8500a significantly lowered FPG, glucose AUC_0–3h, and 2hr-PPG compared with placebo. The glucose-lowering effect was maintained up to 12 weeks. DS-8500a did not lower any of the above parameters to a greater extent than sitagliptin. Compared with placebo and sitagliptin, DS-8500a 50 and 75 mg significantly reduced total cholesterol, LDL-cholesterol, and triglycerides, and significantly increased HDL-cholesterol. All DS-8500a doses were well tolerated. Two cases of clinically relevant drug-related hypoglycemia occurred in the DS-8500a 50-mg group.

Conclusion

DS-8500a was well tolerated and demonstrated significant glucose-lowering effects and favorable changes in lipid profiles up to 12 weeks in Japanese patients with T2DM.

Funding

Daiichi Sankyo Co. Ltd.

     

p53 point mutations in primary human gastric carcinomas

Summary p53 point mutations in primary gastric carcinomas were analyzed by performing cDNA deoxynucleotide sequencing of the gene. Out of 16,9 (56.3%) primary gastric carcinoma cases, including early cancer, showed one or more p53 point mutations in their open-reading frame, and 4 out of 9 cases had a p53 point mutation within highly conserved domains. The characteristics of the p53 mutation spectrum observed in primary tumors were (a) frequent mutation at an A:T pair (50%, 7 out of 14 mutations), (b) high transversion incidence (29%, 4 out of 14 mutations), (c) no transition at CpG, and (d) no G:C to T:A transversion. Our results suggest that p53 mutation is a common event in gastric carcinoma occurring from the early stage of progression with its specific mutation spectrum.Abbreviation PCR-SSCP polymerase chain reaction single-strand conformation polymorphism     

Prevalence of total knee arthroplasty and its predictive factors in Japanese patients with rheumatoid arthritis: Analysis using the NinJa cohort

Objectives. The aim of this study was to clarify the prevalence and the predictive factors for undergoing total knee arthroplasty (TKA) among patients with rheumatoid arthritis (RA).

Methods. The data of 1,134 patients with RA who were enrolled in the Japanese nationwide cohort database NinJa in 2003 and consecutively followed up until 2009 were analyzed.

Results. Seventy-six patients underwent TKA during the observation period. The yearly progression of the modified Health Assessment Questionnaire or mHAQ score from 2003 to 2004, but not the yearly progression of the Disease Activity Score in 28 Joints or DAS28 or patient visual analog scale (VAS) score, was significantly higher in the patients who underwent TKA than those who did not.

Multivariate analysis showed that knee involvement in the disease, high Steinbrocker stage (III or IV), and high patient VAS score at the time of enrollment were powerful predictive factors, with hazard ratios of 4.01, 3.71, and 1.20, respectively.

According to survival analysis with TKA as an endpoint, patients with knee involvement in the disease at the time of enrollment had a significantly worse 5-year survival rate than did those without knee involvement (83.5% vs. 97.0%, respectively).

Conclusion. Several factors were elucidated as predictive factors for undergoing TKA among patients with RA.     

Enhanced wound healing by topical administration of mesenchymal stem cells transfected with stromal cell-derived factor-1

The objective of this study was to investigate the ability of mesenchymal stem cells (MSC) genetically engineered with stromal cell-derived factor-1 (SDF-1) to heal skin wounds. When transfected with SDF-1 plasmid DNA, MSC which were isolated from the bone marrow of rats, secreted SDF-1 for 7 days. In vitro cell migration assay revealed that the SDF-1-engineered MSC (SDF-MSC) enhanced the migration of MSC and dermal fibroblasts to a significantly greater extent than MSC. The SDF-MSC secreted vascular endothelial growth factor, hepatocyte growth factor, and interleukin 6 at a significantly high level. A skin defect model of rats was prepared and MSC and SDF-MSC were applied to the wound to evaluate wound healing in terms of wound size and histological examinations. The wound size decreased significantly faster with SDF-MSC treatment than with MSC and PBS treatments. The length of the neoepithelium and the number of blood vessels newly formed were significantly larger. A cell-tracing experiment with fluorescently labeled cells demonstrated that the percent survival of SDF-MSC in the tissue treated was significantly high compared with that of MSC. It was concluded that SDF-1 genetic engineering is a promising way to promote the wound healing activity of MSC for a skin defect.     

Pentraxin 3 as a new biomarker of peritoneal injury in peritoneal dialysis patients

It is well known that bioincompatible peritoneal dialysate plays a central role in the development of peritoneal fibrosis. Peritoneal inflammation continues even after the cessation of peritoneal dialysate stimulation. It is important to establish the definition of persistent inflammation in the peritoneal cavity at the cessation of peritoneal dialysis (PD). The objective of the present study was to determine whether pentraxin 3 (PTX3) in peritoneal effluent (PE) may be a new biomarker in PD patients. Serum, PE, and peritoneal specimens were obtained from 50 patients with end-stage kidney disease at Juntendo University Hospital. Samples of 19 patients were obtained at the initiation of PD and those of 31 patients at the cessation of PD. PTX3, high-sensitivity CRP, and MMP-2 and IL-6 were analyzed. An immunohistological examination using an anti-PTX3 antibody was performed. Expressions of PTX3 were observed in endothelial cells, fibroblasts, and mesothelial cells in the peritoneum. The PTX3 level in PE at the cessation of PD was significantly higher than that at the initiation of PD. Effluent PTX3 levels in patients with a history of peritonitis or a PD duration of more than 8 years were significantly higher than those in patients without peritonitis or patients with a PD duration of <8 years. The PTX3 level was significantly correlated with MMP-2 and IL-6 levels in PE, as well as the thickness of the submesothelial compact zone and the vasculopathy. It appears that PTX3 may be a new biomarker of peritoneal inflammation and progressive fibrosis.     

Fecoflowmetric Analysis of Anorectal Motor Function in Postoperative Anal-Preserving Surgery Patients With Low Rectal Cancer Comparison With the Wexner Score and Anorectal Manometry

The aim of this study was to elucidate whether fecoflowmetry (FFM) could evaluate more detailed evacuative function than anorectal manometry by comparing between FFM or anorectal manometric findings and the clinical questionnaires and the types of surgical procedure in the patients who received anal-preserving surgery. Fifty-three patients who underwent anal-preserving surgery for low rectal cancer were enrolled. The relationships between FFM or the manometric findings and the clinical questionnaires and the types of procedure of anal-preserving surgery were evaluated. There were significant differences between FFM markers and the clinical questionnaire and the types of the surgical procedure, whereas no significant relationship was observed between the manometric findings and the clinical questionnaire and the types of the surgical procedure. FFM might be feasible and useful for the objective assessment of evacuative function and may be superior to manometry for patients undergoing anal-preserving surgery.Key words: Anorectal manometry, Anal-preserving surgery, Fecoflowmetry, Incontinence, Rectal cancerSphincter preservation has been one of the key issues of rectal cancer surgery. Low anterior resection (LAR)¹ and internal and external sphincter resection (ISR and ESR) are anal-preserving surgeries.^2,3 The aim of these procedures is to restore the normal process of defecation, along with its function, and to improve the quality of life of patients by avoiding permanent colostomy. However, anal-preserving surgery is often associated with evacuative dysfunction and various degrees of incontinence.^4–7Most studies that have assessed the evacuation function have used clinical questionnaires, which are subjective and may vary according to the patient perception.⁷ There are many factors that can affect the evacuative function, such as the stool consistency, rectal capacity, anal sphincters, pelvic floor muscles, and intra-abdominal pressure. Although manometry with or without the clinical score has also commonly been used, fecoflowmetry (FFM) has been reported to be more accurate and useful for assessing the postoperative anorectal motor function.^8–13 FFM was first introduced by Shafik and is a dynamic method for examining the anorectal motor activity that simulates the natural act of defecation.¹⁴ Some studies have shown its usefulness in postoperative patients with anorectal disease,^8–11 but only a few studies have been performed to examine the evacuative function following anal-preserving surgery.^12,13 The aim of this study was to evaluate the evacuative function in the postoperative period following anal-preserving surgery in patients with low rectal cancer using FFM, and to compare the results with the Wexner score and anorectal manometry.¹⁵     

Hobson’s choice two-stage hepatectomy for multiple and bilobar colorectal liver metastases with portal vein embolization: report of two cases

Liver resection is recognized as the preferred treatment for patients with colorectal liver metastases (CLM) because it offers long-term survival; it is the only hope for a cure. However, in the majority of cases, liver surgery is contraindicated due to the small volume of the future remnant liver. To extend the surgical indications for CLM, a planned two-stage hepatectomy procedure with portal vein embolization (PVE) was developed specifically for patients with multiple and bilobar CLM. The rationale for performing the procedure was a concern about the possible overgrowth of intrafuture remnant liver lesions following PVE, and it was therefore recommended for all multiple bilobar CLM cases, even when one-stage hepatectomy was technically feasible. We recently performed Hobson’s choice two-stage hepatectomy in two cases for reasons different from those of the original planned two-stage hepatectomy. In the present report, we describe our Hobson’s choice two-stage hepatectomy strategy, which provided favorable short-term outcomes.