AimsTo investigate efficacy and safety of the sodium–glucose co‐transporter 2 (SGLT2) inhibitor canagliflozin administered as add‐on therapy to the dipeptidyl peptidase‐4 (DPP‐4) inhibitor teneligliptin in patients with type 2 diabetes mellitus (T2DM).Materials and methodsWe conducted a multicentre, randomized, double‐blind, placebo‐controlled, phase 3 clinical trial in Japanese patients with T2DM who had inadequate glycaemic control with teneligliptin. Patients were randomized to receive teneligliptin 20 mg plus either canagliflozin 100 mg (T + C, n = 70) or placebo (T + P, n = 68) once daily. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. Other endpoints included changes in fasting plasma glucose, body weight, proinsulin/C‐peptide ratio, homeostatic model assessment 2‐%B and adverse events. Patients also underwent mixed‐meal tolerance tests.ResultsThe difference between the T + C and T + P groups for HbA1c change from baseline to week 24 was −0.88% (least‐squares mean, P < .001). Fasting plasma glucose, body weight and the proinsulin/C‐peptide ratio were significantly lower in the T + C group than in the T + P group. Homeostatic model assessment 2‐%B improved with T + C compared with T + P. The T + C group exhibited a decrease in the 2‐hour postprandial plasma glucose and plasma glucose area under the curve (AUC)0‐2h in a mixed‐meal tolerance test. No significant between‐group differences were observed for C‐peptide AUC0 ‐2h or glucagon AUC0 ‐2h after meals. Incidences of adverse events were 60.0% and 47.1% in the T + C and T + P groups, respectively. No hypoglycaemia was observed.ConclusionsCanagliflozin administered as add‐on therapy to teneligliptin was effective and well tolerated in Japanese T2DM patients.
Dipeptidyl peptidase‐4 (DPP‐4) inhibitors and sodium glucose co‐transporter 2 (SGLT2) inhibitors are frequently used in combination for the treatment of type 2 diabetes mellitus (T2DM). We examined the efficacy and safety of teneligliptin (a DPP‐4 inhibitor) added to canagliflozin (an SGLT2 inhibitor) monotherapy in Japanese patients with poorly controlled T2DM as part of the development of a fixed‐dose combination of teneligliptin and canagliflozin.Japanese patients treated with canagliflozin (100 mg) for ≥12 weeks were randomized to receive add‐on teneligliptin (20 mg; C + T group) or placebo (C + P group) for 24 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to Week 24. The between‐group differences in reductions from baseline to Week 24 were significantly greater in the C + T group for HbA1c (−0.94%; P < .001). The incidence of adverse events was similar in both groups (55.8% and 49.4% in the C + T and C + P groups, respectively). No episodes of hypoglycaemia were reported. Teneligliptin added to ongoing canagliflozin monotherapy improved glycaemic control and was well tolerated in Japanese patients with inadequately controlled T2DM.
AimTo evaluate the long‐term safety and efficacy of canagliflozin as add‐on therapy in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with teneligliptin monotherapy.MethodsThis open‐label 52‐week study was conducted in Japan. Patients received canagliflozin 100 mg added to teneligliptin 20 mg orally once daily for 52 weeks. The safety endpoint was the incidence of adverse events (AEs). The efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and body weight from baseline to week 52 (with last observation carried forward).ResultsOverall, 153 patients entered the treatment period and 142 completed the study. The overall incidence rates of AEs and drug‐related AEs were 69.9% and 22.9%, respectively. Most AEs and drug‐related AEs were mild or moderate in severity. There were no previously undescribed safety signals. The mean changes in HbA1c, FPG and body weight were −0.99% (95% confidence interval [CI] −1.12 to −0.85), −38.6 mg/dL (95% CI −43.4 to −33.9) and −3.92% (95% CI −4.53 to −3.31), respectively. These effects were maintained for 52 weeks without attenuation. HbA1c and body weight were both decreased in 82.24% of patients at the end of the treatment period. Reductions in postprandial glucose were observed at weeks 24 and 52.ConclusionsNo new safety risks with this combination were identified, and sustained improvements in HbA1c, FPG and body weight were observed. The findings suggest that long‐term co‐administration of canagliflozin with teneligliptin is well tolerated and effective in Japanese patients with T2DM who have inadequate glycaemic control on teneligliptin alone.
The assessment of bleeding risk in patients with coronary artery disease (CAD) is clinically important. We recently developed the Total Thrombus-Formation Analysis System (T-TAS) for the quantitative analysis of thrombus formation using microchips with thrombogenic surfaces. Here, we assessed the utility of T-TAS parameters in predicting 1-year bleeding events in patients with CAD. Methods: The study subjects were 561 consecutive patients who underwent coronary angiography (CAG) between August 2013 and September 2016 for suspected CAD. Blood samples collected at the time of CAG were used for T-TAS to compute the area under the curve (AUC) (AR10-AUC30) in the AR chip. Patients were divided into three groups according to AR10-AUC30 (low: ≤ 1603, intermediate, and high: 1765, n 187 each). Oneyear bleeding events were defined by the Platelet Inhibition and Patient Outcomes criteria. Results: Bleeding occurred in 21 (3.7%) patients and was classified as major (8 [1.4%]) and minor (13 [2.3%]). The AR10-AUC30 levels were significantly lower in the bleeding group than the non-bleeding group (median [interquartile range] 1590 [1442-1734] vs. 1687 [1546-1797], p 0.04). Univariate Cox regression analysis demonstrated that low AR10-AUC30 , high prothrombin time-international normalized ratio levels, and diabetes correlated with bleeding events. Multivariate Cox regression analysis identified low AR10-AUC30 levels as a significant determinant of bleeding events. Kaplan-Meier survival curves showed a higher rate of bleeding events in the low than the high AR10-AUC30 group (p 0.007). Conclusions: The results highlight the potential usefulness of the AR10-AUC30 levels in the prediction of 1-year bleeding events in patients with CAD treated with various antithrombotic therapies. (AF) and venous thromboembolism. However, there is no adequate monitoring system that can evaluate antithrombotic drugs. Bleeding events are one of the major concerns in patients treated with these drugs. Bleeding events after PCI are associated with early and late mortality 1-4). The reported incidence of major bleeding events in patients with stable coronary artery disease (CAD) is 0.6%/year, and major bleeding events are significantly associated with mortality 5). Furthermore, approximately 5%-8% of patients who Copyright©2019 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
Background Cardiac fibrosis plays a crucial role in the pathogenesis of dilated cardiomyopathy (DCM). HE4 (human epididymis protein 4) is a secretory protein expressed in activated fibroblasts that exacerbates tissue fibrosis. In the present study, we investigated the clinical utility of HE4 measurement in patients with DCM and its pathophysiological role in preclinical experiments in vivo and in vitro. Methods and Results We measured serum HE4 levels of 87 patients with DCM. Endomyocardial biopsy expressed severe fibrosis only in the high HE4 group ( P <0.0001). Echocardiography showed that left ventricular end‐diastolic diameter tends to decrease over time (58±7.3 to 51±6.6 mm; P <0.0001) in the low HE4 group (<59.65 pmol/L [median value]). HE4 was significantly associated with risk reduction of mortality and cardiovascular hospitalization in multivariate Cox model. In vivo, HE4 was highly expressed in kidney and lung tissue of mouse, and scarcely expressed in heart. In genetically induced DCM mouse model, HE4 expression increased in kidney but not in heart and lung. In vitro, supernatant from HE4‐transfected human embryonic kidney 293T cells enhanced transdifferentiation of rat neonatal fibroblasts and increased expression of fibrosis‐related genes, and this was accompanied by the activation of extracellular signal‐regulated kinase signaling in cardiac fibroblasts. Treatment with an inhibitor of upstream signal of extracellular signal‐regulated kinase or a neutralizing HE4 antibody canceled the profibrotic properties of HE4. Conclusions HE4 functions as a secretory factor, activating cardiac fibroblasts, thereby inducing cardiac interstitial fibrosis. HE4 could be a promising biomarker for assessing ongoing fibrosis and a novel therapeutic target in DCM. Registration URL: https://upload.umin.ac.jp/cgi‐open‐bin/ctr ; Unique identifier: UMIN000043062.
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