Yawara Niijima

Effect of a Novel Calcium Channel Blocker on Abnormal Nocturnal Blood Pressure in Hypertensive Patients

The authors examined the effect of cilnidipine, a unique L/N‐type calcium channel blocker, on abnormal nocturnal blood pressure (BP) dipping in Japanese hypertensive patients in the real world. The Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering by N‐Channel Blocker Cilnidipine (ACHIEVE‐ONE), a large‐scale clinical study, was designed to evaluate the effects of cilnidipine in daily medical practice. Among the study, 24‐hour ambulatory BP data were obtained from 615 patients and classified according to their nocturnal dipping status as extreme dippers, dippers, nondippers, or risers. A 12‐week treatment with cilnidipine significantly reduced 24‐hour BP in all groups (P<.001). Changes in nocturnal systolic BP (SBP) from baseline were −17.9 mm Hg from 154.6 mm Hg in risers and −11.9 mm Hg from 142.1 mm Hg, −6.6 mm Hg from 128.5 mm Hg, and 0.1 mm Hg from 115.8 mm Hg in nondippers, dippers, and extreme dippers, respectively. Changes from baseline in nocturnal SBP reduction rate were 8.2% in risers (P<.001) but −7.0% in extreme dippers (P<.001), while no change was observed in the nighttime SBP reduction rate for the total patients (−0.2%±9.6%, P=.617). Cilnidipine partially, but significantly, restored abnormal nocturnal dipping status toward a normal dipping pattern in hypertensive patients.

Elevated 1-h plasma glucose following 75-g oral glucose load is a predictor of arterial stiffness in subjects with normal glucose tolerance.

The study aimed to investigate arterial stiffness in subjects with normal glucose tolerance.

Drug-induced Liver injury Caused by Ipragliflozin Administration with Causality Established by a Positive Lymphocyte Transformation Test (LTT) and the Roussel Uclaf Causality Assessment Method (RUCAM): A Case Report

INTRODUCTION AND AIM The inability to distinguish cancer (CSCs) from normal stem cells (NSCs) has hindered attempts to identify safer, more effective therapies for hepatocellular carcinoma (HCC). The aim of this study was to document and compare cell membrane potential differences (PDs) of CSCs and NSCs derived from human HCC and healthy livers respectively and determine whether altered GABAergic innervation could explain the differences. MATERIAL AND METHODS Epithelial cell adhesion molecule (EpCAM) positive stem cells were isolated from human liver tissues by magnetic bead separations. Cellular PDs were recorded by microelectrode impalement of freshly isolated cells. GABAA receptor subunit expression was documented by reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence. RESULTS CSCs were significantly depolarized (-7.0 ± 1.3 mV) relative to NSCs (-23.0 ± 1.4 mV, p < 0.01). The depolarized state was associated with different GABAA receptor subunit expression profiles wherein phasic transmission, represented by GAGAAa3 subunit expression, was prevalent in CSCs while tonic transmission, represented by GABAAa6 subunit expression, prevailed in NSCs. In addition, GABAA subunits a3, |33, y3 and S were strongly expressed in CSCs while GABAAn expression was dominant in NSCs. CSCs and NSCs responded similarly to GABAA receptor agonists (APD: 12.5 ± 1.2 mV and 11.0 ± 3.5 mV respectively). CONCLUSION The results of this study indicate that CSCs are significantly depolarized relative to NSCs and these differences are associated with differences in GABAA receptor subunit expression. Together they provide new insights into the pathogenesis and possible treatment of human HCC.A 75-year old male patient had been regularly visiting our hospital for the management of his type 2 diabetes mellitus since he was diagnosed at age 64 years. When he developed hypoglycemic episodes with sulfonylurea, ipragliflozin (50 mg/day) was started to replace the sulfonylurea therapy. However, 49 days after starting ipragliflozin, his AST increased from 13 to 622 U/L, ALT increased from 9 to 266 U/L, ALP increased from 239 to 752 U/L, and (Υ-GTP) increased from 19 to 176 U/L. ZTT was 3.5 U, TTT was 0.4 U, and total bilirubin was 0.7 mg/dL. IgM hepatitis A antibody, hepatitis B antigen, hepatitis C virus antibody, IgM CMV antibody, and IgM EB VCA antibody were negative, whereas a lymphocyte transformation test for ipragliflozin was positive. Abdominal CT scan showed mild fatty liver but no sign of nodular lesions. Following admission to our hospital, he received liver supportive therapy with the discontinuation of ipragliflozin therapy. He was discharged from the hospital 18 days later with AST and ALT levels reduced to 20 U/L and 13 U/L, respectively. Based on the clinical presentation of this patient, it is highly important to monitor liver function along with other possible clinical complications (e.g., dehydration, ketosis, and urinary tract infection) associated with SGLT2 inhibitortherapy.

Renal threshold for glucose reabsorption predicts diabetes improvement by sodium-glucose cotransporter 2 inhibitor therapy

In the present study we examined the efficacy of sodium‐glucose cotransporter 2 inhibitors on improvement of glycated hemoglobin (HbA1c) in comparison with the renal threshold for glucose reabsorption in patients with type 2 diabetes mellitus. Patients visited the hospital once a month for a regular follow‐up examination with the determination of blood glucose and HbA1c levels, and urinary glucose concentration from spot urine samples. Patient samples were compared before and after ipragliflozin administration. We defined the renal threshold for glucose reabsorption as the lowest blood glucose level that correlated with the first detectable appearance of urine glucose. These data showed a significant negative correlation between improvement of HbA1c level and renal threshold for glucose reabsorption in patients treated with the sodium‐glucose cotransporter 2 inhibitor. These findings show that patients who have a higher renal threshold for glucose reabsorption can be expected to more effectively respond to sodium‐glucose cotransporter 2 inhibitor therapy in terms of lowering HbA1c levels.

Sodium glucose co-transporter 2 inhibitors successfully attenuated seasonal change of glycated haemoglobin A1c

Previous studies suggested that glycated haemoglobin (HbA1c) levels are highest in winter and lowest in summer.[1–4][1] Potential susceptibilities to seasonal change of HbA1c include inappropriate dietary calorie intake and insufficient physical activity in winter. In our hospital, the majority of

Interstitial pneumonia during administration of dipeptidyl peptidase-4 inhibitors.

Recognizing that case reports do not document a causal protein-A and surfactant protein-D were above the relationship, we report three clinical cases in which individuals receiving dipeptidyl peptidase (DPP)-4 inhibitor treatment developed interstitial pneumonia, with increases in the high molecular weight glycoprotein Krebs von den Lungen-6 (KL-6; normal range <500 U/mL). Case 1 was an 80-year-old Japanese female treated with alogliptin for type 2 diabetes mellitus and suffering dry cough. Serum levels of KL-6 (Fig. 1a) and surfactant

Interstitial pneumonia during administration of DPP4 inhibitors

Recognizing that case reports do not document a causal protein-A and surfactant protein-D were above the relationship, we report three clinical cases in which individuals receiving dipeptidyl peptidase (DPP)-4 inhibitor treatment developed interstitial pneumonia, with increases in the high molecular weight glycoprotein Krebs von den Lungen-6 (KL-6; normal range <500 U/mL). Case 1 was an 80-year-old Japanese female treated with alogliptin for type 2 diabetes mellitus and suffering dry cough. Serum levels of KL-6 (Fig. 1a) and surfactant

Serum sodium ion level influenced by daily salt intake after administration of sodium-glucose cotransporter 2 inhibitors

Although sodium–glucose cotransporter 2 (SGLT2) inhibitors increase the excretion of sodium into urine, hyponatraemia is rare, consequent averse effect. In this study, we examined whether salt (sodium ion) intake affects serum sodium levels in 20 patients with type 2 diabetes mellitus after receiving SGLT2 inhibitors. The patients underwent regular follow-up examinations at one-month interval during which blood glucose, serum sodium and HbA1c levels were assessed, and daily salt intake was estimated according to Tanaka’s formula. The samples from before and after starting canagliflozin (100mg/day) were compared. The data showed significant positive correlation between the changes in serum sodium levels and daily salt intake in patients after receiving SGLT2 inhibitors. This indicates that patients who reduce their daily salt intake while under SGLT2 inhibitor medication may experience hyponatraemia. Although salt restriction is important to treat patients with type 2 diabetes mellitus and hypertension, daily salt intake should be considered carefully when SGLT2 inhibitors are administered.

Metformin administration attenuates dipeptidyl peptidase-4 inhibitor-induced increases in Krebs von den Lungen-6 (KL-6) levels: Letter to the Editor

Suga et al. reported that patients with idiopathic interstitial pneumonia had accompanying type 2 diabetes mellitus (T2DM). Kuse et al. Ohara et al. and our group recently reported cases of dipeptidyl peptidase-4 (DPP-4) inhibitor-induced interstitial pneumonia. Although metformin has been reported to reverse established lung fibrosis, it has also been reported to have no effect on clinically relevant outcomes in patients with idiopathic pulmonary fibrosis. Given the lack of clarity regarding the benefits of metformin in patients with T2DM who are prescribed DPP-4 inhibitors, we compared Krebs von den Lungen6 (KL-6) levels between patients prescribed DPP-4 inhibitors and those prescribed both a DPP-4 inhibitor and metformin. The study protocol was reviewed and approved by the Kan-etsu Chuo Hospital Review Board and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants. Statistical analyses were performed and two-tailed P < 0.05 was considered significant. Fifty-four patients were prescribed DPP-4 inhibitors and KL-6 levels were measured in all these patients; 25 patients were prescribed metformin. Thus, patients were categorized into two groups, those taking a DPP-4 inhibitor alone (without metformin; n = 29) and those taking a DPP-4 inhibitor plus metformin (n = 25). Concentrations of KL-6 were significantly higher in those taking the DPP-4 inhibitor alone than in those also taking metformin (mean [ SD] 300.76 155.39 vs 223.96 73.83 U/mL, respectively [P = 0.0281]; reference range < 500 U/mL). Transient increases in KL-6 levels beyond the upper limit of normal was observed in four patients taking the DPP-4 inhibitors along. In the first patient, the KL-6 concentration 2 months after starting the DPP-4 inhibitor was 567 U/mL, and normalized 3 months after cessation of the DPP-4 inhibitor. In the second patient, the KL-6 concentrations 2 and 3 months after starting the DPP-4 inhibitor were 530 and 617 U/mL, respectively; KL-6 levels normalized 2 months after cessation of the DPP-4 inhibitor. In the third patient, KL6 concentrations 4 and 5 months after starting the DPP4 inhibitor were 565 and 591 U/mL, respectively, returning to normal 2 months after cessation of the DPP-4 inhibitor. In the fourth patient, the KL-6 concentrations 2 and 6 months after starting the DPP-4 inhibitor were 745 and 825 U/mL, respectively, and these levels normalized 4 months after stopping the DPP-4 inhibitor. No increases in KL-6 concentrations were seen in any patient in the DPP-4 inhibitor plus metformin group. Despite the small sample size, this clinical study provides important information. One strength of this study is that KL-6 concentrations were measured in all patients with T2DM who were prescribed DPP-4 inhibitors. We confirmed that KL-6 concentrations were in the normal range before patients started on the DPP-4 inhibitor. Moreover, KL-6 concentrations were transiently elevated, but normalized after cessation of the DPP-4 inhibitor. The frequency of increases in KL-6 concentrations due to DPP-4 inhibitor administration was 7.4%, although all participating patients had normal findings on chest X-ray examinations. This incidence is higher than that reported for statin-induced interstitial pneumonia. Metformin may prevent or delay interstitial lung diseases caused by administration of DPP-4 inhibitors. However, KL-6 levels need to be determined in patients being treated with metformin alone.

Elevated 1-h post-challenge glucose levels associated with increased arterial stiffness.

In a previous cross-sectional study involving subjects with normal glucose tolerance (NGT), we reported a positive correlation between brachial–ankle pulse wave velocity (baPWV), a measure of arterial stiffness), and 1-h post-challenge glucose (PG). Furthermore, the subpopulation of NGT subjects defined by 1-h PG ≥183mg/dL (corresponding to impaired glucose tolerance, as determined with a 2-h PG) exhibited arterial stiffness, as evidenced by higher baPWV values despite fasting plasma glucose (FPG) and 2-h PG values being within the normal range. These findings suggest that if NGT subjects convert to higher 1-h PG levels from a normal 1-h PG range, they will develop arterial stiffness. To address this issue, we performed a clinical study on 40 NGT subjects (23 men, 17 women; mean (± SD) age 60.9± 9.7 years), who underwent an annual comprehensive medical check-up at Kan-etsu Chuo Hospital from 2007 to 2015. In addition, over this 9-year period, these individuals underwent an annual 75-g oral glucose tolerance test (OGTT) and an assessment for arterial stiffness using baPWV. Plasma glucose concentrations and baPWV were measured as described previously. Based on the 75-g OGTT, NGT subjects alone were selected according to 2006 World Health Organization (WHO) criteria. The study protocol was reviewed and approved by Kan-etsu Chuo Hospital Review Board and conformed to the Declaration of Helsinki. Written informed consent was obtained from each subject prior to their participation in the study. Data are presented as the mean±SD. Statistical analyses were performed using SPSS version 10.0 (IBMSPSS, Chicago, IL, USA), and two-tailed P< 0.05 was considered significant. The NGT subjects in the present study were identified as individuals with all measured parameters within