Published papers

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Objectives: A subtype prediction score for primary aldosteronism has not yet been developed and validated using a large dataset. This study aimed to develop and validate a new subtype prediction score and to compare it with existing scores using a large multicenter database. Methods: In total, 1936 patients with primary aldosteronism were randomly assigned to the development and validation datasets, constituting 1290 and 646 patients, respectively. Three prediction scores were generated with or without confirmatory tests, using logistic regression analysis. In the validation dataset, new and existing prediction scores were compared using receiver operating characteristic curve, net reclassification improvement, and integrated discrimination improvement analyses. Results: The new prediction score is simply calculated using serum potassium levels [>3.9 mmol/l (four points); 3.5-3.9 mmol/l (three points)], the absence of adrenal nodules during computed tomography (three points), a baseline plasma aldosterone concentration of <210.0 pg/ ml (two points), a baseline aldosterone/renin ratio of less than 620 (two points), and female sex (one point). Using the validation dataset, we found that a new subtype prediction score of at least 8 had a positive predictive value of 93.5% for bilateral hyperaldosteronism. The new prediction score for bilateral hyperaldosteronism was better than the existing prediction scores in the receiver operating characteristic curve and net reclassification improvement analyses. Conclusion: The new prediction score has clear advantages over the existing prediction scores in terms of diagnostic accuracy, feasibility, and the potential for generalization in a large population. These data will help healthcare professionals to better select patients who require adrenal venous sampling.

© The Author(s) 2018. Background: Glycated albumin reflects 2–3-week glycaemic controls, and in addition to glycated haemoglobin, it has been used as a glycaemic control indicator. We presumed that glycated albumin also has seasonal variations and is related to temperature, similar to glycated haemoglobin. Methods: The subjects were diabetic outpatients from April 2007 to March 2013. This resulted in the enrolment of 2246 subjects and the collection of a total of 53,968 measurements. Mean glycated haemoglobin, glycated albumin, and plasma glucose were calculated for each month over six years. The associations of the measures with each other and the average temperature for each month in Tokyo were assessed using Spearman rank correlation coefficients. Results: Plasma glucose was highest in January and lowest in May. Glycated haemoglobin was highest in March and lowest in September. Glycated albumin was highest in May and lowest in December. Glycated albumin tended to have a disjunction with plasma glucose in winter. Glycated haemoglobin had seasonal variation, but glycated albumin did not. Plasma glucose and glycated haemoglobin showed significant negative correlations with temperature (rs = −0.359, P < 0.001, rs = −0.449, P < 0.001, respectively), but glycated albumin did not. However, glycated albumin was inter-correlated with plasma glucose (rs = 0.396, P < 0.001) and glycated haemoglobin (rs = 0.685, P < 0.001), and glycated haemoglobin was inter-correlated with plasma glucose (rs = 0.465, P < 0.001). Conclusion: Glycated albumin and glycated haemoglobin showed different seasonal variations from each other over the six-year study period. Thus, further studies to identify factors that contribute to glycated albumin are needed.

© 2019 © 2019 S. Karger AG, Basel. Copyright: All rights reserved. The DNA repair system is essential for the maintenance of genome integrity and is mainly investigated in the areas of aging and cancer. The DNA repair system is strikingly cell-type specific, depending on the expression of DNA repair factors; therefore, different DNA repair systems may exist in each type of kidney cell. Importance of DNA repair in the kidney is suggested by renal phenotypes caused by both genetic mutations in the DNA repair pathway and increased stimuli of DNA damage. Recently, we reported the importance of DNA double-strand break repair in glomerular podocytes and its involvement in the alteration of DNA methylation status, which regulates podocyte phenotypes. In this review, we summarize the roles of the DNA repair system in the kidneys and possible associations with altered kidney DNA methylation, which have been infrequently reported together. Investigations of DNA damage repair and epigenetic changes in the kidneys may achieve a profound understanding of kidney aging and diseases.

© 2018 Nakao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Lifestyle interventions can substantially improve obesity and cardiometabolic risks. However, evidence of long-term benefits of national intervention is sparse. We aimed to evaluate the long-term effectiveness of a nationwide program for abdominal obesity. Methods A retrospective cohort study was performed using a longitudinal nationwide individual data in subjects aged 40–74 years who underwent checkups in fiscal year (FY) 2008. Lifestyle interventions were provided via interview in subjects with abdominal obesity and at least one cardiometabolic risk factor. Subjects who attended the lifestyle intervention (participants) were compared to those who did not attend (non-participants). Outcomes were waist circumferences (WC) and body mass index (BMI) reduction, reversal of metabolic syndrome (MetS), and changes in cardiometabolic risks. We used a three-step process with robust analytic approaches to account for selection bias that included traditional multivariate analysis, propensity-score matching and instrumental variable (IV) analyses. Results Of 19,969,722 subjects, 4,370,042 were eligible for analyses; 111,779 participants and 907,909 non-participants. A higher percentage of participants had 5% reductions in obesity profiles at year 3, compared to non-participants (WC, 21.4% vs 16.1%; BMI, 17.6% vs 13.6%; p<0.001 each). Participants also had higher reversal for MetS (adjusted odds ratio 1.31; 95% confidence interval: 1.29–1.33; p<0.001). Greater reductions in cardiometabolic risks were observed in participants. Those results were confirmed in analyses using a propensity score-matched cohort (n = 75,777, each) and IV analyses. Limitations of this work include the use of non-randomized national data in Japan to assess the effectiveness of the nationwide preventive program. Conclusions In the nationwide lifestyle intervention for abdominal obesity, the at-risk population achieved significant reductions in WC, BMI, and cardiometabolic risks in 3 years. This study provides evidence that the nationwide program effectively achieved long-term improvement in abdominal obesity and cardiometabolic risks.

© 2019, The Author(s). The stimulation of mineralocorticoid receptors is linked to the development of hypertension and cardiovascular or renal damage in patients with diabetes, and the blockade of these receptors may be an effective treatment option. This open-label study with a 12-week treatment period assessed the antihypertensive (primary) and antialbuminuric (secondary) efficacy and safety of esaxerenone as an add-on therapy to a renin–angiotensin system inhibitor in hypertensive patients with type 2 diabetes and albuminuria (urinary albumin-creatinine ratio 30 to <1000 mg/g•Cr). Esaxerenone was administered over 12 weeks at a starting dosage of 1.25 mg/day, which was gradually titrated to 2.5 mg/day and 5 mg/day at weeks 4, 6, or 8 according to the dosage-escalation criteria based on serum K+ levels, the estimated glomerular filtration rate, and the likelihood/occurrence of hypotension. Of the 51 patients enrolled, 44 (86.3%) reached an esaxerenone dosage of 2.5 or 5 mg/day. The changes from the baseline in sitting systolic and diastolic blood pressures were −13.7 mmHg (p < 0.05) and −6.2 mmHg (p < 0.05), respectively. Significant decreases in blood pressure occurred regardless of age, baseline systolic blood pressure, glycated hemoglobin level, and estimated glomerular filtration rate. The urinary albumin-creatinine ratio decreased by 32.4% from the baseline (p < 0.05). Two consecutive serum K+ measurements ≥ 5.5 mEq/L occurred in one patient but resolved after dosage reduction. Esaxerenone showed antihypertensive and antialbuminuric effects and a low risk of hyperkalemia with dosage titration from 1.25 mg in Japanese hypertensive patients with type 2 diabetes and albuminuria receiving a renin–angiotensin system inhibitor.

© 2019, Springer Nature Limited. This was a phase 2, multicenter, randomized, double-blind, placebo-controlled, open-label comparator study to investigate the efficacy and safety of esaxerenone (CS-3150), a novel non-steroidal mineralocorticoid receptor blocker, in Japanese patients with essential hypertension. Eligible patients (n = 426) received esaxerenone (1.25, 2.5, or 5 mg/day), placebo, or eplerenone (50–100 mg/day) for 12 weeks. The primary efficacy endpoint was the change from baseline in sitting systolic and diastolic blood pressure (BP). Safety endpoints included adverse events and serum K+ elevation. There were significant dose–response reductions in the 2.5 and 5 mg/day esaxerenone groups for sitting BP (both p < 0.001) and 24-h BP (both p < 0.0001) compared with placebo, with a mean (95% confidence interval) change in sitting BP of −7.0 (−9.5 to −4.6)/−3.8 (−5.2 to −2.4) mmHg in the placebo group, and −10.7 (−13.2 to −8.2)/−5.0 (−6.4 to −3.6) mmHg, −14.3 (−16.8 to −11.9)/−7.6 (−9.1 to −6.2) mmHg, and −20.6 (−23.0 to −18.2)/ −10.4 (−11.8 to −9.0) mmHg for the 1.25, 2.5, and 5 mg/day esaxerenone groups, respectively, while the change was −17.4 (−19.9 to −15.0)/−8.5 (−9.9 to −7.1) mmHg for eplerenone. The incidence of adverse events was similar in all treatment groups. Serum K+ levels initially increased in proportion with esaxerenone dose but were stable from week 2 until week 12. Plasma esaxerenone concentration increased in proportion with the dose. In conclusion, esaxerenone is an effective and tolerable treatment option for patients with essential hypertension.

© 2019 The Authors Aims: To evaluate the efficacy and safety of switching to insulin glargine 300 U/mL (Gla-300) from insulin glargine 100 U/mL (Gla-100) in Japanese patients with type 2 diabetes (T2DM). Methods: This was a 12-month retrospective study comprising 109 patients. Primary endpoint was glycated hemoglobin (HbA1c) level at month 12. Secondary endpoints were hypoglycemia for the overall study period as well as body weight and insulin dose at month 12. Results: Similar glycemic control was achieved with mean (standard deviation) HbA1c level of 7.7 (1.1)% (61 [12] mmol/mol) at baseline and 7.7 (1.3)% (61 [14] mmol/mol) at month 12. Fewer confirmed (<3.0 mmol/L [< 54 mg/dL]) or severe hypoglycemic events were observed (0.52 vs. 0.85 events per patient-year; rate ratio 0.61; 95% confidence interval 0.38–0.97; p = 0.037), but the percent of patients experiencing ≥1 hypoglycemic event did not differ. There was no difference in confirmed (≤3.9 mmol/L [≤ 70 mg/dL]) or severe hypoglycemia and nocturnal hypoglycemia. Conclusions: In Japanese patients with T2DM who switched to Gla-300 from Gla-100, similar glycemic control was achieved with fewer confirmed (<3.0 mmol/L [< 54 mg/dL]) or severe hypoglycemic events over a 12-month period, although the absolute benefit was marginal.

© 2018 Elsevier B.V. Activation of mineralocorticoid receptor (MR) is evoked by aldosterone, and it induces hypertension and cardiovascular disease when it's concomitant with excessive salt loading. We have proposed the notion of “MR-associated hypertension” in which add-on therapy of MR blockers is effective even though serum aldosterone level is within normal range. To elucidate its underlying molecular mechanism, we focused on the effect of epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) activation on MR activity. Epidermal growth factor (EGF) administration increased MR transcriptional activity through EGFR/ERK pathway and increased protein level by counteracting MR ubiquitylation in vitro. EGF administration in vivo also increased MR protein level and target gene expression in kidney, which were decreased by EGFR inhibitor. In addition, the administration of EGFR inhibitor lowered systolic blood pressure and MR activity in DOCA/salt-treated mice. In conclusion, EGFR/ERK pathway activation is considered as one of the underlying mechanisms of aberrant MR activation and EGFR/ERK pathway blockade could be an alternative approach for the prevention of MR-related cardiovascular events.

© 2019 International Society for Peritoneal Dialysis. Background: Muscle wasting, common and progressive in uremic patients, is associated with a high probability for morbidity, lower health-related quality of life (HRQOL), and mortality. However, exercise tolerance in peritoneal dialysis (PD) patients has not been fully elucidated. The aim of this study was to evaluate exercise capacity, its determinants, and its association with HRQOL in PD patients. ♦♦ Methods: Outpatients treated with PD at Keio University Hospital from December 2016 to March 2018 were included in this single-center cross-sectional observational study. Exercise capacity was assessed by incremental shuttle walking test (ISWT) and handgrip and quadriceps strength. In addition to evaluation of PD-related parameters, HRQOL was assessed by the Kidney Disease Quality of Life-Short Form questionnaire. ♦♦ Results: Among the 50 recruited PD outpatients, age and PD vintage were 63.8 ± 9.6 and 3.8 ± 2.8 years, respectively. Physical examination revealed ISWT of 312.0 ± 138.2 m, handgrip strength of 27.5 ± 6.9 kg, and quadriceps strength of 23.3 ± 10.0 kg. Multivariate analysis showed that younger age and male sex were significantly associated with higher ISWT and handgrip and quadriceps strength. Skeletal mass index (SMI) remained a significant predictor of handgrip and quadriceps strength. Moreover, only ISWT was strongly correlated with higher HRQOL scores, including physical, mental, and kidney-specific domains, even after adjustment for age and sex. ♦♦ Conclusions: Exercise tolerance in PD patients was partially determined by age, sex, and SMI. Moreover, this is the first study to demonstrate the strong relationship between aerobic capacity and HRQOL in PD patients.

In this study, we examined the association between chronic kidney disease (CKD) and insulin resistance. In a patient cohort with nondiabetic stages 2-5 CKD, estimated glomerular filtration rate (eGFR) was negatively correlated and the plasma aldosterone concentration was independently associated with the homeostasis model assessment of insulin resistance. Treatment with the mineralocorticoid receptor blocker spironolactone ameliorated insulin resistance in patients, and impaired glucose tolerance was partially reversed in fifth/sixth nephrectomized rats. In these rats, insulin-induced signal transduction was attenuated, especially in the adipose tissue. In the adipose tissue of nephrectomized rats, nuclear mineralocorticoid receptor expression, expression of the mineralocorticoid receptor target molecule SGK-1, tissue aldosterone content, and expression of the aldosterone-producing enzyme CYP11B2 increased. Mineralocorticoid receptor activation in the adipose tissue was reversed by spironolactone. In the adipose tissue of nephrectomized rats, asymmetric dimethylarginine (ADMA; an uremic substance linking uremia and insulin resistance) increased, the expression of the ADMA-degrading enzymes DDAH1 and DDAH2 decreased, and the oxidative stress increased. All of these changes were reversed by spironolactone. In mature adipocytes, aldosterone downregulated both DDAH1 and DDAH2 expression, and ADMA inhibited the insulin-induced cellular signaling. Thus, activation of mineralocorticoid receptor and resultant ADMA accumulation in adipose tissue has, in part, a relevant role in the development of insulin resistance in CKD.

BACKGROUND: Plasma levels of low-density lipoproteins (LDLs) are decreased through stimulation of their hepatic uptake by statins via an LDL receptor. However, it is unclear whether statins equally stimulate the hepatic uptake of all LDL subfractions. OBJECTIVE: We compared the effects of atorvastatin on 3 LDL subfractions, and their associations with LDL-receptor activities, in Japanese patients with polygenic hypercholesterolemia (PHC), familial combined hyperlipoproteinemia (FCHL), and familial hypercholesterolemia (FH). MATERIALS AND METHODS: Atorvastatin was administered to patients with PHC (n = 11), FCHL (n = 16), and FH (n = 13). We measured plasma levels of lipids, remnant-like particle cholesterol, apoproteins, and cholesterol in lipoprotein fractions. Sequential ultracentrifugation was performed to subfractionate the plasma lipoproteins, and lymphocyte LDL-receptor activities were estimated using flow cytometry. RESULTS: The average daily dosage of atorvastatin was 10, 27, and 40 mg in patients with PHC, FCHL, and FH, respectively; after 12 months of atorvastatin treatment, LDL cholesterol (LDL-C) plasma levels decreased by 44%, 50%, and 53%, respectively (all, P < .0001). Atorvastatin reduced low-density LDL-C plasma levels in patients with PHC (48% reduction), FCHL (53%), and FH (46%) (all, P < .0001). Plasma levels of medium-density and high-density LDL-C were also significantly reduced in the 3 patient groups (all, P = .0147). LDL-receptor activity was negatively correlated with baseline levels of medium-density LDL-C and with the decreases in plasma md-LDL-C levels. CONCLUSION: Atorvastatin decreased the levels of the 3 LDL fractions. The md-LDL decrease appeared to be mainly because of stimulation of LDL-receptor activity.

AIMS: Serum bilirubin concentration is associated with diabetic retinopathy in patients with type 2 diabetes. This study investigated the relationships between serum bilirubin concentration and the severity of diabetic retinopathy. In addition, the importance of bilirubin was compared with factors that were previously shown to be associated with the incidence of diabetic retinopathy. METHODS: A total of 674 patients with type 2 diabetes were investigated in this cross-sectional study. Serum total bilirubin concentration was compared between patients with and without diabetic retinopathy, and according to the severity of retinopathy. Univariate and multivariate analyses were performed to evaluate the association of retinopathy with total bilirubin concentration, duration of diabetes, body mass index, systolic blood pressure, and haemoglobin A1c. RESULTS: Serum total bilirubin concentration was significantly lower in patients with retinopathy than in those without. Patients with severer retinopathy showed lower total bilirubin concentration, longer diabetes duration, and higher systolic blood pressure. These three parameters were independent explanatory factors for diabetic retinopathy. CONCLUSIONS: Total bilirubin concentration is lower in patients with type 2 diabetes complicated with severer retinopathy. Thus, bilirubin might protect against retinopathy in patients with type 2 diabetes.

BACKGROUND: The lipodystrophy-like phenotype has been suggested in early chronic kidney disease (CKD). It includes adipose tissue atrophy, systemic insulin resistance (IR), dyslipidemia and ectopic lipid accumulation. To elucidate its pathogenesis, we investigated the role of two uremic toxins that affect insulin sensitivity: an endogenous nitric oxide synthase inhibitor, and asymmetric dimethylarginine (ADMA) and indoxyl sulfate (IS). METHODS: Six-week-old Sprague-Dawley rats were rendered CKD by subtotal nephrectomy (Nx) and compared with sham-operated rats. Cultured 3T3-L1 fibroblasts were differentiated into mature adipocytes with or without ADMA. Transgenic (Tg) mice overexpressing each isoform of ADMA degrading enzyme, dimethylarginine dimethylaminohydrolase 1 (DDAH1) and DDAH2 were subject to Nx and their phenotypes were investigated. RESULTS: In Nx rats, IR was evident and insulin stimulation failed to activate insulin signaling in adipose tissues. Adipose tissue weight, adipocyte size and adipocyte differentiation marker expressions decreased as a consequence of IR in Nx. Tissue lipid content in the liver and muscle increased in Nx rats. Tissue levels of ADMA, IS and oxidative stress increased in the adipose tissue of Nx rats. Both DDAH1 and DDAH2 expressions decreased, and a putative IS receptor, aryl hydrocarbon receptor, expression increased in the adipose tissue of Nx rats. ADMA inhibited adipocyte differentiation, triglyceride accumulation and insulin signaling, which were reversed by pretreatment with cGMP. In each type of Tg mice overexpressing DDAH1 or DDAH2, all lipodystrophy-like phenotypes induced by Nx were reversed. CONCLUSIONS: In mild CKD, dysregulation of the ADMA/DDAH pathway in adipose tissue triggers lipodystrophy-like phenotype changes, including ectopic fat depositions.

Besides an established medication for hypercholesterolemia, bile acid binding resins (BABRs) present antidiabetic effects. Although the mechanisms underlying these effects are still enigmatic, glucagon-like peptide-1 (GLP-1) appears to be involved. In addition to a few reported mechanisms, we propose prohormone convertase 1/3 (PC1/3), an essential enzyme of GLP-1 production, as a potent molecule in the GLP-1 release induced by BABRs. In our study, the BABR colestimide leads to a bile acid-specific G protein-coupled receptor TGR5-dependent induction of PC1/3 gene expression. Here, we focused on the alteration of intestinal bile acid composition and consequent increase of total TGR5 agonistic activity to explain the TGR5 activation. Furthermore, we demonstrate that nuclear factor of activated T cells mediates the TGR5-triggered PC1/3 gene expression. Altogether, our data indicate that the TGR5-dependent intestinal PC1/3 gene expression supports the BABR-stimulated GLP-1 release. We also propose a combination of BABR and dipeptidyl peptidase-4 inhibitor in the context of GLP-1-based antidiabetic therapy.

BACKGROUND: The role of gut microbiota in the progression of chronic kidney disease (CKD) has not been fully elucidated. METHODS: Renal failure was induced in 6-week-old spontaneously hypertensive rats by 5/6 nephrectomy (Nx). We analyzed the gut microbiota population to identify the relevant species potentially involved in inducing renal damage. Human colon Caco-2 cells were used to delineate the mechanism involved in the molecular changes in the gut of Nx rats. RESULTS: Nx rats showed an increase in Bacteroides (Bact) and a decrease in Lactobacillus (Lact) species compared with sham-operated rats. Lact, but not Bact, populations were significantly associated with urinary protein excretion. Treatment of Nx rats with 1 x 10(10) CFU/kg/day Lact ameliorated increased urinary protein excretion and higher serum levels of the uremic toxins, indoxyl sulfate and p-cresyl sulfate, and serum urea nitrogen levels. Lact also attenuated systemic inflammation in Nx rats, as evaluated by serum lipopolysaccharide, interleukin-6 and C-reactive protein levels. Histologically, renal sclerosis in Nx rats was restored by Lact treatment. A reduction in the expression of tight junction proteins and the Toll-like receptor 2 (TLR2), a putative Lact receptor, in the colons of Nx rats were mitigated by Lact. Treatment of Caco-2 cells with indole downregulated tight junction protein expression, which was abolished by exposure to Lact. The effects of Lact were reversed by treatment with OxPAPC, a TLR inhibitor. Similarly, the increase in the permeability of the Caco-2 cell monolayer was reversed by the administration of Lact. Lact upregulated TLR2 expression in Caco-2 cells. Lact also attenuated the increase in serum indoxyl sulfate and urea levels and urinary protein excretion in Nx rats even in the pseudogerm-free environment. CONCLUSIONS: Lact supplementation mitigated the systemic inflammation and proteinuria associated with renal failure, suggesting that in the gut microbiota, Lact plays a protective role against the progression of CKD.

INTRODUCTION: The prorenin receptor ((P)RR) contributes to the regulation of the tissue renin-angiotensin system (RAS) and the function of V-ATPase, which are essential for Wnt signaling. Thus, (P)RRs may be involved in the control both of feto-placental and maternal circulation during pregnancy. This study was conducted to clarify how placental (P)RR expression and plasma soluble (P)RR [s(P)RR] levels are associated with blood pressure elevations and renal function during pregnancy. METHODS: We conducted a cross-sectional study, conducted at Saitama medical center in 2010-2013. Preeclamptic women (n = 16) diagnosed according to the criteria of Japan Society of Obstetrics and Gynecology and normotensive pregnant women (n = 15) participated in the study. We measured the expression of (P)RR in the placenta, plasma s(P)RR levels, systolic blood pressure (SBP), and estimated glomerular filtration rate (eGFR). RESULTS: Placental expression of (P)RR was significantly higher in preeclamptic women than in normotensive pregnant women. The plasma s(P)RR levels were significantly higher in preeclamptic women than in normotensive pregnant women. Systolic blood pressure (SBP) was positively correlated with placental (P)RR levels (P = 0.0001) and plasma s(P)RR levels (P = 0.005) in all pregnant women. In preeclamptic women, SBP was positively correlated with placental (P)RR levels (P = 0.004), but not with plasma s(P)RR levels (P = 0.15). The eGFR was negatively correlated with placental (P)RR levels (P = 0.02) and plasma s(P)RR levels (P = 0.0002) in all pregnant women. In preeclamptic women, eGFR was negatively correlated with plasma s(P)RR levels (P = 0.006), but not with placental (P)RR levels (P = 0.93). DISCUSSION: Placental (P)RR can be involved in blood pressure regulation via the tissue RAS. On the other hand, plasma s(P)RR may be involved in the pathogenesis of decreased renal function in preeclampsia.

OBJECTIVE: This retrospective study evaluated the long-term efficacy of sitagliptin and the factors contributing to its glucose-lowering effect. METHODS: Six hundred and sixteen dipeptidyl peptidase-4 inhibitor-naive outpatients with type 2 diabetes who began sitagliptin treatment between December 1, 2009 and December 31, 2011 were included in this study. The inclusion criteria were that the patient had regularly visited our hospital for a period of >/=700 days from the initiation of sitagliptin treatment and the measurement of hemoglobin A1c (HbA1c) had been performed at 0, 3, 6, 12, 18, and 24 months after the initiation of treatment. From the population of 616 patients, 447 and 169 had received sitagliptin for >/=700 and <700 days, respectively. The primary endpoint was DeltaHbA1c at 24 months. The factors associated with the hypoglycemic effect of sitagliptin were also investigated. RESULTS: Sitagliptin treatment significantly decreased the level of HbA1c, and the hypoglycemic effect was sustained for at least 2 years. The baseline HbA1c level, duration of diabetes, Deltabody weight value, and DeltaHbA1c value at 3 months were independently associated with the hypoglycemic effect of sitagliptin. CONCLUSION: Sitagliptin has a long-term hypoglycemic effect in type 2 diabetes patients. A patient's DeltaHbA1c at 3 months may be a predictor of their DeltaHbA1c at 24 months.

AIMS: To clarify the efficacy and safety of adding sitagliptin to insulin therapy in Japanese patients with suboptimally controlled type 2 diabetes (T2DM). STUDY DESIGN AND METHODS: This was a 24-week, prospective, randomized, open-labeled, controlled trial. Patients with T2DM who were suboptimally controlled despite receiving at least twice daily injection of insulin were enrolled in the study. The patients were randomized to continuation of insulin treatment (Insulin group) or addition of sitagliptin 50 to 100 mg daily to insulin treatment (Ins+Sita group). The primary outcome was change in HbA1c at week 24. RESULTS: Adding sitagliptin to insulin significantly reduced HbA1c from 7.9 +/- 1.0% at baseline to 7.0 +/- 0.8% at week 24 (P <0.0001), while there was no significant change in HbA1c in the Insulin group (7.8 +/- 0.7% vs. 7.8 +/- 1.1%, P = 0.32). The difference in HbA1c reduction between the groups was 0.9% (95% confidence interval, 0.4 to 1.5, P = 0.01). There was no significant weight gain in either group. Incidence of hypoglycemia was significantly reduced in the Ins+Sita group compared with the Insulin group. Treatment satisfaction was improved in the Ins+Sita group. Baseline HbA1c level and beta cell function were associated with the magnitude of reduction in HbA1c in the Ins+Sita group. CONCLUSION: Adding sitagliptin to insulin reduced HbA1c without weight gain or increase in hypoglycemia, and improved treatment satisfaction in Japanese patients with T2DM who were suboptimally controlled despite at least twice daily injection of insulin. TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000004678.

There is little information on direct comparison between metformin and glucagon-like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 +/- 0.80% vs. -0.80 +/- 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM.

Peritoneal dialysis (PD) is an excellent dialysis mo- dality, but it is underutilized in the United States and Japan. In the present study, we evaluated the impact of interventional nephrology in PD on the impres- sions held by patients and nurses about selection of a renal replacement therapy and the complications associated with PD therapy. Over aperiod of 7 years, PD catheter insertion in 120 patients with end-stage renal disease (age: 63.0 +/- 13.3 years) was performed by nephrologists at Keio University Hospital or Saitama Medical Center. A questionnaire survey evaluating the advantages and disadvantages of this interventional nephrology approach in PD was distributed to 72 PD patients and to 53 nurses in charge of those patients. After interventional nephrology in PD was adopted, the number of patients selecting PD therapy increased. The incidence of peritonitis was relatively low (1 episode in 101.1 patient-months). Responses to the questionnaire survey showed that neither patients nor nurses were concerned about catheter insertion by physicians, and no communication problems between the patients, nurses, and physicians were reported. Approximately 60% of the nurses specializing in PD therapy showed higher motivation with interventional nephrology, which might have a favorable effect on the selection of PD therapy, on the incidence of peritonitis, and on the tripartite communication between patients, nurses, and physicians.