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Takeshi Osonoi, Shinichiro Shirabe, Miyoko Saito, Mitsuru Hosoya, Norie Watahiki, Satako Douguchi, Kensuke Ofuchi, Makoto Katoh Naka Kinen Clinic, Naka-shi, Ibaraki, JapanCorrespondence: Makoto Katoh, Naka Kinen Clinic, 745-5 Nakadai, Naka-shi, Ibaraki, 311-0113, Japan, Tel +81 29 353 2800, Fax +81 29 295 5400, Email m-katou@kensei-kai.comPurpose: In this study, we examined the effects of dapagliflozin on changes in hematopoiesis, iron metabolism, and body composition indices in elderly type 2 diabetic patients with renal impairment and investigated the potential of dapagliflozin to treat renal anemia.Patients and Methods: The participants were elderly type 2 diabetics with renal impairment, and the indices of diabetes management, hematopoiesis, iron metabolism, and body composition were compared before and after dapagliflozin treatment.Results: Fourteen subjects were given dapagliflozin 5 mg once daily for 12 weeks, three of whom had eligibility criteria deviations, such as serum ferritin < 50 ng/mL. For this purpose, 14 subjects were analyzed as full analysis set (FAS) and 11 as per-protocol set (PPS). FAS analysis revealed that dapagliflozin had no effect on hemoglobin A1c after 12 weeks but significantly decreased body mass index, significantly increased hemoglobin, hematocrit, and red blood cell count, significantly decreased log ferritin level only of iron metabolism index, and no important change in body water content. PPS analysis, on the other hand, revealed that dapagliflozin 12-week treatment showed a significant decrease in log hepcidin, serum iron, and transferrin saturation.Conclusion: These findings suggest that a 12-week course of dapagliflozin causes an increase in hemoglobin levels due to its hematopoietic effects in elderly type 2 diabetics with renal impairment, but that these effects may be independent of body water loss and iron metabolism improvement.Keywords: dapagliflozin, anemia, hemoglobin, iron metabolism, body composition

Takeshi Osonoi, Miyoko Saito, Naoya Koda, Satako Douguchi, Takako Nakano, Kensuke Ofuchi, Makoto Katoh Naka Kinen Clinic, Ibaraki, JapanCorrespondence: Makoto KatohNaka Kinen Clinic, 745-5 Nakadai, Naka-Shi, Ibaraki 311-0113, JapanTel +81-29-353-2800Fax +81-29-295-5400Email m-katou@kensei-kai.comPurpose: We retrospectively evaluated the long-term effect of dipeptidyl peptidase (DPP)-4 inhibitors on estimated glomerular filtration rate (eGFR) slopes, and then evaluated the beneficial interaction between DPP-4 inhibitor initiation and baseline use of α-glucosidase inhibitor and/or metformin in patients with diabetic kidney disease.Patients and Methods: Altogether, 1512 patients with type 2 diabetes were receiving DPP-4 inhibitor therapy over 1 year and were followed up for a maximum of 2 years before and after 7 years of treatment. The decline in renal function was estimated as the slope of the individual linear regression line of eGFR over 2-year follow-up. Prescription data on medications before and after DPP-4 inhibitor treatment were examined.Results: The mean length of DPP-4 inhibitor treatment was 5.3 ± 2.6 years. The baseline mean eGFR slope (mL/min/1.73m2/year) was − 2.24 ± 6.05. After DPP-4 inhibitor treatment, mean eGFR slope was significantly improved (− 1.53 ± 6.36, P < 0.01) in patients with type 2 diabetes. This effect appeared more pronounced for baseline use of α-glucosidase inhibitor and/or metformin in patients with diabetic kidney disease. These non-users showed a trend towards attenuation or no effects.Conclusion: In the present study, patients treated with DPP-4 inhibitors had a significantly slower annual loss of kidney function. The benefit appears pronounced in α-glucosidase inhibitor and metformin users with advanced renal dysfunction. These results suggest that the beneficial effects of DPP-4 inhibitors on kidney function may have occurred in the presence of an α-glucosidase inhibitor and/or metformin.Keywords: DPP-4 inhibitor, α-glucosidase inhibitor, metformin, eGFR slope, type 2 diabetes

It is likely that the C allele of the polymorphism at position 29 of the translated sequence of transforming growth factor (TGF)-[beta]1 gene, which codes a pleiotropic cytokine expressed in a variety of cells, is a susceptibility allele for cerebral infarction in Japanese type 2 diabetic patients. [ABSTRACT FROM AUTHOR]

Abstract: It is well known that oxidative stress plays critical roles in the pathogenesis of atherosclerosis. In this study, we enrolled 1746 type 2 diabetic subjects, determined 4 common genetic variants related to oxidative stress (glutamate-cysteine ligase modifier subunit (GCLM) C-588T, myeloperoxidase G-463A, human paraoxonase 1 Gln192Arg and NAD(P)H oxidase p22phox C242T polymorphisms), and measured carotid intima-media thickness (IMT) as a surrogate marker for atherosclerosis. GCLM C-588T polymorphism was associated with average IMT (AveIMT) (r =0.090, p =0.0008), but the association between the other 3 polymorphisms and AveIMT did not reach the statistical significance. However, AveIMT was significantly greater as the total number of 4 concomitant “pro-oxidant alleles” in each subject was increased (r =0.108, p <0.0001). Furthermore, the number of “pro-oxidant alleles” was a risk factor for a high AveIMT independently of conventional risk factors (p =0.0003). In conclusion, accumulation of oxidative stress-associated alleles was associated with carotid atherosclerosis in type 2 diabetic patients. [Copyright &y& Elsevier]

Aim: No pharmacotherapeutic treatment has been established for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). This trial compared the effects of pemafibrate and omega-3-acid ethyl ester on hepatic function in patients with hypertriglyceridemia complicated by MASLD., Methods: Patients with hypertriglyceridemia complicated by MASLD were enrolled, randomly assigned to the pemafibrate or omega-3-acid ethyl ester group, and followed for 24 weeks. The primary endpoint was the change in alanine aminotransferase (ALT) from baseline to week 24. The secondary endpoints included other hepatic enzymes, lipid profiles, and hepatic fibrosis biomarkers., Results: A total of 80 patients were enrolled and randomized. The adjusted mean change in ALT from baseline to week 24 was significantly lower in the pemafibrate group (-19.7±5.9 U/L) than in the omega-3-acid ethyl ester group (6.8±5.5 U/L) (intergroup difference, -26.5 U/L; 95% confidence interval, -42.3 to -10.7 U/L; p=0.001). Pemafibrate significantly improved the levels of other hepatic enzymes (aspartate aminotransferase and gamma-glutamyl transpeptidase), lipid profiles (triglycerides, total cholesterol, high-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol), and hepatic fibrosis biomarkers (Mac-2 binding protein glycan isomer and Fibrosis-4 index). No cases of discontinuation due to adverse drug reactions were identified in either group, and there were no safety concerns., Conclusions: Pemafibrate is recommended over omega-3-acid ethyl ester for lipid management and MASLD treatment in patients with hypertriglyceridemia complicated by MASLD. The study results may contribute to the development of future treatment strategies for patients with MASLD/MASH.

Aim: To evaluate glycaemic control, body weight, and safety outcomes following treatment with tirzepatide or dulaglutide in patients with type 2 diabetes (T2D) with a baseline haemoglobin (HbA1c) level of ≤8.5% (≤69 mmol/mol) versus >8.5% (>69 mmol/mol)., Materials and Methods: SURPASS J-mono was a 52-week, multicentre, randomized, double-blind, parallel, active-controlled, phase 3 study conducted in Japan. In this exploratory subgroup analysis of SURPASS J-mono, we examined mean change in HbA1c and body weight and the incidence of adverse events (AEs) in patients with a baseline HbA1c of ≤8.5% versus >8.5% after treatment with tirzepatide (5, 10 or 15 mg) or dulaglutide 0.75 mg., Results: Of 636 randomized participants, 203 had a baseline HbA1c of >8.5% and 433 had a baseline HbA1c of ≤8.5% (range ≥7.0% to ≤10.0%). Both subgroups showed significantly greater reductions in HbA1c and body weight with any-dose tirzepatide versus dulaglutide 0.75 mg, with greater HbA1c reductions observed in patients with a baseline HbA1c of >8.5% treated with tirzepatide (least squares mean [LSM] differences of -3.13% to -3.86%) or dulaglutide (LSM -1.81%) compared with patients with a baseline HbA1c of ≤8.5% (LSM -2.00% to -2.32%) or dulaglutide (LSM -1.05%; treatment-by-baseline HbA1c subgroup interaction P ≤ 0.001). For the tirzepatide treatment arms, LSM change from baseline in body weight ranged from -6.7 to -10.7 kg for the baseline HbA1c ≤8.5% subgroup and from -4.0 to -10.6 kg for the baseline HbA1c >8.5% subgroup, compared with -0.6 kg and -0.4 kg, respectively, for the dulaglutide arm. The incidence of hypoglycaemia was low, with no substantial difference in hypoglycaemia or treatment-emergent AEs between subgroups., Conclusions: Regardless of baseline HbA1c (≤8.5% or >8.5%), tirzepatide at doses of 5, 10 and 15 mg is effective in Japanese patients with T2D compared with dulaglutide 0.75 mg in terms of glycaemic control and body weight reduction, with an adequate safety profile consistent with previous reports., (© 2023 Eli Lilly Japan K.K and The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims/hypothesis: Previous studies have suggested that glucose variability may accelerate atherosclerosis progression in people with type 2 diabetes. Current guidelines recommend assessing glycaemic control using continuous glucose monitoring (CGM), which provides a comprehensive glycaemic profile to supplement HbA 1c measurement. However, the association between CGM-derived metrics and atherosclerosis progression is not entirely clear., Methods: This exploratory study used baseline data and data obtained after 104 weeks from an ongoing prospective, multicentre, observational study. Six hundred study participants with type 2 diabetes and no apparent history of symptomatic cardiovascular disease underwent CGM and ultrasonographic atherosclerosis measurements of the carotid arteries, including the intima-media thickness (IMT) and grey-scale median (GSM), at baseline and 104 weeks. Non-invasive ultrasonic tissue characterisation of the carotid artery wall or plaque using the GSM reflects vascular composition. Multivariate regression models were used to analyse the association between CGM-derived indices, mainly time in range (TIR) and CV, and changes in carotid atherosclerosis index values., Results: Over the 104-week study period, there were modest increases in mean IMT (from 0.759±0.153 to 0.773±0.152 mm, p<0.001) and thickened-lesion GSM (from 43.5±19.5 to 53.9±23.5 units, p<0.001), but no significant changes in common carotid artery maximum-IMT (from 1.109±0.442 to 1.116±0.469 mm, p=0.453) or mean GSM (from 48.7±19.3 to 49.8±20.8 units, p=0.092). In a linear regression model with adjustment for possible atherosclerotic risk factors, including HbA 1c , TIR and CV at baseline were significantly associated with the annual change in mean GSM (regression coefficient per 10% increase in TIR 0.52; 95% CI 0.06, 0.98; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.12; 95% CI -0.22, -0.02; Hochberg-adjusted p value 0.038). TIR and CV at baseline were also significantly associated with the annual change in thickened-lesion GSM (regression coefficient per 10% increase in TIR 0.95; 95% CI 0.12, 1.79; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.19; 95% CI -0.36, -0.01; Hochberg-adjusted p value 0.038). Participants who achieved target CGM-derived metrics at baseline, as proposed by an international consensus, showed significant annual changes in mean GSM compared with those who did not (0.94±6.88 vs -0.21±6.19 units/year, p=0.007)., Conclusions/interpretation: TIR and CV were significantly associated with changes in the tissue characteristics of the carotid artery wall., Trial Registration: University Hospital Medical Information Network Clinical Trials Registry, number UMIN000032325., (© 2023. The Author(s).)

We previously reported in the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A) that alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuated the progression of carotid atherosclerosis in subjects with type 2 diabetes and no history of cardiovascular disease. This extension study of the SPEAD-A trial investigated whether early alogliptin initiation improved long-term cardiovascular outcomes. The SPEAD-A trial randomized 341 subjects with type 2 diabetes to either alogliptin or conventional treatment to investigate the effects of alogliptin on atherosclerosis. All subjects who completed that trial were eligible for this prospective, observational cohort study. The primary endpoint was the first occurrence of a major cardiovascular event, defined as death due to any cause, acute myocardial infarction, or stroke. During the 520-week follow-up period, composite primary outcome events occurred in only a few subjects in each group [8 (5.4%) in the alogliptin group and 9 in the conventional treatment group (5.9%)]. There were no significant differences in the incidence rate of the primary outcome between the two groups. Post hoc Poisson regression analysis showed no significant difference between the two groups in the incidence rate of composite recurrence events for the same outcomes as the primary endpoint. On the other hand, this incidence rate was significantly lower in subjects who received DPP-4 inhibitors before an initial cardiovascular event than in those who did not (5.8 vs. 13.3 per 1000 person-years, respectively, p = 0.04). Early initiation of alogliptin was not associated with a reduced risk of composite cardiovascular disease, which could be attributed to fewer events and/or the addition of DPP-4 inhibitors during the follow-up period., (© 2023. Springer Nature Limited.)

Background: This study aimed to assess the long-term effects of tofogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes lacking an apparent history of cardiovascular disease., Methods: This was a prospective observational 2-year extension study of the "Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)" trial, a 2-year randomized intervention study. The primary endpoints represented changes in the carotid intima-media thickness (IMT). Secondary endpoints included brachial-ankle pulse wave velocity (baPWV) and biomarkers for glucose metabolism, lipid metabolism, renal function, and cardiovascular risks., Results: The mean IMT of the common carotid artery (IMT-CCA) significantly decreased in both the tofogliflozin (- 0.067 mm, standard error 0.009, p < 0.001) and conventional treatment groups (- 0.080 mm, SE 0.009, p < 0.001) throughout the follow-up period; however, no significant intergroup differences in the changes (0.013 mm, 95% confidence interval (CI) - 0.012 to 0.037, p = 0.32) were observed in a mixed-effects model for repeated measures. baPWV significantly increased in the conventional treatment group (82.7 ± 210.3 cm/s, p = 0.008) but not in the tofogliflozin group (- 17.5 ± 221.3 cm/s, p = 0.54), resulting in a significant intergroup difference in changes (- 100.2 cm/s, 95% CI - 182.8 to - 17.5, p = 0.018). Compared to the conventional treatment group, tofogliflozin significantly improved the hemoglobin A1c and high-density lipoprotein cholesterol levels, body mass index, abdominal circumference, and systolic blood pressure. The frequencies of total and serious adverse events did not vary significantly between the groups., Conclusions: Tofogliflozin was not associated with improved inhibition of carotid wall thickening but exerted long-term positive effects on various cardiovascular risk factors and baPWV while showing a good safety profile., (© 2023. The Author(s).)

Background: Imeglimin is a novel type 2 diabetes (T2D) drug that is expected to improve mitochondrial function. In its phase 3 clinical trials in Japanese patients with T2D, the hemoglobin A1c (HbA1c) decrease following imeglimin administration was slow, reaching a plateau after 20-24 weeks of treatment. In general, the erythrocyte lifespan may be a factor when HbA1c shows an abnormal value. Therefore, this study will comparatively evaluate HbA1c and other markers of glycemic control in patients with T2D after imeglimin administration and also examine the effects of imeglimin on erythrocytes. Methods: This single-arm, open-label, prospective, exploratory study is designed to evaluate the divergence between HbA1c and glycoalbumin (GA) or 1,5-anhydroglucitol (1,5-AG) and the glycemic reduction rate in 30 patients with T2D with inadequate glycemic control when imeglimin 2,000 mg is administered for 6 months. In addition, we will examine the effect on erythrocytes, the presumed cause of this divergence. We will measure sustained glycemic variability using flash glucose monitoring and examine the relationship between changes in these indices and HbA1c. Moreover, because prolonged erythrocyte lifespan is a possible cause of falsely high HbA1c levels, erythrocyte lifespan, erythrocyte deformability, and hemoglobin concentration will be evaluated as effects of imeglimin on erythrocytes. Furthermore, if imeglimin has an ameliorative effect on erythrocyte deformability, it may improve peripheral arterial disease; thus, we will also evaluate the toe-brachial pressure index, a measure of this effect. Discussion: In this study, if imeglimin administration results in diverging rates of hypoglycemic effect between HbA1c and GA or 1,5-AG and prolongs erythrocyte lifespan, GA and 1,5-AG, rather than HbA1c, will be considered appropriate measures of the hypoglycemic effect in the early stages of imeglimin administration. If imeglimin improves erythrocyte deformability, it may also be a new treatment strategy for peripheral arterial disease, a chronic complication of T2D. Ethics and dissemination: The study protocol was scientifically and ethically reviewed and approved by the Certified Clinical Research Review Board of Toho University (approval number: THU22002). The study protocol was registered in the Japan Registry of Clinical Trials (jRCT) in December 2022 (jRCTs031220489)., Competing Interests: TO received research funding from Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Bayer Yakuhin, Ltd., Fuji Yakuhin Co., Ltd., Mochida Pharmaceutical Co. Ltd., Kowa Pharmaceutical Co., Ltd. and Gilead Sciences, and honoraria for lectures from Novo Nordisk Pharma Co., Ltd., and Sumitomo Pharma Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Osonoi, Shirabe, Saito, Hosoya, Douguchi, Ofuchi and Katoh.)

Background: Dotinurad is a novel uricosuric drug in Japan with selective and potent urate transporter 1 (URAT1) inhibitory activity. This study aims to evaluate the efficacy and safety of dotinurad in hyperuricemic patients with type 2 diabetic kidney disease by comparing serum levels of urate and plasma and urinary levels of indoxyl sulfate excreted via the urate excretion transporter ATP binding cassette subfamily G member 2 (ABCG2), as indices, with baseline levels after switching from febuxostat to dotinurad., Methods: This single-center, single-arm, open-label, prospective, exploratory study aims to evaluate the effect of switching from febuxostat to dotinurad on serum urate levels and its background factors. The study will include 50 hyperuricemic patients with type 2 diabetic kidney disease and urate levels exceeding 6 mg/dL despite administration of febuxostat 20 mg/day for at least 3 months. The primary outcome is the achievement rate of serum urate levels of ≤6 mg/dL after 24 weeks of treatment with dotinurad at 0.5 mg to a maximum of 4 mg once daily. Secondary outcomes include the changes in serum urate levels, plasma and urinary indoxyl sulfate levels, and renal injury-related markers from baseline to observation points at weeks 4, 12, and 24., Discussion: The study hypothesizes that switching to dotinurad may reduce the plasma levels of indoxyl sulfate and increase its urinary levels in patients with hyperuricemia. These suggest that dotinurad can potently lower the serum urate level by inhibiting URAT1 without adversely affecting ABCG2. Thus, findings of this study are expected to provide useful insights into the treatment of hyperuricemia associated with type 2 diabetic kidney disease and the discovery of new possibilities for dotinurad., Ethics and Dissemination: Prior to the study, its study protocol was scientifically and ethically reviewed and approved by the Japan Physicians Association Clinical Research Review Board (approval number: JPA007-2204-02). In addition, patients who provide written informed consent will participate in the study. The results of this study will be published through submission to a peer-reviewed scientific journal., Clinical Trial Registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs031220080, identifier jRCTs031220080., Competing Interests: TO received research funding from Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Bayer Yakuhin, Ltd., Kowa Pharmaceutical Co., Ltd. and Gilead Sciences, and honoraria for lectures from Novo Nordisk Pharma Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Osonoi, Saito, Hosoya, Douguchi, Ofuchi and Katoh.)

Context: Current guidelines recommend assessing glycemic control using continuous glucose monitoring (CGM) and hemoglobin A1c (HbA1c) measurement., Objective: This study aimed to clarify the characteristics of patients who might benefit from CGM metrics in addition to HbA1c monitoring., Methods: CGM metrics, specifically time in range (TIR), time below range (TBR), and time above range (TAR), were determined in 999 outpatients with type 2 diabetes and compared between HbA1c categories (HbA1c < 53 mmol/mol [7.0%, HbA1c <  53], HbA1c 53-63 mmol/mol [7.0-7.9%, HbA1c 53-63], HbA1c 64-74 mmol/mol [8.0-8.9%, HbA1c 64-74], and HbA1c ≥ 75 mmol/mol [9.0%, HbA1c ≥  75]) and between patients with identical HbA1c categories who were stratified by age, types of antidiabetic agents, and renal function., Results: For HbA1c <  53 category, patients aged ≥ 65 years had a significantly higher nocturnal TBR than those aged < 65 years. For HbA1c <  53 and HbA1c 53-63 categories, patients receiving insulin and/or sulfonylureas had a significantly higher TAR and TBR, and a lower TIR than those not receiving these drugs, and for HbA1c 64-74 category, they had a significantly higher TBR. For HbA1c <  53, HbA1c 53-63, and HbA1c 64-74 categories, patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 had a significantly higher TBR during some periods than those with an eGFR ≥ 60., Conclusion: Higher HbA1c levels do not always protect against hypoglycemic episodes. Our data demonstrate that using CGM metrics to complement HbA1c monitoring is beneficial, especially in older people, users of insulin and/or sulfonylureas, and patients with chronic kidney disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Barley reportedly reduces postprandial hyperglycemia in healthy individuals. However, its effects in patients with type 2 diabetes mellitus (T2DM) undergoing antidiabetic therapy remains unclear. This study aimed to clarify the effects of barley intake on postprandial hyperglycemia in T2DM patients who use metformin or acarbose., Methods: T2DM patients who were undergoing dietary therapy without medications (naive), with metformin, or with acarbose ( n  = 10/group) were recruited. They were instructed to eat white rice twice per day for 5 days, followed by barley-mixed rice twice per day for 6 or 7 days. Subsequently, blood glucose fluctuations in the interstitial fluid glucose were measured using a continuous glucose monitoring device. Meal tolerance tests were performed using test diets containing white rice and barley-mixed rice before and after the trial, respectively., Results: Postprandial hyperglycemia was lower in patients taking barley-mixed rice than in those taking white rice in each group. However, the AUC of blood glucose concentration in the acarbose-treated patients showed only a trend. Mean amplitude of glycemic excursions (MAGEs) decreased in patients who consumed barley-mixed rice. Additionally, although MAGEs in the naive decreased, it did not in the metformin- ( P  = 0.098) and acarbose-treated ( P  = 0.29) patients., Conclusion: Barley-mixed rice lowers postprandial glucose concentrations in treatment-naive and metformin-treated T2DM patients, and shows a trend in acarbose-treated patients. Therefore, using barley-containing diets as dietary therapy may be useful in improving glycemic control in diabetes patients., Trial Registration: UMIN000028623., Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00552-z., Competing Interests: Conflict of interestTM and TK are employees of Hakubaku Co. Ltd. The remaining authors declare no conflict of interest., (© The Japan Diabetes Society 2021.)

Introduction: Treatment-related quality of life (QOL) is an important aspect of diabetes management. We evaluated the influence of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, tofogliflozin, on treatment-related QOL in Japanese patients with type 2 diabetes mellitus (T2DM)., Methods: This is the prespecified subanalysis study of the "Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)" trial. Treatment-related QOL was evaluated at baseline, week 26, week 52, and week 104 after the initiation of the study using the Diabetes Therapy-Related QOL questionnaire (DTR-QOL). Among the 340 patients in the original UTOPIA study, a total of 252 patients (127, tofogliflozin group; 125, conventional treatment group) who completed the DTR-QOL questionnaire at baseline were the study subjects of the current subanalysis., Results: The tofogliflozin and conventional treatment groups exhibited almost comparable baseline clinical characteristics, while the use of antihypertensive drugs and lipid-lowering agents was significantly lower in the tofogliflozin treatment group than in the conventional treatment group. Tofogliflozin treatment increased the total score of DTR-QOL7 from baseline (P < 0.001), while conventional treatment did not change it. There were statistically significant differences in delta change in the total DTR-QOL7 score and DTR-QOL7 Q4, Q5, Q6, and Q7 scores from the baseline to week 104 between the treatment groups. Delta changes in HbA1c (Spearman's correlation coefficient, ρ =  - 0.30, P < 0.001), fasting blood glucose (ρ =  - 0.16, P = 0.031), BMI (ρ =  - 0.19, P = 0.008), and waist circumference (ρ =  - 0.17, P = 0.024) at week 104 were negatively associated with delta change in the total QOL7 score., Conclusions: Our data indicated that tofogliflozin treatment improved treatment-related QOL compared to conventional treatment in Japanese patients with T2DM, in accordance with the improvement of major cardiovascular risk factors., Trial Registration: UMIN000017607., (© 2021. The Author(s).)

Introduction: Preventing the development and progression of diabetic microvascular complications through optimal blood glucose control remains an important challenge. Whether metrics based on continuous glucose monitoring are useful for the management of diabetic microvascular complications is not entirely clear., Research Design and Methods: This is an exploratory analysis of an ongoing prospective, multicenter, 5-year follow-up observational study. Study participants included 999 outpatients with type 2 diabetes who underwent continuous glucose monitoring at baseline. Associations between continuous glucose monitoring-derived metrics and the severity of diabetic retinopathy or albuminuria were investigated using multivariable proportional odds models., Results: The overall prevalence of diabetic retinopathy was 22.2%. Multivariate analysis with proportional odds models demonstrated that continuous glucose monitoring-derived metrics related to intraday and interday glucose variability are significantly associated with the severity of diabetic retinopathy, even after adjusting for various possible risk factors. However, significant relationships were not observed after adjusting for hemoglobin A1c (HbA1c) levels. The prevalence of microalbuminuria and macroalbuminuria was 20.3% and 6.7%, respectively. Similarly, multivariate analysis demonstrated that those metrics are significantly associated with the severity of albuminuria. These relationships remained significant even after further adjusting for HbA1c levels., Conclusions: Continuous glucose monitoring-derived metrics related to intraday and interday glucose variability are significantly associated with the severity of diabetic retinopathy or albuminuria in patients with type 2 diabetes. Thus, evaluating these metrics might possibly be useful for risk assessment of diabetic microvascular complications. Trial registration number UMIN000032325., Competing Interests: Competing interests: TO and HW have received research funds from Abbott Japan. HW is a member of the advisory board of Abbott Japan. All other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: We demonstrated that the mRNA induction of S100s in rat peripheral leukocytes by severe hyperglycemia was reduced by inhibiting postprandial hyperglycemia. Here, we compared inflammatory gene expression in peripheral leukocytes between type 2 diabetes mellitus (T2DM) patients undergoing dietary therapy alone and healthy volunteers, and between T2DM patients undergoing dietary therapy alone and those undergoing such therapy in combination with drug therapy using the α-glucosidase inhibitor miglitol., Methods: T2DM patients who had undertaken dietary therapy alone or in combination with drug therapy using miglitol for ≥ 8 weeks and healthy volunteers were subjected to a meal tolerance test and glucose concentration, neutrophil elastase concentration, and mRNA expression analyses of peripheral leukocytes by microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) immediately before and 180 min after a meal., Results: Blood glucose concentrations 60 min after a meal were lower in T2DM patients with dietary + miglitol therapy than in those with dietary therapy alone. Neutrophil elastase concentrations at 60 and 120 min after a meal were lower in T2DM patients with dietary + miglitol therapy than in those with dietary therapy alone. Expression levels of S100A8 in a fasting state and S100A6, S100A8, and S100A9 180 min after a meal were higher in T2DM patients with dietary therapy alone than in healthy volunteers. Expression levels of S100A12 in a fasting state and 180 min after a meal were higher in T2DM patients with dietary therapy alone than in T2DM patients with dietary + miglitol therapy., Conclusions: S100 genes were more highly expressed in T2DM patients with dietary therapy than in healthy volunteers.

Aims/introduction: There are few studies to investigate the relationship between macronutrients and longitudinal changes in arterial stiffness in patients with type 2 diabetes mellitus. This exploratory study sought to determine whether macronutrients were correlated with increased arterial stiffness independently of conventional atherosclerotic risk factors., Materials and Methods: The study participants comprised 733 type 2 diabetes outpatients who had no apparent history of cardiovascular diseases. The dietary schedule was assessed with a validated, brief, self-administered diet history questionnaire. At baseline and at years 2 and 5, brachial-ankle pulse wave velocity was measured. A multivariable linear mixed-effects model was used to determine the predictive values of macronutrients and atherosclerotic risk factors for longitudinal changes in brachial-ankle pulse wave velocity., Results: There was a significant increase in brachial-ankle pulse wave velocity values over the 5-year follow-up period. In a multivariable linear mixed-effects model that adjusted for age and sex, lower saturated fatty acid intake was significantly correlated with persistently higher brachial-ankle pulse wave velocity, independently of other atherosclerotic risk factors. Lower intake of dairy products in particular showed this correlation., Conclusions: Our data showed that lower saturated fatty acids intake was correlated with persistently higher brachial-ankle pulse wave velocity in type 2 diabetes patients. Among food sources of saturated fatty acids, lower dairy products specifically were correlated with elevated brachial-ankle pulse wave velocity. This might be because the consumption of dairy products in Japan is much lower than in Western countries., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Hyperkalemia is associated with many chronic diseases and renin-angiotensin-aldosterone system inhibitor therapy. Sodium zirconium cyclosilicate (SZC), an oral, highly selective cation-exchanger, is approved for the treatment of hyperkalemia., Methods: This phase 3, multicenter, open-label, single-arm, flexible-dose study assessed the safety and efficacy of SZC in Japanese patients with hyperkalemia during a correction phase of up to 3 days and long-term (1 year) maintenance phase (NCT03172702)., Results: Overall, 150 patients received treatment during both study phases; the study population was generally representative of hyperkalemic Japanese patients in clinical practice. Most patients (78.7%) had three doses of SZC during the correction phase. All but one patient received SZC for ≤ 48 h before transitioning to the maintenance phase. In the maintenance phase, mean (standard deviation; SD) exposure to the study drug was 319.4 (98.1) days and mean (SD) dose was 7.38 (2.85) g/day. Adverse events (AEs) were reported in 131 patients (87.3%); most were mild. The most common treatment-related AEs as evaluated by investigators were constipation (6.7%), peripheral edema (4.0%), and hypertension (2.7%). In the correction phase, 78.7% of patients were normokalemic at 24 h and 98.7% within 48 h; ≥ 65.5% maintained normokalemia throughout the maintenance phase., Conclusion: After a year of exposure, SZC treatment was well tolerated by Japanese patients and potassium levels were well controlled.

Background: Previous studies have suggested that high mean glucose levels and glycemic abnormalities such as glucose fluctuation and hypoglycemia accelerate the progression of atherosclerosis in patients with type 2 diabetes. Although continuous glucose monitoring (CGM) that could evaluate such glycemic abnormalities has been rapidly adopted, the associations between CGM-derived metrics and arterial stiffness are not entirely clear., Methods: This exploratory cross-sectional study used baseline data from an ongoing prospective, multicenter, observational study with 5 years of follow-up. Study participants included 445 outpatients with type 2 diabetes and no history of apparent cardiovascular disease who underwent CGM and brachial-ankle pulse wave velocity (baPWV) measurement at baseline. Associations between CGM-derived metrics and baPWV were analyzed using multivariate regression models., Results: In a linear regression model, all CGM-derived metrics were significantly associated with baPWV, but HbA1c was not. Some CGM-derived metrics related to intra-day glucose variability, hyperglycemia, and hypoglycemia remained significantly associated with baPWV after adjusting for possible atherosclerotic risk factors, including HbA1c. Based on baPWV ≥ 1800 cm/s as indicative of high arterial stiffness, multivariate logistic regression found that some CGM-derived metrics related to intra-day glucose variability and hyperglycemia are significantly associated with high arterial stiffness even after adjusting for possible atherosclerotic risk factors, including HbA1c., Conclusions: Multiple CGM-derived metrics are significantly associated with baPWV and high arterial stiffness in patients with type 2 diabetes who have no history of apparent cardiovascular disease. These metrics might be useful for identifying patients at high risk of developing cardiovascular disease.

Background: Tofogliflozin, an SGLT2 inhibitor, is associated with favorable metabolic effects, including improved glycemic control and serum lipid profile and decreased body weight, visceral adipose tissue, and blood pressure (BP). This study evaluated the effects of tofogliflozin on the brachial-ankle pulse wave velocity (baPWV) in patients with type 2 diabetes (T2DM) without a history of apparent cardiovascular disease., Methods: The using tofogliflozin for possible better intervention against atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. As one of the prespecified secondary outcomes, changes in baPWV over 104 weeks were evaluated in 154 individuals (80 in the tofogliflozin group and 74 in the conventional treatment group) who completed baPWV measurement at baseline., Results: In a mixed-effects model, the progression in the right, left, and mean baPWV over 104 weeks was significantly attenuated with tofogliflozin compared to that with conventional treatment (- 109.3 [- 184.3, - 34.3] (mean change [95% CI] cm/s, p = 0.005; - 98.3 [- 172.6, - 24.1] cm/s, p = 0.010; - 104.7 [- 177.0, - 32.4] cm/s, p = 0.005, respectively). Similar findings were obtained even after adjusting the mixed-effects models for traditional cardiovascular risk factors, including body mass index (BMI), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, systolic blood pressure (SBP), hypertension, smoking, and/or administration of drugs, including hypoglycemic agents, antihypertensive agents, statins, and anti-platelets, at baseline. The findings of the analysis of covariance (ANCOVA) models, which included the treatment group, baseline baPWV, and traditional cardiovascular risk factors, resembled those generated by the mixed-effects models., Conclusions: Tofogliflozin significantly inhibited the increased baPWV in patients with T2DM without a history of apparent cardiovascular disease, suggesting that tofogliflozin suppressed the progression of arterial stiffness. Trial Registration UMIN000017607. Registered 18 May 2015. ( https://www.umin.ac.jp/icdr/index.html ).

Aims/introduction: We investigated the effect of FreeStyle Libre TM on glycemic control in Japanese type 2 diabetes patients treated with basal-bolus insulin therapy., Materials and Methods: This prospective, 90-day single-arm study enrolled 94 adults with type 2 diabetes treated with insulin. A 14-day masked baseline phase was followed by an 11-week treatment phase during which participants used the device to monitor glucose levels. The primary end-point was time spent in hypoglycemia (<70 mg/dL) for baseline versus study end (days 76-90). Secondary end-points included other measures of glycemic control, along with patient satisfaction using the Japanese Diabetes Treatment and Satisfaction Questionnaire., Results: Time spent in hypoglycemia was low at baseline (0.51 ± 0.93 h/day) and did not significantly decrease at study end (0.47 ± 0.63 h/day, P = 0.6354). Time in range, time in hyperglycemia and estimated A1c all improved versus baseline (by +1.7 ± 3.0 h/day, -1.6 ± .4 h/day and -0.4 ± 0.8%, respectively, P < 0.0001 in each). Finger stick tests fell from 2.9 ± 1.3 to 1.9 ± 1.4/day, and mean scanning frequency during the intervention phase was 11.3/day. The mean treatment satisfaction score increased by 11.8 ± 5.3 (P < 0.0001). Two severe hypoglycemia-related adverse events were reported; one of which was possibly related to the device. Three participants reported mild device-related skin trauma, site discomfort or subcutaneous bleeding., Conclusions: Use of FreeStyle Libre by Japanese type 2 patients diabetes treated with basal-bolus insulin therapy showed a low baseline of hypoglycemia, and enabled improved glycemic control and treatment satisfaction., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Sodium zirconium cyclosilicate (SZC) is an oral potassium binder approved to treat hyperkalemia in adults in a number of countries, including Japan., Methods: This phase 2/3, randomized, double-blind, placebo-controlled, dose-response study (ClinicalTrials.gov: NCT03127644) was designed to determine the efficacy and safety of SZC in Japanese adults with hyperkalemia. Patients with serum potassium (sK + ) concentrations ≥ 5.1- ≤ 6.5 mmol/L were randomized 1:1:1 to SZC 5 g, SZC 10 g, or placebo three times daily for 48 h (six doses total). The primary efficacy endpoint was the exponential rate of change in sK + over 48 h. The proportion of patients with normokalemia (sK + 3.5-5.0 mmol/L) at 48 h and adverse events (AEs) were also evaluated., Results: Overall, 103 patients (mean age, 73.2 years; range 50-89 years) received SZC 5 g (n = 34), SZC 10 g (n = 36), or placebo (n = 33). The exponential rate of sK + change from 0 to 48 h versus placebo was - 0.00261 (SZC 5 g) and - 0.00496 (SZC 10 g; both P < 0.0001). At 48 h, the proportions of patients with normokalemia were 85.3%, 91.7%, and 15.2% with SZC 5 g, SZC 10 g, and placebo, respectively. No serious AEs were reported. Hypokalemia (sK +  < 3.5 mmol/L) occurred in two patients in the SZC 10 g group; normokalemia was re-established within 6 days and no treatment-related AEs were reported., Conclusion: SZC is effective and well tolerated in Japanese patients with hyperkalemia.

Background: Liraglutide was administered to patients with type 2 diabetes, and its effects on estimated glomerular filtration rate (eGFR) slopes and albuminuria were retrospectively evaluated. Methods: This study included 568 patients with type 2 diabetes who received liraglutide therapy (up to 0.9 mg/day) >1 year and were followed-up for a maximum of 2 years before and 7 years after treatment. The decline in renal function was estimated as the slope of the individual linear regression line of eGFR over the follow-up time. Spot urine samples were collected to measure albuminuria, which were calculated using creatinine levels. In addition, HbA1c, body weight, blood pressure, and heart rate were monitored. Results: The mean liraglutide treatment period was 3.1 ± 2.0 years. The mean baseline eGFR slope [mL/(min ·1.73 m 2 ·year)] was -2.75 ± 6.04. After liraglutide treatment, the mean eGFR slope significantly improved (-1.42 ± 4.30, P  < 0.01). This effect appeared more pronounced for baseline eGFRs <45 mL/(min ·1.73 m 2 ). Albuminuria, HbA1c, body weight, and systolic blood pressure levels were significantly reduced after treatment with liraglutide for 1 year, whereas diastolic blood pressure and heart rates were increased. Conclusions: Patients treated with liraglutide experienced a significantly slower annual decline in kidney function. The benefit appeared more pronounced in patients with the development and progression of diabetic kidney disease. These results suggest that the benefits of liraglutide on kidney function identified in clinical trials appear to be well generalizable to clinical practice.

Background: This study aimed to investigate the preventive effects of tofogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD) by monitoring carotid intima-media thickness (IMT)., Methods: This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study included 340 subjects with T2DM and no history of apparent CVD recruited at 24 clinical units. Subjects were randomly allocated to either the tofogliflozin treatment group (n = 169) or conventional treatment group using drugs other than SGLT2 inhibitors (n = 171). Primary outcomes were changes in mean and maximum common carotid IMT measured by echography during a 104-week treatment period., Results: In a mixed-effects model for repeated measures, the mean IMT of the common carotid artery (mean-IMT-CCA), along with the right and left maximum IMT of the CCA (max-IMT-CCA), significantly declined in both the tofogliflozin (- 0.132 mm, SE 0.007; - 0.163 mm, SE 0.013; - 0.170 mm, SE 0.020, respectively) and the control group (- 0.140 mm, SE 0.006; - 0.190 mm, SE 0.012; - 0.190 mm, SE 0.020, respectively). Furthermore, the tofogliflozin and the conventional treatment group did not significantly differ in the progression of the mean-IMT-CCA (mean change (95% CI) 0.008 (- 0.009, 0.025) mm, P = 0.34), along with the right (mean change (95% CI) 0.027 (- 0.005, 0.059) mm, P = 0.10) and the left max-IMT-CCA (mean change (95% CI) 0.020 (- 0.030, 0.070), P = 0.43). Similar findings were obtained even after adjusting for traditional CV risk factors and/or administration of drugs at baseline. Relative to the control treatment effects, tofogliflozin significantly reduced the HbA1c, blood glucose level, body weight/body mass index, abdominal circumference, and systolic blood pressure, and significantly increased the HDL-C. The total and serious adverse events incidences did not significantly vary between the treatment groups., Conclusions/interpretation: No IMT changes were observed between the tofogliflozin and the conventional treatment groups. However, tofogliflozin is a safe and effective treatment option for managing primary CVD risk factors in this population. Clinical Trial Registration UMIN000017607 ( https://www.umin.ac.jp/icdr/index.html ).

Objective: While certain lifestyle habits may be associated with arterial stiffness, there is limited literature investigating the relationship between lifestyle habits and longitudinal changes in arterial stiffness in patients with type 2 diabetes mellitus (T2DM). This is an exploratory study to determine whether lifestyle habits, in addition to conventional atherosclerotic risk factors, are associated with increased arterial stiffness., Research Design and Methods: The study participants comprised 734 Japanese outpatients with T2DM and no history of apparent cardiovascular diseases. Lifestyle habits were analyzed using self-reported questionnaires, and brachial-ankle pulse wave velocity (baPWV) was measured at baseline, and at years 2 and 5. A multivariable linear mixed-effects model was used to determine the predictive value of lifestyle habits and possible atherosclerotic risk factors for longitudinal change in baPWV., Results: Over 5 years of follow-up, baPWV values significantly increased. In a multivariable linear mixed-effects model that adjusted for age and gender, a low frequency of breakfast intake was significantly associated with persistently high baPWV, independently of other lifestyle habits. Furthermore, in a multivariable linear mixed-effects model that included both lifestyle habits and possible atherosclerotic risk factors, a low frequency of breakfast intake remained the only independent predictive factor for persistently high baPWV. Subjects who ate breakfast less frequently tended to have additional unhealthy lifestyle habits and atherosclerotic risk factors., Conclusions: Our analyses suggest that breakfast skipping is an independent lifestyle habit that is associated with persistently increased arterial stiffness in patients with T2DM., Trial Registration Number: UMIN000010932., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: To investigate canagliflozin-induced changes in postprandial total glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels in patients with type 2 diabetes mellitus (T2DM)., Methods: Forty-five patients with T2DM who had inadequate glycemic control (glycated hemoglobin ≥ 6.5%) with diet and exercise alone (n = 15, drug naïve) and in combination with either a stable dose of the α-glucosidase inhibitor acarbose (n = 15) or metformin (n = 15) received canagliflozin, a sodium-glucose cotransporter 2 inhibitor, at 100 mg once daily for 12 weeks. The primary endpoint was the change from baseline to week 12 in postprandial glucose and plasma levels of total GLP-1 and GIP during a meal tolerance test (MTT)., Results: Canagliflozin significantly reduced postprandial blood glucose (mean difference - 40.2 mg/mL at 60 min) and increased postprandial total GLP-1 (mean difference 1.8 pg/mL at 60 min) during an MTT. A transient reduction in the postprandial GIP level at only 30 min (mean difference - 80.3 pg/mL) during an MTT was observed. No changes in postprandial GLP-1 or GIP levels were seen after canagliflozin treatment as an add-on to acarbose in patients with T2DM. Acarbose treatment significantly decreased postprandial total GIP levels (P < 0.05) and tended to increase postprandial total GLP-1 levels (P = 0.07) compared to the other two treatments prior to canagliflozin., Conclusion: Canagliflozin 100 mg increased postprandial total GLP-1 levels in the absence of acarbose, suggesting that it may upregulate GLP-1 secretion through delayed glucose absorption in the upper intestine, as with the α-glucosidase inhibitor., Trial Registration: University Hospital Medical Information Network, UMIN000018345., Funding: Mitsubishi Tanabe Pharma Corporation.

Introduction: This open-label, parallel-group, exploratory study examined the effects of two dipeptidyl peptidase 4 (DPP4) inhibitors on glycemic variability (GV) in patients with type 2 diabetes., Methods: Randomized patients with glycated hemoglobin A1c of at least 6.5% to less than 8.5% received trelagliptin 100 mg (n = 13) once weekly or alogliptin 25 mg (n = 14) once daily for 29 days. Continuous glucose monitoring was performed before the start of the treatment period (baseline) and from day 21 to 29, inclusive. The primary endpoint was change from baseline in the standard deviation (SD) of 24-h blood glucose values, measured daily for 7 days (day 22-28) of the treatment period. Secondary and additional efficacy endpoints included changes in glycemic parameters and the rate of DPP4 inhibition, respectively. Adverse events (AEs) were monitored to assess safety., Results: Mean change from baseline in the SD of 24-h blood glucose (95% confidence interval) at day 28 was - 7.35 (- 15.13, 0.44) for trelagliptin and - 11.63 (- 18.67, - 4.59) for alogliptin. In both treatment groups, glycemic parameters improved and the rate of DPP4 inhibition was maintained. Three patients reported AEs; no severe treatment-emergent AEs were reported in either group., Conclusion: Once-weekly trelagliptin and once-daily alogliptin improved glycemic control and reduced GV without inducing hypoglycemia., Trial Registration: ClinicalTrials.gov (NCT02771093) and JAPIC (JapicCTI-163250)., Funding: Takeda Pharmaceutical Company, Ltd.

Introduction: A recent study demonstrated that large glucose fluctuations were associated with an increased incidence of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) and acute myocardial infarction. However, it is unknown whether glucose fluctuations are related to the incidence of CVD or the progression of atherosclerosis in patients with T2DM with no apparent history of CVD. In this protocol, we will be investigating the relationships of glucose fluctuations evaluated by continuous glucose monitoring (CGM) to the incidence of composite cardiovascular events and the progression of atherosclerosis in patients with T2DM who had no apparent history of CVD., Methods: This is a prospective, multicenter, 5-year follow-up observational study. Between April 2018 and October 2019, 1000 participants are expected to be recruited at 34 medical institutions. CGM using FreeStyle Libre Pro is useful for evaluating glucose fluctuations by continuously monitoring glucose levels in interstitial fluid for up to 14 days. The primary study outcome is the relationship between fluctuations in glucose levels evaluated by CGM and the incidence of composite cardiovascular events. Secondary outcomes include the relationships of fluctuations in glucose levels evaluated by CGM to changes in carotid intima media thickness evaluated by echography or grayscale median (an index of tissue characteristics of the carotid wall), brachial-ankle pulse wave velocity, development or progression of diabetic retinopathy or nephropathy, quality-of-life-related diabetes therapy, quality of sleep, development of dementia, and autonomic nerve function., Planned Outcome: This protocol is designed to investigate the relationship between glucose fluctuations and the incidence of composite cardiovascular events. We completed the registration of 1000 participants in March 2019. Thus, results will be available in 2024. We expect that evaluating glucose fluctuations will aid the identification of patients with a high probability of developing CVD., Trial Registration: ClinicalTrials.gov identifier, UMIN000032325.

Aims: No pharmacological therapies are approved for non-alcoholic fatty liver disease (NAFLD). Luseogliflozin, a sodium glucose cotransporter 2 inhibitor, has been developed for the treatment of adults with type 2 diabetes (T2DM). The aim of this prospective, single-arm study is to evaluate the efficacy of luseogliflozin on hepatic fat content and glycated hemoglobin (HbA1c) in T2DM patients with NAFLD., Methods: Forty T2DM patients with NAFLD were treated with luseogliflozin 2.5 mg/day for 24 weeks. Primary end-points were changes in HbA1c and hepatic steatosis evaluated by magnetic resonance imaging-hepatic fat fraction from baseline. Secondary end-points were changes in metabolic and hepatic function-related parameters, including hepatic fibrosis markers (Fibrosis-4 index, NAFLD fibrosis score, type IV collagen 7S. and Wisteria floribunda agglutinin-positive Mac-2 binding protein)., Results: Not only HbA1c and transaminase activities but also hepatic fat content were significantly decreased after 24 weeks of therapy with luseogliflozin. The reduction of hepatic fat content was significantly correlated with the reduction of alanine aminotransferase. Although hepatic fibrosis markers were unchanged, serum ferritin levels reduced and serum albumin significantly increased after the treatment., Conclusion: Luseogliflozin can be a novel promising agent for the treatment of T2DM patients with NAFLD. Prospective randomized controlled trials are warranted to confirm this impact of luseogliflozin onT2DM with NAFLD., (© 2018 The Japan Society of Hepatology.)

Background: Albuminuria characterizes the progression of kidney injury. The effect of canagliflozin on the excretion of microalbumin was assessed for investigating its renoprotective potential in Japanese patients with type 2 diabetes mellitus (T2DM)., Patients and Methods: Twenty Japanese patients with T2DM and microalbuminuria were enrolled and administered with 100 mg of canagliflozin once a day for 12 weeks. These subjects were admitted to the clinic at the start and end of the treatment period for 24-h urine collection. The primary endpoint was the percentage change in geometric mean 24-h urinary albumin excretion from baseline to week 12., Results: The urinary albumin level decreased by 42.0% (95% confidence interval: 21.9-57.0; P = 0.0011) after 12 weeks of canagliflozin treatment. A number of blood and urinary parameters also significantly decreased, including hemoglobin A1c, fasting plasma glucose, estimated glomerular filtration rate, and creatinine clearance, while hematocrit was elevated. Among the biomarkers associated with kidney injury and inflammation, the urinary level of the oxidative stress marker 8-hydroxy-2'-deoxyguanosine was also decreased. There were no meaningful correlations noted between changes in urinary albumin excretion and other parameters/biomarkers. No severe adverse events were reported over the 12-week treatment period., Conclusions: The results of this study indicate that canagliflozin decreases microalbuminuria in Japanese patients with T2DM. Albuminuria could be reduced as a result of changes in various physiological pathways; therefore, it is imperative that future, large-scale, studies attempt to determine the detailed mechanisms involved. Canagliflozin may offer a novel therapeutic option for Japanese patients with T2DM and incipient nephropathy.

Aim: It remains unclear whether measures used in carotid ultrasonography such as the intima-media thickness (IMT) and ultrasonic tissue characterization of the carotid using the gray-scale median (GSM) can add prognostic information beyond the conventional cardiovascular risk markers in patients with diabetes., Methods: This study employed a combined analysis of data obtained in five longitudinal studies including a total of 3263 patients with diabetes but without apparent cardiovascular disease (CVD) at baseline. The associations between carotid ultrasonography measures and the first occurrence of CVD (488 cases), which were defined as cardiovascular death, coronary artery diseases, stroke, or peripheral artery disease, were analyzed., Results: Common carotid artery (CCA)-mean-IMT, CCA-max-IMT, Max-IMT, plaque-GSM, and the presence of low-GSM echolucent plaques at baseline were prognostic factors for CVD even after adjustment for conventional risk factors. Time-dependent receiver-operating-characteristic (ROC) curve analysis indicated that the use of CCA-mean-IMT, CCA-max-IMT, and Max-IMT in addition to the conventional risk factors improved significantly the prediction of occurrence of CVD. Increments in the CCA-mean-IMT (hazard ratio [HR] 2.37 for every 0.1-mm/year increment [95% confidence interval [CI]: 1.63-3.47], p＜0.001), Max-IMT (HR 1.51 for every 0.1-mm/year increment [95% CI: 1.07-2.14], p=0.020), and Mean-GSM (HR 0.22 for every 10-U/year increment [95% CI: 0.06-0.76], p=0.016) during the observation period were also prognostic factors for CVD even after adjusting for the baseline value of the respective measure., Conclusions: Addition of carotid ultrasonography measures to conventional risk factors significantly improved the stratification of patients by cardiovascular risk. Changes over time in carotid ultrasonography measures may be used as therapeutic outcome measures.

Aims/introduction: The present multicenter, cross-sectional survey was initiated to evaluate self-monitoring of blood glucose (SMBG)-associated mental distress among patients with diabetes., Materials and Methods: The survey was carried out in patients with type 1 diabetes and type 2 diabetes using SMBG recruited from 42 medical institutions. Profiles of Mood States 2 and diabetes therapy-related quality of life questionnaires were used to evaluate mood status and health-related quality of life. Two original questionnaires were also developed to evaluate SMBG 'importance,' 'painfulness' and 'confidence' among patients, and to evaluate physician attitudes to SMBG use., Results: Questionnaires from 517 type 1 diabetes and 1,648 type 2 diabetes patients showed that 46.0% of type 1 diabetes and 37.5% of type 2 diabetes patients reported 'painfulness,' and that these patients reporting 'painfulness' showed significantly higher Profiles of Mood States 2 scores, lower diabetes therapy-related quality of life scores and higher glycated hemoglobin compared with those not reporting 'painfulness,' whereas the number of their daily SMBG tests were comparable. Patients reporting 'painfulness' also reported that SMBG use was significantly less important. Whether or not patients recognized the importance of SMBG use was well correlated with the frequency of physicians checking patient diaries., Conclusions: Type 1 diabetes and type 2 diabetes patients reporting 'painfulness' in SMBG use had more mental distress, lower health-related quality of life and higher glycated hemoglobin regardless of their number of daily SMBG tests. The importance of SMBG use was recognized less by patients experiencing pain, and the importance of SMBG use was recognized more in medical institutions in which physicians regularly checked SMBG diaries to provide meaningful feedback to patients in clinical settings., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: The aim of the present study was to evaluate the efficacy and safety of ipragliflozin in treating Japanese type 2 diabetes patients with inadequate glycemic control by investigating diurnal variations of blood glucose and body composition., Materials and Methods: This was an investigator-initiated, multicenter, prospective study with a 6-month treatment period. The primary outcome investigated was change in hemoglobin A1c levels from baseline. Secondary outcomes included changes in fasting plasma glucose, insulin resistance, variations in 24-h glucose levels detected by continuous glucose monitoring, bodyweight, body composition, waist circumference and serum lipids. Adverse events were evaluated throughout the study., Results: A total of 98 patients completed the study. Over the 6-month period, ipragliflozin-treated patients showed reduction in hemoglobin A1c levels by 0.3%, fasting plasma glucose levels by 13.0 mg/dL, bodyweight by 2.1 kg, body fat mass by 1.5 kg and extracellular water by 0.3 kg, as well as a decrease in systolic/diastolic blood pressures. Significant reductions from baseline in mean amplitude of glucose excursions and standard deviation, and the reduced frequency of hyperglycemia were confirmed. High-density lipoprotein cholesterol was also significantly improved. Notably, the subgroup analysis of hemoglobin A1c levels, bodyweight, waist circumference, and body composition based on age, sex and body mass index showed similar reductions within each subgroup. The incidences of adverse events and adverse drug reactions were 20.0% and 1.0%, respectively, over the 6-month period., Conclusions: Ipragliflozin is a useful oral antidiabetic medication for patients with a wide range of background characteristics., (© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: To assess the safety and efficacy of monotherapy with once-weekly subcutaneous (s.c.) semaglutide vs sitagliptin in Japanese people with type 2 diabetes (T2D)., Methods: In this phase IIIa randomized, open-label, parallel-group, active-controlled, multicentre trial, Japanese adults with T2D treated with diet and exercise only or oral antidiabetic drug monotherapy (washed out during the run-in period) received once-weekly s.c. semaglutide (0.5 or 1.0 mg) or once-daily oral sitagliptin 100 mg. The primary endpoint was number of treatment-emergent adverse events (TEAEs) after 30 weeks., Results: Overall, 308 participants were randomized and exposed to treatment, with similar baseline characteristics across the groups. In total, 2.9% of participants in both the semaglutide 0.5 mg and the sitagliptin group prematurely discontinued treatment, compared with 14.7% in the semaglutide 1.0 mg group. The majority of discontinuations in the semaglutide 0.5 and 1.0 mg groups were attributable to adverse events (AEs). More TEAEs were reported in semaglutide- vs sitagliptin-treated participants (74.8%, 71.6% and 66.0% in the semaglutide 0.5 mg, semaglutide 1.0 mg and sitagliptin groups, respectively). AEs were mainly mild to moderate. Gastrointestinal AEs, most frequently reported with semaglutide, diminished in frequency over time. The mean glycated haemoglobin (HbA1c [baseline 8.1%]) decreased by 1.9% and 2.2% with semaglutide 0.5 and 1.0 mg, respectively, vs 0.7% with sitagliptin (estimated treatment difference [ETD] vs sitagliptin -1.13%, 95% confidence interval [CI] -1.32; -0.94, and -1.44%, 95% CI -1.63; -1.24; both P < .0001). Body weight (baseline 69.3 kg) was reduced by 2.2 and 3.9 kg with semaglutide 0.5 and 1.0 mg, respectively (ETD -2.22 kg, 95% CI -3.02; -1.42 and -3.88 kg, 95% CI -4.70; -3.07; both P < .0001)., Conclusions: In Japanese people with T2D, more TEAEs were reported with semaglutide than with sitagliptin; however, the semaglutide safety profile was similar to that of other glucagon-like peptide-1 receptor agonists. Semaglutide significantly reduced HbA1c and body weight compared with sitagliptin., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: This study investigated the safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin (100 mg/day) and low-dose metformin (500 or 750 mg/day)., Research Design and Methods: Fifty patients were randomly allocated to the control group (maintaining the initial low-dose of metformin) and the dose increase group (up-titrating of metformin to 1,500-2,250 mg/day) for 24 weeks. The primary outcome was change in HbA1c from baseline to 24 weeks., Results: Among the 25 patients allocated to the dose increase group, four patients were not able to complete the study protocol because of gastrointestinal symptoms. HbA1c in the dose increase group was significantly but modestly lower than in the control group (change in HbA1c: 0.22 ± 0.57 vs. -0.15 ± 0.58%, group comparison, P < 0.05). The dose increase group did not gain weight during the study period, and no hypoglycemic events were reported in both groups. The rate of gastrointestinal symptoms in the dose increase group was profoundly higher than in the control group (32 vs. 0%, P < 0.01)., Conclusions: In Japanese patients with type 2 diabetes treated with vildagliptin and low-dose metformin, metformin up-titration significantly but modestly improved glycemic control without hypoglycemia and weight gain.

Introduction: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are anti-diabetic agents that improve glycemic control with a low risk of hypoglycemia and ameliorate a variety of cardiovascular risk factors. The aim of the ongoing study described herein is to investigate the preventive effects of tofogliflozin, a potent and selective SGLT2 inhibitor, on the progression of atherosclerosis in subjects with type 2 diabetes (T2DM) using carotid intima-media thickness (IMT), an established marker of cardiovascular disease (CVD), as a marker., Methods: The Study of Using Tofogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, blinded-endpoint, multicenter, and parallel-group comparative study. The aim was to recruit a total of 340 subjects with T2DM but no history of apparent CVD at 24 clinical sites and randomly allocate these to a tofogliflozin treatment group or a conventional treatment group using drugs other than SGLT2 inhibitors. As primary outcomes, changes in mean and maximum IMT of the common carotid artery during a 104-week treatment period will be measured by carotid echography. Secondary outcomes include changes in glycemic control, parameters related to β-cell function and diabetic nephropathy, the occurrence of CVD and adverse events, and biochemical measurements reflecting vascular function., Conclusion: This is the first study to address the effects of SGLT2 inhibitors on the progression of carotid IMT in subjects with T2DM without a history of CVD. The results will be available in the very near future, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent CVD., Funding: Kowa Co., Ltd., Clinical Trial Registration: UMIN000017607.

Aims/introduction: Despite being the most common complication of diabetes, the pattern of clinical development of diabetic neuropathy is not well-known. In the present study, we retrospectively examined sequential changes in nerve conduction studies (NCS) for 4 years to characterize the way neuropathic changes develop in patients with type 2 diabetes., Materials and Methods: We randomly selected 158 patients with type 2 diabetes who newly visited Naka Memorial Clinic, Ibaraki, Japan, and underwent serial 4-year NCS. Records of clinical profile, signs and symptoms of neuropathy, and NCS data from median and tibial nerves were extracted to determine the progression of neuropathy. NCS data were represented by motor nerve conduction velocities, amplitudes of compound muscle action potentials (CMAPs) and minimal latencies of F-wave., Results: The prevalence of clinical neuropathy in 158 cases was 30% at baseline and 29% at the end of the study, with improvement of glycated hemoglobin (8.6-6.9%). Over 4 years, there were no changes of the signs and symptoms of neuropathy. Motor nerve conduction velocities were slightly improved or consistent at the fourth year compared with those at the beginning (+1.5% in median nerve, P < 0.05; +0.8%, not significant in the tibial nerve). The extent of the glycated hemoglobin correction correlated with the improvement of motor nerve conduction velocity. In contrast, CMAPs of both median and tibial nerves were decreased (-11.6%, P < 0.01; -3.7%, P < 0.05, respectively). For the decrease in CMAPs, no specific risk factors were identified by logistic regression analysis., Conclusions: The present study showed progressive decline of CMAPs despite improved glycemic controls or the lack of NCV slowing in patients with early type 2 diabetes., (© 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: While conventional cardiovascular risk factors and certain lifestyle habits are associated with arterial stiffness in patients with type 2 diabetes mellitus (T2DM), it is still unknown whether they are actually associated with arterial stiffness even after adjustment for conventional cardiovascular risk factors and lifestyle habits. The aim of this study was to identify variables that are associated with brachial-ankle pulse wave velocity (baPWV)., Methods: The study participants comprised 724 Japanese T2DM outpatients free of history of cardiovascular diseases. Lifestyle habits were analyzed using self-reported questionnaires. The associations among conventional cardiovascular risk factors and lifestyle habits with baPWV were investigated by multivariable linear regression analysis., Results: The mean age of the study subjects was 57.8 ± 8.6 years, and 62.8% of those were males. The mean HbA1c was 7.0±1.0%, and the estimated duration of T2DM was 9.9 ± 7.2 years. Multiple linear regression analysis that included age and gender demonstrated that age and male sex were positively associated with baPWV. In a model adjusted for numerous conventional cardiovascular risk factors and lifestyle habits, age, duration of T2DM, systolic blood pressure, serum uric acid, urinary albumin excretion and poor sleep quality were positively associated with baPWV, while body mass index was negatively associated with baPWV., Conclusions: In Japanese T2DM, in addition to several conventional cardiovascular risk factors, poor sleep quality was associated with baPWV even after adjustment for numerous conventional cardiovascular risk factors and lifestyle habits.