Publications by authors named "Yosuke Okada"

191 Publications

Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial.

Cardiovasc Diabetol 2021 Jun 28;20(1):105. Epub 2021 Jun 28.

Department of Cardiovascular Medicine, Saga University, 5-5-1 Nabeshima, Saga, 849-8501, Japan.

Backgrounds/aim: Sodium glucose co-transporter 2 inhibitors promote osmotic/natriuretic diuresis and reduce excess fluid volume, and this improves cardiovascular outcomes, including hospitalization for heart failure. We sought to assess the effect of empagliflozin on estimated fluid volumes in patients with type 2 diabetes and cardiovascular disease (CVD).

Methods: The study was a post-hoc analysis of the EMBLEM trial (UMIN000024502), an investigator-initiated, multi-center, placebo-controlled, double-blinded, randomized-controlled trial designed primarily to evaluate the effect of 24 weeks of empagliflozin treatment on vascular endothelial function in patients with type 2 diabetes and established CVD. The analysis compared serial changes between empagliflozin (10 mg once daily, n = 52) and placebo (n = 53) in estimated plasma volume (ePV), calculated by the Straus formula and estimated the extracellular volume (eEV), determined by the body surface area, measured at baseline and 4, 12, and 24 weeks after initiation of treatment. Correlations were examined between the changes from baseline to week 24 in each estimated fluid volume parameter and several clinical variables of interest, including N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration.

Results: In an analysis using mixed-effects models for repeated measures, relative to placebo empagliflozin reduced ePV by - 2.23% (95% CI - 5.72 to 1.25) at week 4, - 8.07% (- 12.76 to - 3.37) at week 12, and - 5.60% (- 9.87 to - 1.32) at week 24; eEV by - 70.3 mL (95% CI - 136.8 to - 3.8) at week 4, - 135.9 mL (- 209.6 to - 62.3) at week 12, and - 144.4 mL (- 226.3 to - 62.4) at week 24. The effect of empagliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in log-transformed NT-proBNP was positively correlated with change in ePV (r = 0.351, p = 0.015), but not with change in eEV.

Conclusions: Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and CVD, and that this effect was maintained for 24 weeks. Given the early beneficial effect of empagliflozin on cardiovascular outcomes seen in similar patient populations, our findings provide an important insight into the key mechanisms underlying the clinical benefit of the drug. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502.
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http://dx.doi.org/10.1186/s12933-021-01295-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237440PMC
June 2021

Work Environment-related Stress Factors are Correlated with Diabetes Development in Workers with Impaired Glucose Tolerance: A 5-year Follow-up Study Using the Brief Job Stress Questionnaire (BJSQ).

J UOEH 2021 ;43(2):183-196

First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.

Several previous studies have investigated the effects of occupational stress on the onset of diabetes mellitus (DM), but there are few studies of occupational stress and DM using the Brief Job Stress Questionnaire (BJSQ), a standard stress check method in Japan. This study aimed to determine the relationship between occupational stress factors and the onset of DM using the BJSQ. We examined 6,620 male company workers aged 40 years and above in 2013, using the BJSQ. Overall, 2,604 subjects with impaired glucose tolerance who were free of mental disorders and DM were followed-up for 5 years and re-examined in 2017. A retrospective data analysis was conducted in 2019. We documented 241 new cases of DM in 2017 (diabetes group). Compared with the non-diabetes group, the subjects in the diabetes group had significantly decreased "skill utilization". A binomial logistic regression analysis (generalized linear model) revealed that "skill utilization" was associated with the risk of DM development in 2017 (odds ratio, 1.632; 95% confidence interval, 1.061-2.510). Our results showed that low skill utilization might increase the risk of diabetes development in Japanese male workers.
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http://dx.doi.org/10.7888/juoeh.43.183DOI Listing
January 2021

Associations of continuous glucose monitoring-assessed glucose variability with intima-media thickness and ultrasonic tissue characteristics of the carotid arteries: a cross-sectional analysis in patients with type 2 diabetes.

Cardiovasc Diabetol 2021 05 4;20(1):95. Epub 2021 May 4.

Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Background: The association between glucose variability and the progression of atherosclerosis is not completely understood. We aimed to evaluate the associations of glucose variability with the progression of atherosclerosis in the early stages.

Methods: We conducted a cross-sectional analysis to investigate the associations of glucose variability, assessed by continuous glucose monitoring, with intima-media thickness (IMT) and gray-scale median (GSM) of the carotid arteries, which are different indicators for the progression of atherosclerosis. We used baseline data from a hospital-based multicenter prospective observational cohort study among Japanese patients with type 2 diabetes without a history of cardiovascular diseases aged between 30 and 80 years. Continuous glucose monitoring was performed by Freestyle Libre Pro, and glucose levels obtained every 15 min for a maximum of eight days were used to calculate the metrics of glucose variability. IMT and GSM were evaluated by ultrasonography, and the former indicates thickening of intima-media complex in the carotid artery wall, while the latter indicates tissue characteristics.

Results: Among 600 study participants (age: 64.9 ± 9.2 (mean ± SD) years; 63.2%: men; HbA1c: 7.0 ± 0.8%), participants with a larger intra- and inter-day glucose variability had a lower GSM and most of these associations were statistically significant. No trend based on glucose variability was shown regarding IMT. Standard deviation of glucose (regression coefficient, β = - 5.822; 95% CI - 8.875 to - 2.768, P < 0.001), glucose coefficient of variation (β = - 0.418; - 0.685 to - 0.151, P = 0.002), mean amplitude of glycemic excursion (β = - 1.689; - 2.567 to - 0.811, P < 0.001), mean of daily differences (β = - 6.500; - 9.758 to - 3.241, P < 0.001), and interquartile range (β = - 4.289; - 6.964 to - 1.614, P = 0.002) had a statistically significant association with mean-GSM after adjustment for conventional cardiovascular risk factors, including HbA1c. No metrics of glucose variability had a statistically significant association with IMT.

Conclusions: Continuous glucose monitoring-assessed glucose variability was associated with the tissue characteristics of the carotid artery wall in type 2 diabetes patients without cardiovascular diseases.
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http://dx.doi.org/10.1186/s12933-021-01288-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097791PMC
May 2021

Associations between continuous glucose monitoring-derived metrics and diabetic retinopathy and albuminuria in patients with type 2 diabetes.

BMJ Open Diabetes Res Care 2021 04;9(1)

Department of Metabolism & Endocrinology, Juntendo University School of Medicine Graduate School of Medicine, Bunkyo-ku, Japan.

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. UMIN000032325.
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http://dx.doi.org/10.1136/bmjdrc-2020-001923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061826PMC
April 2021

Relationship between glycemic intraday variations evaluated in continuous glucose monitoring and HbA1c variability in type 2 diabetes: pilot study.

Diabetol Metab Syndr 2021 Apr 15;13(1):45. Epub 2021 Apr 15.

First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.

Background: HbA1c variability is independent of mean HbA1c, and associated with mortality due to vascular complications. However, the significance of HbA1c variability is unknown at present. In this study, we used flash glucose monitoring (FGM) and evaluated glycemic intraday variations, and then examined the association with HbA1c variability.

Methods: We conducted a retrospective pilot study of 26 patients treated at the Outpatient department for type 2 diabetes mellitus (T2DM), and evaluated the following items associated with blood glucose levels and their changes/variations using FGM. The primary endpoint was factor(s) associated with standard deviation (SD) HbA1c over a 6-month period. To adjust for the effect of varying numbers of HbA1c measurements, we used the adjusted SD of HbA1c.

Results: There were significant correlations between mean HbA1c and each of glucose management indicator, maximum, percent time at glucose > 180 mg/day, mean of daily difference of blood glucose, and high blood glucose index. Adjusted SD HbA1c correlated significantly with percent time at glucose < 70 mg/dL and low blood glucose index. We estimated the regression coefficient of adjusted SD HbA1c using multivariate linear regression analysis, and noted that the presence of hypoglycemia affected Adjusted SD HbA1c (β = 0.130, SE = 0.044, P = 0.008). Hypoglycemia was noted in 17 patients, and adjusted SD HbA1c was significantly higher (p = 0.001) in the hypoglycemic group (0.22 ± 0.12%), compared with the non-hypoglycemic group (0.08 ± 0.05%). The cut-off value of adjusted SD HbA1c was 0.109% in the hypoglycemic group.

Conclusions: The results showed that HbA1c variability is associated with hypoglycemia. For patients with high HbA1c variability, we recommend evaluation for the presence of hypoglycemia and reconsideration of their treatment regimen including their glucose-lowering medications. Trial registration The study protocol and opt-out method of informed consent were approved by the ethics committees of the University of Occupational and Environmental Health (Trial registration: H27-186, Registered 25 Dec 2015).
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http://dx.doi.org/10.1186/s13098-021-00663-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048042PMC
April 2021

[A Case of Thyroid Dysfunction and Isolated Adrenocorticotropin Deficiency after Nivolumab Therapy for Malignant Melanoma].

J UOEH 2021 ;43(1):97-102

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.

The patient was a 34-year-old woman. Surgical resection and chemotherapy had been performed on diagnosis of malignant melanoma in year X-9. Chronic thyroiditis was diagnosed in year X-8, but her thyroid function was normal. In November of the year X-1, the patient, who had metastasis to the left lung and the left main bronchus and radically unresectable metastases with distant metastases, was treated with the anti-PD-1 antibody nivolumab. In December X-1, we initiated levothyroxine sodium for hypothyroidism after the patient suffered indolent thyroiditis due to nivolumab. In March X, the nivolumab treatment was stopped because it proved to be ineffective, then in April, anorexia, fever, and general malaise were noted. Cortisol 5.0 and ACTH 17.5 were confirmed by blood test, and the patient was diagnosed with adrenal insufficiency and was admitted to the hospital. Head MRI showed no organic lesions, and a stress test showed abnormalities only in a CRH test (low response to both ACTH and cortisol). The patient was diagnosed with isolated ACTH deficiency due to nivolumab. Side effects of thyroid dysfunction due to nivolumab are frequently observed in Japan at a rate of 14.3%, and overseas at 5.9%. However, secondary adrenocortical dysfunction is observed in overseas clinical trials at a frequency of only about 0.3%. There are few reports of such complications, and we report this as a rare case.
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http://dx.doi.org/10.7888/juoeh.43.97DOI Listing
January 2021

Enlarged glycemic variability in sulfonylurea-treated well-controlled type 2 diabetics identified using continuous glucose monitoring.

Sci Rep 2021 Mar 1;11(1):4875. Epub 2021 Mar 1.

First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.

Time in range (TIR) is an index of glycemic control obtained from continuous glucose monitoring (CGM). The aim was to compare the glycemic variability of treatment with sulfonylureas (SUs) in type 2 diabetes mellitus (T2DM) with well-controlled glucose level (TIR > 70%). The study subjects were 123 patients selected T2DM who underwent CGM more than 24 h on admission without changing treatment. The primary endpoint was the difference in glycemic variability, while the secondary endpoint was the difference in time below range < 54 mg/dL; TBR < 54, between the SU (n = 63) and non-SU (n = 60) groups. The standard deviation, percentage coefficient of variation (%CV), and maximum glucose level were higher in the SU group than in the non-SU group, and TBR < 54 was longer in the high-dose SU patients. SU treatment was identified as a significant factor that affected %CV (β: 2.678, p = 0.034). High-dose SU use contributed to prolonged TBR < 54 (β: 0.487, p = 0.028). Our study identified enlarged glycemic variability in sulfonylurea-treated well-controlled T2DM patients and high-dose SU use was associated with TBR < 54. The results highlight the need for careful adjustment of the SU dose, irrespective of glycated hemoglobin level or TIR value.
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http://dx.doi.org/10.1038/s41598-021-83999-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921550PMC
March 2021

[Spontaneous resolution of refractory ascites in the late phase after cord blood transplantation in acute myeloid leukemia].

Rinsho Ketsueki 2021 ;62(1):20-24

Division of Hematology, Department of Internal Medicine, National Defense Medical College.

Patients with refractory ascites that develops >3 months after allogenic stem cell transplantation typically have a poor prognosis. We present the case of a 61-year-old man who developed refractory massive ascites approximately 3 months after cord blood transplantation (CBT) and showed complete and spontaneous remission from ascites after 18 months. The patient complained of severe bloating and needed weekly paracentesis to manage the fluid levels. Laboratory tests indicated that the ascites was caused by liver fibrosis. After the patient underwent Keisuke-Matsusaki cell-free and concentrated ascites reinfusion therapy (KM-CART), we were able to decrease the frequency of paracentesis treatments. We planned a transjugular liver biopsy, but the patient contracted pneumocystis pneumonia before the procedure could be performed. Although the pneumonia improved, the ascites worsened again. However, weekly paracentesis spontaneously stopped the progression of ascites and eventually resolved it completely, resulting in the patient's survival.
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http://dx.doi.org/10.11406/rinketsu.62.20DOI Listing
February 2021

Multiple aortic thrombi in essential thrombocythaemia.

Br J Haematol 2021 Jun 2;193(5):862. Epub 2021 Feb 2.

National Defense Medical College Hospital, Saitama, Japan.

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http://dx.doi.org/10.1111/bjh.17353DOI Listing
June 2021

Low Vitamin D Levels are Associated with Vascular Endothelial Dysfunction in Patients with Poorly Controlled Type 2 Diabetes: A Retrospective Study.

J Atheroscler Thromb 2021 Jan 29. Epub 2021 Jan 29.

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.

Aim: This study aimed to determine the association between serum 25-hydroxyvitamin D (25(OH)D) levels and vascular endothelial function in patients with type 2 diabetes (T2D).

Methods: This retrospective study included 113 patients with poorly controlled T2D who were admitted for in-hospital diabetes educational program and underwent measurements of serum 25(OH)D levels and reactive hyperemia index (RHI).

Results: Serum 25(OH)D levels significantly correlated with RHI in T2D patients. Receiver operating characteristic (ROC) curve analysis showed that serum 25(OH)D level of 16.5 ng/mL is the optimal cutoff level for predicting vascular endothelial dysfunction (RHI<1.67), with a sensitivity of 68.5%, specificity of 67.9%, and area under the ROC curve of 0.668 (95% confidence interval [CI]: 0.566-0.770, p=0.002). The mean RHI was significantly lower (1.70±0.54) in patients with low 25(OH)D levels (n=56, 25(OH)D levels <16.5 ng/mL) than that (1.99±0.58; p<0.001) in patients with high 25(OH)D levels (n=57, 25(OH)D level ≥ 16.5 ng/mL). The proportion of patients with RHI<1.67 was higher in the low 25(OH)D group than in the high 25(OH)D group (38% vs. 18%; p<0.001). Multivariate logistic regression analysis identified that serum 25(OH)D level <16.5 ng/mL was associated with increased odds of RHI <1.67 (odds ratio 4.598, 95% CI 1.961-10.783, p<0.001).

Conclusion: The results demonstrated the association of serum 25(OH)D levels with endothelial function in poorly controlled T2D patients and identified serum 25(OH)D level of <16.5 ng/mL as a predictor of RHI <1.67. Serum 25(OH)D level is a potentially useful marker of vascular endothelial dysfunction in poorly controlled T2D patients.
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http://dx.doi.org/10.5551/jat.59113DOI Listing
January 2021

Associations between urinary 6-sulfatoxymelatonin excretion and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes.

J Diabetes Investig 2021 Apr 25;12(4):601-609. Epub 2020 Aug 25.

First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Aims/introduction: There are limited reports on the association between melatonin levels and vascular complications in patients with type 2 diabetes. The aim of this study was to determine the association between urinary 6-sulfatoxymelatonin, which is a urinary metabolite of melatonin, and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes.

Materials And Methods: This retrospective study included patients (167 patients with type 2 diabetes and 27 patients without diabetes adjusted for age and sex) admitted to the hospital who underwent measurement of urinary 6-sulfatoxymelatonin. The urinary 6-sulfatoxymelatonin/creatinine ratio (6-SMT) was calculated.

Results: The natural logarithmically scaled 6-SMT level (Ln 6-SMT) was significantly lower in type 2 diabetes patients (1.9 ± 1.1) compared with patients without diabetes (2.8 ± 1.0, P < 0.001). Multivariate linear regression analysis identified duration of diabetes, smoking status, urinary albumin-to-creatinine ratio, retinopathy and coronary heart disease as factors that could influence Ln 6-SMT levels in type 2 diabetes patients (R  = 0.232, P < 0.001). Ln 6-SMT was associated with decreased odds of diabetic retinopathy, even after adjustment for various confounding factors (odds ratio 0.559, 95% confidence interval 0.369-0.846, P = 0.006). Similarly, Ln 6-SMT was associated with decreased odds of coronary heart disease (odds ratio 0.442, P = 0.030).

Conclusions: Our results showed the presence of low levels of Ln 6-SMT in type 2 diabetes patients relative to patients without diabetes. Furthermore, Ln 6-SMT is an independent risk factor of diabetic retinopathy and coronary heart diseases. These findings suggest that 6-SMT could be a useful biomarker for the prediction of micro- and macrovasculopathies in patients with type 2 diabetes.
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http://dx.doi.org/10.1111/jdi.13374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015816PMC
April 2021

Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry).

BMJ Open Diabetes Res Care 2021 01;9(1)

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Introduction: Given an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.

Research Design And Methods: We registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.

Results: Of the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.

Conclusions: Alogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.
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http://dx.doi.org/10.1136/bmjdrc-2020-001787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812112PMC
January 2021

Associations between continuous glucose monitoring-derived metrics and arterial stiffness in Japanese patients with type 2 diabetes.

Cardiovasc Diabetol 2021 01 7;20(1):15. Epub 2021 Jan 7.

Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1 Bunkyo-ku, Tokyo, Japan.

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.
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http://dx.doi.org/10.1186/s12933-020-01194-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792328PMC
January 2021

Effect of tofogliflozin on arterial stiffness in patients with type 2 diabetes: prespecified sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial.

Cardiovasc Diabetol 2021 01 4;20(1). Epub 2021 Jan 4.

Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.

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 ).
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http://dx.doi.org/10.1186/s12933-020-01206-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784389PMC
January 2021

[Short-term Glucose Lowering Effects of Sodium-glucose Cotransporter 2 Inhibitors Confirmed by Flash Glucose Monitoring in Two Outpatients with Type 1 Diabetes].

J UOEH 2020 ;42(4):359-364

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.

Case 1 was a 41-year-old man with type 1 diabetes. He presented with poor glycemic control [hemoglobin A1c (HbA1c) of 8-9%] despite treatment with more than 20 units/day of insulin and 150 mg of miglitol. Before administration of sodium glucose cotransporter 2 (SGLT2) inhibitor, hyperglycemia was noted mainly at night by Flash Glucose Monitoring (FGM). Administration of ipragliflozin at 50 mg improved the hyperglycemia mainly at night (mean blood glucose, before administration: 205 mg/dl, day 6 of treatment: 119 mg/dl). Two months later, the HbA1c improved to 7.2% without hypoglycemia or ketosis. Case 2 was a 46-year-old woman with type 1 diabetes. She was morbidly obese and presented with poor glycemic control (HbA1c: 9-11%) although she was being treated with more than 50 units/day of insulin and 2,250 mg of metformin. Before administration of SGLT2 inhibitor, hyperglycemia was noted to be mainly nocturnal by FGM. Administration of dapagliflozin at 5 mg improved the hyperglycemia mainly at night on day 2 with improvement in the mean blood glucose level from 188 mg/dl before administration to 128 mg/dl on day 5. Four months later, the HbA1c improved to 8.0% without hypoglycemia and ketosis, and her body weight decreased from 92.1 to 89.8 kg. The hypoglycemic effect of SGLT2 inhibitors is independent of insulin. These agents also have various other effects, including weight loss, improvement of blood pressure and lipid metabolism. Here we report the short-term glucose lowering effects of two SGLT2 inhibitors, as confirmed by FGM, in two outpatients with type 1 diabetes.
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http://dx.doi.org/10.7888/juoeh.42.359DOI Listing
February 2021

Correlations Between Glycemic Parameters Obtained from Continuous Glucose Monitoring and Hemoglobin A1c and Glycoalbumin Levels in Type 2 Diabetes Mellitus.

J UOEH 2020 ;42(4):299-306

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.

It is difficult to detect glycemic excursions using CGM in daily clinical practice. We retrospectively analyzed CGM data in type T2DM to define the correlations between HbA1c and GA levels at admission and the parameters representing glycemic excursions measured by CGM, including the mean amplitude of glycemic excursions (MAGE) and standard deviation (SD). The MAGE correlated significantly with GA and HbA1c, but not with the GA/HbA1c ratio. The SD correlated significantly with GA, HbA1c, and GA/HbA1c. Multivariate analysis identified the GA value to be the most reflective of MAGE. Patients were divided into 2 groups using a MAGE cutoff value of 75 mg/dl, which reflects stable diabetes. There was a significant difference in GA, but not HbA1c, between the groups with low and high mean amplitudes of glycemic excursions. Receiver operating characteristic curve analysis indicated that the cutoff for GA for identifying patients with MAGE of ≤75 mg/dl was 18.1%. Our study identified GA to be the most reflective of glycemic excursions in patients with T2DM. GA can be a useful index of glycemic excursions and treatment optimization to prevent arteriosclerosis.
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http://dx.doi.org/10.7888/juoeh.42.299DOI Listing
February 2021

Glucose-lowering effects of 7-day treatment with SGLT2 inhibitor confirmed by intermittently scanned continuous glucose monitoring in outpatients with type 1 diabetes. A pilot study.

Endocr J 2021 Mar 18;68(3):361-369. Epub 2020 Nov 18.

First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan.

The present study used intermittently scanned continuous glucose monitoring (isCGM) in 10 patients with type 1 diabetes mellitus (T1DM) to evaluate the efficacy and safety of 7-day outpatient treatment with the combination of intensive insulin therapy and sodium-glucose transporter 2 inhibitor (SGLT2-I). All participants wore isCGM and were treated with either 50 mg/day ipragliflozin or 5 mg/day dapagliflozin. The primary outcome, percent time with glucose at 70-180 mg/dL (TIR: time in range), improved significantly following the addition of SGLT2-I (p = 0.005). TIR increased from 36.0% before addition of SGLT2-I to 70.7% on day 7. Although none of the patients achieved TIR of 70% or higher before the addition of SGLT2-I, 6 patients met that criteria TIR on day 7. The secondary outcome measures, standard deviation (SD) of glucose, average plasma glucose, percent time with glucose at >180 mg/dL (TAR: time above range), maximum plasma glucose, high blood glucose index (HBGI) and average nocturnal plasma glucose (midnight to 05:59 AM) detected by isCGM, also improved significantly by SGLT2-I. There were no significant differences in percent time with glucose at <70 mg/dL (TBR: time below range), minimum plasma glucose and low blood glucose index (LBGI). Our results using isCGM in an actual clinical setting showed that 7-day use of SGLT2-I with intensive insulin therapy improved plasma glucose fluctuations and mean plasma glucose levels without inducing hypoglycemia in patients with T1DM.
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http://dx.doi.org/10.1507/endocrj.EJ20-0577DOI Listing
March 2021

A case of systemic lupus erythematosus in which Cushing's syndrome caused by adrenal adenoma accidentally occurred during long-term maintenance therapy with corticosteroids.

Mod Rheumatol Case Rep 2020 01 20;4(1):34-38. Epub 2019 Aug 20.

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

A 30-year-old female patient had been administered 5-mg/day prednisolone for systemic lupus erythematosus. She developed hypertension, dyslipidemia, moon face, central obesity, hypertrichosis, and impaired glucose tolerance. Although iatrogenic Cushing syndrome was initially suspected, we made a diagnosis of Cushing syndrome caused by a right adrenal adenoma, on the basis of the endocrine function test result and imaging findings. After surgery, the Cushingoid signs disappeared. Autoimmune diseases are often treated with corticosteroids; therefore, a differential diagnosis of primary Cushing syndrome should be made adequately.
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http://dx.doi.org/10.1080/24725625.2019.1651488DOI Listing
January 2020

Changes in endothelial function during educational hospitalization and the contributor to improvement of endothelial function in type 2 diabetes mellitus.

Sci Rep 2020 09 21;10(1):15384. Epub 2020 Sep 21.

First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan.

Only a few reports have examined vascular endothelial function before and after educational hospitalization and the factors that affect it in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to assess vascular endothelial function before and after educational hospitalization and identify factors that affect it. In 65 patients with T2DM who underwent peripheral arterial tonometry (EndoPAT) before and after hospitalization, vascular endothelial function (reactive hyperemia index [RHI]), glucose metabolism, lipid metabolism, and blood pressure were assessed before and after hospitalization. The primary endpoint was hospitalization-induced changes in vascular endothelial function. Educational hospitalization significantly improved the natural logarithmically scaled RHI (L_RHI) from 0.555 ± 0.212 to 0.625 ± 0.245 (p = 0.012). Multivariable logistic regression analysis identified hypoglycemia during hospitalization as the single factor that significantly altered vascular endothelial function (p = 0.019). The odds of achieving normal vascular endothelial function were 0.08 times lower (95% confidence interval, 0.01-0.67) for each episode of hypoglycemia. Furthermore, multivariable analysis identified hypoglycemia during hospitalization as the single factor that worsened L_RHI. Our study showed that educational hospitalization of patients with T2DM improved vascular endothelial function, and that the development of hypoglycemic episodes had a significant negative impact on normalization of vascular endothelial function.
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http://dx.doi.org/10.1038/s41598-020-72341-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506545PMC
September 2020

Human dendritic cell-derived osteoclasts with high bone resorption capacity and T cell stimulation ability.

Bone 2021 01 29;142:115616. Epub 2020 Aug 29.

The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Fukuoka, Japan. Electronic address:

Osteoclasts are typically differentiated from monocytes (Mo-OC). A subset of osteoclasts (DC-OC) that are differentiated from dendritic cells (DC) has been reported in the arthritic mice model. However, little information is available on DC-OC in humans. The present study applied both in vitro and in vivo experiments to determine the function and pathological significance of DC-OC. DC-OC were differentiated from human monocyte-derived DC and their bone resorption and antigen-presenting functions were investigated. Synovial tissue samples from patients with rheumatoid arthritis were examined for the presence and characteristics of DC-OC. DC-OC differentiated from DC in the presence of M-CSF and RANKL in vitro were demonstrated to be cathepsin K-positive and TRAP-positive multinucleated giant cells. The DC-OC showed stronger bone resorption ability than monocyte-derived osteoclast (Mo-OC) as observed with the pit formation assay. The DC-OC retained CD11c positivity and expressed costimulatory molecules, unlike Mo-OC. T-cells proliferated when co-cultured with DC-OC, but not with Mo-OC. The addition of abatacept to the cocultures reduced T-cell stimulating activity of DC-OC. Abatacept inhibited the differentiation of monocytes into Mo-OC but did not suppress the differentiation of DC into DC-OC. TRAP-positive and CD86-positive DC-OC were detected in the synovial membranes of rheumatoid arthritis patients but not in patients with osteoarthritis. Human DC-OC demonstrated T-cell stimulating activity in addition to osteolytic activity. We further observed this subset of osteoclasts in the inflammatory synovial membrane of patients with rheumatoid arthritis. Such deviations from normal bone metabolism contribute to the inflammation and bone destruction in chronic inflammatory diseases such as rheumatoid arthritis.
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http://dx.doi.org/10.1016/j.bone.2020.115616DOI Listing
January 2021

Relationship between interstitial glucose variability in ambulatory glucose profile and standardized continuous glucose monitoring metrics; a pilot study.

Diabetol Metab Syndr 2020 12;12:70. Epub 2020 Aug 12.

First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu-Shi, 807-8555 Japan.

Background: Treatment indexes using continuous glucose monitoring (CGM) have become standardized internationally, and the use of ambulatory glucose profile (AGP) is currently recommended. However, the relationship between AGP indexes and standardized CGM metrics has not been investigated. Using flash glucose monitoring (FGM), this retrospective study served to evaluate the association of the inter-quartile range (IQR) of AGP with standardized CGM metrics.

Methods: The study subjects were 30 patients with type 2 diabetes mellitus (T2DM) and 23 non-diabetic patients (control group). We evaluated average IQR (AIQR) and standardized CGM metrics. The primary endpoint was the relationship between AIQR and Time in range (TIR) in a 24-h period.

Results: In the T2DM group, the AIQR was notably high and correlated negatively with TIR, and positively with Time above range, average interstitial glucose level, standard deviation of interstitial glucose, coefficient of variation of interstitial glucose, and mean of daily difference in blood glucose (MODD). For the T2DM group, the AIQR was notably lower in patients who achieved TIR > 70%, compared to those who did not. The AIQR cutoff value, as determined by ROC analysis, was 28.3 mg/dl for those who achieved TIR > 70%. No association was detected between the presence of hypoglycemia and AIQR.

Conclusions: Our study is the first to provide the AIQR cutoff value for achieving the TIR target value. The range of interstitial glucose variability in AGP was associated with indexes of intra- and interday variations and hyperglycemia. Our results provide new perspectives in the yet-to-be established methods for evaluation of AGP in practical clinical settings.
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http://dx.doi.org/10.1186/s13098-020-00577-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424649PMC
August 2020

Tofogliflozin does not delay progression of carotid atherosclerosis in patients with type 2 diabetes: a prospective, randomized, open-label, parallel-group comparative study.

Cardiovasc Diabetol 2020 07 9;19(1):110. Epub 2020 Jul 9.

Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

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 ).
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http://dx.doi.org/10.1186/s12933-020-01079-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350187PMC
July 2020

Hyperparathyroidism Which Developed after Resection of a Fibroblast Growth Factor 23-producing Tumor.

Intern Med 2020 Oct 7;59(20):2523-2527. Epub 2020 Jul 7.

First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.

A 53-year-old woman presented with bone pain and was diagnosed with osteomalacia because of hypophosphatemia, hyperphosphatasemia, bone pain, and radiographic findings. Because her intact-fibroblast growth factor 23 (FGF23) levels were high and contrast-enhanced computed tomography revealed a mass in the anterior ethmoid sinus, FGF23-related osteomalacia was diagnosed. The tumor was resected, but she developed hypercalcemia and elevated blood parathyroid hormone (PTH) levels. Primary hyperparathyroidism (PHPT) was diagnosed, and surgical resection was performed. To our knowledge, this is the first case of a FGF23-producing tumor complicated by PHPT. Because PHPT manifested after resecting the FGF23-producing tumor, FGF23 is thus considered to suppress PTH secretion in humans.
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http://dx.doi.org/10.2169/internalmedicine.4412-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662040PMC
October 2020

[Bendamustine and rituximab combination therapy for recurrent indolent B-cell lymphomas: a retrospective single-institution study].

Rinsho Ketsueki 2020 ;61(6):598-604

Division of Hematology, National Defense Medical College Hospital.

This retrospective study evaluated the outcomes of patients treated with combination of bendamustine and rituximab (BR) for recurrent indolent B-cell lymphoma from January 2011 to February 2018 in our department. The cohort included 36 males and 27 females, and majority of the patients (59%) were between 51 and 70 years of age. The disease types were follicular lymphoma (FL) and mantle-cell lymphoma in 42 (67%) and 15 (24%) patients, respectively. Median progression-free survival (PFS) was not reached in patients with FL who completed BR therapy. The analysis of patients who received BR therapy revealed that the number of CD4-positive lymphocytes remained around 200/µl even five years after the end of treatment. BR therapy was a useful treatment option for recurrent indolent B-cell lymphoma, especially in patients with FL, and completion of BR therapy appeared to be important for improved PFS. Furthermore, attention should be paid for potential infections for at least five years after BR therapy because cell-mediated immunodeficiency may become apparent after treatment.
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http://dx.doi.org/10.11406/rinketsu.61.598DOI Listing
July 2020

Case of autoimmune polyendocrine syndrome type 3 complicated with anti-N-methyl-D-aspartic acid-receptor encephalitis.

J Diabetes Investig 2021 Feb 11;12(2):290-292. Epub 2020 Aug 11.

First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is an autoimmune disorder in which autoantibodies in the limbic system bind to GluN1 subunits of NMDA-Rs in the brain. We report a rare case of autoimmune polyendocrine syndrome type 3 complicated by anti-NMDA-R encephalitis. After hospitalization for type 1 diabetes, the 39-year-old patient developed various schizophreniform symptoms and seizures after cold-like symptoms. These findings are consistent with the diagnosis of anti-NMDA-R encephalitis. Immune-related encephalitis was suspected at the early phase of the disease, and cerebrospinal fluid was positive for anti-NMDA-R antibody. Early steroid pulse therapy was initiated during the disease course. The condition improved gradually to full recovery. Early detection and treatment of anti-NMDA-R encephalitis should enhance a positive outcome, considering that besides thyroid diseases and type 1 diabetes, various autoimmune diseases are associated with autoimmune polyendocrine syndrome type 3.
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http://dx.doi.org/10.1111/jdi.13341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858116PMC
February 2021

Secondary analyses to assess the profound effects of empagliflozin on endothelial function in patients with type 2 diabetes and established cardiovascular diseases: The placebo-controlled double-blind randomized effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi-center placebo-controlled double-blind randomized trial.

J Diabetes Investig 2020 Nov 14;11(6):1551-1563. Epub 2020 Jun 14.

Department of Cardiovascular Medicine, Saga University, Saga, Japan.

Aims/introduction: Recent clinical trials on sodium-glucose cotransporter 2 inhibitors showed improved outcomes in patients with type 2 diabetes at a high risk of cardiovascular events. However, the underlying effects on endothelial function remain unclear.

Materials And Methods: The effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi-center placebo-controlled double-blind randomized (EMBLEM) trial in patients with type 2 diabetes and cardiovascular disease showed empagliflozin treatment for 24 weeks had no effect on peripheral endothelial function measured by reactive hyperemia peripheral arterial tonometry. This post-hoc analysis of the EMBLEM trial included a detailed evaluation of the effects of empagliflozin on peripheral endothelial function in order to elucidate the clinical characteristics of responders or non-responders to treatment.

Results: Of the 47 patients randomized into the empagliflozin group, 21 (44.7%) showed an increase in the reactive hyperemia index (RHI) after 24 weeks of intervention, with no apparent difference in the clinical characteristics between patients whose RHI either increased (at least >0) or did not increase. There was also no obvious difference between the treatment groups in the proportion of patients who had a clinically meaningful change (≥15%) in log-transformed RHI. No correlation was found between changes in RHI and clinical variables, such as vital signs and laboratory parameters.

Conclusions: Treatment with empagliflozin for 24 weeks in patients with type 2 diabetes and cardiovascular disease did not affect peripheral endothelial function, and was not related to changes in clinical variables, including glycemic parameters. These findings suggest that the actions of sodium-glucose cotransporter 2 inhibitors other than direct improvement in peripheral endothelial function were responsible, at least in the early phase, for the clinical benefits found in recent cardiovascular outcome trials.
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http://dx.doi.org/10.1111/jdi.13289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610132PMC
November 2020

Rationale and design of an investigator-initiated, multicenter, prospective open-label, randomized trial to evaluate the effect of ipragliflozin on endothelial dysfunction in type 2 diabetes and chronic kidney disease: the PROCEED trial.

Cardiovasc Diabetol 2020 06 13;19(1):85. Epub 2020 Jun 13.

Department of Cardiovascular Medicine, Saga University, Saga, Japan.

Background: Type 2 diabetes (T2D) is associated with renal impairment and vascular endothelial dysfunction. Therefore, this pathological connection is an important therapeutic target. Recent cardiovascular and renal outcome trials demonstrated that sodium glucose cotransporter 2 inhibitors (SGLT2is) consistently reduced the risks of cardiovascular and renal events and mortality in patients with T2D and various other background risks including chronic kidney disease (CKD). However, the precise mechanisms by which SGLT2is accords these therapeutic benefits remain uncertain. It is also unknown whether these SGLT2is-associated benefits are associated with the amelioration of endothelial dysfunction in patients with T2D and CKD.

Methods: The PROCEED trial is an investigator-initiated, prospective, multicenter, open-label, randomized-controlled trial. The target sample size is 110 subjects. After they furnish informed consent and their endothelial dysfunction is confirmed from their decreased reactive hyperemia indices (RHI), eligible participants with T2D (HbA1c, 6.0-9.0%) and established CKD (30 mL/min/1.73 m ≤ estimated glomerular filtration ratio [eGFR] < 60 and/or ≥ urine albumin-to-creatinine ratio 30 mg/g Cr) will be randomized (1:1) to receive either 50 mg ipragliflozin daily or continuation of background treatment (non-SGLT2i). The primary endpoint is the change in RHI from baseline after 24 weeks. To compare the treatment effects between groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for HbA1c (< 7.0% or ≥ 7.0%), age (< 70 y or ≥ 70 y), RHI (< 1.67 or ≥ 1.67), eGFR (< 45 mL/min/1.73 m or ≥ 45 mL/min/1.73 m), and smoking status. Prespecified responder analyses will be also conducted to determine the proportions of patients with clinically meaningful changes in RHI at 24 weeks.

Discussion: PROCEED is the first trial to examine the effects of ipragliflozin on endothelial dysfunction in patients with T2D and CKD. This ongoing trial will establish whether endothelial dysfunction is a therapeutic target of SGLT2is in this population. It will also provide deep insights into the potential mechanisms by which SGLT2is reduced the risks of cardiovascular and renal events in recent outcome trials. Trial registration Unique Trial Number, jRCTs071190054 (https://jrct.niph.go.jp/en-latest-detail/jRCTs071190054).
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http://dx.doi.org/10.1186/s12933-020-01065-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293776PMC
June 2020

Response of thyrotropin-secreting pituitary tumors to preoperative lanreotide therapy. Report of two cases.

Neuro Endocrinol Lett 2020 Apr;41(1):10-16

First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushyu-shi, 807-8555, Japan.

Case 1 was a 51-year-old man diagnosed with thyrotropin (TSH)-secreting pituitary tumor. The octreotide loading test showed suppression of TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. Three months after treatment initiation, tumor shrinkage was observed, and pituitary tumor resection was performed through transsphenoidal surgery. Case 2 was a 47-year-old woman in whom the octreotide loading test showed suppressed TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. After six months of treatment, tumor reduction was observed, and transsphenoidal surgery was performed. In both cases, lanreotide administration before TSH-secreting pituitary tumor resection achieved normalization of thyroid function and tumor shrinkage. Treatment with lanreotide seems effective in patients who show TSH secretion suppression in the octreotide loading test.
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April 2020

Fulminant Type 1 Diabetes with Diversity in Peripheral Blood Lymphocytes: A Case Report.

J UOEH 2020 ;42(1):57-62

First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.

A 29-year-old woman was admitted to our hospital for treatment of fulminant type 1 diabetes (FT1D) with diabetic ketoacidosis. The phenotype of peripheral blood lymphocytes was analyzed using an 8-color flow cytometer. An analysis of the CD4-positive T cells showed a tendency for higher proportions of effector and central memory T cells and a normal proportion of regulatory T (Treg) cells, compared to healthy control. An analysis of B cell differentiation showed higher proportions of switched memory B cells and plasmablasts. The differences in lymphocyte phenotypes between our case and previously reported cases suggest a diversity of FT1D pathology.
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http://dx.doi.org/10.7888/juoeh.42.57DOI Listing
August 2020

Usefulness of the index calculated as the product of levels of fasting plasma glucose and hemoglobin A1c for insulinoma screening.

Endocr J 2020 May 4;67(5):509-513. Epub 2020 Feb 4.

Department of Internal Medicine, Hakuhokai Central Hospital, Hyogo 669-0953, Japan.

Hypoglycemia is the major symptom of insulinoma. Chronic and recurrent hypoglycemia leads to the disappearance of autonomic symptoms and persistence of non-specific symptoms alone, possibly contributing to the delayed diagnosis of insulinoma and accounting for several undiagnosed cases. We previously reported the usefulness of hemoglobin A1c (HbA1c) and glycated albumin as markers for early insulinoma screening; however, their diagnostic prediction performance and diagnostic performance were not satisfactory. We hypothesized that the product of fasting plasma glucose (FPG) and HbA1c levels (FPG × HbA1c index) is low in insulinoma, and this index may be a useful marker for screening. This cross-sectional multicenter study compared 82 insulinoma patients with 100 age-, sex-, and body mass index-matched controls with normal glucose tolerance based on 75-g oral glucose tolerance test. The FPG × HbA1c index was significantly lower in the insulinoma group than in the control group. Receiver operating curve analysis showed that the optimal cutoff point of the FPG × HbA1c index to diagnose insulinoma was 447.1, and the area under the curves (AUCs) of the FPG × HbA1c index and HbA1c were 0.998 and 0.966, respectively. The AUC of the index was significantly higher than that of HbA1c (p = 0.010). Conversely, no significant difference existed between the AUC of the FPG × HbA1c index and that of the FPG/fasting immunoreactive insulin index. Thus, in apparently healthy population, the product of FPG and HbA1c yields a useful index for insulinoma screening in terms of accuracy and versatility.
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http://dx.doi.org/10.1507/endocrj.EJ19-0357DOI Listing
May 2020