Glucose Tolerance and the Risk Factors for Transmission in Japanese SARS-CoV-2/WA-1/2020 Epicenter: A Retrospective Study.

Purpose: The severe pathogenic ancient-type COVID-19, SARS-CoV-2/WA-1/2020 was the predominant gene variant in early 2020 in Japan, however, its transmissibility was uncertain. The period before the public commenced using any personal protective equipment (PPE) was evaluating to describe the transmissibility of the SARS-CoV-2/WA-1/2020. We analyzed the secondary attack rate (SAR) among close contacts and the risk factor for SAR. Methods: This retrospective cohort study included a total of 539 patients who were anticipated for the SARS-CoV-2/WA-1/2020 infection at Toho University Medical Center Omori Hospital from February to May 2020. We selected 54 patients with 1) exclude other pathogens infection, 2) include "Three Cs" condition: crowded places between distance< 6 feet, closed spaces indoor and close contact settings involving contact >15min with a person tested positive for SARS-CoV-2/WA-1/2020 without PPE. We evaluated alternative infection risks: the body mass index (BMI) and diabetes (DM) status (non-DM, pre-DM, and DM) as demographic determinants of transmissibility and infectivity of SARS-CoV2/WA-1/2020 cases during the incubation period. Results: The calculated SAR was 79.3%. BMI was significantly associated with the PCR positivity rate, which was significant in the univariate (CI 95%, 1.02-1.51; P = 0.03) and multivariate (CI 95%, 1.02-1.60; P = 0.03) analyses. Comparing the different BMI groups, the highest BMI group (25.5-35.8 kg/m2) had an elevated risk of SAR compared to the lowest BMI group (14.0-22.8 kg/m2), with an odds ratio of 1.41 (95% CI, 1.02-1.59; P = 0.03). There were no significant differences in the risk of SAR among different DM statuses. Conclusion: The transmissibility of SARS-CoV2/WA-1/2020 was high (79.3%) among household members without PPE who had "Three Cs" exposure. Although pre-DM and established DM did not confer a risk for transmissibility, higher BMI was associated with an increased risk of SAR. Trial Registration: UMIN Clinical Trials Registry, UMIN0000 50905.

A Case of Acute-Onset Type 1 Diabetes Mellitus with Diabetic Ketoacidosis Triggered by COVID-19.

BACKGROUND It is well known that diabetes mellitus contributes to COVID-19 severity. Recently, there have been reports of an increase in the number of children with type 1 diabetes after the COVID-19 pandemic. CASE REPORT A 52-year-old woman presented to the Emergency Department with disturbance of consciousness, accompanied by a 1-day history of thirst, a fever of 38°C, and breathlessness. She had a positive coronavirus antigen test. Her initial vital signs assessment showed a heart rate of 120 beats per minute, blood pressure 90/50 mmHg, temperature 37.3°C, and respiratory rate 30 breaths/minute with an oxygen saturation of 100% with 10 L oxygen inhalation. Her initial laboratory test results showed a blood glucose level of 1507 mg/dl, HbA1c of 10.1%, ketone 2+, and blood gas pH 7.113. The patient was diagnosed with diabetic ketoacidosis (DKA). There were mild inflammatory findings with blood CRP 0.14 mg/dl and a white cell count of 12 400/µL, but no pneumonia on a chest CT scan. Therefore, the patient was diagnosed with COVID-19 and DKA. The patient was positive for anti-glutamic acid decarboxylase (anti-GAD antibody) and had markedly low levels 24-h urine C-peptide (CPR). She was diagnosed with acute-onset type 1 diabetes mellitus, as her blood examination showed a postprandial blood glucose level of 100 mg/dl and HbA1c of 5.7% 2 months before admission. After admission, fluid replacement and continuous intravenous insulin infusion therapy were started, and blood glucose and blood gas pH improved over 10 h. CONCLUSIONS There have been reports of cases of type 1 diabetes consequences of COVID-19, but the mechanism has not been elucidated.

Comparison of the effects of sitagliptin and dapagliflozin on time in range in Japanese patients with type 2 diabetes stratified by body mass index: A sub-analysis of the DIVERSITY-CVR study.

AIMS: To compare the effects of baseline background characteristics in patients treated with dapagliflozin and sitagliptin in the DIVERSITY-CVR study and to analyse the time in range (TIR), a metric for glycaemic control. MATERIALS AND METHODS: This prospective, randomized, multicentre study included 340 Japanese patients with early-stage type 2 diabetes. To examine the effects of dapagliflozin and sitagliptin on glycaemic variability, we re-examined the primary endpoint (glycated haemoglobin [HbA1c] < 7.0%, body weight loss ≥ 3.0%, and avoidance of hypoglycaemia) achievement rate in participants stratified by baseline background characteristics. RESULTS: Sitagliptin was significantly superior in achieving HbA1c level <7.0% in the lower body mass index (BMI) group (71.1% vs. 43.6%; P < 0.05), with no significant differences in other subgroups. In the lower BMI group, the rate of achievement of TIR > 70% after 24-week treatment was significantly higher with sitagliptin than with dapagliflozin (91.9% vs. 69.4%; P < 0.05). In contrast, dapagliflozin was superior to sitagliptin in achieving TIR > 70% in the higher BMI group (85.7% vs. 52.9%; P < 0.01). CONCLUSION: In Japanese patients with early-stage type 2 diabetes, sitagliptin was associated with improved TIR in patients with a lower BMI. Dapagliflozin was effective in patients with a higher BMI.

SGLT2 inhibitor versus carbohydrate-restricted isocaloric diet: reprogramming substrate oxidation in type 2 diabetes.

OBJECTIVE: Based on the whole-body energy metabolism and insulin action, the difference between increased excretion of carbohydrate in urine by SGLT2i and reduced same amount of oral carbohydrate intake are scarce. This study aimed to compare the effect of carbohydrate availability with reduced oral intake (carbohydrate-restricted isocaloric diet: CRIC diet) or lost in urine, as urinary glucosuria on sodium/glucose cotransporter-2 inhibitor (SGLT2i) treatment, focus on the insulin requirement and the macronutrient oxidation within insulin treated type 2 diabetes. METHODS: This is randomized 3-arm open-label prospective study. Subjects treated with titrated basal-bolus insulin regimen subsequent to three diet regimens, control diet (CON), administration of canagliflozin 100 mg/day to CON (SGLT2i), or CRIC diet, with a week admission to the endocrinology ward followed by 12 weeks outpatients' management. The main outcome measures including the total insulin dose (TID) required to achieve euglycemia, fasting and postprandial energy expenditure (EE) and respiratory quotient (RQ) at 1-week and 12-week. RESULTS: We enrolled 23 patients with type 2 diabetes (male/female: 14/9, age: 53.6 ± 14.2 years, body mass index: 26.9 ± 4.8 kg/m2, HbA1c: 12.5 ± 1.6%). The TID was similar with CON and SGLT2i at both 1 and 12-weeks. Although comparable net carbohydrate availability in SGLT2i and CRIC groups, the TID was significantly higher in the CRIC (p = 0.02) compare to the SGLT2i at both 1 and 12-weeks. Fasting EE was similar in all groups, postprandial EE was significantly elevated in the SGLT2i and CRIC groups compared to the CON group (p = 0.03 and 0.04). Compare to the CON, lower basal fasting RQ (p = 0.049) and decreased delta-RQ (postprandial RQ/fasting RQ) indicated continuous lipid substrate utilization in the SGLT2i (p = 0.04) and CRIC (p = 0.03) groups. CONCLUSION: The CRIC diet resulted in a similar fasting and postprandial EE and substrate oxidation compared to the SGLT2i. The increased insulin requirement in the CRIC diet indicates that a relatively highly lipid and protein consumption, compared to the SGLT2i and CON, may influence insulin requirement.

Aldosterone-to-Renin Ratio Is Associated with Diabetic Nephropathy in Type 2 Diabetic Patients: A Single-Center Retrospective Study.

BACKGROUND It is well established that primary aldosteronism (PA) and aldosterone-to-renin ratio (ARR) are associated with kidney disease. The aim of this study was to retrospectively investigate the relationship between ARR, urinary albumin excretion (UAE), and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes from a single center. MATERIAL AND METHODS We included 70 patients with type 2 diabetes, UAE ≤100 mg/day, not taking renin-aldosterone system inhibitors, did not meet the diagnostic criteria for PA, and had an ARR <20. The patients were divided into 3 groups: the normal low (NL) group (33 patients) with a UAE <10 mg/day, the normal (N) group (22 patients) with a UAE of 10-29 mg/day, and the microalbuminuria (M) group (15 patients) with a UAE of 30-100 mg/day. The ARR, plasma renin activity (PRA), and plasma aldosterone (PAC) were compared among groups. RESULTS The ARR was highest in group M (10.1±4.6), 6.5±0.3 in group NL, and 7.0±2.7 in group N. The PRA and PAC were significantly lower in group M (P<0.001). The ARR showed a significant positive correlation with log UAE (r=0.37, P<0.001) and a significant negative correlation with eGFR (r=-0.33, P<0.01). CONCLUSIONS High levels of aldosterone relative to renin, which did not fulfill confirmatory criteria for PA, may be one of the risk factors for the development of diabetic nephropathy in patients with diabetes. The present results are supported by previous research showing that an increased ARR without PA was a risk factor for kidney disease.

Postprandial Glucose Excursions in Asian Versus Non-Asian Patients with Type 2 Diabetes: A Post Hoc Analysis of Baseline Data from Phase 3 Randomised Controlled Trials of IDegAsp.

INTRODUCTION: Increased postprandial glucose (PPG) is associated with high glycated haemoglobin levels and is an independent risk factor for cardiovascular diseases. The aim of this study was to compare PPG increments in Asian versus non-Asian adults with type 2 diabetes (T2D), who were insulin-naïve or insulin-experienced, from the phase 3 insulin degludec/insulin aspart (IDegAsp) clinical trials. METHODS: This was a post hoc analysis of data from 13 phase 3, randomised, parallel-group, open-label IDegAsp trials in patients with T2D. The pooled baseline clinical data were analysed for insulin-naïve and insulin-experienced groups; and each group was split into subgroups of Asian and non-Asian patients, respectively, and analysed accordingly. Baseline self-monitored blood glucose (SMBG) values at breakfast, lunch and the evening meal (before and 90 min after each meal) were used to assess PPG increments. The estimated differences in baseline SMBG increment between the Asian and non-Asian subgroups were analysed. RESULTS: Clinical data from 4750 participants (insulin-naïve, n = 1495; insulin-experienced, n = 3255) were evaluated. In the insulin-naïve group, the postprandial SMBG increment was significantly greater in the Asian versus the non-Asian subgroup at breakfast (estimated difference 28.67 mg/dL, 95% confidence interval [CI] 18.35, 38.99; p < 0.0001), lunch (17.34 mg/dL, 95% CI 6.47, 28.21; p = 0.0018) and the evening meal (16.19 mg/dL, 95% CI 5.04, 27.34; p = 0.0045). In the insulin-experienced group, the postprandial SMBG increment was significantly greater in the Asian versus non-Asian subgroup at breakfast (estimated difference 13.81 mg/dL, 95% CI 9.19, 18.44; p < 0.0001) and lunch (29.18 mg/dL, 95% CI 24.22, 34.14; p < 0.0001), but not significantly different at the evening meal. CONCLUSION: In this post hoc analysis, baseline PPG increments were significantly greater in Asian participants with T2D than in their non-Asian counterparts at all mealtimes, with the exception of the evening meal in insulin-experienced participants. Asian adults with T2D may benefit from the use of regimens that control PPG excursions. CLINICAL TRIAL NUMBERS: NCT02762578, NCT01814137, NCT01513590, NCT01009580, NCT01713530, NCT02648217, NCT01045447, NCT01365507, NCT01045707, NCT01272193, NCT01059812, NCT01680341, NCT02906917.

Quantitative evaluation of insulin-induced abdominal subcutaneous dystrophic tissue using shear wave elastography.

AIMS/INTRODUCTION: Subcutaneous dystrophic tissue (DT) produced by insulin injection causes dysglycemia owing to inadequate absorption of insulin. However, precise techniques for measuring DT have not been established. Shear wave elastography (SWE) is an imaging technology that can quantify tissue stiffness. In this study, insulin injection-induced DT was quantified using SWE to generate whole-abdominal wall subcutaneous tissue by three-dimensional (3D) imaging in patients with type 2 diabetes who were treated with multiple insulin injections. MATERIALS AND METHODS: Seven patients with type 2 diabetes were recruited who received long-standing multiple insulin injections. Using SWE, the shear wave velocity (SWV) of DT and control (normal subcutaneous tissue) was measured. Furthermore, two of seven patients underwent whole-abdominal SWE examination to calculate the proportion of DT. A subcutaneous insulin tolerance test was also performed in both the DT and control tissues. RESULTS: The SWV in DT was significantly higher than that in the control tissue (2.87 [2.66-2.98] vs 1.29 [1.23-1.44] m/s, P < 0.01). The proportion of the DT volume was 0.67% and 5.21% for two individuals from the entire abdominal subcutaneous tissue volume. The area under the curve for the subcutaneously injected insulin aspart concentration at the DT sites was lower than that of the control tissue (75.0 [52.1-111] vs 116 [86.9-152.5] h*mU/L, P = 0.1). CONCLUSIONS: SWE can be useful in quantifying abdominal subcutaneous insulin-induced DT, especially the 3D volume of insulin injection-induced DT from the entire abdominal subcutaneous tissue. This study is the first to examine the volume and distribution of abdominal subcutaneous DT using SWE.

Dipeptidyl peptidase-4 inhibitor improves glycemic variability in multiple daily insulin-treated type 2 diabetes: a prospective randomized-controlled trial.

AIMS: To improve glycemic variability (GV) is crucial in the management of multiple daily insulin (MDI) treatment in diabetes. To evaluate the GV improvement in MDI treated type 2 diabetes (T2D) with low-dose metformin 750 mg/day (LMET), which was popular in the clinical practice in Japan, we compared the effect of adding vildagliptin 100 mg/day (LMET + DPP4i treatment) or increased metformin dose to 1500 mg/day (HMET treatment), in the setting of continuous glucose monitoring (CGM) analysis. MATERIALS AND METHODS: Single-center, open-label, 12 weeks-two period cross-over design. Twenty T2D with inadequately controlled (7.0% < HbA1c ≤ 9.0%) with MDI + LMET were enrolled. Primary endpoints were GV and hypoglycemia derived from CGM indices, performed after each 12 week treatment periods. RESULTS: There was no significant difference in both LMET + DPP4i treatment and HMET treatment, in terms of HbA1c, body weight changes, and total daily dose of insulin to achieve the targeted glycemia. LMET + DPP4i treatment compared to HMET treatment, significantly reduced the calculated GV value, mean (7.15 ± 1.30 vs 7.82 ± 1.60, p = 0.04), standard deviation (1.78 ± 0.55 vs 2.27 ± 1.11, p = 0.03), continuous overlapping net glycemic action (6.44 ± 1.28 vs 7.12 ± 1.69, p < 0.05), J-Index (26.7 ± 11.0 vs 34.9 ± 19.8, p < 0.05), high blood glucose index (3.01 ± 1.96 vs 6.73 ± 4.85, p = 0.02), and mean amplitude of glycemic excursions (4.53 ± 1.35 vs 5.50 ± 2.34, p = 0.03). CONCLUSION: The GV metrics regarding daily and nocturnal hypoglycemia were not significantly different between LMET + DPP4i treatment and HMET treatment. LMET + DPP4i treatment decreased GV associated with hyperglycemia. Adding DPP-4-inhibitor to the lower dose of metformin is an alternative approach to the stable GV in MDI compared to additional high-dose metformin. National Clinical Trial registration in Japan, number is JPRN-UMIN000024663. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00513-6.

Changes in subjective sleep quality in patients with type 2 diabetes who did not use Sleep agents: a cross-sectional study according to age and clinical background.

AIM: Diabetes and aging are both well-established risk factors for insomnia. Therefore, we investigated the changes in subjective sleep quality in relation to clinical backgrounds and age in patients with type 2 diabetes mellitus (T2DM). METHODS: This cross-sectional study included 380 participants with T2DM who were between 18 and 79 years of age from our outpatient clinics. Individuals with any symptoms and medical histories associated with obstructive sleep apnea (OSA) were excluded from the interview and analyses. Data were collected using self-administered questionnaires, namely the Pittsburgh Sleep Quality Index (PSQI) and the Morning-Evening Questionnaire (MEQ), as well as medical records and blood samples. We performed stratified analyses according to age decades. RESULTS: The number of patients in the age groups (in years) was as follows: < 50 (n = 69), 50-60 (n = 52), 60-70 (n = 138), and 70-80 (n = 121). PSQI score was highest in the < 50 group (4.99 ± 2.40), and significantly decreased with age (p < 0.05). Body mass index (BMI) was also highest in the < 50 group (25.5 ± 4.8 kg/m2), and markedly decreased with age (p < 0.01). Interestingly, BMI was significantly correlated with the PSQI score (rs = 0.157, p < 0.05). We also found that younger patients had shorter sleep duration, stronger daytime sleepiness, and a tendency for the evening type. CONCLUSION: Younger T2DM patients had poorer sleep quality and higher BMI. Our findings suggest that insomnia should be accounted for as a potential comorbidity when examining or treating patients with T2DM and obesity even in the younger population.

A Real-World, Prospective, Non-interventional Study of Adults with T2D Switching to IDegAsp from Glargine U100 or U300 in Japan.

INTRODUCTION: This real-world study investigated glycaemic control and quality of life (QoL) in insulin-experienced Japanese patients with type 2 diabetes (T2D) who switched to insulin degludec/insulin aspart (IDegAsp). METHODS: This was a prospective, non-interventional, open-label, single-arm study. Eligible patients were adults (aged ≥ 20 years) with T2D, previously treated with insulin glargine 100 or 300 units/mL (glargine U100/U300) with or without prandial insulin, who switched to IDegAsp as part of routine practice. Change from baseline to end of study (EOS; 26 weeks after initiation or IDegAsp discontinuation) in the following endpoints was assessed by adjusted mixed models for repeated measures: glycated haemoglobin (HbA1c; primary endpoint), fasting plasma glucose (FPG), insulin dose and total Diabetes Therapy-Related Quality of Life (DTR-QoL) score. Non-severe hypoglycaemia was assessed in the 4-week period prior to initiating IDegAsp and in the 4-week period before EOS or discontinuation using negative binomial regression. RESULTS: The full analysis set included 236 patients from 29 centres in Japan with mean (± SD) age 63.2 years (± 12.3), HbA1c 7.7% (± 1.0) and diabetes duration 14.9 (± 9.3) years. After 26 weeks with IDegAsp, HbA1c (estimated change - 0.1% [- 0.2; 0.0]95% confidence interval (CI), p = 0.3036) and FPG (- 7.5 mg/dL [- 23.5; 8.5]95% CI, p = 0.3477) were maintained; there were significant reductions in basal and total insulin dose: estimated change of - 3.4 units/day [- 3.8; - 3.0]95% CI and - 1.0 units/day [- 1.9; - 0.1]95% CI, respectively (both p < 0.05). Non-severe hypoglycaemia rates were similar in the periods before and after initiating IDegAsp, while there was a significant improvement in total DTR-QoL score after 26 weeks with IDegAsp (p = 0.0012). CONCLUSION: These real-world data suggest that switching to IDegAsp from glargine U100 or U300 was well tolerated in a Japanese population with T2D, with no new safety or tolerability signals, and associated with maintenance of glycaemic control and improved QoL. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov: NCT03745157.

A comparison of meal tolerance test and oral glucose tolerance test for predicting insulin therapy in patients with gestational diabetes.

AIMS: To identify factors predicting a need for insulin therapy in gestational diabetes mellitus (GDM) by comparing plasma glucose (PG) levels in a 75-g oral glucose tolerance test (75-g OGTT) with those in a 500-kcal meal tolerance test (MTT) containing 75 g of carbohydrate. SUBJECTS AND METHODS: The MTT was performed in 61 patients who diagnosed with GDM by a 75-g OGTT (age, 33.2 ± 4.5 years; prepregnancy body mass index, 22.6 ± 4.7 kg/m2; number of gestational weeks, 25.1 ± 6.4 weeks). PG and serum insulin levels were measured before the meal and up to 180 min after the meal. The insulin secretion capacity and resistance index were calculated. RESULTS: PG levels increased from 86.8 ± 8.8 mg/dL at fasting to 132.7 ± 20.1 mg/dL at 30 min, and 137.8 ± 27.7 mg/dL at 60 min after MTT in the 35 patients with needed insulin therapy; these levels were significantly higher than those in the 26 patients, who only needed diet therapy. The patients with needed insulin therapy had significantly higher fasting PG levels in the 75-g OGTT, PG levels at fasting and 30 min after the MTT, and homeostasis model assessment of insulin resistance (HOMA-IR), and a significantly lower disposition index (DI) and insulin index than patients treated by diet alone. Receiver operating characteristic curve analysis was performed for factors involved in insulin therapy, with the following cutoff values: fasting PG in the 75-g OGTT, 92 mg/dL; PG 30 min after MTT, 129 mg/dL; HOMA-IR, 1.51; DI, 3.9; HbA1c, 5.4%. Multivariate analysis revealed that the 30-min PG level after MTT and HOMA-IR predicted insulin therapy. CONCLUSION: PG levels at 30 min after MTT may be useful for identifying patients with GDM, who need insulin therapy.

A Real-World, Observational Study of the Initiation, Use, and Effectiveness of Basal-Bolus or Premixed Insulin in Japanese People with Type 2 Diabetes.

INTRODUCTION: Basal-bolus (BB) and premixed insulin regimens may lower fasting plasma glucose (FPG) and postprandial plasma glucose (PPG), but are complex to use and associated with weight gain and hypoglycaemia. Although randomized controlled trials and prospective observational studies in insulin-naïve Japanese patients with type 2 diabetes (T2D) inadequately controlled with oral antidiabetic drugs (OADs) initiating these regimens have been conducted, real-world data are lacking. This study describes the characteristics of patients initiating these regimens in routine clinical practice and identifies the course and outcomes of therapy in the year following initiation. METHODS: Adults with T2D initiating BB or premixed regimens following OAD therapies held in a Japanese electronic medical record database were identified (2010-2019). Subcohorts were determined by treatment changes during ≤ 12 months of follow-up (no change, intensified, switched, discontinued). Outcomes included change in glycated haemoglobin levels (HbA1c), probability of first reaching HbA1c < 7% (stratified by baseline OAD number, HbA1c and age), and hypoglycaemia incidence. RESULTS: The main cohorts comprised 1315 BB and 1195 premixed therapy initiators. Most individuals (67.9%) initiated BB as inpatients; 50.8% switched at a mean of 47.6 days. Mean HbA1c lowering was - 2.5% for BB and - 1.4% for premixed regimens (no change cohorts). Overall, a greater proportion achieved HbA1c < 7% if they were (at baseline) taking fewer OADs, in a lower HbA1c category, and aged ≥ 65 years. Hypoglycaemia incidence (< 70 mg/dl) was higher with BB than premixed regimens and lower in patients aged < 65 years. CONCLUSION: Greater HbA1c reductions, but a higher incidence of hypoglycaemia, were reported with BB versus premixed regimens, while both cohorts demonstrated clinically meaningful reductions in HbA1c during follow-up. After initiation, most premixed regimens remained unchanged, whereas switches from BB to less intensive regimens were numerous, in accordance with the use of BB for a limited duration to improve FPG and PPG control.

Pre-Existing Diabetes Limits Survival Rate After Immune Checkpoint Inhibitor Treatment for Advanced Lung Cancer: A Retrospective Study in Japan.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) are promising in the treatment of advanced cancer, their use is associated with immune-related adverse events (irAEs) that affect endocrine organ systems. Although development of irAEs was associated with improved cancer-specific survival, the risk of irAEs is unclear. We investigated the association of pre-ICI comorbidities-including diabetes-with irAEs, overall survival (OS), and progression-free survival (PFS) in advanced lung cancer. METHODS: Patients with lung cancer who were treated with ICIs during the period from September 1, 2015 through July 31, 2018 were retrospectively enrolled. All data were collected from the NEPTUNE database of university patients. Hazard ratios were estimated by using Cox regression weighted for propensity scores. Odds ratios were calculated by logistic regression and adjusted for unbalanced variables. The Kaplan-Meier method was used to compare OS, and the generalized Wilcoxon test was used to compare median survival. RESULTS: Among the 88 patients identified, 22 (25.0%) had diabetes (DM) before ICI treatment and 57 (75.0%) did not (non-DM); irAEs developed in 12.2% of patients with DM and in 9.1% of patients in non-DM (p=0.87). Diabetes status was not associated with irAE risk in relation to baseline characteristics (age, sex, TNM staging, thyroid and renal function) or in propensity score-matched analysis (age, TNM staging). During a mean follow-up of 30 months, OS and cancer-specific PFS were significantly higher in patients who developed irAEs (Kaplan-Meier estimates, p=0·04 and 0·03, respectively). In propensity score-matched analysis, diabetes was significantly associated with lower OS (multivariate hazard ratio, 0·36; 95% CI, 0·13-0·98) unrelated to irAEs. Irrespective of irAEs, PFS was also lower among patients with DM than among non-DM patients (Kaplan-Meier estimate, p=0·04). CONCLUSION: Pre-existing diabetes was associated with higher mortality in advanced lung cancer, regardless of irAE development during treatment with ICI.

Simplification of complex insulin regimens using canagliflozin or liraglutide in patients with well-controlled type 2 diabetes: A 24-week randomized controlled trial.

AIMS/INTRODUCTION: We investigated the potential use of canagliflozin, in comparison with liraglutide, as an alternative to bolus insulin in patients with well-controlled type 2 diabetes mellitus receiving multiple daily insulin injection therapy. MATERIALS AND METHODS: In 40 patients, with glycated hemoglobin (HbA1c) levels <7.5% controlled by multiple daily insulin injection therapy, all bolus insulin was randomly switched to canagliflozin (100 mg/day) or liraglutide (0.3-0.9 mg/day) for 24 weeks. Basal insulin was continued with dose adjustment according to a predefined algorithm. The end-points were the change in the HbA1c level, glycemic variability assessed by continuous glucose monitoring, body mass index, insulin dose, quality of life (QOL) and safety assessments. Factors influencing the changes in QOL were also assessed using a simple regression analysis. RESULTS: The change in HbA1c from baseline was comparable between the treatments. Both treatments maintained the HbA1c level to the baseline levels with stable glucose variability and no severe hypoglycemia for 24 weeks, decreased total insulin dose, and significantly increased the QOL score. The change in QOL was significantly associated with injection frequency. CONCLUSIONS: For patients with well-controlled type 2 diabetes mellitus, under the support of basal insulin, complex insulin regimens can be simplified by replacing all bolus insulin with once-daily canagliflozin or liraglutide, which improves patients' QOL.

A prospective randomized study comparing effects of empagliflozin to sitagliptin on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes: the ASSET study.

BACKGROUND: While the cardioprotective benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been established in patients with cardiovascular disease (CVD), their advantages over other anti-diabetic drugs at earlier stages remain unclear. We compared the cardioprotective effects of empagliflozin, an SGLT2 inhibitor, with those of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, focusing on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes mellitus (T2DM) without CVD complications. METHODS: This was a prospective, randomized, open-label, blinded-endpoint, parallel-group trial that enrolled 44 Japanese patients with T2DM. The patients were randomized for 12-week administration of empagliflozin or sitagliptin. Pericardial fat accumulation and myocardial triglyceride content were evaluated by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Echocardiography, 123I-ß-methyl-iodophenyl pentadecanoic acid myocardial scintigraphy, and laboratory tests were performed at baseline and after the 12-week treatment period. RESULTS: The patients were middle-aged (50.3 ± 10.7 years, mean ± standard deviation) and overweight (body mass index 29.3 ± 4.9 kg/m2). They had a short diabetes duration (3.5 ± 3.2 years), HbA1c levels of 7.1 ± 0.8%, and preserved cardiac function (ejection fraction 73.8 ± 5.0%) with no vascular complications, except for one baseline case each of diabetic nephropathy and peripheral arterial disease. After the 12-week treatment, no differences from baseline were observed between the two groups regarding changes in pericardial, epicardial, and paracardial fat content; myocardial triglyceride content; cardiac function and mass; and cardiac fatty acid metabolism. However, considering cardiometabolic biomarkers, high-density lipoprotein cholesterol and ketone bodies, including ß-hydroxybutyric acid, were significantly increased, whereas uric acid, plasma glucose, plasma insulin, and homeostasis model assessment of insulin resistance were significantly lower in the empagliflozin group than in the sitagliptin group (p < 0.05). CONCLUSIONS: Although the effects on cardiac fat and function were not statistically different between the two groups, empagliflozin exhibited superior effects on cardiometabolic biomarkers, such as uric acid, high-density lipoprotein cholesterol, ketone bodies, and insulin sensitivity. Therefore, when considering the primary preventive strategies for CVD, early supplementation with SGLT2 inhibitors may be more beneficial than DPP-4 inhibitors, even in patients with early-stage T2DM without current CVD complications. CLINICAL TRIAL REGISTRATION: UMIN000026340; registered on February 28, 2017. https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000030257.

Risk of hypoglycemia in Japanese people with type 2 diabetes mellitus who initiated or switched to insulin glargine 300 U/mL: A subgroup analysis of 12-month post-marketing surveillance study (X-STAR study).

AIMS: This study investigated the hypoglycemia risk in people with type 2 diabetes (T2D) who initiated or switched to insulin glargine 300 U/mL (Gla-300) by stratifying them by age and renal function. METHODS: We examined data from 4621 people with T2D (1227 insulin-naïve and 3394 insulin-experienced) of the X-STAR study, a prospective, observational, 12-month study conducted from December 2015 to August 2018 in Japan. Participants were stratified by age (<65, 65 to <75, and ≥75 years) and estimated glomerular filtration rate (eGFR) (≥90, 60 to <90, 30 to <60, and <30 mL/min/1.73 m2). Hypoglycemia was defined according to the Ministry of Health, Labour and Welfare manual of Japan. RESULTS: No apparent increase in the proportion of people who experienced hypoglycemia was found in all subgroups. The proportions were 2.9-3.5% and 2.7-5.2% of insulin-naïve and insulin-experienced people, respectively, for age subgroups, and 2.4-4.7% and 4.6-4.8%, respectively, for eGFR subgroups. The result was similar for HbA1c levels below and at or above 7.0% in all age subgroups. CONCLUSIONS: Our study found no apparent increase in the hypoglycemia risk in people with older age and renal impairment who were administered Gla-300. These results would provide reassuring information on Gla-300 use.

Real-world data on the use of insulin glargine 300 U/mL in Japanese patients with type 1 diabetes: twelve-month results from a post-marketing surveillance study (X-STAR study).

BACKGROUND: With limited real-world insulin glargine 300 U/mL (Gla-300) data among Japanese patients with type 1 diabetes mellitus (T1DM) available, the authors describe its effectiveness and safety in Japanese T1DM patients switching to Gla-300. RESEARCH DESIGN AND METHODS: X-STAR was a 12-month prospective, observational, post-marketing study in Japanese patients with diabetes mellitus from 2015 to 2018: insulin-experienced T1DM patients initiating Gla-300 were analyzed. RESULTS: Of 774 patients, mean (±standard deviation) HbA1c (%) and fasting plasma glucose (mg/dL) decreased from 8.27 ± 1.55 to 8.15 ± 1.35 (by -0.12 ± 1.30 [p = 0.013]) and 167.9 ± 92.6 to 153.9 ± 70.9 (by -13.9 ± 103.8 [p = 0.067]) from baseline to month 12, respectively. A total of 16.3% achieved HbA1c <7.0% at month 12. Gla-300 dose increased by 1.13 ± 3.18 U/day (0.02 ± 0.05 U/kg/day) (p < 0.001), with a + 0.22 ± 2.70 (p = 0.037) body-weight change (kg) from baseline 60.83 ± 12.81 to 12-month 61.06 ± 12.89. Adverse drug reactions (ADRs) and serious ADRs occurred in 9.82% and 0.78% of the patients, respectively. Hypoglycemia was the most common ADR (9.30%). In total, 88.9% adhered to Gla-300 administration schedules, whereas <40% adhered to exercise and dietary instructions, respectively. CONCLUSIONS: Gla-300 showed no unprecedented safety concerns for insulin-experienced T1DM patients in Japanese clinical settings. Our results provide insights into strategies for blunted Gla-300 up-titration dose, despite insufficient HbA1c control and lifestyle modification.

Current state of hypnotic use disorders: Results of a survey using the Japanese version of Benzodiazepine Dependence Self-Report Questionnaire.

AIMS: Benzodiazepine receptor agonists (BZ-RAs) are frequently prescribed to treat insomnia; however, their long-term use is not recommended. To introduce an appropriate pharmaco-therapy, the current state and background factors of BZ-RAs' dependence must be elucidated. In this study, we developed a Japanese version of the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ-J) and conducted a study of BZ-RAs' use disorder. METHODS: The Bendep-SRQ-J was created with permission from the original developer. Subjects were inpatients and outpatients receiving BZ-RAs between 2012 and 2013. Clinical data collected were Bendep-SRQ-J scores, sleep disorders for which BZ-RAs were prescribed, physical comorbidities, psychotropic drugs, and lifestyle factors. Logistic analysis was performed to extract factors associated with severe symptoms. RESULTS: Of the 707 patients prescribed BZ-RAs, 324 had voluntarily tapered or discontinued their drugs. Logistic analysis showed that the total number of drugs administered in the last 6 months correlated with both worsening of symptoms or conditions. This was more notable among younger patients, and the proportion of patients with severe symptoms or conditions increased with the increasing number of drugs. CONCLUSION: Using the Bendep-SRQ-J, we elucidated the current state of BZ-RA dependence. Nearly half of the patients were non-compliant. The proportion of patients with severe symptoms or disease conditions increased with the increase in the number of drugs administered. These findings highlight the need for clinicians to be aware of the likelihood of benzodiazepine dependence, especially in young patients and patients prescribed multiple hypnotics.

Chronotherapeutic efficacy of suvorexant on sleep quality and metabolic parameters in patients with type 2 diabetes and insomnia.

AIMS: This study aimed to assess the chronotherapeutic efficacy of suvorexant on subjective sleep parameters and metabolic parameters in patients with type 2 diabetes and insomnia. METHODS: Thirteen patients with type 2 diabetes who met the Pittsburg Sleep Quality index criteria for primary insomnia took suvorexant 20 mg/day (15 mg/day for ≥65 years) for 14 ± 2 weeks. The following parameters were assessed before and after the treatment: sleep diary for sleep duration and quality (i.e., sleep onset latency, waking after sleep onset, and sleep efficiency [sSE]), Insomnia Severity Index, clinical and biochemical data, continuous glucose monitoring (CGM), and validated self-administered questionnaire on food intake. RESULTS: Suvorexant significantly improved sSE, abdominal circumference, and sucrose intake (all p < 0.05), but did not change HbA1c, CGM parameters, or body weight. Correlation analysis revealed that changes in sSE were associated with those in HbA1c and body weight (r = -0.61 and r = -0.66, respectively; both p < 0.05). CONCLUSIONS: Suvorexant significantly improved sleep quality and obesity-associated parameters in patients with type 2 diabetes in 14 weeks. Improvements in sleep quality were associated with improvements in glycemic control. Sleep disorder treatment using suvorexant may provide metabolic benefits for patients with type 2 diabetes.