The joint association of diabetes distress and depressive symptoms with all-cause mortality in Japanese individuals with type 2 diabetes: a prospective cohort study (Diabetes Distress and Care Registry in Tenri [DDCRT 20]).

AIMS/HYPOTHESIS: The independent association of depressive symptoms and diabetes distress with mortality risk in individuals with diabetes has not been evaluated. We examined the temporal joint association of diabetes distress and depressive symptoms at baseline and the subsequent risk of all-cause mortality. METHODS: The longitudinal data of 3118 individuals with type 2 diabetes were obtained from a large Japanese diabetes registry. To assess the joint association of diabetes distress and depressive symptoms at baseline with the subsequent risk of all-cause mortality, the Cox proportional hazards model was used with adjustment for potential confounders. RESULTS: The mean age, BMI and HbA1c levels were 64.7 years, 24.6 kg/m2 and 58.6 mmol/mol (7.5%), respectively, and 38.1% of the participants were women. In the multivariable-adjusted models evaluating the diabetes distress and depressive symptoms separately, the HRs for all-cause mortality were 1.67 (95% CI 1.14, 2.43; p = 0.008) and 1.40 (95% CI 1.05, 1.85; p = 0.020), respectively. In such models evaluating the joint association of diabetes distress and depressive symptoms, compared with individuals without diabetes distress or depressive symptoms (DD-/DS-), the HRs for all-cause mortality for the group without diabetes distress but with depressive symptoms (DD-/DS+), with diabetes distress but without depressive symptoms (DD+/DS-), and with diabetes distress and depressive symptoms (DD+/DS+) were 1.34 (95% CI 0.99, 1.86; p = 0.056), 1.96 (95% CI 1.10, 3.50; p = 0.023) and 1.71 (95% CI 1.06, 2.77; p = 0.029), respectively. We did not observe a significant interaction between diabetes distress and depressive symptoms with all-cause mortality risk (p = 0.2636). In the stratified analysis by sex, a significant joint association of diabetes distress and depressive symptoms with the risk of all-cause mortality was observed only in men. CONCLUSIONS/INTERPRETATION: Diabetes distress and depressive symptoms were independently associated with all-cause mortality risk in male participants with type 2 diabetes, but we did not observe a significant interaction between diabetes distress and depressive symptoms in relation to all-cause mortality. Graphical abstract.

Association between diabetes distress and all-cause mortality in Japanese individuals with type 2 diabetes: a prospective cohort study (Diabetes Distress and Care Registry in Tenri [DDCRT 18]).

AIMS/HYPOTHESIS: The absence of data on the direct association between diabetes-specific distress and all-cause mortality in individuals with diabetes prompted us to examine the temporal association between Problem Areas in Diabetes (PAID) survey scores and the subsequent risk of all-cause mortality in a cohort of individuals with type 2 diabetes. METHODS: Longitudinal data from 3305 individuals with diabetes were obtained from a large Japanese diabetes registry. Independent correlations between quintiles of PAID total scores or PAID scores of ≥40 and all-cause mortality (median follow-up of 6.1 years) were examined using Cox proportional hazards models with adjustment for potential confounders. RESULTS: The study population included 1280 women and 2025 men with a mean age of 64.9 years, BMI of 24.6 kg/m2 and HbA1c level of 58.7 mmol/mol (7.5%). In the multivariable-adjusted model, compared with the first quintile of PAID scores, the multivariable-adjusted HRs (95% CIs) for all-cause mortality for the second to fifth quintiles were 1.11 (0.77, 1.60; p = 0.56), 0.87 (0.56, 1.35; p = 0.524), 0.95 (0.63, 1.46; p = 0.802) and 1.60 (1.09, 2.36; p = 0.016), respectively. Compared with a PAID score of <40, the multivariable-adjusted HR for all-cause mortality of those with a score of ≥10 was 1.56 (95% CI 1.17, 2.08; p = 0.002). In subgroup analyses, the association between PAID score and all-cause mortality was found in men (HR 1.76; 95% CI 1.26, 2.46) but not in women (HR 1.09; 95% CI 0.60, 2.00), with a significant interaction between diabetes distress and sex (p = 0.0336). CONCLUSIONS/INTERPRETATION: We observed a significant positive association between high diabetes distress and all-cause mortality in men with diabetes.

Effects of linagliptin versus voglibose on treatment-related quality of life in patients with type 2 diabetes: sub-analysis of the L-STEP study.

Treatment-related quality of life (QOL) is an important aspect of diabetes management. However, no studies have compared the influence of dipeptidyl peptidase-4 inhibitors versus alpha-glucosidase inhibitors on treatment-related QOL. This prespecified sub-analysis of the Linagliptin Study of Effects on Postprandial blood glucose (L-STEP) compared the effects of linagliptin (5 mg once daily) and voglibose (0.2 mg/meal thrice daily) on treatment-related QOL in Japanese patients with type 2 diabetes (T2DM) inadequately controlled with diet and exercise therapy. Among 366 subjects in the original study, 182 in the linagliptin group and 173 in the voglibose group were included in this analysis. The outcome of this study was change in QOL as assessed by the Diabetes Therapy-Related Quality of Life 17 (DTR-QOL17) questionnaire from baseline to week 12. Compared with baseline data, total DTR-QOL17 scores were significantly higher after 12 weeks of linagliptin and voglibose treatment. The change in the total DTR-QOL17 score and the score of one domain, burden on social activities and daily activities, was significantly greater in the linagliptin group than in the voglibose group. In addition, only linagliptin treatment was identified as a factor associated with an increased total DTR-QOL17 score. Linagliptin is superior to voglibose in terms of improving treatment-related QOL in Japanese patients with T2DM.

Serum uric acid levels are associated with increased risk of newly developed diabetic retinopathy among Japanese male patients with type 2 diabetes: A prospective cohort study (diabetes distress and care registry at Tenri [DDCRT 13]).

OBJECTIVE: We assessed the prospective association between baseline serum uric acid levels and consequent risk of developing diabetic retinopathy. RESEARCH DESIGN AND METHODS: Data for 1839 type 2 diabetes patients without diabetic retinopathy were obtained from a Japanese diabetes registry. A Cox proportional hazards model with time-varying exposure information by sex was used and adjusted for potential confounders to assess the independent correlations between baseline serum uric acid levels and incidence rate of diabetic retinopathy. RESULTS: Newly developed diabetic retinopathy was recognized in 188 patients (10.2%) during the observation period of 2 years. Compared to the first serum uric acid quartile level, the multivariate adjusted hazards ratio for diabetic retinopathy development in male patients was 1.97 (95% CI, 1.14-3.41; P = .015), 1.92 (95% CI, 1.18-3.13; P = .008), and 2.17 (95% CI, 1.40-3.37; P = .001) for the second, third, and fourth serum uric acid quartile levels, respectively. But this was not the case with female patients. CONCLUSION: Higher serum uric acid levels were associated with increased risk of developing diabetic retinopathy in male patients with type 2 diabetes, but not in female patients. Serum uric acid may be a useful biomarker for predicting the future risk of developing diabetic retinopathy in male patients with type 2 diabetes.

Safety and effectiveness of long-term growth hormone therapy in Japanese patients with adult growth hormone deficiency: a postmarketing, multicenter, observational study.

We aimed to evaluate the long-term safety and effectiveness of growth hormone (GH) therapy in Japanese patients with adult growth hormone deficiency (AGHD). In this observational, multicenter study, Norditropin® (Novo Nordisk A/S, Bagsvaerd, Denmark) was administered as injections of 0.021 mg/kg/week as a starting dose divided into 6-7 doses/week. The dose was increased according to clinical response. Patients' data were obtained from medical records. Measurements (lipids, glucose metabolism, and body composition) taken at baseline; 3, 6, and 12 months; and yearly until the end of the study were collected. Adverse drug reactions (ADRs), serious ADRs, and serious adverse events (SAEs) were evaluated. Of 387 registered patients, 334 were eligible for safety. After GH treatment initiation, a marked decrease in total cholesterol was observed earlier in the child-onset group than in the adult-onset group. LDL-cholesterol also decreased, but no significant differences in changes in LDL-cholesterol between adult-onset and child-onset groups were found. A significant increase in HDL-cholesterol starting 1 year after GH treatment initiation was found in the adult-onset group. There was no effect of GH treatment on glucose metabolism. Because of the small number of dual-energy X-ray absorptiometry data, the overall assessment of changes of body composition was difficult. Fifty-six (16.8%), 12 (3.6%), and 35 (10.5%) patients experienced ADRs, serious ADRs, and SAEs, respectively. This study demonstrated a favorable long-term safety and effectiveness profile of GH therapy in AGHD patients in the real-life Japanese clinical practice setting.

Therapy-Related Satisfaction and Quality of Life for Japanese People with Diabetes Using Rapid-Acting Insulin Analogs: A Web-Based Survey.

INTRODUCTION: People with diabetes require insulin to regulate blood glucose (BG); rapid-acting insulin analogs (RAIA) represent one approach for BG management. New fast-acting RAIA administered at the start of a meal suppress postprandial BG better than conventional RAIA. New RAIA are expected to confer higher treatment satisfaction and improved quality of life (QOL) than conventional RAIA. METHODS: This cross-sectional, web-based survey in Japan (November 2022) included people with diabetes (type 1/2), aged ≥ 18 years, registered in the Rakuten Insight Diabetes Panel, using new and/or conventional RAIA. RAIA-specific satisfaction was evaluated by questions on RAIA use (scores: 1 [not at all satisfied]; 7 [very satisfied]) and QOL by the Diabetes Therapy-Related (DTR)-QOL questionnaire (scores: 0-100, 100 = best) for the whole population (primary endpoint) and for new versus conventional RAIA users (secondary endpoint). Multiple regression models were used to compare new versus conventional RAIA users. RESULTS: The analysis population comprised 217 people with diabetes (new RAIA, n = 109; conventional RAIA, n = 108). Mean (standard deviation) RAIA-specific satisfaction scores ranged from 5.1 (1.2) to 5.4 (1.2); DTR-QOL total score was 51.6 (20.4). RAIA satisfaction scores were numerically higher for new versus conventional RAIA users; no difference in DTR-QOL total score was observed. DTR-QOL satisfaction with treatment domain score was significantly higher in new versus conventional RAIA users (least squares mean difference [standard error]: 7.3 [3.1]; 95% confidence interval: 1.2, 13.4; P = 0.0197). RAIA-specific satisfaction was higher among patients who discussed BG sufficiently with their doctor versus those who did not. CONCLUSIONS: New RAIA users have greater treatment satisfaction than conventional RAIA users. QOL was similar among new and conventional RAIA users, except for satisfaction with treatment, which was significantly higher among new RAIA users. Detailed explanations from the doctor to the person with diabetes about the relationship between new RAIA and BG status are essential. A graphical plain language summary is available with this article.

The Japanese version of Problem Areas in Diabetes Scale: a clinical and research tool to assess emotional functioning among people with diabetes.

Introduction: The purpose of this study was to develop the Japanese version of the Problem Areas in Diabetes (PAID) scale, a measure of emotional adjustment to diabetes that has been translated into Japanese by our group. Materials and methods: A total of 418 Japanese people with diabetes attending our outpatient clinic participated (n = 65 type 1 and n = 353 type 2). We assessed the internal reliability of the PAID, examined correlations of the PAID with conceptually related psychosocial constructs, evaluated mean differences in the PAID between diabetes treatment groups, and examined correlations of the PAID with diabetes self-care behaviours and selected treatment outcomes. Results: Results showed that the PAID had excellent reliability (Cronbach alpha = 0.934). The PAID correlated significantly with the Diabetes Treatment Satisfaction Questionnaire (r = -0.593, p < 0.0001) and the positive wellbeing (r = -0.396, p < 0.0001), negative wellbeing (r = -0.640, p < 0.0001) and energy (r = -0.444, p < 0.0001) subscales of the Wellbeing Questionnaire. Adherence to diet was negatively correlated with PAID score (r = -0.263, p < 0.0001). The frequency of recent hypoglycemia and number of chronic complications (retinopathy, nephropathy and neuropathy) were positively correlated with PAID scores. PAID was weakly correlated with HbA1c (r = 0.13, p = 0.01). Conclusions: In conclusion, the Japanese version of the PAID demonstrated good internal reliability and evidence of concurrent and discriminant validity. The PAID measures the impact of diabetes, diabetes treatment and treatment outcomes on the emotions of people with diabetes. The results provide encouraging evidence for the clinical utility of the PAID in Japanese people with diabetes.

Treatment Satisfaction and Quality of Life with Tirzepatide Versus Dulaglutide Among Japanese Patients with Type 2 Diabetes: Exploratory Evaluation of the SURPASS J-mono Trial.

INTRODUCTION: Treatment satisfaction in diabetes management is vital to achieving long-term clinical outcomes. This analysis evaluated treatment satisfaction among patients with type 2 diabetes (T2D) after 52 weeks of treatment with once-weekly tirzepatide (5, 10, and 15 mg) compared with dulaglutide 0.75 mg. METHODS: This exploratory analysis of the phase 3 SURPASS J-mono trial assessed treatment satisfaction using the Japanese translation of the Diabetes Treatment Satisfaction Questionnaire status (DTSQs) and change versions (DTSQc). Subgroup analyses were post hoc and conducted for the DTSQc overall treatment satisfaction score based on age (< 65 or ≥ 65 years), sex (male or female), baseline body mass index (BMI; < 25 or ≥ 25 kg/m2), and baseline glycated hemoglobin (≤ 8.5% or > 8.5%). RESULTS: Baseline DTSQs scores were similar among patients across all treatment arms. Overall, trends showed higher satisfaction among patients who received any tirzepatide dose compared with those who received dulaglutide after 52 weeks of treatment. Mean overall DTSQc treatment satisfaction scores at week 52 were significantly higher with tirzepatide 5, 10, and 15 mg versus dulaglutide 0.75 mg (11.5, 12.1, and 12.3, respectively, vs 8.9; P < 0.001). The DTSQc perceived frequency scores for unacceptable hyperglycemia were significantly lower with tirzepatide 5, 10, and 15 mg versus dulaglutide 0.75 mg (- 1.7, - 1.8, and - 2.3, respectively, vs - 0.6; P < 0.001), while scores for unacceptable hypoglycemia were similar across all treatment arms, ranging from - 0.8 to - 1.1. Subgroup analyses showed increased treatment satisfaction with tirzepatide compared with dulaglutide in the < 65 years (P < 0.001) and baseline BMI ≥ 25 kg/m2 subgroups (P < 0.01 or < 0.001) and similar treatment satisfaction across treatment arms in the ≥ 65 years and BMI < 25 kg/m2 subgroups. CONCLUSION: Patients with T2D reported higher treatment satisfaction with once-weekly tirzepatide (5, 10, and 15 mg) compared with dulaglutide 0.75 mg after 52 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03861052.

Diabetes Distress Is Associated With Future Risk of Progression of Diabetic Nephropathy in Adults With Type 2 Diabetes: A Prospective Cohort Study (Diabetes Distress and Care Registry at Tenri [DDCRT23]).

OBJECTIVES: Our aim in this study was to investigate the prospective association between diabetes distress assessed with Problem Areas in Diabetes (PAID) survey scores at baseline and the subsequent risk of development or progression of diabetic nephropathy in people with type 2 diabetes. METHODS: Longitudinal data were acquired from 2,845 individuals with type 2 diabetes registered in a Japanese diabetes registry. A Cox proportional hazards model was used to adjust for possible confounders to examine the prospective association between baseline diabetes distress (PAID score ≥40) and the development or progression of albuminuria. RESULTS: Mean patient age, body mass index, and glycated hemoglobin level were 64.8 years, 24.5 kg/m2, and 57.4 mmol/mol (7.5%), respectively. We did not observe a significant association between diabetes distress and the subsequent risk of diabetic nephropathy development from normoalbuminuria to microalbuminuria/macroalbuminuria (multivariable-adjusted hazard ratio [HR]=0.95 over 4.2 years, 95% confidence interval [CI] 0.77 to 1.17, p=0.640); however, we identified a significant association for progression from microalbuminuria to macroalbuminuria (multivariable-adjusted HR=1.34 over 7.0 years, 95% CI 1.01 to 1.80, p=0.045). Stratification by sex revealed a significant association between diabetes distress and the subsequent risk of progressing diabetic nephropathy (HR=1.45, 95% CI 1.06 to 1.98, p=0.019) in males, but not females (HR=1.42, 95% CI 0.95 to 2.14, p=0.087). CONCLUSIONS: Diabetes distress at baseline, assessed using the PAID survey, was associated with a subsequent risk of progressing diabetic nephropathy independent of possible confounders in males, but not females, with type 2 diabetes.

Risk of Lactic Acidosis in Hospitalized Diabetic Patients Prescribed Biguanides in Japan: A Retrospective Total-Population Cohort Study.

Patient data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) are used to assess the effect of biguanide administration on rates of lactic acidosis (LA) in hospitalized diabetes mellitus (DM) patients. In this retrospective cohort study (from April 2013 to March 2016), we compare DM inpatients prescribed biguanides to DM inpatients who were not prescribed biguanides to quantify the association between biguanides and incidence of LA. In total, 8,111,848 DM patient records are retrieved from the NDB. Of the 528,768 inpatients prescribed biguanides, 782 develop LA. Of the 1,967,982 inpatients not prescribed biguanides, 1310 develop LA. The rate ratio of inpatients who develop LA and are administered biguanides to those who developed LA without receiving biguanides is 1.44 (95% CI, 1.32-1.58). Incidence rates and rate ratios for both sexes are elevated in the group prescribed biguanides for patients aged 70 years and older, markedly in those 80 years and older: 40.12 and 6.31 (95% CI, 4.75-8.39), respectively, for men and 34.96 and 5.40 (95% CI, 3.91-7.46), respectively, for women. Biguanides should be used conservatively in patients older than 70 years, particularly for those with comorbidities, and with caution in patients 80 years and older.

Treatment Burden on Once-Weekly Omarigliptin Versus Daily Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes: Randomized Controlled Trial (ONWARD-DPP4 Study).

INTRODUCTION: Preference for quality of life is important in deciding the treatment strategy for patients with type 2 diabetes mellitus. This study aimed to assess the effect of omarigliptin on patients' psychological attitudes and responses compared with daily dipeptidyl peptidase-4 inhibitors (DPP4is) by measuring the burden of pharmacotherapy using the Diabetic Treatment Burden Questionnaire (DTBQ). METHODS: Patients with type 2 diabetes mellitus who were taking daily DPP-4is were enrolled and randomized to a group that switched to omarigliptin or a group that continued daily DPP4is and were monitored for 12 weeks. The primary endpoint was the change in the DTBQ score from baseline to week 12. The secondary endpoints included changes in blood test results, medication preferences and medication adherence. RESULTS: The DTBQ total score significantly decreased from baseline to week 12 in both groups; however, no significant intergroup differences were observed. The DTBQ subscale, implementation and flexibility burden scores significantly decreased in the group that switched to omarigliptin, although no significant intergroup difference in the change was observed. DTBQ scores and medication preferences were associated with improvements in the DTBQ scores. CONCLUSION: Although this study failed to demonstrate the improvement of DTBQ total score by switching from daily DPP4is to omarigliptin compared with continuing the daily DPP4is, the DTBQ subscale score implementation and flexibility burden score were significantly improved only in the group that switched to omarigliptin, suggesting the possibility of switching from daily DPP4is to omarigliptin to decrease the patients' medication burden. TRIAL REGISTRATION: jRCTs031200437.

Association between dipeptidyl peptidase-4 inhibitors and increased risk for bullous pemphigoid within 3 months from first use: A 5-year population-based cohort study using the Japanese National Database.

AIMS/INTRODUCTION: We assessed the association between dipeptidyl peptidase-4 inhibitors (DPP-4is) and bullous pemphigoid (BP) and time-dependent changes in the risk for developing BP after DPP-4i initiation. MATERIALS AND METHODS: The present population-based, real-world study was carried out using the Japanese National Database dataset collected between 2013 and 2018. To assess independent correlations between DPP-4is and the development of BP, the self-controlled case series method was used. RESULTS: Among the cohort followed up for a median of 1,540 days, 53,027 patients were likely to develop BP. The possible incidence rate of BP in all 150,328,339 patients was 10.4/100,000 person-years. Among the 9,705,814 patients with type 2 diabetes, 15,634 were likely to develop BP. The possible incidence rate of BP in patients with type 2 diabetes was 38.1/100,000 person-years, whereas that in patients with type 2 diabetes who did and did not use DPP-4is was 40.7 and 30.0/100,000 person-years, respectively. Analysis of the 28,705 patients with type 2 diabetes likely to develop BP after initial DPP-4i use showed a risk ratio of 2.15 (95% confidence interval [CI] 1.75-2.63), 1.70 (95% CI 1.37-2.11), 1.44 (95% CI 1.15-1.82), 1.25 (95% CI 0.98-1.59), 0.84 (95% CI 0.63-1.10), 0.84 (95% CI 0.64-1.11) and 1.05 (95% CI 0.92-1.20), for the risk period of ≤30, 31-60, 61-90, 91-120, 121-150, 151-180 and 181-365 days, respectively. CONCLUSIONS: Although DPP-4is were associated with increased risk for BP, the risk was particularly significant within 3 months from first use.

The age of death in Japanese patients with type 2 and type 1 diabetes: A descriptive epidemiological study.

This study clarified the age of death in patients with or without diabetes using the largest health insurance database in Japan. This population-based retrospective cohort study was performed using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) data. The ages of death between people with and without diabetes were compared. A total of 142,277,986 patients (74,488,962 women and 67,789,024 men) over 6 years, including 4,647,016 females, and 6,507,817 males with diabetes, were included. 2,786,071 females and 2,975,876 males died over 6 years, including 652,699 females and 954,655 males with diabetes. The average age of death in patients with diabetes was 2.6 years less than that of patients without diabetes. This descriptive epidemiological study illustrated the difference in age at death of patients with and without diabetes.

Appropriate definition of diabetes using an administrative database: A cross-sectional cohort validation study.

AIMS/INTRODUCTION: The purpose of the present study was to quantify errors in the diagnosis of diabetes for use in the national database, using a sufficient population size. MATERIALS AND METHODS: A claims database constructed by the JMDC (Tokyo, Japan), using standardized disease classifications and anonymous record linkage, was used in this validation study. We included patients with health insurance claims data from April 2005 to March 2019 in the JMDC claims database. We excluded patients without a record of specific health checkups in Japan. Sample size calculation was based on a 5% prevalence of diabetes and 0.4% absolute accuracy (i.e., 1,250,000 individuals), to calculate the sensitivity, specificity, positive predictive value and negative predictive value. RESULTS: In total, 2,999,152 patients were included in this study, of which 165,515 were classified as having diabetes based on specific health checkups (validation cohort prevalence of 5.5%). The newly devised algorithm had three elements - the diagnosis-related codes for diabetes without suspected flag, the medication codes for diabetes and then these two codes on the same record - and yielded a sensitivity of 74.6%, positive predictive value of 88.4% and Kappa Index of 0.80 (the highest values). CONCLUSIONS: In future claims database studies, our validated algorithms will be useful as diagnostic criteria for diabetes.

Predictive Validity of Each Item of the 8-Item Short-Form Health Survey for All-Cause Mortality in Japanese patients with type 2 diabetes: A prospective Cohort Study (Diabetes Distress and Care Registry at Tenri [DDCRT 19]).

AIMS: While health-related quality of life (HRQOL) is reported to be associated with mortality, this assessment was made using surveys with a large number of questions, not specifically focused on populations with diabetes, or in western countries alone. We thus evaluated the predictive validity of summary scores, and each item score of the 8-Item Short-Form Health Survey in Japanese individuals with type-2 diabetes. MATERIALS AND METHODS: Longitudinal data from 3269 individuals with diabetes were obtained from a large Japanese diabetes registry. To assess the independent correlation between the 10-point scores of the SF-8 physical component summary (PCS) and mental component summary (MCS), each item score, and all-cause mortality, the Cox proportional hazards model was used with adjustment for potential confounders. RESULTS: Mean cohort parameters included age (64.9 years [SD 11.2]), body mass index (24.6 kg/m2 [SD, 3.9]), and HbA1c level (7.5% [SD, 1.2]; or 58.6 mmol/mol [SD, 12.7]). We recorded 248 deaths during the median follow-up of 7.2 years (incidence ratio, 12.2 per 1000 person-years). Multivariable-adjusted HRs for all-cause mortality were 0.780 (95%CI, 0.674-0.902; p=0.001) and 0.776 (95%CI, 0.656-0.917; p=0.003), respectively, for 10-point increment of PCS and MCS scores. Higher score of any single item of SF-8 was associated with lower risk of all-cause mortality even after adjusting for possible confounders. CONCLUSIONS: As assessed by the SF-8, higher PCS, MCS, and any single 1-item scores were associated with lower risk of all-cause mortality in Japanese individuals with type 2 diabetes.

Effect of Orally Administered Semaglutide Versus Dulaglutide on Diabetes-Related Quality of Life in Japanese Patients with Type 2 Diabetes: The PIONEER 10 Randomized, Active-Controlled Trial.

INTRODUCTION: In the randomized Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 10 trial, once-daily orally administered semaglutide-the first oral glucagon-like peptide 1 receptor agonist (GLP-1RA)-was similarly tolerated with comparable (at 7 mg) or better (at 14 mg) efficacy versus the injectable GLP-1RA dulaglutide 0.75 mg. Health-related quality of life (HRQoL) in PIONEER 10 was assessed using the Japanese-specific Diabetes Therapy-Related Quality of Life (DTR-QoL) questionnaire. METHODS: The DTR-QoL comprises 29 questions, providing four domain and total scores. Answers were converted to a score between 0 and 100, with higher scores indicating greater HRQoL. Two estimands were prespecified: treatment policy (regardless of treatment discontinuation or rescue medication use) and trial product (assuming on treatment without rescue medication) in all randomized patients. Outcomes were assessed at weeks 26 and 52. RESULTS: Mean baseline DTR-QoL domain scores were similar between treatment arms and were generally lower (giving more scope for improvement) for "anxiety and dissatisfaction with treatment" (62.1-65.3) and "satisfaction with treatment" (53.9-57.9) than "burden on social activities and daily activities" (76.5-77.7) and "hypoglycemia" (83.5-88.2). Using the treatment policy estimand, orally administered semaglutide 7 and 14 mg improved HRQoL versus dulaglutide 0.75 mg for the total score (estimated mean change from baseline [CfB] 7.3 and 8.1 vs 3.3; estimated treatment difference [ETD] 3.9 and 4.8) and the "anxiety and dissatisfaction with treatment" domain (CfB 9.7 and 10.9 vs 3.7; ETD 6.0 and 7.2) at week 52. Orally administered semaglutide 14 mg improved the "satisfaction with treatment" domain versus dulaglutide 0.75 mg (CFB 13.8 vs 5.7; ETD 8.1). DTR-QoL scores for orally administered semaglutide tended to be more durable (sustained over time) than for dulaglutide. Outcomes for the trial product estimand were similar. CONCLUSION: Orally administered semaglutide 7 and 14 mg improved the patients' HRQoL measured by the Japanese-specific DTR-QoL instrument versus dulaglutide 0.75 mg at week 52. TRIAL REGISTRATION: ClinicalTrials.gov NCT03015220.

Comparison of Patient-Led and Physician-Led Insulin Titration in Japanese Type 2 Diabetes Mellitus Patients Based on Treatment Distress, Satisfaction, and Self-Efficacy: The COMMIT-Patient Study.

INTRODUCTION: In Japan, patient-led insulin titration is rare in type 2 diabetes mellitus (T2DM) patients. Few studies have compared the effects of patient-led versus physician-led insulin titration on patient-reported outcomes in Japanese T2DM patients. This study aimed to compare the effects of patient-led and physician-led insulin titration in Japanese insulin-naïve T2DM patients on safety, glycemic control, and patient-reported outcomes (emotional distress, treatment satisfaction, and self-efficacy). METHODS: Ultimately, 125 insulin-naïve Japanese T2DM patients were randomly assigned to either a patient-led insulin self-titration group or a physician-led insulin titration group and monitored for 24 weeks. The primary endpoint was a change in emotional distress as measured using the Problem Areas in Diabetes scale (PAID). Secondary endpoints included treatment satisfaction, as measured with the Diabetes Treatment Satisfaction Questionnaire (DTSQ), self-efficacy as measured using the Insulin Therapy Self-Efficacy Scale (ITSS), glycated hemoglobin (HbA1c) levels, fasting plasma glucose levels, body weight, insulin daily dose, and frequency of hypoglycemia. RESULTS: There was no significant difference between the groups in PAID and DTSQ scores. The results for the primary endpoint should be interpreted taking account that the sample size for the power calculation was not reached. ITSS scores were significantly higher in the patient-led self-titration group. HbA1c and fasting plasma glucose levels were significantly decreased in both groups, but the decrease was significantly larger in the patient-led self-titration group. Although the insulin daily dose was significantly higher in the patient-led self-titration group, severe hypoglycemia did not occur in either group, and the frequency of hypoglycemia was similar in both groups. CONCLUSION: Self-measurement of blood glucose and self-titration of insulin enhanced the patients' self-efficacy without compromising their emotional distress or treatment satisfaction. Also, insulin self-titration was found to be safe and effective; it resulted in better glycemic control without severe hypoglycemia. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (registration number: UMIN000020316).

Association between influenza and the incidence rate of new-onset type 1 diabetes in Japan.

AIM: This study aimed to determine whether there is an association between influenza and new-onset type 1 diabetes. MATERIALS AND METHODS: This population-based retrospective cohort study used data from the National Database of Health Insurance Claims and Specific Health Check-ups of Japan. Influenza was defined based on drug prescriptions and the onset of type 1 diabetes was defined using specific medical codes indicating a diagnosis of type 1 diabetes. The incidence rate ratio of new-onset type 1 diabetes within 180 days after an influenza diagnosis was calculated and it was compared with that at other times using Poisson regression and generalized estimating equations. Sensitivity analyses were performed to confirm the robustness of this finding. RESULTS: The data of 10,400 patients with new-onset type 1 diabetes were analyzed, including 2,196 (952 male 1,244 female) patients diagnosed with influenza between 1 September 2014 and 31 August 2017. Although only patients with type 1 diabetes were included, adjusted analysis showed that individuals had a 1.3-fold (95% confidence interval: 1.15-1.46) higher risk of developing type 1 diabetes in the first 180 days after influenza diagnosis than that at other times. CONCLUSIONS: In this Japanese population-based cohort, the risk of new-onset type 1 diabetes may increase after the diagnosis of influenza. These results, which must be confirmed in other populations, suggest that influenza may be a causal factor for new-onset type 1 diabetes. The molecular mechanisms underlying the potential etiological relationship between influenza and type 1 diabetes should be elucidated.

Incidence of lower limb amputation in people with and without diabetes: a nationwide 5-year cohort study in Japan.

INTRODUCTION: This study was conducted to investigate the incidence and time trend of lower limb amputation (LLA) among people with and without diabetes. RESEARCH DESIGN AND METHODS: This retrospective population-based cohort study was based on the national claims data in Japan, comprising a total population of 150 million. Data of all individuals who had LLA from April 2013 to March 2018 were obtained. We analysed the sex-adjusted and age-adjusted annual LLA rate (every fiscal year) in people with and without diabetes for major and minor amputation. To test for time trend, Poisson regression models were fitted. RESULTS: In the 5-year period, 30 187 major and 29 299 minor LLAs were performed in Japan. The sex-adjusted and age-adjusted incidence of major and minor LLAs was 9.5 (people with diabetes, 21.8 vs people without diabetes, 2.3, per 100 000 person-years) and 14.9 (people with diabetes, 28.4 vs people without diabetes, 1.9, per 100 000 person-years) times higher, respectively, in people with diabetes compared with those without. A significant decline in the annual major amputation rate was observed (p<0.05) and the annual minor amputation rate remained stable (p=0.63) when sex, age and people with and without diabetes were included as dependent variables. CONCLUSIONS: This is the first report of the national statistics of LLAs in Japan. The incidence of major and minor LLAs was 10 and 15 times higher, respectively, in people with diabetes compared with those without. A significant decline in the major amputation rate was observed, and the annual minor amputation rate remained stable during the observation period. This information can help to create an effective national healthcare strategy for preventing limb amputations, which affect the quality of life of patients with diabetes and add to the national healthcare expenditure.

Efficacy and Safety of Once-Weekly Dulaglutide in Type 2 Diabetes Patients Using Insulin: Exploratory Subgroup Analysis by Insulin Regimen.

PURPOSE: In East Asian patients, type 2 diabetes mellitus (T2DM) is characterized primarily by ß-cell dysfunction, with lower insulin secretion than in Caucasian individuals. Therefore, bolus insulin and premixed insulin containing a bolus insulin component are important therapeutic tools in Japan, in addition to basal insulin. This subgroup analysis is stratified by insulin regimen and uses data from a phase 4, randomized, placebo-controlled, double-blind and subsequent open-label study in Japan to assess the efficacy and safety of once-weekly dulaglutide combined with various insulin therapies. METHODS: This multicenter study enrolled Japanese patients with T2DM and inadequate glycemic control [glycated hemoglobin A1c (HbA1c) ≥ 7.5% to ≤ 10.5%] on insulin therapy [basal (B), premixed (PM), or basal bolus (BB)] in combination with or without one or two oral antidiabetic agents. Randomized participants received once-weekly dulaglutide 0.75 mg (n = 120) or placebo (n = 39) during a 16-week double-blind treatment period, and dulaglutide during a 36-week open-label extension. In this subgroup analysis, efficacy measures were changes from baseline in HbA1c, 7-point self-monitored blood glucose profiles, and body weight. Safety measures were incidence of adverse events and hypoglycemia during the first 16 weeks. RESULTS: At week 16, least squares mean differences (95% CI) regarding changes from baseline in HbA1c for each insulin regimen versus placebo were: B: - 1.62% (- 1.96, - 1.28), PM: - 1.78% (- 2.25, - 1.30), and BB: - 1.15% (- 1.54, - 0.77); p < 0.001 dulaglutide vs. placebo for each subgroup. No significant differences in body weight changes were observed between dulaglutide and placebo for any insulin regimen. Gastrointestinal symptoms were the most commonly observed adverse events in dulaglutide-treated patients. Hypoglycemia incidence rates were: B: dulaglutide 38.5% vs. placebo 23.5%; PM: dulaglutide 38.5% vs. placebo 44.4%; BB: dulaglutide 50.0% vs. placebo 30.8%. CONCLUSIONS: Overall, dulaglutide was generally well tolerated and improved glycemic control significantly versus placebo, regardless of insulin regimen. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02750410.