Novel subgroups of obesity and their association with outcomes: a data-driven cluster analysis.

BACKGROUND: Obesity is associated with various complications and decreased life expectancy, and substantial heterogeneity in complications and outcomes has been observed. However, the subgroups of obesity have not yet been clearly defined. This study aimed to identify the subgroups of obesity especially those for target of interventions by cluster analysis. METHODS: In this study, an unsupervised, data-driven cluster analysis of 9,494 individuals with obesity (body mass index ≥ 35 kg/m2) was performed using the data of ICD-10, drug, and medical procedure from the healthcare claims database. The prevalence and clinical characteristics of the complications such as diabetes in each cluster were evaluated using the prescription records. Additionally, renal and life prognoses were compared among the clusters. RESULTS: We identified seven clusters characterised by different combinations of complications and several complications were observed exclusively in each cluster. Notably, the poorest prognosis was observed in individuals who rarely visited a hospital after being diagnosed with obesity, followed by those with cardiovascular complications and diabetes. CONCLUSIONS: In this study, we identified seven subgroups of individuals with obesity using population-based data-driven cluster analysis. We clearly demonstrated important target subgroups for intervention as well as a metabolically healthy obesity group.

Antithyroid drug-induced leukopenia and G-CSF administration: a long-term cohort study.

Although antithyroid drug (ATD)-induced agranulocytosis is a significant concern, its risks associated with long-term use and re-administration are not fully elucidated. Therefore, we performed this study to determine the incidence of ATD-induced leukopenia and G-CSF administration using administrative claims database. Retrospective cohort study. This study was performed using the DeSC Japanese administrative claims database. A total of 12,491 patients with newly diagnosed Graves' disease (GD) who received methimazole or propylthiouracil between April 2014, and February 2021 among 3.44 million patients in the database were included in the study. We measured the six-year incidence of leukopenia and granulocyte colony-stimulating factor (G-CSF) administration. The incidence of leukopenia and G-CSF administration was 1.34% (168 patients) and 0.30% (38 patients), respectively. Leukopenia had a dose-dependent and biphasic incidence. The incidence of leukopenia and G-CSF administration was 37.2 (0.7%) and 8.0 (0.2%) per 1000 person-years during the first 72 days of ATD initiation, whereas it was 3.1 and 0.7 per 1000 person-years during the subsequent 6 years, respectively. The incidence of both outcomes was comparable between first administration and re-administration of ATD. The incidence of ATD-induced leukopenia and G-CSF administration was high in the first 72 days, with a reduced risk for at least 6 years thereafter. The incidence was similar between first administration and re-administration. ATD, a standard therapy, is often administered for a long period; therefore, our findings can guide the treatment of GD.

Adrenal Crisis Associated With COVID-19 Vaccination in Patients With Adrenal Insufficiency.

Vaccination is generally recommended for patients with adrenal insufficiency receiving glucocorticoid replacement therapy because they are at risk of experiencing adrenal crisis during infections. Conventional vaccinations, such as those for influenza virus, have rarely been associated with adrenal crisis in patients with adrenal insufficiency; therefore, increasing the glucocorticoid dose during vaccination is not necessarily recommended. The COVID-19 mRNA vaccines exhibit a higher degree of adverse reactions, including fever and general fatigue, than those of conventional vaccines. Here, we present 3 cases of adrenal crisis associated with mRNA COVID-19 (BNT162b2) vaccination in patients with secondary adrenal insufficiency. Two patients presented with adrenal crisis after the second dose, whereas 1 presented with adrenal crisis after the first dose. Within 24 hours of vaccination, all patients presented with fatigue and appetite loss, and 2 patients were febrile. None of them increased their glucocorticoid dosage at the time of vaccination, leading to an adrenal crisis. To date, 9 cases of adrenal crisis, including ours, associated with COVID-19 vaccination have been reported. Considering the high degree of adverse reactions to COVID-19 vaccination, administration of prophylactic stress dose of glucocorticoids is strongly recommended, particularly in patients with symptomatic adverse reactions, to protect them from adrenal crisis.

Dipeptidyl peptidase-4 inhibitors reduce the incidence of first cardiovascular events in Japanese diabetic patients.

BACKGROUND: Dipeptidyl Peptidase-4 (DPP-4) inhibitors do not suppress cardiovascular events in diabetic patients with a history of cardiovascular disease. However, the effect of DPP-4 inhibitors on cardiovascular events in Japanese diabetic patients is unclear. Therefore, we investigated whether DPP-4 inhibitors alter the incidence of cardiovascular events in Japanese diabetic patients without a history of cardiovascular events. METHODS: The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study conducted from 2002 to 2008. After completion of the JPAD trial, we followed up the patients until 2019. Patients who had had a cardiovascular event by the 2013 follow-up were excluded from the study. JPAD patients were divided into a DPP-4 group and a non-DPP-4 group based on whether they were taking DPP-4 inhibitors at the 2013 follow-up because few patients took DPP-4 inhibitors before 2013. We investigated the incidence of cardiovascular events consisting of coronary events, cerebrovascular events, heart failure requiring hospitalization, and aortic and peripheral vascular disease in 1099 JPAD patients until 2019. RESULTS: During the observation period from 2013 to 2019, 37 (7%) first cardiovascular events occurred in the DPP-4 group (n = 518) and 66 (11%) in the non-DPP-4 group (n = 581). The incidence of cardiovascular events was significantly lower in the DPP-4 group than in the non-DPP-4 group (Log-Rank P = 0.0065). Cox proportional hazards model analysis revealed that the use of DPP-4 inhibitors (hazard ratio 0.65; 95% confidence interval 0.43-0.98; P = 0.038) was an independent factor after adjustment for age ≥ 65 years, hypertension, statin usage, and insulin usage. CONCLUSIONS: Our findings have demonstrated that the use of DPP-4 inhibitors may be associated with a reduced incidence of first cardiovascular events in Japanese diabetic patients. The results require confirmation in randomized controlled trials.

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.

Kidney function deterioration is dependent on blood pressure levels: 11.2 year follow-up in diabetic patients.

There is little evidence of how blood pressure level over 10 years affects the decline of estimated glomerular filtration rate (eGFR) in diabetic patients. The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, randomized, clinical trial done from 2002 to 2008. After completion of the JPAD trial, we followed up the patients until 2019 as a cohort study. We defined late-stage kidney disease (LSKD) as eGFR < 30 ml/min/1.73 m2 or hemodialysis. Based on the mean value of systolic blood pressure (SBP) obtained average 7 times during the follow-up, we divided the patients into three groups: a high SBP group (n = 607, SBP ≥ 140 mm Hg); a moderate SBP group (n = 989, 140 > SBP ≥ 130 mm Hg); or a low SBP group (n = 913, SBP < 130 mm Hg). There was no significant deference in the mean eGFR among the high SBP, moderate SBP and low SBP groups on registration. The incidence rate of LSKD was significantly higher in the high SBP (HR 2.02, 95% CI 1.36-3.01) and moderate SBP (HR 1.54, 95% CI 1.07-2.20) groups than in the low SBP group (Log-Rank P = 0.0018). Cox proportional hazards model analysis revealed that the high SBP (HR, 1.57, P = 0.049) and moderate SBP (HR, 1.52, P = 0.037) were independent factors after adjustment for proteinuria ≥ ± , age ≥ 65 years, men, body mass index ≥ 24 kg/m2, duration of diabetes ≥ 7.0 years, statin usage, eGFR ≥ 60 ml/min/1.73 m2, hemoglobin A1c ≥ 7.2%, and smoking status. Our 11.2 year follow-up study demonstrated that mean SBP was independently associated with the progression to LSKD in diabetic patients. These findings may become new evidence that SBP less than 130 mm Hg is recommended for diabetic patients to prevent progression to LSKD.

Prevention of Contrast-Induced Nephropathy After Cardiovascular Catheterization and Intervention With High-Dose Strong Statin Therapy in Japan　- The PREVENT CINC-J Study.

BACKGROUND: Previous studies have reported that high-dose strong statin therapy reduces the incidence of contrast-induced nephropathy (CIN) in statin naïve patients; however, the efficacy of high-dose strong statins for preventing CIN in real-world clinical practice remains unclear. The aim of this study was to evaluate the efficacy of strong statin therapy in addition to fluid hydration for preventing CIN after cardiovascular catheterization.Methods and Results: This prospective, multicenter, randomized controlled trial included 420 patients with chronic kidney disease who underwent cardiovascular catheterization. They were assigned to receive high-dose pitavastatin (4 mg/day × 4 days) on the day before and of the procedure and 2 days after the procedure (Statin group, n=213) or no pitavastatin (Control group, n=207). Isotonic saline hydration combined with a single bolus of sodium bicarbonate (20 mEq) was scheduled for administration to all patients. In the control group, statin therapy was continued at the same dose as that before randomization. CIN was defined as a ≥0.5 mg/dL increase in serum creatinine or ≥25% above baseline at 48 h after contrast exposure. Before randomization, 83% of study participants were receiving statin treatment. The statin group had a higher incidence of CIN than the control group (3.0% vs. 0%, P=0.01). The 12-month rate of major adverse cardiovascular events was similar between the 2 groups. CONCLUSIONS: High-dose pitavastatin increases the incidence of CIN in this study population.

Incidence of atrial fibrillation in elderly patients with type 2 diabetes mellitus.

INTRODUCTION: The incidence of atrial fibrillation (AF), a significant risk factor for cardiovascular disease (CVD), is increasing worldwide. Type 2 diabetes mellitus (T2D) and advanced age are recognized as major risk factors for AF, but herein, we evaluated the incidence of AF in elderly patients with T2D and compared the prognosis between these patients with/without AF. RESEARCH DESIGN AND METHODS: The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD2) study is a follow-up cohort study of the JPAD trial, a randomized controlled clinical trial initiated in 2002 in 2535 Japanese patients with T2D, to examine whether low-dose aspirin prevents CVD. After completion of that trial, we followed up the patients until 2019 and evaluated the incidence of AF. We also compared the incidence of cerebral cardiovascular events in elderly patients with T2D with/without AF. RESULTS: During the median follow-up period of 10.9 years, 132 patients developed AF (incidence rate: 5.14/1000 person-years). The adjusted HRs for cerebral cardiovascular events, stroke, coronary artery disease, heart failure, and all-cause death in elderly patients with T2D with versus without AF were 1.65 (95% CI 1.03 to 2.66), 1.54 (95% CI 0.81 to 2.93), 1.96 (95% CI 1.03 to 3.73), 5.17 (95% CI 2.46 to 10.89), and 1.82 (95% CI 1.24 to 2.67), respectively. CONCLUSIONS: Annually, 1 in 200 elderly Japanese patients with T2D are estimated to develop AF. Because elderly patients with T2D with AF are at an elevated risk for CVD, careful follow-up of this patient subgroup is necessary. TRIAL REGISTRATION NUMBER: NCT00110448.

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.

The balance of comprehensive coagulation and fibrinolytic potential is disrupted in patients with moderate to severe COVID-19.

Coagulation and fibrinolytic mechanisms are enhanced in patients with coronavirus (COVID-19), but disturbances in the balance of both functions in COVID-19 patients remain unclear. We assessed global coagulation and fibrinolysis in plasma from 167 COVID-19 patients (mild/moderate/severe: 62/88/17, respectively) on admission using clot-fibrinolysis waveform analysis (CFWA). Maximum coagulation velocity (|min1|) and maximum fibrinolysis velocity (|FL-min1|) were expressed as ratios relative to normal plasma. Ten patients (6.0%) developed thrombosis, 5 (3.0%) had bleeding tendency, and 13 (7.8%) died during admission. FDP levels increased with severity of COVID-19 symptoms (mild/moderate/severe; median 2.7/4.9/9.9 µg/mL, respectively). The |min1| ratios were elevated in all categories (1.27/1.61/1.58) in keeping with enhanced coagulation potential, with significant differences between mild cases and moderate to severe cases. The |FL-min1| ratios were also elevated in all groups (1.19/1.39/1.40), reflecting enhanced fibrinolytic potential. These data identified coagulation dominance in moderate to severe cases, but balanced coagulation and fibrinolysis in mild cases. There were significant differences in FDP and TAT, but no significant differences in |min1| or |FL-min1| ratios, between patients with and without thrombosis. CFWA monitoring of coagulation and fibrinolysis dynamics could provide valuable data for understanding hemostatic changes and disease status in COVID-19 patients.

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.

Adrenal insufficiency in immunochemotherapy for small-cell lung cancer with ectopic ACTH syndrome.

SUMMARY: Ectopic ACTH (adrenocorticotrophic hormone) syndrome (EAS) is rarely associated with small-cell lung cancer (SCLC). Although chemotherapy is initially effective for SCLC, complicated EAS scarcely improves. Recently, immune checkpoint inhibitors have been used to treat SCLC. Atezolizumab plus chemotherapy for SCLC improved progression-free survival compared to conventional chemotherapy. However, little has been reported on the efficacy of the combination therapy for SCLC with EAS. We report a 72-year-old male who presented with 4-week history of leg oedema, proximal myopathy, weight loss, and worsened symptoms of diabetes and hypertension. Laboratory findings revealed hypokalaemia, increased plasma ACTH, and serum cortisol levels. Cortisol levels were not suppressed by the high-dose dexamethasone test. Chest and abdominal CT revealed a right lower lobe tumour with multiple metastases on the hilar lymph nodes, liver, lumbar spine, and bilateral enlarged adrenal glands. The patient was diagnosed with stage 4B SCLC with EAS. Hypercortisolaemia was then treated with metyrapone and atezolizumab plus chemotherapy, which was started for SCLC. After 10 days, the tumour shrank noticeably, and the ACTH level drastically decreased concomitantly with low cortisol levels with symptoms of fever, appetite loss, and general fatigue. Hydrocortisone treatment was initiated, and the symptoms resolved immediately. We describe a case of SCLC with EAS treated with atezolizumab plus chemotherapy, presenting with adrenal insufficiency. Close observation is required for patients with adrenal insufficiency receiving atezolizumab plus chemotherapy because of its stronger effect. Furthermore, advances in cancer therapy and care for endocrine paraneoplastic syndrome needs to be adapted. LEARNING POINTS: The immune checkpoint inhibitor atezolizumab has recently been approved for the treatment of small-cell lung cancer (SCLC). Approximately 1-6% of tumour ectopically produce ACTH and cause ectopic ACTH syndrome (EAS) as an endocrine paraneoplastic syndrome. The use of combined chemotherapy and atezolizumab in the ectopic ACTH syndrome secondary to small-cell lung cancer may cause a precipitous fall in circulating ACTH/cortisol, resulting in symptomatic adrenal insufficiency The advances in cancer therapy and treatment for endocrine paraneoplastic syndrome need to be adapted.

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.

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.

Association Between Statins and Cancer Incidence in Diabetes: a Cohort Study of Japanese Patients with Type 2 Diabetes.

BACKGROUND: The antitumor effect of statins has been highlighted, but clinical study results remain inconclusive. While patients with diabetes are at high risk of cancer, it is uncertain whether statins are effective for cancer chemoprevention in this population. OBJECTIVE: This study evaluated the association between statins and cancer incidence/mortality in patients with type 2 diabetes. DESIGN: This study was a follow-up observational study of the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, which was a randomized controlled trial of low-dose aspirin in Japanese patients with type 2 diabetes. PARTICIPANTS: This study enrolled 2536 patients with type 2 diabetes, age 30-85 years, and no history of atherosclerotic cardiovascular disease, from December 2002 until May 2005. All participants recruited in the JPAD trial were followed until the day of any fatal event or July 2015. We defined participants taking any statin at enrollment as the statin group (n = 650) and the remainder as the no-statin group (n = 1886). MAIN MEASURES: The primary end point was the first occurrence of any cancer (cancer incidence). The secondary end point was death from any cancer (cancer mortality). KEY RESULTS: During follow-up (median, 10.7 years), 318 participants developed a new cancer and 123 died as a result. Cancer incidence and mortality were 10.5 and 3.7 per 1000 person-years in the statin group, and 16.8 and 6.3 per 1000 person-years in the no-statin group, respectively. Statin use was associated with significantly reduced cancer incidence and mortality after adjustment for confounding factors (cancer incidence: adjusted hazard ratio [HR], 0.67; 95% CI, 0.49-0.90, P = 0.007; cancer mortality: adjusted HR, 0.60; 95% CI, 0.36-0.98, P = 0.04). CONCLUSIONS: Statin use was associated with a reduced incidence and mortality of cancer in Japanese patients with type 2 diabetes.

Microscopic hematuria is a risk factor for end-stage kidney disease in patients with biopsy-proven diabetic nephropathy.

INTRODUCTION: There are fewer reports about whether the presence of hematuria affects the progression of chronic kidney disease in patients with diabetic nephropathy. We analyzed whether microscopic hematuria in diabetic nephropathy is a risk factor for end-stage kidney disease (ESKD). RESEARCH DESIGN AND METHODS: The present study was a retrospective cohort study of patients with biopsy-proven diabetic nephropathy. We recruited 397 patients with diabetic nephropathy, which was confirmed by renal biopsy between June 1981 and December 2014 and followed them until October 2018 or death. Patients with microscopic hematuria before renal biopsy were defined as the hematuria group (n=91), and the remainder as the no-hematuria group (n=306). The main outcome was the occurrence of ESKD, which was defined by the requirement of permanent renal replacement therapies. RESULTS: The systolic and diastolic blood pressure, serum creatinine and proteinuria were significantly higher, and the estimated glomerular filtration rate was significantly lower in the hematuria group compared with the no-hematuria group. Pathological evaluations revealed that glomerular, tubulointerstitial and vascular lesions in the hematuria group were significantly more severe. During a median of 10.1 years, 44 and 52 patients developed ESKD in the hematuria group and the no-hematuria group, respectively. Survival analyses showed that the incidence of ESKD was significantly higher in the hematuria group compared with the no-hematuria group (log-rank, p<0.0001). The multivariable Cox proportional hazards models revealed a significant association between hematuria and the incidence of ESKD after adjusting for clinically relevant factors, including proteinuria and renal pathology (adjusted HR 1.64, 95% CI 1.03 to 2.60). The subgroups of men, proteinuria ≥0.5 g/day, and systolic blood pressure ≥132 mm Hg showed a stronger association between hematuria and ESKD than their opposing subgroups. CONCLUSIONS: Microscopic hematuria is a risk factor for ESKD in diabetic nephropathy, independent of proteinuria and renal pathology.

Incidence and seasonality of type 1 diabetes: a population-based 3-year cohort study using the National Database in Japan.

INTRODUCTION: To investigate the incidence of type 1 diabetes by age group (0-19, 20-39, 40-59, ≥60 years) in Japan and whether there is seasonality in this incidence. RESEARCH DESIGN AND METHODS: The incidence of type 1 diabetes from September 2014 to August 2017 was estimated using 2013-2018 data from the National Database of Health Insurance Claims and Specific Health Check-ups of Japan. The incidence rate was analyzed using Tango's Index and the self-controlled case series method. RESULTS: Overall, 10 400 of the 79 175 553 included individuals were diagnosed with type 1 diabetes. The incidence of type 1 diabetes from September 2014 to August 2017 was 4.42/100 000 person-years. The incidence rates for men aged 0-19, 20-39, 40-59, and ≥60 years were 3.94, 5.57, 5.70, and 3.48, respectively. Among women, the incidence rates for the same age ranges were 5.22, 4.83, 4.99, and 3.31, respectively. Tango's index showed that the incidence rate of type 1 diabetes was significantly associated with seasons among those aged 0-19 years. Further, the self-controlled case series method showed a significant interaction between age and season, with the incidence of type 1 diabetes being higher in spring for patients younger than 20 years of age. CONCLUSIONS: In Japan, men aged 40-59 years and women aged 0-19 years are the groups with the highest incidence of type 1 diabetes. Further, the incidence of younger-onset diabetes in Japan was higher in spring (from March to May).

Absolute risk of acute coronary syndrome after severe hypoglycemia: A population-based 2-year cohort study using the National Database in Japan.

AIMS/INTRODUCTION: Although the epidemiological relationship between hypoglycemia and increased risk of acute coronary syndrome (ACS) has been well established, the time period for increased risk of ACS after a severe hypoglycemic episode remains unknown. The present study aimed to determine the ACS risk after a severe hypoglycemic episode. MATERIALS AND METHODS: We carried out a retrospective population-based cohort study based on national claims data in Japan. We retrieved data of diabetes patients aged ≥35 years collected from April 2014 to March 2016. The absolute risk of ACS was defined as the occurrence of an emergency percutaneous coronary intervention after a severe hypoglycemic episode. RESULTS: In total, data of 7,909,626 patients were included in the analysis. The absolute risk of ACS was 2.9 out of 1,000 person-years in all patients. ACS risk in patients with severe hypoglycemic episodes was 3.0 out of 1,000 person-years. Severe hypoglycemic episodes increased the absolute risk of ACS in patients aged ≥70 years, but not in patients aged <70 years. The absolute risk of ACS was 10.6 out of 1,000 person-years within 10 days of a severe hypoglycemic episode. There was a significant trend between shorter duration after an episode and higher ACS risk. CONCLUSIONS: Severe hypoglycemia was associated with an increased risk of ACS in elderly diabetes patients. ACS risk increased with a shorter period after a severe hypoglycemic episode, suggesting that severe hypoglycemia leads to an increased risk of ACS in diabetes patients. These findings show that it is important to avoid severe hypoglycemia while treating diabetes, particularly in elderly patients.

Proteinuria is independently associated with the incidence of primary cardiovascular events in diabetic patients.

BACKGROUND: Albuminuria is a risk factor for cardiovascular events in diabetic patients, but it is unknown whether proteinuria is also a risk factor for cardiovascular events in these patients. METHODS: The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was performed between 2002 and 2008 to examine the efficacy of low-dose aspirin therapy for the primary prevention of cardiovascular events in type 2 diabetes patients. After the JPAD trial was completed, we continued to follow up the patients until 2015. Among the 2536 patients participating in the JPAD study, 42 were excluded because proteinuria was not checked at registration. We divided the patients into two groups: proteinuria group (n = 446; proteinuria ± or greater) and non-proteinuria groups (n = 2048; proteinuria -). We compared the incident rate of cardiovascular events between the two groups. RESULTS: During the observation period [median, 10.3 (10.2-10.5) years], 332 patients had a first cardiovascular event. Among 332 patients, 136 patients had cerebrovascular events and 54 patients had acute myocardial infarction. The incidence rate of cardiovascular events was significantly higher in the proteinuria group compared with the non-proteinuria group (HR 1.75, 95%CI 1.36-2.23, p < 0.0001). The incidence rate of cerebrovascular events was also significantly higher in the proteinuria group than in the non-proteinuria group (HR 1.71, 95%CI 1.14-2.49, p = 0.0064). The Cox proportional hazards model revealed that proteinuria was independently associated with cardiovascular events in diabetic patients without a history of cardiovascular events after adjusting for age, gender, body mass index, hemoglobin A1c level, duration of diabetes, and estimated glomerular filtration rate. CONCLUSIONS: Proteinuria was independently associated with the incidence of primary cardiovascular events in diabetic patients. Proteinuria detected by the dipstick test, which is simple and inexpensive, is useful as a first step in the risk assessment of diabetic patients.

Sex Difference in Effects of Low-Dose Aspirin on Prevention of Dementia in Patients With Type 2 Diabetes: A Long-term Follow-up Study of a Randomized Clinical Trial.

OBJECTIVE: To evaluate and compare the efficacy of long-term use of low-dose aspirin for the prevention of dementia in men and women. RESEARCH DESIGN AND METHODS: This study is a follow-up cohort study of the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial, which was a randomized, open-label, standard care-controlled trial examining the effects of low-dose aspirin on cardiovascular events. We followed up 2,536 Japanese patients with type 2 diabetes (T2D) enrolled in the JPAD trial from 2002 to 2017. The primary outcome of this post hoc analysis was the incidence of dementia, which was defined by the prescription of antidementia drugs or admission due to dementia. RESULTS: Among the originally enrolled patients, 2,121 (84%) retained their original allocation. During a median follow-up of 11.4 years, 128 patients developed dementia. The overall effect of low-dose aspirin on the prevention of dementia adjusted for age, sex, and other established risk factors was not significant (hazard ratio [HR] 0.82, 95% CI 0.58-1.16). However, a significant reduction was seen in the risk of dementia in women (HR 0.58, 95% CI 0.36-0.95), but not in men (HR 1.27, 95% CI 0.75-2.13) (P interaction = 0.03). CONCLUSIONS: Long-term use of low-dose aspirin may reduce the risk for dementia in women with T2D.