On the Commemorative Ceremony and Symposium for the 20th Anniversary of Food Safety Commission, Cabinet Office, Government of Japan.

Food Safety Commission, Cabinet Office, Government of Japan (FSCJ) was established in 2003 and marked its 20th anniversary in 2023. FSCJ held a commemorative ceremony and symposium to celebrate its 20th anniversary at Mita conference hall (Mita, Minato-ku, Tokyo) on September 1st, 2023, which attracted a total of 164 on-site attendees including six media companies, as well as 460 online viewers. FSCJ Chairperson Dr. YAMAMOTO gave a summary of each session; Session 1 outlined the various future challenges against which risk assessment organizations must prepare. In Session 2, panelists shared information on the development of new evaluation methodologies and international collaborations in order to meet various global demands and issues. In Session 3, the FSCJ introduced its future initiatives and called for international collaboration in sharing information and expertise to address data gaps and emerging issues, to which all panelists expressed their support. The importance of personnel development to tackle these challenges was also raised. In concluding the seminar, Dr. YAMAMOTO expressed that the common understanding gained from this occasion was the most fruitful achievement, owing to the international colleagues who shared their thought-provoking presentations and insights.

Impacts of Febuxostat on Cerebral and Cardiovascular Events in Elderly Patients with Hyperuricemia: Post Hoc Analysis of a Randomized Controlled Trial.

A recent meta-analysis found no benefit of uric acid-lowering therapy including febuxostat on death, cardiovascular events, or renal impairment. However, there may be populations that benefit from febuxostat in reducing mortality and cerebral and cardiovascular events. The aim of the present study was to examine the clinical benefit of febuxostat in elderly patients stratified by age using Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED) data. FREED was a randomized study involving patients aged 65 years or older with hyperuricemia and risk factors for cerebral, cardiovascular, or renal diseases. A total of 1,070 patients were included in this post hoc analysis, divided into 2 age groups: 65-74 years and ≥ 75 years. Patients were randomized into febuxostat and non-febuxostat groups, with uric acid levels monitored for 36 months. The primary composite end point included cerebral, cardiovascular, and renal events. In patients aged between 65 and 74 years, febuxostat significantly reduced the risk of future cerebral and cardiorenovascular events. However, no effects of febuxostat were found in the older population aged ≥ 75 years. Heterogeneity in potential interactions between the age and febuxostat treatment was particularly observed in non-fatal cerebral and cardiovascular events and all-cause death. Patients aged ≥ 75 years exhibited more pre-existing factors associated with cerebral and cardiorenovascular events than those aged 65-74 years. The effectiveness of febuxostat varies by age group, with potential benefits for patients aged 65-74 years. The effects of febuxostat are complex and it is important to consider patient characteristics in its clinical use.

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.

Effects of Nutrition Education Program for the Japan Diet on Serum Phospholipid Fatty Acid Compositions in Patients with Dyslipidemia: Re-analysis of Data from a Previous Randomized Controlled Trial.

AIM: We investigated changes in serum phospholipid fatty acid compositions with intake of the Japan Diet (JD) (higher consumption of fish, soybeans, vegetables, seaweed/mushrooms/konjak, and unrefined cereals with reduced consumption of animal fat, meat and poultry with fat, sweets and alcoholic drinks) recommended by the Japan Atherosclerosis Society. METHODS: A randomized parallel controlled clinical trial on JD intake was conducted on Japanese patients with dyslipidemia. Nutrition education, based on the JD or partial JD (PJD) at baseline and at 3 months, was provided and the participants were followed up for 6 months. Fatty acids comprising serum phospholipids were measured in the JD (n=44) and PJD (n=44) groups. RESULTS: Fatty acid intakes of C20:4, C20:5 and C22:6 increased in the JD group as compared with the PJD group. The percentages of serum phospholipid, C22:1 and C20:5 increased, while those of C18:1, C20:3(n-6) and C20:4(n-6) decreased in the JD as compared with the PJD group at 3 months. Changes in the phospholipid concentrations of C20:5, C22:5 and C22:6 reflected those intake volumes. Serum phospholipid C20:5 and C22:6 showed inverse correlations with C18:1, C18:2, and C20:3(n-6) at baseline and the changes at 3 and 6 months. In contrast, no correlation was observed between C20:4(n-6) and those n-3 fatty acids. The ratios of fatty acid concentrations, C16:1/C16:0 and C18:1/C18:0, decreased, but the ratio of C20:4(n-6)/C20:3(n-6) increased in the JD group. CONCLUSION: Nutrition education on the JD changed serum phospholipid fatty acid profiles in favor to prevent against cardiovascular risk factors in patients with dyslipidemia.

Febuxostat and renal outcomes: post-hoc analysis of a randomized trial.

Effect of urate-lowering on renal outcomes in patients at high-risk for cardiovascular disease with hyperuricemia without gout is not known. We conducted a post hoc analysis of a randomized trial (Febuxostat for Cerebral and　CaRdiorenovascular Events PrEvEntion StuDy [FREED]). The FREED trial enrolled 1070 asymptomatic, hyperuricemic elderly patients with at least one risk factor for cardiovascular disease, divided into febuxostat (n = 537) and non-febuxostat (n = 533) groups. We compared the effect of these treatments on renal outcomes including 40% decline in estimated glomerular filtration rate, new onset of microalbuminuria and development or worsening macroalbuminuria. The relative risk of developing or worsening macroalbuminuria was 56% lower in the febuxostat group (hazard ratio, 0.44; 95% CI, 0.24-0.82; P = 0.0098). However, the risks for other outcomes were comparable. In patients with asymptomatic hyperuricemia without gout, febuxostat reduces the risk of development or worsening of macroalbuminuria.

C-reactive Protein Levels and Cardiovascular Outcomes After Febuxostat Treatment in Patients with Asymptomatic Hyperuricemia: Post-hoc Analysis of a Randomized Controlled Study.

PURPOSE: Inflammation plays an important role in the initiation and progression of atherosclerosis, leading to poor clinical outcomes. Hyperuricemia is associated with the activation of the Nod-like receptor protein 3 inflammasome. Here, we investigated whether inhibition of inflammation using febuxostat lowered the risk of cardiovascular events. METHODS: This is a post-hoc analysis of the randomized trial, Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED). In total, 1067 patients (736 men and 331 women) were included in the analysis. We compared the serial changes in high-sensitivity C-reactive protein (hs-CRP) levels between febuxostat and non-febuxostat groups and assessed the correlation between the changes in uric acid (UA) and hs-CRP levels after febuxostat treatment. We also determined whether febuxostat could reduce a hard endpoint, defined as a composite of cardiovascular events and all-cause mortality. RESULTS: Serum UA levels in the febuxostat group were significantly lower than those in the non-febuxostat group after randomization (p < 0.05). However, hs-CRP levels were comparable between the two groups during the study. No significant correlation was observed between the changes in UA and hs-CRP levels after febuxostat treatment. The hard endpoints did not differ significantly between the two groups. In patients with baseline hs-CRP levels > 0.2 mg/dL or those administered 40 mg of febuxostat, the drug did not reduce hs-CRP levels or decrease the hard endpoint. CONCLUSION: Febuxostat reduced the UA levels but did not affect the CRP levels, and therefore may fail to improve cardiovascular outcomes after treatment. TRIAL REGISTRATION: ClinicalTrial.gov (NCT01984749). https://clinicaltrials.gov/ct2/show/NCT01984749.

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.

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.

Effect of febuxostat on clinical outcomes in patients with hyperuricemia and cardiovascular disease.

BACKGROUND: We previously reported on the FREED study, which found that febuxostat reduced the risk of adverse clinical outcome in patients with asymptomatic hyperuricemia without gout. We have now investigated outcomes in subgroups of FREED patients with and without a history of cardiovascular disease (CVD). METHODS: We performed a post hoc subgroup analysis of 1070 patients randomized to the febuxostat or non-febuxostat group and followed for 36 months. RESULTS: At baseline, 234 patients (21.9%) had a history of CVD, including 86 patients with stroke (36.8%), 90 with coronary artery disease (38.5%), 74 with heart failure (31.6%), and 25 with vascular disease (10.7%). The risk for the primary composite endpoint, i.e., cerebral, cardiovascular, and renal events and all deaths, was higher in patients with CVD than in those without CVD (34.2% vs 23.7%; p < 0.001). Treatment with febuxostat lowered rates of the primary composite endpoint in patients with CVD (hazard ratio [HR] 0.601, 95% CI 0.384 to 0.940, p = 0.026), and these effects were consistently observed in subgroups with and without CVD (p = 0.227 for treatment by subgroup interaction). Furthermore, in the subgroup with CVD, all-cause mortality was significantly lower in the febuxostat group than in the non-febuxostat group (HR 0.160, 95% CI 0.047 to 0.547, p = 0.004), with a significant subgroup interaction (p = 0.007 for treatment by subgroup interaction). CONCLUSIONS: In patients with asymptomatic hyperuricemia without gout, febuxostat reduces the risk of the composite of cerebral, cardiovascular, and renal events and death in the secondary prevention setting.

Effects of Dietary Education Program for the Japan Diet on Cholesterol Efflux Capacity: A Randomized Controlled Trial.

AIM: Improving cholesterol efflux capacity (CEC) of high-density lipoprotein (HDL) has been regarded as a novel target for preventing cardiovascular disease. HDL reportedly has antioxidant properties which may contribute to its functions. We investigated changes in CEC with intake of the Japan Diet (JD) recommended by the Japan Atherosclerosis Society and the relationship of these changes to serum antioxidant concentrations. METHODS: A randomized parallel controlled clinical trial on JD intake was performed in Japanese patients with dyslipidemia. Ninety-eight participants were randomly divided into the JD (n=49) or the partial JD (PJD) (n=49) group. Nutrition education, based on each diet at baseline and at 3 months, was provided and the participants were followed up for 6 months. RESULTS: Mean CEC was 1.05 in total and correlated positively with HDL-cholesterol (p＜0.001) at baseline. CEC did not change while oxygen radical absorbance capacity (ORAC) was decreased in both groups (p＜0.001). Although serum total carotenoid increased in both groups, serum α-tocopherol decreased in the JD group as compared to the PJD group (p＜0.05). CEC correlated positively with HDL ORAC at baseline (p=0.021) and with serum total carotenoid at 3 and 6 months (p=0.005, 0.035). Changes in CEC correlated positively with changes in HDL ORAC at 3 months and serum total tocopherol at 3 and 6 months (p＜0.001). CONCLUSION: CEC was not changed by JD education in Japanese patients with dyslipidemia who already had normal CEC at baseline. CEC was suggested to be positively associated with serum α- and γ-tocopherol and HDL ORAC.

Optimal uric acid levels by febuxostat treatment and cerebral, cardiorenovascular risks: post hoc analysis of a randomized controlled trial.

OBJECTIVES: Hyperuricaemia is recognized as an independent risk marker for cardiovascular and renal diseases. However, uric acid is a powerful free-radical scavenger, and the optimal level of serum uric acid (SUA) determining outcomes is unknown. This study explored whether interventional treatments for excessive SUA reduction were harmful and what constituted the optimal lowering of SUA levels for the prevention of events in patients with asymptomatic hyperuricaemia. METHODS: This was a post hoc analysis of a randomized trial (Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy [FREED]) in which 1070 older patients with asymptomatic hyperuricaemia were enrolled and allocated to febuxostat (n = 537) or non-febuxostat treatment group (n = 533). We assessed the relationship between the endpoint (withdrawal or study completion) SUA levels and clinical outcomes. Primary endpoint was defined as a composite of all-cause mortality, cerebral and cardiorenovascular events. RESULTS: In the febuxostat group, patients achieving SUA levels ≤4 mg/dl (hazard ratio: 2.01 [95% CI: 1.05, 3.87]), >4 to ≤5 mg/dl (2.12 [1.07, 4.20], >6 to ≤7 mg/dl (2.42 [1.05, 5.60]), and >7 mg/dl (4.73 [2.13, 10.5]) had significantly higher risks for a primary composite event than those achieving SUA levels >5 to ≤6 mg/dl (P = 0.003 [log-rank test]). This J-shaped relationship applied to patients with renal impairment (P = 0.007 [Gray's test]) and was not significant in the non-febuxostat treatment group (P = 0.212 [log-rank test]). CONCLUSION: Optimal SUA level by febuxostat treatment is 5-6 mg/dl for reducing all-cause mortality, cerebral, cardiovascular and renal events. Excessive SUA reduction may be harmful in older hyperuricaemic populations. TRIAL REGISTRATION: ClinicalTrial.gov, https://clinicaltrials.gov, NCT01984749.

Effects of Nutrition Education Program for the Japan Diet on Serum LDL-Cholesterol Concentration in Patients with Dyslipidemia: A Randomized Controlled Trial.

AIM: The Japan Diet (JD) recommended by the Japan Atherosclerosis Society based on the traditional Japanese diet is presumably favorable for preventing atherosclerotic cardiovascular diseases, but few high-quality controlled clinical trials have examined its benefits as compared with other diets. We studied effects of nutrition education for JD intake as compared with partial JD (PJD) intake on serum lipids and inflammatory parameters in subjects with dyslipidemia. METHODS: A randomized parallel controlled clinical trial was conducted on outpatients with dyslipidemia. Participants were randomly divided into the JD or the PJD group. Face-to-face nutrition education based on each diet at baseline and at 3 months, as well as monthly counseling by mail during the intervening 3-month period, were provided and participants practiced up to 6 months. Both groups were advised to reduce consumptions of animal fat/ fatty meat/poultry, confections, and alcoholic drinks. Additionally, the JD group participants were recommended to consume more fish, soybean products especially natto, vegetables, and seaweed/mushrooms/konjak, and to switch from refined to unrefined cereals or barley. RESULTS: Mean LDL-cholesterol was 125 +/- 29 mg/dL at baseline, and the JD group ( n=49) showed a greater mean LDL-cholesterol decrease than the PJD group (n=49) [- 8 mg/dL in JD vs 1 mg/dL in PJD, difference, -9 mg/dL (95%CI, -17 to 0) p=0.043)], and triglyceride (p=0.023) and insulin (p=0.033) reductions were larger in the JD group than in the PJD group at 6 months. CONCLUSION: Nutrition education for JD intake was suggested to improve serum lipid and metabolic parameters in patients with dyslipidemia.

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.

Rationale and design of the EMPYREAN study.

AIMS: A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA-REG OUTCOME trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus. METHODS AND RESULTS: This ongoing study is a prospective, randomized, open-label, multicentre investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are conducted using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non-linear least squares method for square analysis. The primary endpoint is the change in the low-frequency (0.04-0.15 Hz)/high-frequency (0.15-0.4 Hz) ratio from baseline to 24 weeks. CONCLUSIONS: This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes.

Quadricuspid aortic valve repair by neo-cuspidization of an accessory cusp using autologous pericardium.

We present a successful case of the management of a 46-year-old woman with an abnormal aortic valve formed by four cusps (three equal large cusps and one smaller cusp; type B according to the Hurwitz and Roberts classification) with a marked loss of coaptation that caused a severe aortic insufficiency (AI). The patient underwent an aortic valvuloplasty of the defect using the glutaraldehyde (GA)-pretreated autologous pericardium, restoring the subnormal function and competency of the aortic valve. The postoperative course was unremarkable. The early follow-up showed a trivial AI and a significant reduction of regurgitant volume was identified in a cardiac magnetic resonance imaging (MRI) when compared to the preoperative state (27.2 vs. 2.1 ml). The follow-up transthoracic echocardiography 1 year after the surgery showed mild AI.

Comparison of Food and Nutrient Intakes between Japanese Dyslipidemic Patients with and without Low-Density Lipoprotein Cholesterol Lowering Drug Therapy: A Cross-Sectional Study.

AIM: We aimed to clarify actual food and nutrient intakes in Japanese patients with dyslipidemia. We also compared food and nutrient intakes between patients with and without low-density lipoprotein cholesterol (LDL-C) lowering drug therapy. METHODS: Food and nutrient intakes were assessed employing 3-day weighted dietary records in this cross-sectional study of 104 Japanese outpatients with dyslipidemia, age 30-65 years, not given dietary counseling. Anthropometric and biochemical parameters were measured after an overnight fast. Food and nutrient intakes were compared between patients with versus without LDL-C lowering drug prescriptions. Stepwise multiple regression analysis was performed to identify relationships between the serum LDL-C concentrations and food intakes. RESULTS: Of the 104 patients, 43.3% were prescribed LDL-C lowering drugs, primarily statins. Of the total patients, 83% had lipid intakes over 25% of total energy consumption (%E), exceeding the recommendation for dyslipidemia by the Japan Atherosclerosis Society. Similarly, 77% had saturated fatty acid intakes over 7%E, and 88% had cholesterol intakes over 200 mg per day. Dietary fiber consumption was low (＜25 g) in 97% of patients. Those taking LDL-C lowering drugs consumed less "meat, poultry and processed meat products" and "cereals", and more "fish", "fruits" and "nuts", than patients not taking these drugs (p＜0.05). Food intakes correlating with LDL-C concentrations independently of drug therapy differed between patients taking versus not taking these medications. CONCLUSION: Our results support the necessity of diet therapy for patients with dyslipidemia regardless of whether LDL-C lowering drugs are prescribed.The clinical trial registration number: UMIN000022955.

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.

Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy.

AIMS: To compare the occurrence of cerebral, cardiovascular, and renal events in patients with hyperuricaemia treated with febuxostat and those treated with conventional therapy with lifestyle modification. METHODS AND RESULTS: This multicentre, prospective, randomized open-label, blinded endpoint study was done in 141 hospitals in Japan. A total of 1070 patients were included in the intention-to-treat population. Elderly patients with hyperuricaemia (serum uric acid >7.0 to ≤9.0 mg/dL) at risk for cerebral, cardiovascular, or renal disease, defined by the presence of hypertension, Type 2 diabetes, renal disease, or history of cerebral or cardiovascular disease, were randomized to febuxostat and non-febuxostat groups and were observed for 36 months. Cerebral, cardiovascular, and renal events and all deaths were defined as the primary composite event. The serum uric acid level at endpoint (withdrawal or completion of the study) in the febuxostat (n = 537) and non-febuxostat groups (n = 533) was 4.50 ± 1.52 and 6.76 ± 1.45 mg/dL, respectively (P < 0.001). The primary composite event rate was significantly lower in the febuxostat group than in non-febuxostat treatment [hazard ratio (HR) 0.750, 95% confidence interval (CI) 0.592-0.950; P = 0.017] and the most frequent event was renal impairment (febuxostat group: 16.2%, non-febuxostat group: 20.5%; HR 0.745, 95% CI 0.562-0.987; P = 0.041). CONCLUSION: Febuxostat lowers uric acid and delays the progression of renal dysfunction. REGISTRATION: ClinicalTrials.gov (NCT01984749).

One quarter of total myocardial infarctions are silent manifestation in patients with type 2 diabetes mellitus.

BACKGROUND: Silent events with newly developed Q waves in electrocardiogram (ECG) [silent myocardial infarction (MI)] in diabetic patients is reported to be independently associated with an increased risk of fatal MI. However, the incidence rate of silent MI in diabetic patients has yet to be clarified. We sought to determine the incidence rate of first symptomatic MI and silent MI in diabetic patients. METHODS: We conducted a prospective cohort study on patients enrolled in the Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial which was started in 2002. It is a randomized controlled trial to examine the efficacy of low-dose aspirin therapy for the primary prevention of atherosclerotic events in type 2 diabetic patients. No patients had Q waves in their ECG before entry to the JPAD trial. We followed-up 1825 patients until July 2015 after completion of the JPAD trial in 2008. The median follow-up period was 10.3 years. We collected 1648 patients' ECGs to identify patients with silent MI. RESULTS: Symptomatic MI occurred in 65 patients and silent MI occurred in 22 patients. The incidence rate of symptomatic MI was 4.26 per 1000 patient-years and 1.44 for silent MI in diabetic patients. Thus, 25% of total MIs were silent. Cause-specific Cox proportional hazard model indicated that age (hazard ratio 1.06, 95% confidence interval; 1.03-1.10, p=0.0004) and long history of diabetes (1.00, 1.01-1.07, p=0.01) were independently associated with symptomatic MI, but these were not associated with silent MI. CONCLUSIONS: We demonstrated that incidence rate of first silent MI and that proportion of silent MI to all MIs was 25% in diabetic patients without a history of atherosclerotic events. Diabetic patients frequently need ECG screening for detection of silent MI.