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Aims To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. Methods and results In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0–10.0% (42–86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), −0.0155–0.0182] mm and 0.0015 (95% CI, −0.0155–0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of −0.0001 mm (95% CI, −0.0191–0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [−0.1% (95% CI, −0.2–0.1); P = 0.359]. Conclusion Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.

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

Coronary angiography (CAG) sometimes shows nonobstructive coronary arteries in patients with suspected angina or acute coronary syndrome (ACS). The high prevalence of nonobstructive coronary artery disease (CAD) in those patients has recently been reported not only in Japan but also in Western countries, and is clinically attracting attention. Coronary spasm is considered to be one of the leading causes of both suspected stable angina and ACS with nonobstructive coronary arteries. Coronary spasm could also be associated with left ventricular dysfunction leading to heart failure, which could be improved following the administration of calcium channel blockers. Because we rarely capture spontaneous attacks of coronary spasm with electrocardiograms or Holter recordings, an invasive diagnostic modality, acetylcholine (ACh) provocation test, can be useful in detecting coronary spasm during CAG. Furthermore, we can use the ACh-provocation test to identify high-risk patients with coronary spasm complicated with organic coronary stenosis, and then treat with intensive care. Nonobstructive CAD includes not only epicardial coronary spasm but also microvascular spasm or dysfunction that can be associated with recurrent anginal attacks and poor quality of life. ACh-provocation test could also be helpful for the assessment of microvascular spasm or dysfunction. We hope that cardiologists will increasingly perform ACh-provocation test to assess the pathophysiology of nonobstructive CAD.

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-020-06167-5) contains supplementary material, which is available to authorized users.

To test our hypothesis that the magnitude of reduction in hsCRP achieved by antihypertensive medications may predict the benefit for cardiovascular outcomes in hypertensive individuals, we performed subanalysis of the ATTEMPT-CVD study. The hypertensive participants enrolled in the ATTMEPT-CVD study were categorized into two groups according to whether achieved reduction in hsCRP levels at 6 months after initiation of antihypertensive medications from baseline was equal to or greater than 40% (responder group) or less than 40% (non-responder group). Baseline characteristics and blood pressure during follow-up period were similar between the groups. For women, the incidence of cardiovascular events was significantly less in responder group than non-responder group (P This trial was registered with ClinicalTrials.gov, number NCT01075698.

Introduction The aim of this study was to evaluate the efficacy and safety of ultra-rapid lispro (URLi) versus lispro in a subgroup analysis of Japanese adults with type 2 diabetes mellitus (T2DM) from the phase 3 PRONTO-T2D trial. Methods After an 8-week lead-in period during which patients transitioned to insulin lispro 3 times a day before main meals in association with basal insulin (glargine or degludec), the patients were randomized to 26 weeks of double-blind URLi or lispro injected immediately prior to meals. The primary endpoint was change in hemoglobin A1c (HbA1c) from baseline to week 26 between URLi and lispro. The multiplicity-adjusted objectives were 1- and 2-h postprandial glucose (PPG) excursions after a test meal and change in HbA1c from baseline to week 26 in the URLi and lispro groups. Results Results were obtained from prespecified exploratory analyses of 26-week data in Japanese patients randomized to receive URLi (n = 47) or lispro (n = 46). Mean baseline HbA1c levels significantly improved during the lead-in period to a baseline value of 7.50% and 7.60% in patients subsequently randomized to the URLi and lispro treatment groups, respectively. At week 26, the least squares mean (LSM) difference in HbAc1 between the URLi and lispro groups was 0.13% (95% confidence interval [CI] − 0.12 to 0.39) (1.4 mmol/mol, 95% CI − 1.3 to 4.2). Although there were no significant differences in PPG excursions at any time-point, numerically smaller PPG excursions were consistently observed from 30 min to 3 h during the mixed-meal tolerance test in patients on URLi compared to those on lispro. LSM differences in PPG excursions at week 26 were − 10.5 mg/dL (95% CI − 32.7 to 11.7) (− 0.58 mmol/L, 95% CI − 1.82 to 0.65) at 1 h and − 14.9 mg/dL (95% CI − 40.3 to 10.5) (− 0.83 mmol/L, 95% CI − 2.24 to 0.58) at 2 h. There were no significant differences between treatments in rates of severe/overall hypoglycemia or incidence of treatment-emergent adverse events. Conclusions URLi administered as prandial insulin in combination with basal insulin provides effective glycemic control when administered immediately before a meal in Japanese patients with T2DM. URLi was well tolerated in this population. Trial Registration ClinicalTrials.gov, NCT03214380.

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, 1,067 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> 0.2 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 decrease cardiovascular outcomes after treatment. Trial Registration: ClinicalTrial.gov (NCT01984749).https://clinicaltrials.gov/ct2/show/NCT01984749

Currently, the gold standard for diagnosing diabetic kidney disease (DKD) is the measurement of the urinary albumin-to-creatinine ratio (UACR), but it has been clarified that there are many cases of decreased renal function and atypical nephropathy without the development of albuminuria (1,2). Given these diversified pathologies of DKD, it is necessary to identify new biomarkers that can predict renal prognosis at an earlier disease stage. In this retrospective case-control study, we performed posttranslational modification analysis of plasma albumin by electrospray ionization time-of-flight mass spectrometry (3,4) in 257 outpatients with type 2 diabetes at a single center to evaluate association between the posttranslational modifications of albumin and DKD progression. In fact, 257 patients with type 2 diabetes (179 men and 78 women) aged 49–80 years (mean ± SD 67.1 ± 10.7) who visited the Jinnouchi Clinic, Diabetes Care Center, in Kumamoto, Japan, between April 2014 and June 2017 were enrolled, and the follow-up period was 2 years. According to Kidney Disease: Improving Global Outcomes (KDIGO) glomerular filtration rate (GFR) categories in chronic kidney disease, the subjects were classified into five estimated (e)GFR stages (Fig. 1 A ). Figure 1 A : Characteristics of patients enrolled in this study ( n = 257; 179 men, 78 women). B : The mass peaks of each posttranslational form of serum albumin in patients with type 2 diabetes. C and …

Background: Many studies have reported that dipeptidyl peptidase (DPP)-4 inhibitors do not significantly reduce cardiovascular events (CVE). We sought to evaluate whether DPP-4 inhibitors effected the incidence of CVE in diabetic patients with no history of atherosclerotic 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 done from 2002 to 2008. After completion of the JPAD trial, we followed up with the patients until 2019. We defined the cardiovascular events as the following: acute myocardial infarction; stable angina; unstable angina; sudden cardiac death; stroke; transient ischemic attack; heart failure requiring hospitalization; aortic disease; and peripheral artery disease. JPAD patients were divided into a DPP-4 Group and a non-DPP-4 Group based on whether or not they were taking DPP-4 inhibitors at the 2013 follow-up. We investigated the incidence of CVE in 1,107 JPAD patients who had had at least one follow-up by 2019. Results: During the observation period from 2013 to 2019, there were 37 (7%) CVE in the DPP-4 Group (n=520) and 66 (11%) in the non-DPP-4 Group (n=587). The incidence of CVE was significantly lower in the DPP-4 Group than in the non-DPP-4 Group (Log-Rank P=0.0074, Figure). Cox proportional hazards model analysis revealed that use of DPP-4 inhibitors (HR, 0.65: 0.43-0.98, P=0.04) was an independent factor after adjustment for age ≥65 years, hypertension, dyslipidemia, and, insulin usage (Figure). Conclusions: Our study demonstrated that the use of DPP-4 inhibitors was associated with a reduced incidence of CVE after adjustment in diabetic patients without a history of atherosclerotic events. It is necessary to be aware of the cardiovascular event-suppressing effect of DPP-4 inhibitors on diabetic patients.

Background: We sought to evaluate whether there was a difference in the incidence rate of cardiovascular event (CVD) among different hemoglobin (Hb) A1c levels in diabetic patients without a history of atherosclerotic 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 done from 2002 to 2008. After completion of the JPAD trial, we followed up with the patients until 2019. We defined the cardiovascular events as the following: acute myocardial infarction; stable angina; unstable angina; sudden cardiac death; stroke; transient ischemic attack; aortic disease; and peripheral artery disease. Among 2,535 JPAD patients, HbA1c levels of the JPAD patients were recorded on average 8 times. Based on the mean value of HbA1c, we divided the patients into three groups: a High HbA1c Group (n=899, HbA1c ≥7.5%); a Moderate HbA1c Group (n=581, 7.5% >HbA1c ≥7.0 %); or, a Low HbA1c Group (n=1055, 7.0% >HbA1c). We compared the incidence of CVD among the three groups. Results: The mean HbA1c (%) was 8.6 in the High HbA1c Group, 7.4 in the Moderate HbA1c Group, and 6.6 in the Low HbA1c Group on registration. During an 11.56-year follow-up, the incidence of CVD was significantly higher in the High HbA1c Group (P2 , duration of diabetes ≥7.0% years, medications, eGFR ≥60 ml/min/1.73m 2 , and systolic blood pressure ≥140 mm Hg (Figure). Conclusions: Our study demonstrated that HbA1c ≥7.5% was independently associated with the incidence of CVD in diabetic patients without a history of atherosclerotic events while 7.5% >HbA1c ≥7.0 % was not.

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 m

AIMS The prediction of future heart failure (HF) in stable outpatients is often difficult for general practitioners and cardiologists. Recently, the H2 FPEF score (0-9 points) has been proposed for the discrimination of HF with preserved ejection fraction from non-cardiac causes of dyspnoea. The six clinical and echocardiographic variables that constitute the H2 FPEF score include the following: (i) obesity (H); (ii) the use of ≥2 antihypertensive drugs (H); (iii) atrial fibrillation (F); (iv) pulmonary hypertension (P); (v) an age > 60 years (E); and (vi) E/e' > 9 (F). We performed an external validation study that investigated whether the H2 FPEF score could predict future HF-related events in stable outpatients with cardiovascular risk factor(s) in Japan. METHODS AND RESULTS In this prospective cohort study, after exclusion of 195 from 551 consecutive, stable Japanese outpatients with at least one cardiovascular risk factor who were enrolled between September 2010 and July 2013, the remaining 356 outpatients (171 men, 185 women, mean age 73.2 years) were eligible for the analysis. We calculated the H2 FPEF score (0-9 points), and followed up the patients for an average of 517 days. In all of the 356 patients, the mean H2 FPEF score was 3.1 ± 1.8, and 15 developed HF-related events during the follow-up period, including cardiovascular death (n = 2) and hospitalization for HF decompensation (n = 13). Multivariate Cox proportional hazards analysis showed that the H2 FPEF score was an independent predictor of future HF-related events (P < 0.001 for all three models). Kaplan-Meier survival curves showed a significantly higher probability of HF-related events in the outpatients with a high H2 FPEF score (P < 0.001). In receiver operating characteristic (ROC) curve analysis, the H2 FPEF score was significantly associated with the occurrence of future HF-related events (P < 0.001). In ROC curve analysis, the sensitivity, specificity, and positive likelihood ratio of a H2 FPEF score of 7 points to predict HF-related events were 47%, 96%, and 11.4%, respectively. CONCLUSIONS The H2 FPEF score could provide useful information for future HF-related events in stable outpatients with cardiovascular risk factor(s) in Japan.

Background: Renal function deterioration accompanied by an acute decrease in estimated glomerular filtration rate (eGFR) was observed early after starting sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy. It is unclear how much and how frequently the initial acute decline in eGFR (IAD-eGFR) would occur after SGLT2i administration, and the effects of IAD-eGFR on subsequent renal function are unknown in type 2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD). Methods: We retrospectively recruited T2DM patients with CKD (stage 3b; 30 ? eGFR < 45 mL/min/1.73 m 2 ) and who were newly treated with add-on SGLT2i. We further investigated the effects of SGLT2i therapy on eGFR early after starting treatment (1 - 3 months) and after 6 months of treatment. We examined the factors associated with a large IAD-eGFR (? 10%) using logistic regression analyses. Results: Eighty-seven patients (male, 74.7%; mean age, 69.8 years; median hemoglobin A1c, 7.3%; mean eGFR, 37.8 mL/min/1.73 m 2 ) were analyzed. The mean minimum eGFR early after SGLT2i administration was 34.9 mL/min/1.73 m 2 , which was significantly lower than before treatment (mean, -7.7%). Seventy patients (80.5%) had IAD-eGFR, and 36 patients (41.4%) had a large IAD-eGFR (? 10%). Overall, the mean eGFR was 38.2 at 6 months after starting SGLT2i administration. In patients with a large IAD-eGFR (? 10%), the eGFR decreased by 72.2% at 6 months to 35.5 mL/min/1.73 m 2 , showing a significant decline from the pretreatment value. In patients without a large IAD-eGFR, eGFR increased by 66.7% at 6 months to 40.0 mL/min/1.73 m 2 . Multiple logistic regression analysis showed that patients with a large IAD-eGFR had a significant association with a high estimated daily salt intake. Conclusions: SGLT2i treatment frequently induced a significant decrease in eGFR early after starting therapy, but eGFR tended to recover after 6 months in T2DM patients with CKD stage 3b. A large IAD-eGFR (? 10%) caused by SGLT2i may lead to subsequent deterioration in renal function, and it was significantly associated with a higher estimated daily salt intake. These results suggest that a more effective renoprotective therapeutic strategy using SGLT2i may be implemented by avoiding the occurrence of a large IAD-eGFR. Further prospective studies are warranted. J Clin Med Res. 2020;12(11):724-733 doi: https://doi.org/10.14740/jocmr4351

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) (Pinteraction = 0.03). CONCLUSIONS Long-term use of low-dose aspirin may reduce the risk for dementia in women with T2D.

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 Conclusion Febuxostat lowers uric acid and delays the progression of renal dysfunction. Registration ClinicalTrials.gov (NCT01984749).

Diabetes mellitus is a heterogeneous and complex metabolic disorder characterized by hyperglycemia secondary to either resistance to insulin actions on the liver and peripheral tissues, insufficient insulin secretion from pancreatic β-cells, or both. An integrated balance between blood insulin levels and whole-body insulin sensitivity could theoretically provide the clinical effectiveness of insulin action. Peripheral blood insulin concentrations might be determined by the capacity of endogenous pancreatic β-cell insulin secretion and the degree of the whole body insulin clearance. Here, we report a non-obese normoinsulinemic Japanese diabetic patient with elevated insulin clearance assessed by a hyperinsulinemic-euglycemic clamp examination and increased insulin secretion measured by daily urinary excretion of C-peptide immunoreactivity. We propose this unique pathogenic condition of diabetes with normoinsulinemia and elevated insulin clearance as “type 2 Japanese diabetes mellitus (T2JDM).”

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).We performed a post hoc subgroup analysis of 1070 patients randomized to the febuxostat or non-febuxostat group and followed for 36 months.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).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.

We investigated the effects of the SGLT2 inhibitor luseogliflozin on blood and urinary glucose and body weight.Luseogliflozin 2.5 mg was administered once daily for 24 weeks to 30 outpatients with type 2 diabetes. Urinary glucose concentration, continuous glucose monitoring values, HbA1c, fasting glucose, and body weight were evaluated. Correlations with urinary glucose, subcutaneous/visceral fat mass, insulin, EPA/AA ratio, plasma free fatty acids, ghrelin, blood ketones, plasma 1,5-anhydro-D-glucitol were evaluated.Urinary glucose significantly increased from 11.1 ± 11.8 g at Week -4 to 84.5 ± 46.8 g at Week 24. HbA1c significantly declined from 7.88 ± 0.88% to 7.36 ± 1.13% at Week 24. Mean blood glucose significantly decreased from 149.6 ± 41.8 to 131.6 ± 31.1 mg/dL at Week 24. Subcutaneous and visceral fat mass was also significantly decreased, as were AST and ALT (P 0.01). Blood urea nitrogen was significantly increased, and urate significantly decreased from 5.04 ± 1.07 to 4.53 ± 0.94 mg/dL. The homeostasis model assessment ratio remained significantly improved throughout the treatment period. Acyl ghrelin levels remained constant but des-acyl ghrelin increased significantly.Luseogliflozin monotherapy resulted in an improvement in blood glucose, a decrease in body weight, and decreased insulin resistance. Luseogliflozin appears to be an effective therapy for obese diabetics.

Background: Insulin resistance (IR) assessment is important in treating type 2 diabetes mellitus (T2DM). We thus compared body muscle-to-fat ratio (BMFR) and fat-to-muscle ratio (FMR) values against M/I values as clinical index of IR. Methods: Subject included 118 untreated T2DM patients. Hyperinsulinemic-euglycemic clamp examination was performed to calculate the M/I as index of IR. Body composition was measured by impedance analysis using InBody770. Results: Simple linear regression analyses confirmed correlations between M/I and BMFR (B: 0.756 (P < 0.01), coefficients of determination (R 2 ): 0.572, mean absolute error (MAE): 3.19, and root mean squared error (RMSE): 4.14), and between M/I and FMR (B: -0.601 (P < 0.01), R 2 : 0.362, MAE: 3.97, and RMSE: 5.05). Against the M/I values, BMFR also showed better goodness-of-fit than did FMR. In comparing correlation coefficients, the BMFR absolute B value was significantly larger than that of FMR (P = 0.027). Conclusions: BMFR is more useful than FMR in quantifying IR in patients with T2DM because the correlation between BMFR and the insulin sensitivity index M/I is significantly greater than that between FMR and M/I. J Clin Med Res. 2021;13(7):387-391 doi: https://doi.org/10.14740/jocmr4401

Introduction: Blood pressure (BP) is a significant predictor for chronic kidney disease (CKD). Hypothesis: We sought to evaluate whether the progression of CKD in diabetic patients, without a history of atherosclerotic events, is dependent on BP control. Methods: The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up the patients until 2019. We defined late-stage kidney disease (LSKD) as estimated glomerular filtration rate (eGFR) 2 or hemodialysis. Among 2,536 JPAD patients, 27 patients were excluded for eGFR 2 on registration. BP of the JPAD patients was recorded on average 8 times. Based on the mean value of systolic BP (SBP), we divided the patients into three groups: a High BP Group (n=607, SBP≥140 mm Hg); a Moderate BP Group (n=989, 140>SBP≥130 mm Hg); or a Low BP Group (n=913, SBP Results: The mean eGFR (ml/min/1.73m 2 ) was 75.1 in the High BP Group, 72.6 in the Moderate BP Group, and 75.7 in the Low BP Group on registration. During a 11.2-year follow-up, the incidence of LSKD was significantly higher in the High BP and Moderate BP Groups than in the Low BP Group (P2 , duration of diabetes ≥7.0 years, statin usage, aspirin usage, eGFR≥60 ml/min/1.73m 2 , and hemoglobin A1c ≥7.2 % (Figure). Conclusions: Our study demonstrated that SBP was independently associated with the progression to LSKD in diabetic patients, without a history of atherosclerotic events. SBP less than 130 mm Hg is recommended for diabetic patients to prevent progression to LSKD.

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.

Background: Large randomized clinical trials of patients with type 2 diabetes mellitus (T2DM) and at high risk for cardiovascular disease revealed that sodium-glucose cotransporter 2 (SGLT2) inhibitors significantly reduced renal events. However, the trials included small numbers of patients with moderate-to-severe chronic kidney disease (CKD). Therefore, the renoprotective effects of SGLT2 inhibitors remain unknown in T2DM patients complicated with impaired renal function. We examined if SGLT2 inhibitors conferred beneficial effects on kidney function in T2DM patients with CKD. Methods: We retrospectively recruited T2DM patients who were newly treated with add-on of SGLT2 inhibitors and suffered from moderate-to-severe renal impairment with CKD stages 3b-4 (15 < estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m 2 ), at initiation of SGLT2 inhibitor therapy. We analyzed T2DM patients with moderate-to-severe renal impairment who continued to use SGLT2 inhibitors for at least 1 year. We investigated the effects of SGLT2 inhibitor therapy on 1-year changes in eGFR and urinary protein excretion before and after the treatment. Results: We analyzed 42 T2DM patients with median eGFR of 40.4 mL/min/1.73 m 2 . One-year SGLT2 inhibitor therapy lowered median hemoglobin A1c (HbA1c) levels from 7.6% to 7.5% (not significant). Body weight and blood pressure were significantly decreased, and hemoglobin was significantly increased. The median value of eGFR after 1 year of SGLT2 inhibitor therapy was 41.0 mL/min/1.73 m 2 , with no significant difference compared with baseline. The annual decline in eGFR improved significantly after SGLT2 inhibitor therapy (eGFR: (median), pre: -3.8, vs. post: 0.1 mL/min/1.73 m 2 per year, P < 0.01). We also found a significant decrease in urinary protein excretion after SGLT2 inhibitor therapy (urinary protein-to-creatinine ratio: (median), pre: 0.36, vs. post: 0.23 g/g creatinine, n = 35, P < 0.01). Conclusions: This study revealed the promising observations that add-on treatment with SGLT2 inhibitors exerted significant renoprotective effects, culminating in improvements in annual decline in eGFR and urinary protein excretion in T2DM patients with CKD stages 3b-4, but did not significantly reduce HbA1c. Further prospective clinical trials are warranted to fully elucidate the effects of SGLT2 inhibitors on glycemic control and renal function in T2DM patients with moderate-to-severe renal impairment. J Clin Med Res. 2019;11(4):267-274 doi: https://doi.org/10.14740/jocmr3761

Labile HbA1c migrates in the #C fraction with modified hemoglobin (Hb) (such as carbamylated Hb, acetaldehyde Hb, and acetylated Hb) when HbA1c is measured by Arkray's high-performance liquid chromatography (HPLC). We previously reported the usefulness of #C levels for the screening of variant Hb without diabetes mellitus. Because the #C levels are affected by plasma glucose levels, we investigated the usefulness of plasma glucose adjusted #C (PGa#C) for the screening of variant Hb complicated with diabetes mellitus. In this study, nine types of variant Hb in nine diabetic patients were included. HbA1c and the #C fraction were measured by Arkray's HPLC. Furthermore, we established a calculation formula for PGa#C by using the regression equation of #C and plasma glucose of 2,299 diabetic patients without variant Hb. If the cutoff value of PGa#C for the screening of variant Hb with diabetes mellitus was set at 1.3% or lower and 2.3% or higher, sensitivity and specificity were 89% and 99.8%, respectively. The PGa#C levels in all four slow moving variant Hb with diabetes were less than 1.3%, while the PGa#C levels of fast moving variant Hb with diabetes were abnormal values in four out of five patients [high #C level in one and low #C levels in three patients]. The screening of variant Hb with diabetes with high sensitivity and high specificity was possible by using the same cutoff values for the reference range of PGa#C as the #C values reported in non-diabetic subjects.

Aims We examined dapagliflozin-induced changes in liver fat accumulation. Methods We prospectively recruited Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM) [hemoglobin A1c (HbA1c) >7.0%]. Dapagliflozin (5 mg/day) or non-sodium glucose cotransporter 2 inhibitors (SGLT2i) was added to the patients’ treatment regimen for 6 months. Changes in liver fat accumulation were assessed by the liver-to-spleen (L/S) attenuation ratio using abdominal computed tomography (CT). Results This study enrolled 55 Japanese T2DM patients. The L/S ratio significantly increased in the dapagliflozin group compared with the non-SGLT2i group. Abdominal subcutaneous fat area (SFA), visceral fat area, total fat area assessed by abdominal CT, aspartate aminotransferase, alanine aminotransferase (ALT), and γ-glutamyl transpeptidase decreased significantly only in the dapagliflozin group. Changes in the L/S ratio showed a significant negative relationship with changes in abdominal SFA, ALT, and non-esterified fatty acid. In sub-group analyses of non-insulin users, hepatic insulin extraction was assessed by the plasma C-peptide-to-insulin ratio, which was significantly increased in the dapagliflozin group but not in the non-SGLT2i group. Conclusion In patients with inadequately controlled T2DM, additional dapagliflozin-treatment significantly reduced the liver fat accumulation associated with a decrease in abdominal SFA.

OBJECTIVE This study analyzed the efficacy of low-dose aspirin in cancer chemoprevention in patients with diabetes. RESEARCH DESIGN AND METHODS This study was a posttrial follow-up of the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial. Participants in the JPAD trial (2,536 Japanese patients with type 2 diabetes and without preexisting cardiovascular disease) were randomly allocated to receive aspirin (81 or 100 mg daily) or no aspirin. After that trial ended in 2008, we followed up with the participants until 2015, with no attempt to change the previously assigned therapy. The primary end point was total cancer incidence. We investigated the effect of low-dose aspirin on cancer incidence. RESULTS During the median follow-up period of 10.7 years, a total of 318 cancers occurred. The cancer incidence was not significantly different between the aspirin and no-aspirin groups (log-rank, P = 0.4; hazard ratio [HR], 0.92; 95% CI, 0.73–1.14; P = 0.4). In subgroup analyses, aspirin did not affect cancer incidence in men, women, or participants aged ≥65 years. However, it decreased cancer incidence in participants aged CONCLUSIONS Low-dose aspirin did not reduce cancer incidence in Japanese patients with type 2 diabetes.

Background: We examined whether the sodium-glucose cotransporter-2 inhibitor (SGLT2i) dapagliflozin can improve urine albumin-to-creatinine ratio (UACR) associated with a reduction in body weight or body fat in patients with type 2 diabetes mellitus (T2DM). Methods: We prospectively recruited T2DM patients having inadequate glycemic control (hemoglobin A1c (HbA1c) > 7.0%) not on SGLT2i therapy. We treated the patients with add-on dapagliflozin treatment or intensification of non-SGLT2 inhibitor therapies for 6 months. We measured UACR, urine N-acetyl-β-glucosaminidase (uNAG), and body composition including total body fat mass (TBFM) as assessed by bioelectrical impedance analysis. We also investigated changes in length and radiation attenuation properties of the kidneys and abdominal fat area using computed tomography. Results: We enrolled 62 patients with a mean HbA1c of 8.0%. The HbA1c and fasting blood glucose were significantly decreased in both the dapagliflozin-group and non-SGLT2i-group, with no significant difference between the two groups. Dapagliflozin treatment, but not non-SGLT2i treatment, significantly decreased UACR and uNAG. The changes in UACR and uNAG were significantly greater in the dapagliflozin group compared with the non-SGLT2i group. Dapagliflozin treatment, but not non-SGLT2i treatment, significantly decreased the body weight, TBFM, and abdominal fat area and significantly increased kidney length and radiation attenuation. The percentage change in UACR was significantly correlated with changes in TBFM, but not with body weight. By multivariate logistic regression analysis, dapagliflozin treatment was significantly associated with the improvement of UACR. Conclusions: Add-on treatment with dapagliflozin exhibited significant renoprotective effects, with improvement of UACR and uNAG and increased kidney length and radiation attenuation in patients with uncontrolled T2DM. J Clin Med Res. 2018;10(6):466-477 doi: https://doi.org/10.14740/jocmr3419w

Background: Smoking cessation in newly diagnosed type 2 diabetes patients is reported to be associated with amelioration of metabolic parameters and blood pressure (BP), and the reduction of microalbuminuria. The aim of this study is to demonstrate changes in BP, pulse rate (PR), and microalbuminuria in already diagnosed diabetes patients who quit smoking. Methods: We retrospectively evaluated diabetes outpatients who were habitual smokers, and who visited to our smoking cessation clinic. Patients were divided into two groups based on their smoking status at the termination of a 3-month smoking cessation program (smoking cessation group and smoking group), and analyzed systolic and diastolic BPs, PR, HbA1c, and body weight at the start date, and at 1, 3, 6, and 12 months thereafter. The urinary albumin-to-creatinine ratio was also measured at the start date and at 12 months. Results: Thirty-five patients met our criteria. Mean diabetes duration was 12 years. Eighteen patients (52%) quit smoking. Success or failure of smoking cessation depended on nicotine dependence rather than good or bad glycemic control. Both BP and PR decreased significantly after 1 month or later in the smoking cessation group without worsening HbA1c, while both parameters did not show any changes in the smoking group. Microalbuminuria was also ameliorated significantly at 12 months compared with that at the start date in the smoking cessation group (95.8 ± 92.9 mg/gCr vs. 75.5 ± 96.3 mg/gCr, P = 0.0059), while it did not show a significant change in the smoking group. (61.9 ± 43.5 mg/gCr vs. 97.7 ± 90.4 mg/gCr, P = 0.1039). Conclusions: Smoking cessation might cause a reduction in chronic kidney disease progression through ameliorating microalbuminuria without metabolic adverse effects in patients already diagnosed with diabetes mellitus. J Clin Med Res. 2018;10(6):478-485 doi: https://doi.org/10.14740/jocmr3400w

The overall goal in the treatment of type 2 diabetes mellitus (T2DM) is remission. However, the effects of a sodium-glucose cotransporter 2 inhibitor (SGLT2i) on remission of T2DM are unknown. We herein report a case involving an overweight 43-year-old man who completely recovered from T2DM after SGLT2i therapy (dapagliflozin at 5 mg/day). In the pretreatment period, he had a body mass index (BMI) of 26.0 kg/m2, hemoglobin A1c (HbA1c) concentration of 10.3%, advanced insulin resistance, pancreatic β-cell dysfunction, and fatty liver. Eighteen months after comprehensive therapy, including the administration of an SGLT2i and metformin, his BMI had decreased to 21.3 kg/m2 and his glycemic control was almost normal (HbA1c of 5.3%) despite discontinuation of all hypoglycemic medications. This report is the first to propose the usefulness of the combination therapy of SGLT2i and metformin for achieving normal body weight and remission of newly diagnosed T2DM in a real-world clinical situation.