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Aims/Introduction This study investigated the impact of the dipeptidyl peptidase‐4 inhibitor, anagliptin, on hepatic insulin clearance (HIC) in Japanese type 2 diabetes patients and explored its relationship to glycemic status. Materials and Methods Data on 765 participants in anagliptin phase 2 and 3 studies were analyzed. Adjusted changes in variables during 12 weeks of anagliptin therapy were compared with a placebo. HIC was calculated as the ratio, C‐peptide area under the curve 0–120 min to insulin area under the curve 0–120 min, after a meal tolerance test. To explore the effects of baseline HIC levels on variables, participants receiving anagliptin were divided according to quartiles of baseline HIC. Furthermore, multivariate analysis investigated the association between baseline HIC levels and glycemic status. Results Anagliptin significantly reduced glycosylated hemoglobin levels (P, Anagliptin affected hepatic insulin clearance (HIC) levels according to HIC baseline levels. Anagliptin reduced HIC in the relatively higher HIC group (baseline HIC ≥median). Anagliptin increased HIC in the relatively lower HIC group (baseline HIC

Background To determine the impact of metabolic syndrome (MetS) and/or metabolic dysfunction-associated fatty liver disease (MAFLD), which are pathophysiologically similar and include insulin resistance, on the development of new-onset cardiovascular disease with and without type 2 diabetes and according to sex. Methods This study included 570,426 individuals without a history of cardiovascular disease who were enrolled in a nationwide claims database from 2008 to 2016 and were classified by the presence or absence of MetS and/or MAFLD stratified by the presence or absence of type 2 diabetes and sex. The fatty liver index was used to determine the presence or absence of fatty liver that required a diagnosis of MAFLD. Risks of developing coronary artery disease (CAD) and cerebrovascular disease (CVD) in each category were analyzed using a multivariate Cox proportional hazard model. Results During a median follow-up of 5.2 years, 2252 CAD and 3128 CVD events occurred. Without type 2 diabetes the hazard ratio (HR) (95% CI) for CAD/CVD compared with neither MAFLD nor MetS was 1.32 (1.17–1.50)/1.41(1.28–1.57) for MAFLD only (without MetS), 1.78 (1.22–2.58)/1.66 (1.34–2.06) for MetS only (without MAFLD), and 2.10 (1.84–2.39)/1.73 (1.54–1.95) for MAFLD + MetS. For those with type 2 diabetes, the HR for CAD for MAFLD only (compared with neither MAFLD nor MetS) was 1.29 (1.06–1.58), for MetS only 1.34 (0.84–2.13), and for MAFLD + MetS 1.22 (1.02–1.47). For CVD, there was a significant increase in HR only in MAFLD + MetS [1.44 (1.18–1.76)]. The results of the analysis stratified by sex showed that MAFLD had a greater impact in men, and MetS had a greater impact in women regarding the development of CAD. Conclusions Distinguishing between MetS and/or MAFLD in the presence or absence of type 2 diabetes and according to sex may aid in accurately identifying patients at high risk of cardiovascular disease.

BackgroundThe prevalence of diabetes is rising, and diabetes develops at a younger age in East Asia. Although lower limb amputation negatively affects quality of life and increases the risk of cardiovascular events, little is known about the rates and predictors of amputation among persons with diabetes from young adults to those in the “young-old” category (50–72 y).MethodsWe analyzed data from a nationwide claims database in Japan accumulated from 2008 to 2016 involving 17,288 people with diabetes aged 18–72 y (mean age 50.2 y, HbA1c 7.2%). Amputation occurrence was determined according to information from the claims database. Cox regression model identified variables related to lower limb amputation.ResultsThe mean follow-up time was 5.3 years, during which time 16 amputations occurred (0.17/1000 person-years). Multivariate Cox regression analysis showed that age (hazard ratio [HR] 1.09 [95% confidence intervals] 1.02–1.16,p = 0.01) and HbA1c (HR 1.46 [1.17–1.81],p ConclusionsAge and HbA1c were associated with amputations among diabetic individuals, and the rates of amputation were significantly greater in those ≥60 years old and with HbA1c ≥8.0%.

Aim To compare the long‐term efficacy of sodium‐glucose co‐transporter‐2 inhibitors and dipeptidyl peptidase‐4 inhibitors as second‐line drugs after metformin for patients not at high risk of atherosclerotic cardiovascular disease (ASCVD). Materials and methods In a 52‐week randomized open‐label trial, we compared ipragliflozin and sitagliptin in Japanese patients diagnosed with type 2 diabetes, without prior ASCVD and treated with metformin. The primary endpoint was a glycated haemoglobin (HbA1c) reduction of ≥0.5% (5.5 mmol/mol) without weight gain at 52 weeks. Results Of a total of 111 patients (mean age 59.2 years, mean body mass index [BMI] 26.6 kg/m2, 61.3% men), 54 patients received ipragliflozin and 57 received sitagliptin. After 52 weeks, achievement of the primary endpoint was not significantly different (37.0% and 40.3%; P = 0.72). HbA1c reduction rate at 24 weeks was greater for sitagliptin (56.1%) than for ipragliflozin (31.5%; P = 0.01). From 24 to 52 weeks, the HbA1c reduction with sitagliptin was attenuated, with no significant difference in HbA1c reduction after 52 weeks between sitagliptin (54.4%) and ipragliflozin (38.9%; P = 0.10). Improvements in BMI, C‐peptide and high‐density lipoprotein cholesterol were greater with ipragliflozin than with sitagliptin. Adverse events occurred in 17 patients with ipragliflozin and in 10 patients with sitagliptin (P = 0.11). Conclusion The HbA1c‐lowering effect at 24 weeks was greater with sitagliptin than with ipragliflozin, but with no difference in efficacy related to HbA1c and body weight at 52 weeks. However, some ASCVD risk factors improved with ipragliflozin.

Aims Little is known about the relationship between medication adherence for oral hypoglycemic agents (OHAs) and glycemic control after adjusting healthy adherer effect in large scale study. Thus, adjusting for health-related behaviors, we investigated the clinical variables associated with medication adherence and the relationship between medication adherence and glycemic control using a large claims database. Methods Analyzed were 8805 patients with diabetes whose medication records for OHA were available for at least 1 year. Medication adherence was evaluated by the proportion of days covered (PDC). Multivariate logistic regression model was used to identify clinical variables significantly associated with non-adherence. Multiple regression analysis evaluated the relationship between PDC and HbA1c after adjusting for health-related behaviors. Results Mean PDC was 80.1% and 32.8% of patients were non-adherence. Logistic analysis indicated that older age and taking concomitant medications were significantly associated with adherence while skipping breakfast (odds ratio 0.66 [95% CI 0.57–0.76]), late-night eating (0.86 [0.75–0.98]), and current smoking (0.89 [0.80–0.99]) were significantly associated with non-adherence. Conclusions Skipping breakfast, late-night eating and current smoking were significantly associated with medication adherence, suggesting that clinicians pay attention to those health-related behaviors to achieve good medication adherence.

Background: To examine the association between muscular and performance fitness (MPF) and the incidence of glaucoma. Methods: A total of 27,051 glaucoma-free participants aged 20–87 years underwent physical fitness tests between April 2001 and March 2002. The MPF index was calculated using an age- and sex-specific summed z-score from grip strength, vertical jump, single-leg balance, forward bending, and whole-body reaction time. The participants were divided into quartiles according to the MPF index and each physical fitness test. Participants were followed up for the development of glaucoma, which was defined based on physician-diagnosed glaucoma at an annual health examination between April 2002 and March 2008. Hazard ratios for the incidence of glaucoma were estimated using Cox proportional hazards models. Results: During follow-up, 303 participants developed glaucoma. Compared with the lowest MPF index group, hazard ratio (95% confidence interval) of developing glaucoma was 0.64 (0.46–0.89) for the highest MPF index group (P for trend = .001). Vertical jump and whole-body reaction time were associated with incident glaucoma (P for trend = .01 and Conclusion: Higher MPF is associated with lower incidence of glaucoma.

ObjectivesIt has been hypothesised that smoking intensity may be related to occupational stress. This study aimed to investigate whether stress, including problems with superiors or co-workers, is a driver of smoking.DesignCross-sectional study.Setting and participants59 355 employees (34 865 men and 24 490 women) across multiple occupations who completed a self-reported questionnaire-based occupational stress survey between April 2016 and March 2017 in Niigata Prefecture.Main outcome measuresStress scores for the Brief Job Stress Questionnaire subscales summed up after assigning high points for high stress and converted to Z-scores based on the mean of all participants. Heavy smokers (HS) smoked ≥15 cigarettes/day and light smokers (LS) smoked ResultsThe main subscale items that were significantly associated with smoking status in both genders included ‘physical burden’, ‘irritation’ and ‘physical symptoms’. In the analysis that included smoking intensity, the stress score for ‘co-workers’ support’ was significantly lower for LS men than NS men (NS 0.091±0.98, LS −0.027±1.00, HS 0.033±0.99), and was significantly higher for HS women than NS women (NS −0.091±1.00, LS −0.080±1.05, HS 0.079±1.03). However, the stress score for ‘co-workers’ support’ was low among LS women aged ≤39 years in the manufacturing industry.ConclusionsIt was speculated that LS men and some LS women gained ‘co-workers’ support’ using smoking as a communication tool while reducing the degree of smoking. The existence of such ‘social smokers’ suggested that to promote smoking cessation, measures are essential to improve the communication between workers in addition to implementing smoking restrictions in the workplace.

This network meta-analysis aimed to assess the current efficacy of decreasing the uric acid (UA) level with drugs to reduce mortality in patients with heart failure (HF). Electronic literature searches using EMBASE and MEDLINE of studies published from 1 Jan 1950 to 26 Dec 2019 were conducted for randomized controlled trials or non-randomized cohort studies that included at least one group of patients who took UA-lowering drugs and with a study outcome of all-cause mortality. A random-effects network meta-analysis was performed within a frequentist framework. Hierarchy of treatments was expressed as the surface under the cumulative ranking curve (SUCRA) value, which is in proportion to mean rank (best is 100%). Nine studies, which included seven different types of groups, were eligible for analysis. The “untreated uricemia” group in which patients had hyperuricemia but without treatment had a significantly higher risk of mortality than the “no uricemia” group in which patients had no hyperuricemia (relative risk (RR)(95% confidence interval (CI), 1.43 (1.08–1.89)). The “start-allo” group wherein patients started to take allopurinol did not have a significantly lower risk of mortality than the “untreated uricemia” group (RR (95% CI), 0.68 (0.45–1.01)). However, in the “start-allo” group the SUCRA value was comparable to that in the “no uricemia” group (SUCRA: 65.4% for “start-allo”; 64.1% for “no uricemia”). Results suggested that allopurinol therapy was not associated with a significantly improved prognosis in terms of mortality but could potentially counteract the adverse effects associated with longstanding hyperuricemia in HF patients.

Despite mounting evidence of the positive relationship between diabetes mellitus (DM) and heart failure (HF), the entire context of the magnitude of risk for HF in relation to DM remains insufficiently understood. The principal reason is because new‐onset HF (HF occurring in participants without a history of HF) and recurrent HF (HF re‐occurring in patients with a history of HF) are not discriminated. This meta‐analysis aims to comprehensively and separately assess the risk of new‐onset and recurrent HF depending on the presence or absence of DM. We systematically searched cohort studies that examined the relationship between DM and new‐onset or recurrent HF using EMBASE and MEDLINE (from 1 Jan 1950 to 28 Jul 2019). The risk ratio (RR) for HF in individuals with DM compared with those without DM was pooled with a random‐effects model. Seventy‐four and 38 eligible studies presented data on RRs for new‐onset and recurrent HF, respectively. For new‐onset HF, the pooled RR [95% confidence interval (CI)] of 69 studies that examined HF as a whole [i.e. combining HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF)] was 2.14 (1.96–2.34). The large between‐study heterogeneity (I2 = 99.7%, P

Aims Obesity and hepatic fat accumulation diminish hepatic insulin clearance, which can cause hyperinsulinaemia. Sodium/glucose‐cotransporter 2 inhibitors (SGLT2‐is) improve insulin resistance and hyperinsulinaemia by weight loss via increased urinary glucose excretion in type 2 diabetes. However, there are few reports of the influence of SGLT2‐is on hepatic insulin clearance. We examined the impact of an SGLT2‐i on hepatic insulin clearance and explored the clinical influence associated with changes in hepatic insulin clearance via an SGLT2‐i and the mechanism of the effects of SGLT2‐i. Materials and methods Data were analysed from 419 patients with type 2 diabetes controlled by diet and exercise. Patients received a placebo or the SGLT2‐i tofogliflozin (TOFO) (placebo: n = 56; TOFO: n = 363) orally once daily for ≥24 weeks. Hepatic insulin clearance was calculated from the ratio of areas under the curve (AUC) of C‐peptide and insulin levels derived from oral meal tolerance test data (C‐peptide AUC0‐120 min/insulin AUC0‐120 min: HICCIR). The correlation of HICCIR via the SGLT2‐i with other clinical variables was analysed using multivariate analysis. Results HICCIR was significantly increased via TOFO at week 24. Furthermore, with TOFO insulin and triglyceride (TG) levels were significantly reduced (P

Recently, an increasing number of cohort studies have suggested using machine learning (ML) to predict type 2 diabetes mellitus. However, its predictive ability remains inconclusive. This meta-analysis evaluated the current ability of ML algorithms for predicting incident type 2 diabetes mellitus.We systematically searched longitudinal studies published from 1 January 1950 to 17 May 2020 using MEDLINE and EMBASE. Included studies had to compare ML's classification with the actual incidence of type 2 diabetes mellitus, and present data on the number of true positives, false positives, true negatives and false negatives. The dataset for these four values was pooled with a hierarchical summary receiver operating characteristic and a bivariate random effects model.There were 12 eligible studies. The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 0.81 (95% confidence interval [CI] 0.67-0.90), 0.82 [95% CI 0.74-0.88], 4.55 [95% CI 3.07-6.75] and 0.23 [95% CI 0.13-0.42], respectively. The area under the summarized receiver operating characteristic curve was 0.88 (95% CI 0.85-0.91).Current ML algorithms have sufficient ability to help clinicians determine whether individuals will develop type 2 diabetes mellitus in the future. However, persons should be cautious before changing their attitude toward future diabetes risk after learning the result of the diabetes prediction test using ML algorithms.

Previous cohort study reported that high physical activity was associated with a low risk of self-reported hearing loss in women. However, no studies have examined the association between physical activity and the development of hearing loss as measured using an objective assessment of hearing loss in men and women. Here, we used cohort data to examine the association between leisure-time physical activity and incidence of objectively assessed hearing loss in men and women. Participants included 27 537 Japanese adults aged 20-80 years without hearing loss, who completed a self-administered physical activity questionnaire between April 2001 and March 2002. The participants were followed up for the development of hearing loss as measured by audiometry between April 2002 and March 2008. During follow-up, 3691 participants developed hearing loss. Compared with the none physical activity group, multivariable adjusted hazard ratios (HRs) for developing hearing loss were 0.93 (95% confidence interval (CI), 0.86-1.01) and 0.87 (0.81-0.95) for the medium (

It is unclear whether genetic interactions are involved in the association between vegetable intake and reduced body mass index (BMI) or obesity. We conducted a comprehensive search for single nucleotide polymorphisms (SNPs) which are associated with the interaction between vegetable intake frequency and BMI or obesity. We performed a genome-wide association analysis to evaluate the genetic interactions between self-reported intake of vegetables such as carrot, broccoli, spinach, other green vegetables (green pepper and green beans), pumpkin, and cabbage with BMI and obesity, which is defined as a BMI ≥ 25.0 kg/m2 in the Japanese population (n = 12,225). The mean BMI and prevalence of obesity was 23.9 ± 3.4 kg/m2 and 32.3% in men and 22.1 ± 3.8 kg/m2 and 17.3% in in women, respectively. A significant interaction was observed between rs4445711 and frequency of carrot intake on BMI (p = 4.5 × 10−8). This interaction was slightly attenuated after adjustment for age, sex, alcohol intake, smoking, physical activity and the frequency of total vegetable intake (p = 2.1 × 10−7). A significant interaction was also observed between rs4445711 and frequency of carrot intake on obesity (p = 2.5 × 10−8). No significant interactions that were the same as the interaction between frequency of carrot intake and rs4445711 were observed between the intake frequency of broccoli, spinach, other green vegetables, pumpkin or cabbage and BMI or obesity. The frequency of carrot consumption is implicated in reducing BMI by the intermediary of rs4445711. This novel genetic association may provide new clues to clarify the association between vegetable intake and BMI or obesity.

Background Although both a history of cerebrovascular disease (CVD) and glucose abnormality are risk factors for CVD, few large studies have examined their association with subsequent CVD in the same cohort. Thus, we compared the impact of prior CVD, glucose status, and their combinations on subsequent CVD using real-world data. Methods This is a retrospective cohort study including 363,627 men aged 18–72 years followed for ≥ 3 years between 2008 and 2016. Participants were classified as normoglycemia, borderline glycemia, or diabetes defined by fasting plasma glucose, HbA1c, and antidiabetic drug prescription. Prior and subsequent CVD (i.e. ischemic stroke, transient ischemic attack, and non-traumatic intracerebral hemorrhage) were identified according to claims using ICD-10 codes, medical procedures, and questionnaires. Results Participants’ mean age was 46.1 ± 9.3, and median follow up was 5.2 (4.2, 6.7) years. Cox regression analysis showed that prior CVD + conferred excess risk for CVD regardless of glucose status (normoglycemia: hazard ratio (HR), 8.77; 95% CI 6.96–11.05; borderline glycemia: HR, 7.40, 95% CI 5.97–9.17; diabetes: HR, 5.73, 95% CI 4.52–7.25). Compared with normoglycemia, borderline glycemia did not influence risk of CVD, whereas diabetes affected subsequent CVD in those with CVD- (HR, 1.50, 95% CI 1.34–1.68). In CVD-/diabetes, age, current smoking, systolic blood pressure, high-density lipoprotein cholesterol, and HbA1c were associated with risk of CVD, but only systolic blood pressure was related to CVD risk in CVD + /diabetes. Conclusions Prior CVD had a greater impact on the risk of CVD than glucose tolerance and glycemic control. In participants with diabetes and prior CVD, systolic blood pressure was a stronger risk factor than HbA1c. Individualized treatment strategies should consider glucose tolerance status and prior CVD.

Our purpose in the research was to clarify the impact of medication adherence to oral hypoglycemic agents during a 1-year period and subsequent glycemic control on the risk of micro- and macrovascular diseases.Examined was a nationwide claims database on 13,256 individuals with diabetic eye disease without requiring prior treatment, 7,862 without prior initiation of dialysis, 15,556 without prior coronary artery disease, 16,243 without prior cerebrovascular disease, and 19,386 without prior heart failure from 2008 to 2016 in Japan. Medication adherence was evaluated by the proportion of days covered. Patients were considered to have poor adherence if the proportion of days covered was80%. Multivariate Cox regression model identified risks of micro- and macrovascular diseases.In each group, mean age was 53 to 54 years, HbA1c was 7.1% to 7.2%, and median follow-up period was 4.6 to 5.1 years, and the percentage of poor adherence was approximately 30%. During the study period, 532 treatment-requiring diabetic eye disease, 75 dialysis, 389 coronary artery disease, 316 cerebrovascular disease, and 144 heart failure events occurred. Multivariate Cox regression model revealed that the hazard ratio (95% confidence interval) of dialysis in the poor adherence group was 2.04 (1.27-3.30) compared with the good adherence group. The hazard ratios in the poor adherence/poor glycemic control group were 3.34 (2.63-4.24) for treatment-requiring diabetic eye disease, 4.23 (2.17-8.26) for dialysis, 1.69 (1.23-2.31) for coronary artery disease, and 2.08 (1.25-3.48) for heart failure compared with the good adherence/good glycemic control group.Poor medication adherence was an independent risk factor for the initiation of dialysis, suggesting that clinicians must pay close attention to these patients.

Although vitamin B6 has been suspected to prevent the progression of diabetic retinopathy, evidence of this in patients with type 2 diabetes based on longitudinal studies is sparse. This study investigated the relationship between vitamin B6 intake and the incidence of diabetic retinopathy in Japanese patients with type 2 diabetes. The study was part of an examination of a nationwide cohort of patients with type 2 diabetes aged 40–70 years with HbA1c ≥ 48 mmol/mol. After excluding nonresponders to a dietary survey using the Food Frequency Questionnaire based on food groups, 978 patients were analyzed. Primary outcome was the 8-year risk of a diabetic retinopathy event, and Cox regression analyses estimated hazard ratios (HRs) for retinopathy according to vitamin B6 intake adjusted for age, gender, body mass index, HbA1c, smoking, energy intake, and other confounders. Mean vitamin B6 intake in quartiles ranged from 1.1 to 1.6 mg/day, and half of the participants had vitamin B6 intake below the recommended daily dietary allowance according to dietary reference intakes in Japanese adults (men 1.4 mg/day; women 1.2 mg/day). After adjusting for confounders, HRs for diabetic retinopathy in the 2nd, 3rd, and 4th quartile groups of vitamin B6 intake compared with the 1st quartile group were 1.17 (95% confidence interval 0.81–1.69, p = 0.403), 0.88 (0.58–1.34, p = 0.550), and 0.50 (0.30–0.85, p = 0.010), respectively. Findings suggested that high vitamin B6 intake was associated with a lower incidence of diabetic retinopathy in Japanese with type 2 diabetes.

Purpose To determine the degree of control of multiple risk factors under real-world conditions for coronary artery disease (CAD) according to the presence or absence of diabetes mellitus (DM) and to determine whether reaching multifactorial targets for blood pressure (BP), low-density lipoprotein-cholesterol (LDL-C), HbA1c, and current smoking is associated with lower risks for CAD. Methods We investigated the effects on subsequent CAD of the number of controlled risk factors among BP, LDL-C, HbA1c, and current smoking in a prospective cohort study using a nationwide claims database of 220,894 individuals in Japan. Cox regression examined risks over a 4.8-year follow-up. Results The largest percentage of participants had two risk factors at target in patients with DM (39.6%) and subjects without DM (36.4%). Compared with those who had two targets achieved, the risks of CAD among those who had any one and no target achieved were two and four times greater, respectively, regardless of the presence of DM. The effect of composite control was sufficient to bring CAD risk in patients with DM below that for subjects without DM with any two targets achieved, whereas the risk of CAD in the DM group with all four risk factors uncontrolled was 9.4 times more than in the non-DM group who had achieved two targets. Conclusions These findings show that composite control of modifiable risk factors has a large effect in patients with and without DM. The effect was sufficient to bring CAD risk in patients with DM below that in the non-DM group who had two targets achieved.

Background: Simple physical fitness test can be a useful potential predictor of type 2 diabetes (T2DM). We examined the association between performances on simple physical fitness tests and the incidence of T2DM. Methods: This longitudinal study was conducted in 21,802 nondiabetic Japanese (6,649 women) aged 20 to 92 years, who underwent all physical fitness tests at baseline (April 2001 to March 2002). From April 2001 to March 2008, physical fitness tests, including grip strength, vertical jump, single-leg balance with eyes closed, forward bending, whole-body reaction time, and supine legs-up, were performed every year. Participants had physical fitness tests at least two times during the period. T2DM was also annually determined based on fasting blood glucose, glycated hemoglobin, and self-reported diabetes during the period. Discrete-time logit models were used to examine the influence of the serial level of each physical fitness test on the incidence of T2DM. Results: During the entire study period, 972 participants developed diabetes. Lower relative grip strength (grip strength/body weight) and single-leg balance performance were associated with a higher incidence of T2DM. For relative grip strength, as compared with the fourth quartile group, the odds ratios for other groups ranged from 1.16 to 1.56 (P for trend < 0.001). For single-leg balance, the odds ratios ranged from 1.03 to 1.49 (P for trend < 0.001). Conclusion: The performance of a simple single-leg balance test as well as that of a grip strength test were negatively associated with the risk of T2DM among Japanese.

Context Although calorie loss from increased urinary glucose excretion continues after long-term treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2is), the mechanisms of the attenuated weight loss due to SGLT2is are not well known. Objective To examine the mechanism of the attenuated weight loss during long-term treatment with an SGLT2i, tofogliflozin, focusing on the antilipolytic effect of insulin on adipose tissue. Design and Participants An integrated analysis was performed using data from two phase 3 studies of 52 weeks of tofogliflozin administration. The antilipolytic effect was evaluated using adipose tissue insulin resistance (Adipo-IR) calculated from the product of the levels of fasting insulin (f-IRI) and fasting free fatty acids (f-FFAs). Results Data from 774 patients with type 2 diabetes (mean age, 58.5 years; glycosylated hemoglobin, 8.1%; body mass index, 25.6 kg/m2; estimated glomerular filtration rate, 83.9 mL/min/1.73m2; 66% men) were analyzed. Weight loss plateaued between weeks 24 and 52 after decreasing significantly. f-IRI levels decreased significantly from baseline to week 24, and the decrease was maintained until Week 52. f-FFA levels significantly increased, peaked at week 24, then declined from weeks 24 to 52. Adipo-IR levels declined progressively throughout the 52 weeks (−3.6 mmol/L·pmol/L and −6.2 mmol/L·pmol/L at weeks 24 and 52, respectively; P < 0.001 baseline vs weeks 24 and 52 and week 24 vs week 52). Higher baseline Adipo-IR levels were independently associated with greater weight loss at week 52. Conclusion The improved antilipolytic effect in adipose tissue may attenuate progressive lipolysis, leading to attenuating future weight loss induced by an SGLT2i in patients with type 2 diabetes.

Background: We investigated the association between various food groups and obesity in Japanese patients with type 2 diabetes. Methods: 2070 patients with type 2 diabetes who attended 26 diabetes clinics throughout Japan were analyzed and were divided into obese and non-obese groups. Intakes of food groups determined by a food frequency questionnaire were compared. Odds ratios for obesity for quartiles of individual food groups were calculated using a logistic regression model. Results: Non-obese patients consumed a larger variety of food groups than obese patients, with the diets of non-obese individuals closer to the traditional Japanese diet characterized by fish, seaweed, and soybeans/soy products. Among 21 food groups, low vegetable intake and high sweets intake were the most strongly associated with obesity in both men and women. Low intake of both fruits and vegetables and the combination of high intake of sweets and low intake of fruits were associated with obesity. Conclusions: Food groups and their combinations that were strongly associated with obesity in Japanese patients with type 2 diabetes were identified. Our findings also suggested an inverse association between the traditional Japanese diet and obesity.

This study investigates the associations between sodium intake and diabetes complications in a nationwide cohort of elderly Japanese patients with type 2 diabetes aged 65–85. Data from 912 individuals regarding their dietary intake at baseline is analyzed and assessed by the Food Frequency Questionnaire based on food groups. Primary outcomes are times to diabetic retinopathy, overt nephropathy, cardiovascular disease (CVD), and all-cause mortality during six years. We find that mean sodium intake in quartiles ranges from 2.5 g to 5.9 g/day. After adjustment for confounders, no significant associations are observed between sodium intake quartiles and incidence of diabetes complications and mortality, except for a significant trend for an increased risk of diabetic retinopathy (p = 0.039). Among patients whose vegetable intake was less than the average of 268.7 g, hazard ratios (HRs) for diabetic retinopathy in patients in the second, third, and fourth quartiles of sodium intake compared with the first quartile were 0.87 (95% CI, 0.31–2.41), 2.61 (1.00–6.83), and 3.70 (1.37–10.02), respectively. Findings indicate that high sodium intake under conditions of low vegetable intake is associated with an elevated incidence of diabetic retinopathy in elderly patients with type 2 diabetes.

Purpose To evaluate the accuracy of various claims-based definitions of diabetes-related complications (coronary artery disease [CAD], heart failure, cerebrovascular disease and dialysis). Methods We evaluated data on 1379 inpatients who received care at the Niigata University Medical & Dental Hospital in September 2018. Manual electronic medical chart reviews were conducted for all patients with regard to diabetes-related complications and were used as the gold standard. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each claims-based definition associated with diabetes-related complications based on Diagnosis Procedure Combination (DPC), International Classification of Diseases, Tenth Revision (ICD-10) codes, procedure codes and medication codes were calculated. Results DPC-based definitions had higher sensitivity, specificity, and PPV than ICD-10 code definitions for CAD and cerebrovascular disease, with sensitivity of 0.963-1.000 and 0.905-0.952, specificity of 1.000 and 1.000, and PPV of 1.000 and 1.000, respectively. Sensitivity, specificity, and PPV were high using procedure codes for CAD and dialysis, with sensitivity of 0.963 and 1.000, specificity of 1.000 and 1.000, and PPV of 1.000 and 1.000, respectively. DPC and/or ICD-10 codes + medication were better for heart failure than the ICD-10 code definition, with sensitivity of 0.933, specificity of 1.000, and PPV of 1.000. The PPVs were lower than 60% for all diabetes-related complications using ICD-10 codes only. Conclusion The DPC-based definitions for CAD and cerebrovascular disease, procedure codes for CAD and dialysis, and DPC or ICD-10 codes with medication codes for heart failure could accurately identify these diabetes-related complications from claims databases.

Pediatric obesity is associated with clustered cardiometabolic risk and the future incidence of cardiovascular disease. However, few studies have determined the effect of pediatric obesity in Asia, where obesity is less common than in Western countries. We aimed to clarify whether weight status including underweight and slightly overweight is associated with metabolic risk factors in Japanese adolescents.We performed a cross-sectional analysis of 2241 adolescents aged 13-14 years. Participants were classified as underweight, normal weight, slightly overweight, overweight, or obese according to the International Obesity Task Force. The clustered cardiometabolic risk (Z-CMR) was estimated by summing standardized sex-specific Z scores of mean arterial pressure (MAP), non-high-density lipoprotein cholesterol (non-HDLC), and HbA1c.Linear regression analysis showed that MAP, non-HDL-C, and Z-CMR were higher in the slightly overweight, overweight, and obese groups than in the normal weight group after adjusting for confounders. Compared with the normal weight group, the slightly overweight, overweight, and obese groups had higher prevalence of high BP [odds ratios (ORs): 1.38 (95% CI, 1.03, 1.85); 2.63 (1.77, 3.91); and 2.39 (1.57, 3.64), respectively]. Compared with the normal weight group, underweight boys, but not girls, had a lower prevalence of high Z-CMR [OR=0.20 (0.05, 0.84)].Adolescents classified as slightly overweight had higher levels of BP, serum lipids, and clustered cardiometabolic risk than those classified as normal weight. This observation showed significant associations between weight status and cardiometabolic risk factors during adolescence even in East Asians.

To determine associations between severity of hypertension and risk of starting dialysis in the presence or absence of diabetes mellitus (DM). A nationwide database with claims data on 258 874 people with and without DM aged 19-72 years in Japan was used to elucidate the impact of severity of hypertension on starting dialysis. Initiation of dialysis was determined from claims using International Classification of Diseases-10 codes and medical procedures. Using multivariate Cox modeling, we investigated the severity of hypertension to predict the initiation of dialysis with and without DM. Hypertension was significantly associated with the initiation of dialysis regardless of DM. The incidence of starting dialysis in those with systolic blood pressure (SBP) ≤119 mm Hg and DM (DM+) was almost the same as in those with SBP ≥150 mm Hg and absence of DM (DM−). In comparison with SBP ≤119 mm Hg, SBP ≥150 mm Hg significantly increased the risk of the initiation of dialysis about 2.5 times regardless of DM+ or DM−. Compared with DM− and SBP ≤119 mm Hg, the HR for DM+ and SBP ≥150 mm Hg was 6.88 (95% CI 3.66 to 12.9). Although the risks of hypertension differed only slightly regardless of the presence or absence of DM, risks for starting dialysis with DM+ and SBP ≤119 mm Hg were equivalent to DM− and SBP ≥150 mm Hg, indicating more strict blood pressure interventions in DM+ are needed to avoid dialysis. Future studies are required to clarify the cut-off SBP level to avoid initiation of dialysis considering the risks of strict control of blood pressure.

OBJECTIVE To determine associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with new-onset coronary artery disease (CAD) or cerebrovascular disease (CVD) according to glucose status. RESEARCH DESIGN AND METHODS Examined was a nationwide claims database from 2008 to 2016 on 593,196 individuals. A Cox proportional hazards model identified risks of CAD and CVD events among five levels of SBP and DBP. RESULTS During the study period 2,240 CAD and 3,207 CVD events occurred. Compared with SBP ≤119 mmHg, which was the lowest quintile of SBP, hazard ratios (95% CI) for CAD/CVD in the 4 higher quintiles (120–129, 130–139, 140–149, ≥150 mmHg) gradually increased from 2.10 (1.73–2.56)/1.46 (1.27–1.68) in quintile 2 to 3.21 (2.37–4.34)/4.76 (3.94–5.75) in quintile 5 for normoglycemia, from 1.39 (1.14–1.69)/1.70 (1.44–2.01) in quintile 2 to 2.52 (1.95–3.26)/4.12 (3.38–5.02) in quintile 5 for borderline glycemia, and from 1.50 (1.19–1.90)/1.72 (1.31–2.26) in quintile 2 to 2.52 (1.95–3.26)/3.54 (2.66–4.70) in quintile 5 for diabetes. A similar trend was observed for DBP across 4 quintiles (75–79, 80–84, 85–89, and ≥90 mmHg) compared with ≥74 mmHg, which was the lowest quintile. CONCLUSIONS Results indicated that cardiovascular risks gradually increased with increases in SBP and DBP regardless of the presence of and degree of a glucose abnormality. Further interventional trials are required to apply findings from this cohort study to clinical practice.

The aim of this study was to investigate the association between habitual dietary intake for patients with diabetes and the content of family support for medical nutritional therapy (MNT). Analyzed were 289 Japanese with type 2 diabetes (men, 58.5%, mean age, 62.0 years, mean HbA1c, 53.4 mmol/mol) who completed the Food Frequency Questionnaire and Diabetes Family Behavior Checklist (DFBC). Relationships of mean values for food group intake to DFBC responses regarding MNT were examined using multivariate analysis of covariance. Positive response to &ldquo, Praise for following diet&rdquo, was associated with lower sweets intake (none: 60.1 g/day, &ge, once monthly: 50.9 g/day, p = 0.038) and higher seasoning intake (none: 21.6 g/day, &ge, once monthly: 24.1 g/day, p = 0.046). Energy intake was higher with positive responses to &ldquo, Eat at the same time that you do&rdquo, (none: 1636 kcal/day, &ge, once monthly: 1818 kcal/day, p = 0.038). &ldquo, Nags about not following diet&rdquo, was associated with higher fish (none: 68.7 g/day, &ge, once monthly: 78.7 g/day, p = 0.042) and salt intake (none: 8.3 g/day, &ge, once monthly: 9.0 g/day, p = 0.014). Eating foods not part of the diabetic diet (none: 218.4 g/day, &ge, once monthly: 246.9 g/day, p = 0.014) resulted in a higher vegetable intake. In females, significant differences in relationships in the overall analysis were reversed. Our results clarified relationships between types of family support of patients with type 2 diabetes and their dietary intake and the importance of sex differences for more effective MNT.

The aim of this study was to investigate the association between protein intake and mortality risk in patients with type 2 diabetes. We analyzed a pooled data of 2494 diabetic patients from two prospective longitudinal studies. Nutritional intake was assessed using a Food Frequency Questionnaire at baseline. Protein intake per body weight (kg) per day was categorized into quartile groups. Adjusted hazard ratios (HRs) and 95% confidence interval (CI) were calculated using Cox regression analysis. During the six-year follow-up, there were 152 incidents of all-cause mortality. The HR for mortality in the lowest quartile of protein intake per body weight compared with the highest quartile was 2.26 (95% CI: 1.34&ndash, 3.82, p = 0.002) after adjustment for covariates. Subgroup analyses revealed significant associations between low protein intake and mortality in patients aged over 75 years or under 65 years. After further adjustment of the total energy intake, a significant association between protein intake and mortality remained in patients aged &ge, 75 years, whereas the association was attenuated in those aged &lt, 65 years. Our results suggest that adequate protein intake is necessary in older diabetic patients over 75 years, whereas with diabetes, whereas whole optimal total energy intake is required in younger patients with type 2 diabetes.

Background: Grip strength reflects systemic muscle strength and mass and is reportedly associated with various metabolic variables. However, its prognostic association with dyslipidemia is unknown. We examined the association of grip strength and other physical fitness markers with the incidence of dyslipidemia among Japanese adults. Methods: A total of 16,149 Japanese (6,208 women) individuals aged 20–92 years who underwent a physical fitness test between April 2001 and March 2002 were included in this cohort study. Grip strength, vertical jump, single-leg balance with eyes closed, forward bending, and whole-body reaction time were evaluated at baseline. Dyslipidemia was annually determined based on fasting serum lipid profiles and self-reported dyslipidemia from April 2001 to March 2008. Results: During the follow-up period, 4,458 (44.9%) men and 2,461 (39.6%) women developed dyslipidemia. A higher relative grip strength (grip strength/body mass index) was associated with a lower incidence of dyslipidemia among both men and women (P for trend

Background Several cross-sectional studies have linked higher physical fitness with better hearing sensitivity but have not established a causal relation; none have used a prospective design that is less susceptible to bias. We used a prospective cohort study to investigate the association between muscular and performance fitness and the incidence of hearing loss. Methods A total of 21,907 participants without hearing loss received physical fitness assessments between April 2001 and March 2002. Muscular and performance fitness index, an age- and sex-specific summed z-score based on grip strength, vertical jump height, single-leg balance, forward bending, and whole-body reaction time was calculated. Participants were classified into quartiles according to the muscular and performance fitness index and each physical fitness test. They were followed up for the development of hearing loss, assessed by pure-tone audiometry at annual health examinations between April 2002 and March 2008. Hazard ratios and 95% confidence intervals for hearing loss incidence were estimated using Cox proportional hazards regression models. Results During follow-up, 2765 participants developed hearing loss. The hazard ratios (95% confidence intervals) for developing hearing loss across the muscular and performance fitness index quartiles (lowest to highest) were 1.00 (reference), 0.88 (0.79-0.97), 0.83 (0.75-0.93), and 0.79 (0.71-0.88) (Ptrend Conclusion Higher muscular and performance fitness is associated with a lower incidence of hearing loss.

Aims To examine the effects of a sodium–glucose co‐transporter 2 (SGLT2) inhibitor, tofogliflozin, on resting heart rate by exploring baseline factors that independently influenced changes in the resting heart rate. Methods Data on 419 participants in tofogliflozin phase 2/3 trials were analysed. Changes in resting heart rate from baseline to week 24 were analysed using an analysis of covariance (ANCOVA) model with groups (tofogliflozin/placebo) as a fixed effect and baseline values as covariates. The antilipolytic effect was evaluated as adipose tissue insulin resistance (Adipo‐IR) and was calculated as the product of fasting insulin and free fatty acid. Multivariate analysis evaluated independent factors for changes in resting heart rate from baseline to week 24. Results Of the participants, 58% were men, and mean age, HbA1c, BMI and resting heart rate were 57.6 years, 65 mmol/mol (8.1%), 25.5 kg/m2 and 66 bpm, respectively. At week 24, adjusted mean difference vs. placebo in the change from baseline was −2.3 bpm [95% confidence interval (CI) −4.6, −0.1] with tofogliflozin. Changes in resting heart rate were positively correlated with changes in Adipo‐IR, whereas reductions in HbA1c, body weight and blood pressure were similar independent of changes in resting heart among quartiles of resting heart rate change. On multivariate analysis, higher baseline resting heart rates and Adipo‐IR values were significantly associated with greater reductions in resting heart rate. Conclusions Tofogliflozin corrected resting heart rate levels in accordance with baseline levels. Correction of high resting heart rates may be attributed to improved adipose tissue insulin resistance, leading to correction of hyperinsulinaemia., What’s new? A high resting heart rate is related to increased cardiovascular and microvascular risks in persons with type 2 diabetes.Tofogliflozin significantly reduced resting heart rate compared with placebo, irrespective of reductions in HbA1c, body weight and blood pressure.Reduction in resting heart rate was associated with improvements in adipose tissue insulin resistance.Higher baseline adipose tissue insulin resistance levels were independently associated with a greater decline in resting heart rate.Correcting the resting heart rate via improved adipose tissue insulin resistance by tofogliflozin treatment might contribute to lowering the risks of cardiovascular diseases.

A high level of physical fitness, especially cardiorespiratory fitness, is associated with lower incidence of hypertension. However, the relationship between flexibility, which is a component of physical fitness, and the incidence of hypertension is unknown. The purpose of this study was to investigate the relationship between flexibility and the incidence of hypertension in a cohort study. A total of 22,972 (14,805 men and 8167 women; median age 49 years) normotensive participants were included in this study. Between April 2001 and March 2002, flexibility (standing forward bending) was measured using a standing trunk flexion meter. The participants were divided into quartiles of flexibility by sex and age group. Hypertension was defined as systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, or a self-reported history of previously diagnosed hypertension or current medication for hypertension at a health examination between April 2002 and March 2008. Hazard ratios and 95% confidence intervals (95% CI) for the incidence of hypertension were estimated using Cox proportional hazards models after adjusting for age, sex, body mass index, exercise habits, smoking status, and drinking status. During 102,948 person years of follow-up (median 5.6 years), 4235 participants developed hypertension. Compared with the lowest flexibility (quartile 1), hazard ratios and 95% CI were 0.96 (0.88 - 1.04) for quartile 2, 0.94 (0.86 - 1.03) for quartile 3, and 0.83 (0.76 - 0.91) for quartile 4. A high level of flexibility was associated with lower incidence of hypertension, independent of other confounding factors.

We aimed to analyze the association between dietary iron intake and obesity assessed by BMI after adjustment for nutrient intake (macronutrients and fiber) and food groups. The study design was cross-sectional. Patients with type-2 diabetes (n = 1567; 63.1% males; mean age 62.3 ± 11.6 years) were included in the study. To assess diet, consumption of typical food groups was determined by a food frequency questionnaire. Obesity was defined as BMI ≥ 25 kg/m2. We performed a binary regression analysis between quartiles of iron intake and obesity by quartiles of age group. A direct linear association was found for the highest quartile of iron intake and obesity in the younger age group of 30 to 54 years (OR = 3.641, 95% CI = 1.020–12.990; p trend = 0.011). Multivariate analysis using food groups as opposed to nutrients revealed a positive trend for obesity in the younger age group after adjusting for lifestyle factors, energy intake and bean and vegetable intake (p trend = 0.023). In all participants, an inverse association was observed before adjustment by vegetable intake (OR = 0.453, 95% CI = 0.300–0.684; p trend = 0.001). Higher iron intake was associated with obesity independent of macronutrient and fiber intake but only in the youngest quartile of age group examined.

Summary Background & aims High intake of fruit and vegetables is recommended for cardiovascular health. However, there have been persistent beliefs that fruits having high concentrations of fructose elevate the level of triglycerides (TG) in blood unlike vegetables. This meta-analysis aims to clarify the relationship between fruit intake and TG or hypertriglyceridemia. Methods Electronic literature searches were conducted for observational studies that investigated the relationship between fruit intake and hypertriglyceridemia or intervention studies that investigated the effect of increasing fruit intake on TG. Each effect size was pooled with an inverse-variance method. Results Five cross-sectional studies and only 2 intervention studies were eligible. The pooled odds ratio (OR) (95% confidence interval (CI)) of the 5 cross-sectional studies for the highest vs. the lowest fruit intake category was 0.79 (0.72–0.87). In these studies, the pooled OR for the highest vs. the lowest vegetable intake category was not significant (OR = 0.92; 95% CI, (0.82–1.03)). A linear dose–response association was observed between increases in fruit intake and ORs for hypertriglyceridemia; the OR (95% CI) for an incrementally increased intake of fruit by 1 serving/day was 0.91 (0.84–0.98). Conclusion This meta-analysis suggests that high intake of fruit but not vegetables is inversely associated with hypertriglyceridemia. More trials are needed to clarify whether increasing fruit intake would reduce the level of TG and/or incident hypertriglyceridemia.

Background and aims Oxidized low-density lipoprotein (oxLDL) causes the development of atherosclerosis and kidney injury. Although circulating oxLDL levels were reportedly increased in type 2 diabetic patients with macroalbuminuria, it remains unclear whether albuminuria or the reduced glomerular filtration rate (GFR) is independently associated with the circulating oxLDL level. This study aimed to elucidate the association between the stage of diabetic nephropathy and serum malondialdehyde-modified LDL (MDA-LDL) and the ratio of MDA-LDL to LDL-cholesterol (MDA-LDL/LDL). Methods and results This retroactive cross-sectional study used data from 402 patients with type 2 diabetes. Patients undergoing hemodialysis were excluded. Serum MDA-LDL levels were significantly increased with increases in severity of albuminuria (103 ± 44 U/L, 109 ± 54 U/L, and 135 ± 72 U/L for normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively; P for trend = 0.020) but not according to the estimated GFR (eGFR). An increased MDA-LDL/LDL ratio was significantly associated with both increased albuminuria (35 ± 13, 37 ± 14, and 40 ± 15 for normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively; P for trend = 0.003) and reduced eGFR (34 ± 13, 36 ± 13, 38 ± 12, and 51 ± 28 for grade 1, 2, 3 and 4, respectively; P for trend = 0.002). Multiple linear regression analysis showed that neither the albumin excretion rate nor eGFR but ln-transformed triglycerides and LDL-C levels were independent determinants of both serum MDA-LDL levels and MDA-LDL/LDL ratios. Conclusion Serum MDA-LDL levels and MDA-LDL/LDL ratios were increased in those with dyslipidemia associated with diabetic kidney disease.

AIM Hepatic insulin clearance (HIC) is important in regulating plasma insulin levels. Diminished HIC causes inappropriate hyperinsulinaemia, and both obesity and fatty liver (FL), which are known to decrease HIC, can be found either together in the same patient or on their own. The mechanism by which obesity reduces HIC is presumed to be mediated by FL. However, few reports have examined the role of FL in the relationship between obesity and HIC in type 2 diabetes (T2D) patients. Therefore, our study investigated the association of HIC with clinical factors, including insulin sensitivity indices, focusing on the presence or absence of FL and obesity in T2D patients. METHOD Baseline data from 419 patients with T2D (279 men, 140 women; mean age: 57.6 years; body mass index: 25.5kg/m2) controlled by diet and exercise were analyzed. HIC was calculated from the ratio of fasting c-peptide to fasting insulin levels (HICCIR). Correlation analyses between HICCIR and clinical variables were performed using Pearson's product-moment correlation coefficients and single regression analysis in all participants and in those with obesity and FL either alone or in combination. RESULTS HICCIR was significantly correlated with whole-body insulin sensitivity indices and influenced by FL, but only in the FL group was obesity independently influenced HIC level. HICCIR decreased in those with both FL and obesity compared with those with only one such complication. CONCLUSION HICCIR may be used to evaluate whole-body insulin sensitivity in T2D. Also, compared with obesity, the influence of FL strongly contributed to a reduced HIC. TRIAL REGISTRATION NUMBER These trials were registered by the Japan Pharmaceutical Information Centre clinical trials information (JapicCTI) as 101349 and 101351.

Many epidemiological studies have assessed the genetic risk of having undiagnosed or of developing type 2 diabetes mellitus (T2DM) using several single nucleotide polymorphisms (SNPs) based on findings of genome-wide association studies (GWAS). However, the quantitative association of cumulative risk alleles (RAs) of such SNPs with T2DM risk has been unclear. The aim of this meta-analysis is to review the strength of the association between cumulative RAs and T2DM risk. Systematic literature searches were conducted for cross-sectional or longitudinal studies that examined odds ratios (ORs) for T2DM in relation to genetic profiles. Logarithm of the estimated OR (log OR) of T2DM for 1 increment in RAs carried (1-ΔRA) in each study was pooled using a random-effects model. There were 46 eligible studies that included 74,880 cases among 249,365 participants. In 32 studies with a cross-sectional design, the pooled OR for T2DM morbidity for 1-ΔRA was 1.16 (95% confidence interval [CI], 1.13–1.19). In 15 studies that had a longitudinal design, the OR for incident T2DM was 1.10 (95% CI, 1.08–1.13). There was large heterogeneity in the magnitude of log OR (P < 0.001 for both cross-sectional studies and longitudinal studies). The top 10 commonly used genes significantly explained the variance in the log OR (P = 0.04 for cross-sectional studies; P = 0.006 for longitudinal studies). The current meta-analysis indicated that carrying 1-ΔRA in T2DM-associated SNPs was associated with a modest risk of prevalent or incident T2DM, although the heterogeneity in the used genes among studies requires us to interpret the results with caution.

Objective This study aimed to examine the impact of obesity, as defined by body mass index (BMI), and a metabolically unhealthy phenotype on the development of coronary artery disease (CAD) according to glucose tolerance status. Methods This population-based retrospective cohort study included 123,746 Japanese men aged 18–72years (normal glucose tolerance: 72,047; prediabetes: 39,633; diabetes: 12,066). Obesity was defined as a BMI≥25kg/m 2 . Metabolically unhealthy individuals were defined as those with one or more of the following conditions: hypertension, hypertriglyceridaemia and/or low HDL cholesterol. A Cox proportional hazards regression model identified variables related to CAD incidence. Results The prevalences of obese subjects with normal glucose tolerance, prediabetes and diabetes were 21%, 34% and 53%, whereas those for metabolically unhealthy people were 43%, 60% and 79%, respectively. Multivariate analysis showed that a metabolically unhealthy phenotype increases hazard ratios (HRs) for CAD compared with a metabolically healthy phenotype, regardless of glucose tolerance status (normal glucose tolerance: 1.98, 95% CI: 1.32–2.95; prediabetes: 2.91, 95% CI: 1.85–4.55; diabetes: 1.90, 95% CI: 1.18–3.06). HRs for CAD among metabolically unhealthy non-obese diabetes patients and obese diabetes patients with a metabolically unhealthy status were 6.14 (95% CI: 3.94–9.56) and 7.86 (95% CI: 5.21–11.9), respectively, compared with non-obese subjects with normal glucose tolerance and without a metabolically unhealthy status. Conclusion A metabolically unhealthy state can associate with CAD independently of obesity across all glucose tolerance stages. Clinicians may need to consider those with at least one or more conditions indicating a metabolically unhealthy state as being at high risk for CAD regardless of glucose tolerance status.

Background: In order to provide effective dietary guidance, it is necessary to consider dietary intake, which can change over time. This study analyzed changes in the diet of Japanese patients with type 2 diabetes over a 20-year period. Methods: We compared the results of two dietary surveys that used the food frequency questionnaire format. The first was conducted in 1996 by the Japan Diabetes Complications Study (JDCS) (n = 1509; males 53.3%), and the second in 2014–2018 by the Japan Diabetes Clinical Data Management Study (JDDM) (n = 1145; males 65.6%). Both are nationwide representative registries of outpatients with type 2 diabetes in Japan. Results: Over a 20-year period, both men and women with type 2 diabetes had a significant increase in body mass index (BMI). Nonetheless, there was only a small change in energy intake. Conversely, there was a significant increase in fat intake and thus in the fat-to-energy ratio. With regard to food groups, there was a significant increase in meat intake and a decrease in the intake of fish, soybeans/soy products, vegetables, and fruits, with a particularly significant decrease in vegetables. Conclusions: Even in Japan, an industrialized country with a stable socioeconomic environment, there were many significant changes in the dietary intake of patients with type 2 diabetes over the 20-year period.

To investigate the association between dietary energy density (DED) and obesity in people with type 2 diabetes mellitus. Moreover, we compared the strength of the associations of DED with intake of energy and macronutrients in terms of obesity as well as nutritional factors that have long been used for medical nutritional therapy. Cross-sectionally investigated were 1615 outpatients with type 2 diabetes who attended 26 clinics nationwide with diabetes specialists. Odds ratios (ORs) were calculated for the association between obesity and DED, energy, and macronutrients by quintile categories and a 1 SD increment with adjustment for potential confounders. β coefficients were calculated for the association between body mass index (BMI) and each nutritional factor by 1 SD increments in nutritional values. Multi-adjusted OR for obesity between extreme quintiles of DED was 2.99 (95% confidence interval (95% CI): 2.01–3.12). Conversely, the ORs did not differ significantly according to the quintiles of other nutrient factors. Multi-adjusted β coefficient of BMI per 1 SD according to DED was far higher than those of other nutrient factors (β coefficient 0.65, 95% CI: 0.41–0.88). These findings indicated that DED in persons with type 2 diabetes was positively associated with BMI and the prevalence of obesity. DED was also much more potently associated with obesity and BMI than nutritional indicators such as intake of energy or macronutrients.

IntroductionCost-effectiveness analyses are becoming increasingly important in Japan following the introduction of a health technology assessment scheme. The study objective was to develop an economic model to evaluate the cost-effectiveness of two interventions for type 2 diabetes in a Japanese population.Research design and methodsThe Japan Diabetes Complications Study/Japanese Elderly Diabetes Intervention Trial risk engine (JJRE) Cost-Effectiveness Model (JJCEM) was developed, incorporating validated risk equations in Japanese patients with type 2 diabetes from the JJRE. Weibull regression models were developed for progression of the model outcomes, and a targeted literature review was performed to inform default values for utilities and costs. To illustrate outcomes, two simulated analyses were performed in younger (aged 40 years) and older (aged 80 years) Japanese populations, comparing a hypothetical treatment with placebo.ResultsThe model considers a population based on user-defined values for 11 baseline characteristic parameters and simulates rates of diabetic complications over a defined time horizon. Costs, quality-adjusted life years, and an incremental cost-effectiveness ratio are estimated. The model provides disaggregated results for two competing interventions, allowing visualization of the key drivers of cost and utility. A scatterplot of simulations and cost-effectiveness acceptability curve are generated for each analysis.ConclusionsThis is the first cost-effectiveness model for East Asian patients with type 2 diabetes, developed using Japan-specific risk equations. This population constitutes the largest share of the global population with diabetes, making this model highly relevant. The model can be used to evaluate the cost-effectiveness of anti-diabetic interventions in patients with type 2 diabetes in Japan and other East Asian populations.

Objective The aims of this study are to confirm whether the excess mortality caused by depressive symptoms is independent of severe hypoglycemia in patients with type 2 diabetes mellitus (T2DM) and to evaluate the association between all-cause mortality and degrees of severity of depressive symptoms in Japanese patients with T2DM. Methods A total of 1160 Japanese patients with T2DM were eligible for this analysis. Participants were followed prospectively for 3 years and their depressive states were evaluated at baseline by the Center for Epidemiologic Studies Depression Scale (CES-D). Cox proportional hazards model was used to evaluate the relative risk of all-cause mortality and was adjusted by possible confounding factors, including severe hypoglycemia, all of which are known as risk factors for both depression and mortality. Results After adjustment for severe hypoglycemia, each 5-point increase in the CES-D score was significantly associated with excess all-cause mortality (hazard ratio 1.69 [95% CI 1.26–2.17]). The spline curve of HRs for mortality according to total CES-D scores showed that mortality risk was slightly increased at lower scores but was sharply elevated at higher scores. Conclusion A high score on the CES-D at baseline was significantly associated with all-cause mortality in patients with T2DM after adjusting for confounders including severe hypoglycemia. However, only a small effect on mortality risk was found at relatively lower levels of depressive symptoms in this population. Further research is needed to confirm this relationship between the severity of depressive symptoms and mortality in patients with T2DM.

Aims To examine the impact of glucose tolerance status on the development of coronary artery disease (CAD) in working-age men in Japan. Methods This population-based retrospective cohort study included 111,621 men aged 31–60 years [63,558 with normal glucose tolerance (NGT); 37,126 with prediabetes; 10,937 with diabetes]. The Cox proportional-hazards regression model was used to identify variables related to the incidence of CAD. Results Multivariate analysis showed that, compared with NGT, diabetes increased the risk of CAD by 17.3 times (95% CI: 6.36–47.0) at ages 31–40 years, by 2.74 times (95% CI: 1.85–4.05) at ages 41–50 years and by 2.47 times (95% CI: 1.69–3.59) at ages 51–60 years. The HRs for CAD in men with diabetes aged 31–40 equaled that of men with NGT aged 51–60 [18.2 (7.15–46.4) and 19.4 (8.28–45.4), respectively]. Conclusion The impact of diabetes on CAD was markedly greater in men aged 31–40 years compared with those aged 41–60 years.

Aims/Introduction The present meta-analysis aimed to clarify the association of unstable bodyweight with the risk of type 2 diabetes mellitus, an association that has been controversial among longitudinal studies., Materials and Methods An electronic literature search using EMBASE and MEDLINE was followed up to 31 August 2016. The relative risks (RRs) of type 2 diabetes mellitus in individuals with unstable bodyweight were pooled using the inverse variance method., Results Eight studies were eligible for the meta-analysis. The median duration of measurements of weight change and follow-up years for ascertaining type 2 diabetes mellitus were 13.5 and 9.4 years, respectively. The pooled RR for the least vs most stable category was 1.33 (95% confidence interval 1.12–1.57). Between-study heterogeneity was statistically significant (P = 0.048). Whether type 2 diabetes mellitus was ascertained by blood testing explained 66.0% of the variance in the logarithm of RR (P = 0.02). In three studies in which blood testing was carried out, type 2 diabetes mellitus risk was not significant (RR 1.06, 95% confidence interval 0.91–1.25). Furthermore, publication bias that inflated type 2 diabetes mellitus risk was statistically detected by Egger's test (P = 0.09)., Conclusions Unstable bodyweight might be modestly associated with the elevated risk of type 2 diabetes mellitus; although serious biases, such as diagnostic suspicion bias and publication bias, made it difficult to assess this association.

Objective Although glucose abnormality status (GAS), prior coronary artery disease (CAD), and other traditional risk factors affect the incidence of subsequent CAD, their impact in the same cohort has been scantly studied. Research design and methods We analyzed data from a nationwide claims database in Japan that was accumulated during 2008–2016 involving 138,162 men aged 18–72 years. Participants were classified as having normoglycemia, borderline glycemia, or diabetes mellitus (DM) with prior CAD (CAD+) or without prior CAD (CAD−). Cox regression model identified variables related to the incidence of CAD. Results Among CAD−, management of traditional risks differed from those with and without subsequent CAD events. On the other hand, such differences were weaker in borderline glycemia and DM CAD+, and the influence of traditional risk factors on subsequent CAD was not observed. Cox regression model showed that borderline glycemia and DM confer approximately 1.2- and 2.8-fold excess risks of CAD, respectively, compared with CAD− with normoglycemia. CAD+ confers approximately a 5- to 8-fold increased risk. The impacts of DM and prior CAD additively reached a hazard ratio (HR) of 15.74 (95% confidence interval [CI]: 11.82–21.00). However, the HR in those with borderline glycemia and CAD+ was 7.20 (95% CI: 5.01–10.34), which was not different from those with normoglycemia and CAD+. Conclusion Control status of traditional risk factors and impact on subsequent CAD differ among categories of glycemic status with and without prior CAD. Individualizing treatment strategies is needed in consideration of risk factors, such as GAS and CAD+.

Background Evidence of the role of systolic blood pressure (SBP) in development of severe diabetic retinopathy is not strong, although the adverse effect of low diastolic blood pressure has been a partial explanation. We assessed the predictive ability of incident severe diabetic retinopathy between pulse pressure (PP) which considers both SBP and diastolic blood pressure, compared with SBP. Methods and Results Eligible patients (12 242, 83% men) aged 19 to 72 years from a nationwide claims database were analyzed for a median observational 4.8‐year period. Severe diabetic retinopathy was defined as vision‐threatening treatment‐required diabetic eye diseases. Multivariate Cox regression analysis revealed that hazard ratios (95% CI) of treatment‐required diabetic eye diseases for 1 increment of standard deviation and the top tertile compared with the bottom tertile were 1.39 (1.21–1.60) and 1.72 (1.17–2.51), respectively, for PP and 1.22 (1.05–1.41) and 1.43 (0.97–2.11), respectively, for SBP adjusted for age, sex, body mass index, hemoglobin A1c, fasting plasma glucose, lipids, and smoking status. In a model with SBP and PP simultaneously as covariates, the hazard ratios of only PP (hazard ratios [95% CI], 1.57 [1.26–1.96]) but not SBP (0.85 [0.68–1.07]) were statistically significant. Delong test revealed a significant difference in the area under the receiver operating characteristic curve between PP and SBP (area under the receiver operating characteristic curve [95% CI], 0.58 [0.54–0.63] versus 0.54 [0.50–0.59]; P=0.03). The strongest predictor remained as hemoglobin A1c (area under the receiver operating characteristic curve [95% CI], 0.80 [0.77–0.84]). Conclusions After excluding the significant impact of glycemic control, PP in comparison with SBP is a better predictor of severe diabetic retinopathy, suggesting a role of diastolic blood pressure and arterial stiffness in pathology., See Editorial Dart

Background Efficacy of programs for patients with diabetes mellitus (DM) that have promoted family members to help with patients’ self-care activities has been largely inconsistent. This meta-analysis aims to assess the effect of family-oriented diabetes programs for glycemic control (GC). Methods Electronic literature searches were conducted for clinical trials with a parallel design wherein there were two groups according to whether family members were included (intervention group) or not included (control group) and changes in glycohemoglobin A1C (A1C) were assessed as a study outcome. Each effect size (i.e. difference in A1C change between the intervention and control group) was pooled with a random-effects model. Results There were 31 eligible trials consisting of 1466 and 1415 patients in the intervention and control groups, respectively. Pooled A1C change [95% confidence interval (CI)] was −0.45% (−0.64% to −0.26%). Limiting analyses to 21 trials targeted at patients with type 1 DM or 9 trials targeted at patients with type 2 DM, the pooled A1C changes (95% CI) were −0.35% (−0.55% to −0.14%) and −0.71% (−1.09% to −0.33%), respectively. Conclusion This meta-analysis suggests that focusing on the family as well as the individual patient in self-management diabetes programs to improve the performance of self-care activities of patients with DM is effective in terms of proper GC.

Objective Epidemiological longitudinal investigations of the association between not eating three meals regularly and changes in BMI and weight are scarce. The aim of this study was to investigate whether or not regularly eating three meals was associated with changes in BMI and weight in young Japanese men and women. Methods Study participants were 1241 men and 897 women aged 19.0 ± 1.2 and 18.8 ± 0.8 years, respectively, who underwent health checkups at a university in Japan in 2001 as the baseline and subsequently in 2003. Weight and height were measured at baseline and 2 years later. Whether an individual ate three meals regularly was determined by a self-report questionnaire in 2001. Results During the 2-year follow-up, the BMI gain was 0.347 for men and 0.067 for women. In the logistic regression analysis, for men, eating three meals irregularly was significantly associated with a 4% BMI gain (OR 1.60, CI 1.11–2.30), 6% BMI gain (OR 1.72, CI 1.12–2.63), 4 kg weight gain (OR 2.01, CI 1.29–3.13), 6 kg weight gain (OR 1.86, CI 1.02–3.37), and incidence of obesity (BMI ≧ 25)(OR 2.96, CI 1.22–7.17). For women, eating three meals irregularly was significantly associated with a 4% BMI loss (OR 1.99, CI 1.01–3.94), 6% BMI loss (OR 2.79, CI 1.29–6.03), 4 kg weight loss (OR 3.85, CI 1.62–9.12), 6 kg weight loss (OR 7.65, CI 2.06–28.46), and the incidence of underweight (OR 3.95, CI 1.32–11.89). Conclusions The current results suggested that eating three meals irregularly was associated with subsequent BMI and weight gains for men and subsequent BMI and weight losses for women; both groups were around 20 years of age. Self-reported eating behavior in this study might be used to screen and evaluate young Japanese men and women at high risk for changes in BMI and weight in a practical clinical setting.

An 85-year-old woman with diabetes mellitus was admitted to our hospital due to progressive dyspnea. Two months previously, pioglitazone had been newly prescribed for diabetes management. Bilateral ground-glass opacities and progressive respiratory deterioration suggested respiratory failure due to a drug-induced lung injury. With discontinuation of pioglitazone and the administration of a corticosteroid, an improvement in her respiratory condition was achieved, although sequelae remained in some areas of the lungs. Results of drug-induced lymphocyte stimulation tests were positive for pioglitazone. Resumption of other drugs did not reinduce the lung injury. Therefore, a diagnosis of pioglitazone-induced lung injury was made. Although pioglitazone-induced lung injury is very rare, clinicians should keep it in mind when pioglitazone is used.