Low-density lipoprotein particle profiles compared with standard lipids measurements in the association with asymptomatic intracranial artery stenosis.

The Shiga Epidemiological Study of Subclinical Atherosclerosis was conducted in Kusatsu City, Shiga, Japan, from 2006 to 2008. Participants were measured for LDL-p through nuclear magnetic resonance technology. 740 men participated in follow-up and underwent 1.5 T brain magnetic resonance angiography from 2012 to 2015. Participants were categorized as no-ICAS, and ICAS consisted of mild-ICAS (1 to < 50%) and severe-ICAS (≥ 50%) in any of the arteries examined. After exclusion criteria, 711 men left for analysis, we used multiple logistic regression to examine the association between lipid profiles and ICAS prevalence. Among the study participants, 205 individuals (28.8%) had ICAS, while 144 individuals (20.3%) demonstrated discordance between LDL-c and LDL-p levels. The discordance "low LDL-c-high LDL-p" group had the highest ICAS risk with an adjusted OR (95% CI) of 2.78 (1.55-5.00) in the reference of the concordance "low LDL-c-low LDL-p" group. This was followed by the concordance "high LDL-c-high LDL-p" group of 2.56 (1.69-3.85) and the discordance "high LDL-c-low LDL-p" group of 2.40 (1.29-4.46). These findings suggest that evaluating LDL-p levels alongside LDL-c may aid in identifying adults at a higher risk for ICAS.

Evaluating the associations between compliance with CKD guideline component metrics and renal outcomes.

Understanding the association between compliance to the Chronic Kidney Disease (CKD) guidelines in real-world clinical settings and renal outcomes remains a critical gap in knowledge. A comprehensive analysis was conducted using data from a national, multicenter CKD registry. This study included 4,455 patients with an estimated glomerular filtration rate (eGFR) measurement on the index date and eight additional metrics recorded within six months. These metrics comprised serum electrolyte levels, low-density lipoprotein cholesterol, hemoglobin, and the use of renin-angiotensin system inhibitors. The primary outcome was a composite of renal events, defined by a decline in eGFR to < 15 mL/min/1.73 m2 or a reduction of ≥ 30% in eGFR, confirmed by follow-up tests. Over a median follow-up of 513 days, 838 renal events were observed. High serum potassium levels (> 5.4 mmol/L) were associated with increased event rates compared to lower levels. Similarly, low serum sodium-chloride levels (< 33) correlated with higher event rates. Usage of renin-angiotensin system inhibitors, low serum calcium (< 8.4 mg/dL), and high uric acid levels (> 7.0 mg/dL) were also linked to increased events. Conversely, higher hemoglobin levels (≥ 13 g/dL) were associated with lower event rates. Compliance to guidelines, categorized into quartiles based on the number of met metrics, revealed a significantly reduced risk of events in the highest compliance group (meeting 8 metrics) compared to the lowest (0-5 metrics). Compliance to CKD guidelines in clinical practice is significantly associated with improved renal outcomes, emphasizing the need for guideline-concordant care in the management of CKD.

Kidney outcomes of SGLT2 inhibitors among older patients with diabetic kidney disease in real-world clinical practice: the Japan Chronic Kidney Disease Database Ex.

INTRODUCTION: We compared the kidney outcomes between patients with diabetic kidney disease (DKD) aged ≥75 years initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors versus other glucose-lowering drugs, additionally presenting with or without proteinuria. RESEARCH DESIGN AND METHODS: Using the Japan Chronic Kidney Disease Database, we developed propensity scores, implementing a 1:1 matching protocol. The primary outcome included the decline rate in estimated glomerular filtration rate (eGFR), and secondary outcomes incorporated a composite of a 40% reduction in eGFR or progression to end-stage kidney disease. RESULTS: At baseline, the mean age at initiation of SGLT2 inhibitors (n=348) or other glucose-lowering medications (n=348) was 77.7 years. The mean eGFR was 59.3 mL/min/1.73m2 and proteinuria was 230 (33.0%) patients. Throughout the follow-up period, the mean annual rate of eGFR change was -0.80 mL/min/1.73 m2/year (95% CI -1.05 to -0.54) among SGLT2 inhibitors group and -1.78 mL/min/1.73 m2/year (95% CI -2.08 to -1.49) in other glucose-lowering drugs group (difference in the rate of eGFR decline between the groups was 0.99 mL/min/1.73 m2/year (95% CI 0.5 to 1.38)), favoring SGLT2 inhibitors (p<0.001). Composite renal outcomes were observed 38 in the SGLT2 inhibitors group and 57 in the other glucose-lowering medications group (HR 0.64, 95% CI 0.42 to 0.97). There was no evidence of an interaction between SGLT2 inhibitors initiation and proteinuria. CONCLUSIONS: The benefits of SGLT2 inhibitors on renal outcomes are also applicable to older patients with DKD aged≥75 years.

Associations of ALT/AST, a marker of hepatosteatosis, with pulse rate in young women and with blood pressure in middle-aged women independently of abdominal fat accumulation and insulin resistance.

We examined whether alanine aminotransferase/aspartate aminotransferase (ALT/AST), a marker of hepatosteatosis, may be associated with a wider constellation of variables related to metabolic syndrome in Japanese women. Body fat and distribution, and metabolic syndrome-related variables were measured in 311 young and 148 middle-aged women. We had Pearson's correlation analysis and then stepwise multivariate linear regression analyses. In both middle-aged and young women, ALT/AST was associated with homeostasis model assessment insulin resistance (HOMA-IR), trunk/leg fat ratio and pulse rate. In middle-aged women but not in young women, ALT/AST was associated with waist circumference, fasting glucose, triglyceride, HDL cholesterol (inversely), systolic, diastolic and mean blood pressure (BP). Further, in middle-aged women only, the ratio was associated with BMI, percentage body fat, apolipoprotein B and plasminogen activator inhibitor-1. Among these variables, pulse rate in young women and systolic BP in middle-aged women were associated with ALT/AST independently of trunk/leg fat ratio, a sophisticated measures of abdominal fat accumulation,　HOMA-IR, fasting glucose, triglyceride and HDL cholesterol. In conclusion, ALT/AST was associated with pulse rate in young women and with systolic BP in middle-aged women independently of abdominal fat accumulation and insulin resistance. It is noted that their waist circumference averaged < 80 cm and ALT < 30 U/L, suggesting minimum accumulation of abdominal and hepatic fat, respectively, key drivers of insulin resistance and metabolic syndrome. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00689-z.

Higher childhood weight gain, lower skeletal muscle mass, and higher cereal consumption in normal-weight Japanese women with high-percentage trunk fat: a subanalysis study.

Normal-weight but high-percentage trunk fat phenotype was characterized in a setting where adiposity is not associated with educational and socioeconomic status. Body size trajectory since birth, current body composition measured using whole-body dual-energy X-ray absorptiometry, cardiometabolic traits, serum adipokines, and dietary intake were measured cross-sectionally in 251 normal weight Japanese female university students whose fasting triglyceride and homeostasis model assessment-insulin resistance (HOMA-IR) averaged 56 mg/dL and 1.2, respectively. They were grouped according to tertile of percentage trunk fat. Although HOMA-IR did not differ among three groups, high-percentage trunk fat was associated with higher triglyceride and apolipoprotein B, and lower HDL cholesterol and apolipoprotein A1. In multivariate logistic regression analyses, weight-adjusted skeletal muscle mass (OR: 0.13, 95% CI: 0.04-0.38, p < 0.001), weight gain from birth to age 12 years (OR: 1.214、95% CI: 1.008-1.463、p = 0.04), and cereal consumption (OR:1.008, 95% CI: 1.000-1.016, p = 0.04) were associated with high-percentage trunk fat independent of birthweight, HOMA-IR, adipose tissue-insulin resistance index (the product of fasting insulin and free fatty acid), triglyceride, HDL cholesterol, apolipoprotein A1 and B, leptin, adiponectin, blood pressure, and high-sensitivity C-reactive protein. Early childhood growth, lower skeletal muscle mass, and higher cereal consumption may be associated with normal-weight but high-percentage trunk fat phenotype in Japanese female university students in this subanalysis study. Atherogenic profile of lipids and apolipoproteins may be directly related to abdominal fat accumulation.

[Development of a new method for assessing the availability of low-sodium foods in Japan].

Objectives　Food environment improvement involving salt reduction requires improving access to and labeling low-sodium foods. Assessing the implementation status of these measures is also necessary. However, to date, no established methods exist for assessing the availability of low-sodium foods in communities. In this study, we aimed to devise a survey on the availability of low-sodium foods as a community food environment assessment method in order to establish common assessment methods, criteria, and practical measures, as well as standardization nationwide.Methods　A preliminary survey on the availability of low-sodium foods was conducted in Kitakyushu City in four stores with nationwide representation. Consent for providing information on handled product lists was obtained. The on-site lists collected through direct investigation by surveyors were compared with the handled product lists provided by the stores and analyzed to identify survey challenges and examine feasibility and the potential for accuracy. The definition of low-sodium foods, which emerged as a challenge in the preliminary survey, was confirmed. Preliminary survey data were carefully reviewed to establish classification criteria for low-sodium foods and create a low-sodium food list to serve as a reference for on-site surveys. Forms for recording the results of on-site surveys and a survey manual were developed. Registered dietitians conducted on-site surveys using the manual to confirm its applicability.Results　The preliminary survey results revealed that the on-site lists had fewer omissions and greater feasibility than store-provided lists. After clearly defining low-sodium foods, we established classification criteria (three major categories, seven subcategories, and 37 minor categories) considering the ease of on-site investigations and purchases. Three forms for recording survey results were developed, including a standard input form allowing detailed documentation of the availability of individual low-sodium foods, an aggregation form for a quantitative assessment of low-sodium foods availability, and a display form visualizing the availability of low-sodium foods by store. Furthermore, a survey manual was developed explaining the purpose and approach of the low-sodium foods availability survey, definition and classification criteria for low-sodium foods, and the three forms for recording survey results. Findings indicated that all registered dietitians could conduct on-site surveys using the manual and successfully collect and organize data.Conclusion　On-site surveys using the manual and documentation forms enabled easy and accurate assessments of low-sodium foods availability. Thus, this standardized method to assess the availability of low-sodium foods could be a food environment assessment method for regional salt reduction initiatives.

Mortality from major causes and lifestyles by proportions of public assistance recipients among 47 prefectures in Japan: Ecological panel data analysis from 1999 to 2016.

Objective: Comprehensive investigations of correlations between subnational socioeconomic factors and trends in mortality and lifestyle are important for addressing public health problems. Methods: Forty-seven prefectures in Japan were divided into quartiles based on the proportion of public assistance recipients (PPAR). Age-standardized mortality from all causes, cancer, heart disease, and stroke in each prefecture were averaged for these quartiles in 2000, 2005, 2010, and 2015. Data from the National Health and Nutrition Survey were obtained for the following periods: 1999-2001, 2003-2005, 2007-2009, 2012, and 2016. Body mass index (BMI), intake of total energy, vegetable and salt, step count, and prevalence of current smoking and drinking for individuals aged 40-69 years age range were standardized for each prefecture and averaged by quartile. A two-way analysis of variance was used to assess differences in mortality and lifestyle across different years or periods, and quartiles. Results: Mortality rates decreased, with the first (lowest) quartile showing the lowest rates, across all causes, cancer and heart diseases in both sexes. BMI exhibited an increase in men, whereas, BMI in women and other lifestyle factors in both sexes, excluding smoking and drinking in women, exhibited a decrease. BMI, vegetable and salt intake, total energy intake in men, and smoking in women varied across quartiles. Lower quartiles exhibited lower BMI and smoking prevalence but higher energy, vegetables, and salt intake. Conclusions: PPAR exhibited favorable trends and significant differences in mortality related to all causes, cancer and heart disease across both sexes, along with BMI among women.

Kidney outcomes associated with haematuria and proteinuria trajectories among patients with IgA nephropathy in real-world clinical practice: The Japan Chronic Kidney Disease Database.

AIM: Among patients with Immunoglobulin A (IgA) nephropathy, we aimed to identify trajectory patterns stratified by the magnitude of haematuria and proteinuria using repeated urine dipstick tests, and assess whether the trajectories were associated with kidney events. METHODS: Using a nationwide multicentre chronic kidney disease (CKD) registry, we analysed data from 889 patients with IgA nephropathy (mean age 49.3 years). The primary outcome was a sustained reduction in eGFR of 50% or more from the index date and thereafter. During follow-up (median 49.0 months), we identified four trajectories (low-stable, moderate-decreasing, moderate-stable, and high-stable) in both urine dipstick haematuria and proteinuria measurements, respectively. RESULTS: In haematuria trajectory analyses, compared to the low-stable group, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) for kidney events were 2.59 (95% CI, 1.48-4.51) for the high-stable, 2.31 (95% CI, 1.19-4.50) for the moderate-stable, and 1.43 (95% CI, (0.72-2.82) for the moderate-decreasing groups, respectively. When each proteinuria trajectory group was subcategorized according to haematuria trajectories, the proteinuria group with high-stable and with modest-stable haematuria trajectories had approximately 2-times higher risk for eGFR reduction ≥50% compared to that with low-stable haematuria trajectory. CONCLUSION: Assessments of both haematuria and proteinuria trajectories using urine dipstick could identify high-risk IgA nephropathy patients.

Associations of Alanine Aminotransferase/Aspartate Aminotransferase, a Marker of Hepatosteatosis, with Adipose Tissue Insulin Resistance Index and Leptin/Adiponectin Ratio in Japanese Women.

Objective: We assessed whether alanine aminotransferase/aspartate aminotransferase (ALT/AST), a marker of hepatic steatosis, may be associated with adipose tissue dysfunction more closely than hepatic and muscle insulin resistance (IR). Methods: Associations with adipose tissue IR index (AT-IR) calculated as a product of fasting insulin and free fatty acids, leptin/adiponectin ratio, a proxy of adipocyte dysfunction, homeostasis model assessment IR (HOMA-IR), hepatic and muscle IR inferred from plasma insulin kinetics during a 75 grams oral glucose tolerance test (OGTT) were studied in nondiabetic 307 young and 148 middle-aged Japanese women, whose body mass index averaged 20 and 22 kilograms/m2, respectively. Results: On multivariate linear regression analysis in young women, ALT/AST was associated with trunk/leg fat ratio (standardized ß = 0.202, P = 0.007), a marker of abdominal fat accumulation, and AT-IR (standardized ß = 0.185, P = 0.003) independently of HOMA-IR and Matsuda index (R2 = 0.07). In middle-aged women, leptin/adiponectin ratio (standardized ß = 0.446, P < 0.001) and AT-IR (standardized ß = 0.292, P = 0.009) emerged as determinants of ALT/AST independently of trunk/leg fat ratio, OGTT-derived hepatic IR, leptin, and adiponectin (R2 = 0.34). Conclusions: ALT/AST was associated with AT-IR and adipocyte dysfunction more closely than hepatic and muscle IR even in nondiabetic lean Japanese women.

Trends in mortality from major causes and lifestyle factors by per capita prefectural income: Ecological panel data analysis from 1995 to 2016 in Japan.

In Japan, trends in mortality and lifestyle have not been fully investigated according to subnational socioeconomic factors. Forty-seven prefectures (subnational units) were divided into quartiles by annual per capita prefectural income. Age-standardized mortality from all causes, cancer, heart disease, and stroke was averaged by quartile in 1995, 2000, 2005, 2010, and 2015. Data from the National Health and Nutrition Survey were obtained for periods 1 (1995-1997), 2 (1999-2001), 3 (2003-2005), 4 (2007-2009), 5 (2012), and 6 (2016). Body mass index (BMI), the intake of vegetables and salt, the number of steps, and the prevalence of current smoking and drinking for the 40-69-year age range were standardized by 10-year age groups in the 2010 Japanese population and were averaged by quartile. Differences in mortality and lifestyle by year and period, and quartile were tested using a two-way analysis of variance. Mortality decreased in both sexes and mortality in men from all causes, cancer, and stroke differed by quartile, with mortality highest in the first (lowest) quartile. BMI in men and smoking prevalence in women increased, whereas remaining lifestyle factors except for the prevalence of drinking decreased in women. BMI and the number of steps in both sexes and current smoking prevalence in women differed by quartile, with lower quartiles showing a higher BMI and fewer step counts. In conclusion, favorable trends and significant differences in mortality from all causes, cancer, and stroke in men and BMI in women were observed by per capita prefectural income level.

Associations of alanine aminotransferase/aspartate aminotransferase with insulin resistance and ß-cell function in women.

We tested whether alanine aminotransferase/aspartate aminotransferase (ALT/AST), a marker of hepatosteatosis, associates with insulin resistance, ß-cell function and postglucose glycemia. We studied 311 young and 148 middle-aged Japanese women, whose BMI averaged < 23.0 kg/m2. Insulinogenic index and Matsuda index were evaluated in 110 young and 65 middle-aged women. In two groups of women, ALT/AST was associated positively with homeostasis model assessment insulin resistance (HOMA-IR) and inversely with Matsuda index. In middle-aged women only, the ratio was also associated positively with fasting and postload glycemia and HbA1c. The ratio showed negative association with disposition index (a product of insulinogenic index and Matsuda index). On multivariate linear regression analysis, HOMA-IR emerged as a single determinant of ALT/AST in young and middle-aged women (standardized ß: 0.209, p = 0.003 and 0.372, p = 0.002, respectively). ALT/AST was associated with insulin resistance and ß-cell function even in non-obese Japanese women, suggesting a pathophysiologic basis in its prediction of diabetic risk.

Association between serum leptin concentrations and homeostasis model assessment-insulin resistance of 2.5 and higher in normal weight Japanese women.

Normal weight insulin resistant phenotype was characterized in 251 Japanese female university students using homeostasis model assessment-insulin resistance. Birth weight, body composition at age 20, cardiometabolic traits and dietary intake were compared cross-sectionally between insulin sensitive (< 1.6, n = 194) and insulin resistant (2.5 and higher, n = 16) women. BMI averaged < 21 kg/m2 and waist < 72 cm and did not differ between two groups. The percentage of macrosomia and serum absolute and fat-mass corrected leptin concentrations were higher in insulin resistant women although there was no difference in birth weight, fat mass index, trunk/leg fat ratio and serum adiponectin. In addition, resting pulse rate, serum concentrations of free fatty acids, triglycerides and remnant-like particle cholesterol were higher in insulin resistant women although HDL cholesterol and blood pressure did not differ. In multivariate logistic regression analyses, serum leptin (odds ratio:1.68, 95% confidential interval:1.08-2.63, p = 0.02) was associated with normal weight insulin resistance independently of macrosomia, free fatty acids, triglycerides, remnant-like particle cholesterol and resting pulse rate. In conclusion, normal weight IR phenotype may be associated with increased plasma leptin concentrations and leptin to fat mass ratio in young Japanese women, suggesting higher leptin production by body fat unit.

Association between Dietary Patterns and Serum Low Density Lipoprotein Cholesterol in Japanese Women and Men: The Japan Multi-Institutional Collaborative Cohort (J-MICC) Study.

AIMS: The association between dietary patterns and serum low density lipoprotein (LDL) cholesterol would be changing in recent dietary habits in Japan. We investigated the relationship between dietary patterns and serum LDL cholesterol in a large general population. METHODS: From the baseline survey of Japan Multi-Institutional Collaborative Cohort Study between 2005 and 2013, 27,237 participants (13,994 were women) aged 35-69 years were cross-sectionally analyzed. Using a semi-quantitative food frequency questionnaire, five major sex-specific dietary patterns were identified using factor analysis. We assessed serum LDL cholesterol by quintiles of dietary pattern factor score. RESULTS: We identified dietary patterns; "vegetable rich pattern" , "meat and fried food rich pattern" and "high bread and low rice pattern" in women and men; "fish and shellfish rich pattern" and "high confectioneries and low alcohol pattern" in men; "healthy Japanese diet pattern" and "high alcohol and low rice pattern" in women. Serum LDL cholesterol in men was associated with "high bread and low rice pattern" score (Q5 was 4.2 mg/dL higher than Q1, p for trend ＜0.001) and "high confectioneries and low alcohol pattern" scores (Q5 was 9.5 mg/dL higher than Q1, p for trend ＜0.001). In women, serum LDL cholesterol was associated with "high bread and low rice pattern" score (Q5 was 7.1 mg/dL higher than Q1, p for trend ＜0.001). CONCLUSION: Some recent dietary patterns in Japan were associated with serum LDL cholesterol. Serum LDL cholesterol was associated with high bread and low rice pattern in both sex, and high confectioneries and low alcohol pattern in men.

Weight trajectories since birth, current body composition and metabolic traits in young, normal-weight Japanese women with high percentage body fat.

INTRODUCTION: We tested whether normal-weight obesity might be associated with weight trajectories, body composition and metabolic traits. RESEARCH DESIGN AND METHODS: Body size trajectory since birth, body composition at age 20 years and metabolic traits were compared cross-sectionally among normal-weight Japanese women with low (<25.0%, n=67), normal (25.0-34.9%, n=160) and high (≥35.0 %, n=24) percentage body fat. Multivariate logistic regression analyses were used to identify most important determinants of normal-weight obesity (high percentage body fat). RESULTS: Fasting glucose averaged <84 mg/dL, homeostasis model assessment-insulin resistance <1.4 and triglyceride <70 mg/dL and did not differ among three groups. However, waist and trunk/leg fat ratio were higher, and weight-adjusted skeletal muscle mass was lower in normal-weight obesity. Serum and LDL cholesterol, apolipoprotein B (ApoB) and high-sensitivity C reactive protein were higher, and apolipoprotein A1 was lower in normal-weight obesity compared with the other two groups, whereas HDL cholesterol did not differ. Weight gain from birth to age 12 years was higher in normal-weight obesity. In multivariate logistic regression analyses, weight gain until 12 years (OR: 1.17,95% CI 1.02 to 1.34, p=0.02), ApoB (OR: 1.15, 95% CI 1.06 to 1.24, p<0.001) and weight-adjusted skeletal muscle mass (OR: 0.22, 95% CI 0.10 to 0.49, p<0.001) were associated with normal-weight obesity independently of trunk/leg fat ratio, high-sensitivity C reactive protein and apolipoprotein A1. CONCLUSIONS: Normal-weight obesity may be associated with early childhood growth, lower skeletal muscle mass and higher serum ApoB in young Japanese women through mechanisms unrelated to abdominal adiposity, inflammation and insulin resistance.

The associations of the national health and productivity management program with corporate profits in Japan.

OBJECTIVES: Using a dataset from a survey on national health and productivity management, we identified health and productivity factors associated with organizational profitability. METHODS: The Ministry of Economy, Trade and Industry conducted an annual survey on Health and Productivity Management between 2014 and 2021. We assessed the associations of organizational health and productivity management using survey questions collected in 2017 and 2018, with the rate of change in profits from 2017 and 2018 to 2020. We identified factors associated with organizational profitability using eXtreme Gradient Boosting, and calculated SHapley Additive exPlanation (SHAP) values for each factor. RESULTS: Among 1,593 companies (n= 4,359,834 employees), the mean age of employees at baseline was 40.3 years and the proportion of women was 25.8%. A confusion matrix for evaluating model performance had an accuracy of 0.997, precision of 0.993, recall of 0.997, and area under the precision-recall curve of 0.999. The most important factors related to an increase in corporate profits were the percentage of current smokers (SHAP value, 0.121), per-employee cost of health services (0.084) and medical services (0.050); the percentage of full-time employees working in sales departments (0.074) and distribution or customer service departments (0.054); the percentage of employees who slept well (0.055); and the percentage of employees within a company who regularly exercised (0.043). CONCLUSIONS: Employees' lifestyle-related health risk factors and organizations' management systems were associated with organizational profitability. Lifestyle medicine professionals may demonstrate a significant return on investment by creating a healthier and more productive workforce.

Isolated Diastolic Hypertension and Risk of Cardiovascular Disease: Controversies in Hypertension - Pro Side of the Argument.

Isolated diastolic hypertension (IDH), defined as diastolic blood pressure in the hypertensive range but systolic blood pressure not in the hypertensive range, is not uncommon (<20%) among adults with hypertension. IDH often manifests in concurrence with other cardiovascular risk factors. Individuals with IDH tend to have lower awareness of their hypertension compared with those with both systolic and diastolic hypertension. IDH appears to be a largely underrated risk factor for cardiovascular disease events, which may be explained by inconsistent association of IDH with cardiovascular disease events. The inconsistency suggests that IDH is heterogeneous. One size does not seem to fit all in the clinical management of individuals with IDH. Rather than treating IDH as a monolithic low-risk condition, detailed phenotyping in the context of individual comprehensive cardiovascular risk would seem to be most useful to assess an individual's expected net benefit from therapy. In this review, we highlight that the clinical relevance of IDH differs by individual clinical characteristics, and elucidate groups of individuals with IDH that should be wary of cardiovascular disease risks.