A multicentre, double-blind, placebo-controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add-on therapy in type 2 diabetic patients treated with metformin and dapagliflozin.

AIM: To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In a multicentre study, with a randomized, double-blind, placebo-controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24-week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. RESULTS: Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% ± 0.72% to 7.27% ± 0.82%) compared with placebo (from 7.79% ± 0.76% to 7.69% ± 0.86%, corrected mean difference: -0.42% ± 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high-density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. CONCLUSIONS: Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference.

Comparison of laser and traditional lancing devices for capillary blood sampling in patients with diabetes mellitus and high bleeding risk.

PURPOSE: Despite the importance of self-monitoring blood glucose (SMBG) for management of diabetes mellitus (DM), frequent blood sampling is discouraged by bleeding risk due to dual-antiplatelet agent therapy (DAPT) or thrombocytopenia. METHODS: We compared the bleeding time (BT) of sampling by using a laser-lancing-device (LMT-1000) and a conventional lancet in patients with DM and thrombocytopenia or patients undergoing DAPT. BT was measured using the Duke method, and pain and satisfaction scores were assessed using numeric rating scale (NRS) and visual analog scale (VAS). The consistency in the values of glucose and glycated-hemoglobin (HbA1c) sampled using the LMT-1000 or lancet were compared. RESULTS: The BT of sampling with the LMT-1000 was shorter than that with the lancet in patients with thrombocytopenia (60s vs. 85s, P = 0.024). The NRS was lower and the VAS was higher in laser-applied-sampling than lancet-applied sampling in the DAPT-user group (NRS: 1 vs. 2, P = 0.010; VAS: 7 vs. 6, P = 0.003), whereas the group with thrombocytopenia only showed improvement in the VAS score (8 vs. 7, P = 0.049). Glucose and HbA1c sampled by the LMT-1000 and lancet were significantly correlated in both the DAPT-user and the thrombocytopenia groups. CONCLUSION: The LMT-1000 can promote SMBG by shortening BT in subject with thrombocytopenia and by increasing satisfaction score, as well as by showing reliable glucose and HbA1c value.

Gender differences in association between expiratory dynamic airway collapse and severity of obstructive sleep apnea.

OBJECTIVES: Repetitive unbalances and tensions generated by inspiratory efforts against an obstructive upper airway during sleep predispose the development of expiratory central airway collapse. In addition, structures of the upper airway between men and women have differences and could be the reasons for differences in obstructive sleep apnea (OSA) prevalence between genders. The present study aimed to evaluate the association between parameters of expiratory dynamic tracheal collapse measured using chest multidetector CT and objectively measured OSA severity between men and women. MATERIALS AND METHODS: A total of 901 participants who underwent chest CT and overnight in-home polysomnography from the Korean Genome and Epidemiology Study were cross-sectionally analyzed (women: 46.2%). The participants were divided into three groups based on OSA severity by apnea-hypopnea index (AHI). Multivariate linear regression analysis was performed to determine the effects of central airway collapse after adjustment for cardiovascular-related covariates. RESULTS: In a multivariate analysis, percentages of expiratory lumen structure reductions involving area, diameter, and perimeter were associated with AHI (all p values < 0.05) and with OSA severity (moderate-to-severe OSA than no OSA: ß = 3.30%, p = 0.03; ß = 2.05%, p = 0.02; ß = 1.97%, p = 0.02, respectively) in women, whereas men had only a greater percentage of expiratory wall thickness reduction in moderate-to-severe OSA than no OSA (ß = 0.72%, p = 0.003). In addition, women with both mild OSA and moderate-to-severe OSA had higher expiratory tracheal collapse than men without OSA, and a moderate effect of sex was observed (p for interaction = 0.007). CONCLUSION: The expiratory dynamic tracheal collapse was independently associated with severity of OSA in women than in men. CLINICAL RELEVANCE STATEMENT: Differences of pharyngeal structures and inherent features of airways by genders may affect the dissimilarities in vulnerability to sleep apnea between men and women. KEY POINTS: • The expiratory dynamic tracheal collapse was independently associated with severity of OSA in women than in men. • Women with over mild OSA had higher expiratory tracheal collapse than men without OSA, and moderate effect of sex was observed. • Structural differences of airway may affect differences in susceptibility of sleep apnea between genders.

Association of long-term hyperglycaemia and insulin resistance with brain atrophy and cognitive decline: A longitudinal cohort study.

AIM: To investigate the longitudinal changes in brain volume and cognitive function associated with diabetes at midlife, and to examine whether long-term hyperglycaemia, insulin resistance or secretory function is associated with brain atrophy and cognitive decline. MATERIALS AND METHODS: We used data from 2377 participants with both baseline and 4-year follow-up brain magnetic resonance images and neuropsychological measures from the Ansan cohort of the Korean Genome Epidemiology Study. Time-weighted mean glycaemic values were calculated using all measurements over an average duration of 10.6 years from cohort initiation to baseline visits. RESULTS: Type 2 diabetes was associated with greater white matter volume reduction (adjusted volume difference = -1.96 ml, 95% CI: -3.73, -0.18) and executive function decline (adjusted Z score difference = -0.14, 95% CI: -0.23, -0.05) during the follow-up period of 4.2 years. Decline of verbal and visual memory or verbal fluency was not associated with diabetes. Greater executive function decline was associated with higher time-weighted mean HbA1c level over the preceding 10.6 years (P < .001), but not with insulin resistance markers in the diabetes group. Participants with diabetes, whose time-weighted average HbA1c level was maintained above 6.5% over the previous decade, showed greater decline in executive function and global cognition than the normal glucose group. CONCLUSIONS: Long-term hyperglycaemia was a major independent factor associated with rapid cognitive decline in middle-aged adults with diabetes. Maintaining ideal glucose levels in diabetes at midlife might prevent later rapid cognitive decline.

Effects of dapagliflozin compared with glimepiride on body composition in Asian patients with type 2 diabetes inadequately controlled with metformin: The BEYOND study.

AIMS: To evaluate the effect of dapagliflozin on body composition such as total body fat (BF) mass, abdominal visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) areas compared with glimepiride in Korean patients with type 2 diabetes. MATERIALS AND METHODS: This was a 52-week, multicentre, randomized, parallel-group, open-label, Phase IV (NCT02564926) study. Patients with inadequate glycaemic control (glycated haemoglobin ≥7.0% and <10.0%) on metformin monotherapy (≥1000 mg/day) were randomized 1:1 to receive dapagliflozin 10 mg/day or glimepiride 1-2 mg/day for 12 months as an add-on to metformin. Baseline and end of study body composition evaluations included dual-energy X-ray absorptiometry and abdominal computed tomography scans. RESULTS: Of 124 enrolled patients from 14 centres, 121 received study treatment (dapagliflozin: 60; glimepiride: 61) and 106 (85.5%) completed the study. Over 52 weeks, the dapagliflozin group showed the following differences versus the glimepiride group: -2.59 kg BF mass, -1.94% BF%, -17.55 cm2 VAT area, -18.39 cm2 SAT area, -0.46% glycated haemoglobin, -18.25 mg/dl fasting blood glucose, -3.7 kg weight, -2.21 cm waist circumference, -1.37 kg/m2 body mass index, -6.81 mmHg systolic blood pressure and +657.71 ng/ml in adiponectin; all were statistically significant. Both groups had similar incidences of adverse events; however, hypoglycaemic events were mainly (12 of 15) reported in the glimepiride group. CONCLUSION: Dapagliflozin reduced total BF mass, abdominal VAT and SAT areas, and showed better glycaemic control than glimepiride. Being safe and well-tolerated, dapagliflozin appears to be a more favourable alternative to sulphonylureas as add-on therapy after metformin monotherapy failure in Korean patients with type 2 diabetes.

Plasma and urinary extracellular vesicle microRNAs and their related pathways in diabetic kidney disease.

To explore extracellular vesicle microRNAs (EV miRNAs) and their target mRNAs in relation to diabetic kidney disease (DKD), we performed paired plasma and urinary EV small RNA sequencing (n = 18) in patients with type 2 diabetes and DKD (n = 5) and healthy subjects (n = 4) and metabolic network analyses using our own miRNA and public mRNA datasets. We found 13 common differentially expressed EV miRNAs in both fluids and 17 target mRNAs, including RRM2, NT5E, and UGDH. Because succinate dehydrogenase B was suggested to interact with proteins encoded by these three genes, we measured urinary succinate and adenosine in a validation study (n = 194). These two urinary metabolite concentrations were associated with DKD progression. In addition, renal expressions of NT5E and UGDH proteins were increased in db/db mice with DKD compared to control mice. In conclusion, we profiled DKD-related EV miRNAs in plasma and urine samples and found their relevant target pathways.

Implications of fasting plasma glucose variability on the risk of incident peripheral artery disease in a population without diabetes: a nationwide population-based cohort study.

BACKGROUND: Diabetes have been known as a traditional risk factor of developing peripheral artery disease (PAD). However, the study evaluating the impact of long-term glycemic variability on the risk of developing PAD is limited, especially in a general population without diabetes. METHODS: We included 152,931 individuals without diabetes from the Korean National Health Insurance Service-Health Screening Cohort. Fasting plasma glucose (FPG) variability was measured using coefficient variance (FPG-CV), standard deviation (FPG-SD), and variability independent of the mean (FPG-VIM). RESULTS: A total of 16,863 (11.0%) incident cases of PAD were identified during a median follow-up of 8.3 years. Kaplan-Meier curves showed a progressively increasing risk of PAD in the higher quartile group of FPG variability than in the lowest quartile group (log rank P < 0.001). Multivariable Cox proportional hazard analysis showed the hazard ratio for PAD prevalence as 1.11 (95% CI 1.07-1.16, P < 0.001) in the highest FPG-CV quartile than in the lowest FPG-CV quartile after adjusting for confounding variables, including mean FPG. Similar degree of association was shown in the FPG-SD and FPG-VIM. In sensitivity analysis, the association between FPG variability and the risk of developing PAD persisted even after the participants were excluded based on previously diagnosed diseases, including stroke, coronary artery disease, congestive heart failure, chronic kidney disease, or current smokers or drinkers. Subgroup analysis demonstrated that the effects of FPG variability on the risk of PAD were more powerful in subgroups of younger age, regular exercisers, and those with higher income. CONCLUSIONS: Increased long-term glycemic variability may have a significant prognostic effect for incident PAD in individuals without diabetes.

Differentiating pulmonary metastasis from benign lung nodules in thyroid cancer patients using dual-energy CT parameters.

OBJECTIVES: To explore the importance of quantitative characteristics of dual-energy CT (DECT) between pulmonary metastasis and benign lung nodules in thyroid cancer. METHODS: In this retrospective study, we identified 63 patients from our institution's database with pathologically proven thyroid cancer who underwent DECT to assess pulmonary metastasis. Among these patients, 22 had 55 pulmonary metastases, and 41 had 97 benign nodules. If nodules showed increased iodine uptake on I-131 single-photon emission computed tomography-computed tomography or increased size in follow-up CT, they were considered metastatic. We compared the clinical findings and DECT parameters of both groups and performed a receiver operating characteristic analysis to evaluate the optimal cutoff values of the DECT parameters. RESULTS: Patients with metastases were significantly older than patients with benign nodules (p = 0.048). The DECT parameters of the metastatic nodules were significantly higher than those of the benign nodules (iodine concentration [IC], 5.61 ± 2.02 mg/mL vs. 1.61 ± 0.98 mg/mL; normalized IC [NIC], 0.60 ± 0.20 vs. 0.16 ± 0.11; NIC using pulmonary artery [NICPA], 0.60 ± 0.44 vs. 0.15 ± 0.11; slope of the spectral attenuation curves [λHU], 5.18 ± 2.54 vs. 2.12 ± 1.39; and Z-effective value [Zeff], 10.0 ± 0.94 vs. 8.79 ± 0.75; all p < 0.001). In the subgroup analysis according to nodule size, all DECT parameters of the metastatic nodules in all subgroups were significantly higher than those of the benign nodules (all p < 0.05). The cutoff values for IC, NIC, λHU, NICPA, and Zeff for diagnosing metastases were 3.10, 0.29, 3.57, 0.28, and 9.34, respectively (all p < 0.001). CONCLUSIONS: DECT parameters can help to differentiate metastatic and benign lung nodules in thyroid cancer. KEY POINTS: • DECT parameters can help to differentiate metastatic and benign lung nodules in patients with thyroid cancer. • DECT parameters showed a significant difference between benign lung nodules and lung metastases, even for nodules with diameters ≥ 3 mm and < 5 mm. • Among the DECT parameters, the highest diagnostic accuracy for differentiating pulmonary metastases from benign lung nodules was achieved with the NIC and IC, followed by the NICPA and λHU, and their cutoff values were 0.29, 3.10, 0.28, and 3.57, respectively.

Impact of urinary iodine concentration on blood glucose levels and blood pressure: a nationwide population-based study.

PURPOSE: Iodine is a vital trace element for systemic metabolic control as well as thyroid hormone synthesis. Though iodine has significant antioxidant and anti-inflammatory effects, reports on its effects on metabolic disorders are limited and inconsistent. METHODS: Impact of urinary iodine concentrations (UICs) on fasting blood glucose (FBG) levels and blood pressure (BP) in the general Korean population was evaluated adjusting for covariates including thyrotropin level and presence of thyroid diseases. RESULTS: The median UIC was 302.3 µg/L in all participants and was significantly lower in those with dysglycemia (303.6 µg/L in normal participants, 285.1 µg/L in participants with FBG levels of 100-125 mg/dL, and 261.8 µg/L in participants with FBG levels ≥ 126 mg/dL; p = 0.002). Similarly, the UIC was lower in participants with higher BP (311.6 µg/L in normal participants, 288.7 µg/L in prehypertensive participants, and 265.8 µg/L in hypertensive participants; p < 0.001). The multiple linear regression model showed a negative correlation between the UIC and FBG levels (p = 0.002), and the UIC and systolic BP (p < 0.001). One standard deviation increase in the UIC showed odds ratios of 0.84 (95% confidence interval [CI] = 0.73-0.98) for elevated FBG levels (≥ 100 mg/dL) and 0.94 (95% CI = 0.88-0.99) for elevated SBP (≥ 120 mm Hg) after full adjustment. CONCLUSION: Higher UICs were associated with lower FBG and BP levels, independent of thyroid function and other confounding factors in Korea, an iodine-replete country.

Associations between Body Mass Index, Waist Circumference, and Myocardial Infarction in Older Adults Aged over 75 Years: A Population-Based Cohort Study.

Background and Objectives: Body mass index (BMI) is widely used as a standard screening method for obesity and an indicator of related diseases. However, its inability to distinguish between lean body mass and body fat limits its utility. This limitation may be more prominent in older populations, wherein age-related sarcopenia and increased visceral fat due to the redistribution of adipose tissue may preclude a precise estimation of obesity. Many studies suggest that waist circumference (WC) is more strongly related to obesity-related diseases. There are also different opinions on whether the obesity paradox is real or a result of confusing interpretations. This study seeks to determine the association between myocardial infarction (MI), BMI, and WC in older adults and to determine if BMI and WC can reliably predict the risk of cardiovascular disease. Materials and Methods: We conducted a cohort study of older Korean adults aged over 75 years registered in the National Health Insurance System Senior database. Results: The results from the analysis using model 5, which was adjusted for each study variable, showed that the lower the BMI, the higher the hazard ratio (HR) of MI and vice versa. On the other hand, groups with lower than normal WC showed lower HR; even if it was higher, the difference was not statistically significant. Those with abdominal obesity tended to have an increased HR of MI. Conclusions: This study found that HR for MI has a negative relationship with BMI, whereas it has a positive relationship with WC. Furthermore, WC is a more appropriate indicator for predicting the risk of MI in the older population.

Paravertebral Muscles as Indexes of Sarcopenia and Sarcopenic Obesity: Comparison With Imaging and Muscle Function Indexes and Impact on Cardiovascular and Metabolic Disorders.

OBJECTIVE. The objectives of this study were to propose the use of the cross-sectional area of paravertebral muscle (PMA) and the ratio of the PMA to the cross-sectional area of visceral fat (PVR) as new indexes of sarcopenia or sarcopenic obesity through comparison with existing indexes and to show the clinical associations of PMA and PVR with hypertension and diabetes. SUBJECTS AND METHODS. A total of 1270 participants (608 men and 662 women; mean [± SD] age, 63.57 ± 6.94 years) were recruited from a community-based population of elderly individuals. PMA and PVR were measured on single-slice abdominal CT images. Pearson correlation was used to evaluate the correlation of PMA and PVR with widely used imaging and muscle function indexes of sarcopenia and sarcopenic obesity. Tertile categories of PMA and PVR were evaluated to investigate associations with risks for hypertension and diabetes in men and women, by use of separate multivariable logistic regression models. RESULTS. PMA was correlated with the cross-sectional area of thigh muscle on CT, appendicular skeletal muscle mass (ASM) on dual-energy x-ray absorptiometry, height-adjusted ASM (calculated as ASM divided by the height in meters squared), and body mass index (BMI)-adjusted ASM (calculated as ASM divided by BMI) (p < .01). PMA was also correlated with hand grip strength and gait speeds (p < .01). PVR was correlated with height-adjusted ASM and BMI-adjusted ASM (p < .01). A high PVR significantly decreased the odds ratios for hypertension and diabetes in the unadjusted model and the model adjusted for age, smoking, and drinking status. The ratio of the cross-sectional area of thigh muscle to the cross-sectional area of visceral fat and the BMI-adjusted ASM produced results similar to those of PVR in terms of the odds ratios for hypertension and diabetes. CONCLUSION. Single-slice abdominal CT can supply PMA and visceral fat information together. PMA and PVR were found to be reliable indexes of sarcopenia and sarcopenic obesity. A high PVR was associated with low risks for hypertension and diabetes.

Weight-adjusted waist index reflects fat and muscle mass in the opposite direction in older adults.

BACKGROUND: Age-related changes in body composition include decreased muscle mass and preserved or increased fat mass. There is no anthropometric index to assess both muscle and fat mass. METHODS: Using a cross-sectional sample of 602 participants aged ≥65 years from the Ansan Geriatric study, we evaluated the association of weight-adjusted waist index (WWI) with muscle and fat mass and compared these with body mass index (BMI) and waist circumference (WC). WWI was calculated as WC (cm) divided by the square root of body weight (kg). Body composition was measured using bioelectrical impedance analysis, dual-energy X-ray absorptiometry and abdominal computed tomography. RESULTS: WWI positively correlated with total abdominal fat area (TFA) (r = 0.421, P < 0.001), visceral fat area (VFA) (r = 0.264, P < 0.001), and percentage of total tissue fat (r = 0.465, P < 0.001), but negatively correlated with appendicular skeletal muscle mass (ASM) (r = -0.511, P < 0.001) and ASM/height2 (r = -0.324, P < 0.001). Mean ASM was highest in the first quartile of WWI (17.85 kg/m2) and showed a decreasing trend, with the lowest value in the fourth WWI quartile (13.21 kg/m2, P for trend <0.001). In contrast, mean TFA was lowest in the first quartile and highest in the fourth WWI quartile (P for trend <0.001). The probability of combined low muscle mass and high fat mass was >3× higher in the fourth WWI quartile than in the lowest quartile (odds ratio 3.22, 95% confidence interval 1.32-7.83). CONCLUSIONS: WWI is an anthropometric index positively associated with fat mass and negatively associated with muscle mass in older adults.

Sarcopenia is associated with decreased gray matter volume in the parietal lobe: a longitudinal cohort study.

BACKGROUND: Substantial evidence supports an association between physical activity and cognitive function. However, the role of muscle mass and function in brain structural changes is not well known. This study investigated whether sarcopenia, defined as low muscle mass and strength, accelerates brain volume atrophy. METHODS: A total of 1284 participants with sarcopenic measurements and baseline and 4-year follow-up brain magnetic resonance images were recruited from the Korean Genome and Epidemiology Study. Muscle mass was represented as appendicular skeletal muscle mass divided by the body mass index. Muscle function was measured by handgrip strength. The low mass and strength groups were defined as being in the lowest quintile of each variable for one's sex. Sarcopenia was defined as being in the lowest quintile for both muscle mass and handgrip strength. RESULTS: Of the 1284 participants, 12·6%, 10·8%, and 5·4% were classified as the low mass, low strength, and sarcopenia groups, respectively. The adjusted mean changes of gray matter (GM) volume during 4-year follow-up period were - 9·6 mL in the control group, whereas - 11·6 mL in the other three groups (P < 0·001). The significantly greater atrophy in parietal GM was observed in the sarcopenia group compared with the control group. In a joint regression model, low muscle mass, but not muscle strength, was an independent factor associated with a decrease of GM volume. CONCLUSIONS: Sarcopenia is associated with parietal GM volume atrophy, in a middle-aged population. Maintaining good levels of muscle mass could be important for brain health in later adulthood.

Relationship of obstructive sleep apnoea severity and subclinical systemic atherosclerosis.

Obstructive sleep apnoea (OSA) is a common form of sleep disordered breathing. Untreated OSA might accelerate atherosclerosis, potentially increasing the cardiovascular disease burden in patients. The present study aimed to evaluate the association between objectively measured OSA severity and the presence of subclinical systemic atherosclerosis using noninvasive measurements, including tomographic quantification of the calcium burden.A total of 2157 participants of the Korean Genome and Epidemiology Study, who were free of structural heart disease and underwent both in-home polysomnography and chest computed tomography, were cross-sectionally analysed. Participants were divided into three groups based on the severity of OSA: no OSA (apnoea-hypopnoea index (AHI) <5 events·h-1, n=1096), mild OSA (AHI 5- <15 events·h-1, n=700) and moderate-to-severe OSA (AHI ≥15 events·h-1, n=361). Calcium deposits in the thoracic aorta and coronary arteries were measured by the Agatston score.Participants with moderate-to-severe OSA were 1.6 times (95% CI 1.18-2.15 times; p=0.002) more likely to have ascending thoracic aorta calcification (≥100 units) than those without OSA, after adjustment for cardiovascular risk factors. In addition, the association between moderate-to-severe OSA and ascending thoracic aorta calcification of subjects with higher epicardial fat volume was slightly stronger than that in patients without OSA and in the lowest epicardial fat volume tertile (OR 2.11, 95% CI 1.30-3.43).Severity of OSA in the general population was independently associated with subclinical systemic atherosclerosis. These findings highlight the potential importance of severe OSA, especially in subjects with higher epicardial fat, as a possible predictive factor for systemic atherosclerosis and cardiovascular disease.

Hospitalization for heart failure incidence according to the transition in metabolic health and obesity status: a nationwide population-based study.

BACKGROUND: We aimed to investigate the hazard of hospitalization for heart failure (hHF) according to the transitions in metabolic health and obesity status. METHODS: The Korean National Health Insurance Service datasets from 2002 to 2017 were used for this nationwide, longitudinal, population-based study. The hazard of hHF was analyzed according to the eight groups stratified by stability in metabolic health and transition in obesity status among initially metabolically healthy adults who underwent two cycles of health examinations in 2009-2010 and 2013-2014 (N = 7,148,763). RESULTS: During two examinations, 48.43% of the initially metabolically healthy obese (MHO) individuals and 20.94% of the initially metabolically healthy non-obese (MHNO) individuals showed changes in their metabolic health and obesity status. During a mean follow-up of 3.70 years, 3151 individuals were hospitalized for HF. When stable MHNO individuals were set as the reference, transition to metabolically unhealthy phenotype was associated with an increased hazard of hHF; the hazard ratio (HR) and 95% confidence interval (CI) in the individuals who transformed from MHO to metabolically unhealthy non-obese was 2.033 (1.579-2.616). The constant MHO group had a 17.3% increased hazard of hHF compared with the stable MHNO group [HR (95% CI) 1.173 (1.039-1.325)]. Individuals who shifted from MHO to MHNO showed a 34.3% lower hazard of hHF compared with those who maintained the MHO category [HR (95% CI) 0.657 (0.508-0.849)]. CONCLUSION: Dynamic changes in metabolic health and obesity status were observed during a relatively short interval of 3-5 years. Loss of metabolic health was significantly associated with an increased hazard of hHF. Even if metabolic health was maintained, persistent obesity remained as a risk factor for hHF, and transition from MHO to MHNO had a protective effect against hHF. Therefore, the prevention and control of obesity while maintaining metabolic health would be crucial in preventing hHF.

Glucose variability and the risks of stroke, myocardial infarction, and all-cause mortality in individuals with diabetes: retrospective cohort study.

BACKGROUND: Previous research regarding long-term glucose variability over several years which is an emerging indicator of glycemic control in diabetes showed several limitations. We investigated whether variability in long-term fasting plasma glucose (FG) can predict the development of stroke, myocardial infarction (MI), and all-cause mortality in patients with diabetes. METHODS: This is a retrospective cohort study using the data provided by the Korean National Health Insurance Corporation. A total of 624,237 Koreans ≥ 20 years old with diabetes who had undergone health examinations at least twice from 2005 to 2008 and simultaneously more than once from 2009 to 2010 (baseline) without previous histories of stroke or MI. As a parameter of variability of FG, variability independent of mean (VIM) was calculated using FG levels measured at least three times during the 5 years until the baseline. Study endpoints were incident stroke, MI, and all-cause mortality through December 31, 2017. RESULTS: During follow-up, 25,038 cases of stroke, 15,832 cases of MI, and 44,716 deaths were identified. As the quartile of FG VIM increased, the risk of clinical outcomes serially increased after adjustment for confounding factors including duration and medications of diabetes and the mean FG. Adjusted hazard ratios (95% confidence intervals) of FG VIM quartile 4 compared with quartile 1 were 1.20 (1.16-1.24), 1.20 (1.15-1.25), and 1.32 (1.29-1.36) for stroke, MI and all-cause mortality, respectively. The impact of FG variability was higher in the elderly and those with a longer duration of diabetes and lower FG levels. CONCLUSIONS: In diabetes, long-term glucose variability showed a dose-response relationship with the risk of stroke, MI, and all-cause mortality in this nationwide observational study.

Gamma-glutamyl transferase variability and risk of dementia: A nationwide study.

OBJECTIVES: Variability in various biomarkers has emerged as a new clinical indicator for diseases including neurodegenerative disorders. Gamma-glutamyl transferase (GGT) has a potential to be involved in the pathogenesis of dementia due to its function as a marker of oxidative stress and atherosclerosis. We investigated the association between baseline GGT, GGT variability, and dementia risk for the first time in a large population. METHODS: The Korean National Health Insurance Service datasets of claims and preventive health check-ups from 2004 to 2016 were used for this retrospective longitudinal study. The risk of incident dementia (all-cause dementia, Alzheimer's disease, and vascular dementia) was analyzed according to sex-specific quartiles of baseline GGT and GGT variability, and groups categorized by baseline GGT and GGT variability in ≥40-year-old individuals without baseline dementia (N = 6 046 442; mean follow-up 6.32 years). RESULTS: During follow-up, 166 851 cases of new dementia developed. The fully adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident dementia increased in the higher quartiles of baseline GGT and GGT variability (HR [95% CI]: Q2, 1.034 [1.019-1.049]; Q3, 1.090 [1.075-1.105]; Q4, 1.212 [1.196-1.229]). The association between GGT variability quartiles and dementia risk remained significant even after adjusting for log-transformed baseline GGT level. The fully adjusted HRs for dementia was highest in the group with high baseline GGT concentration and the highest GGT variability quartile [HR (95% CI): 1.273 (1.250-1.296)]. CONCLUSIONS: Not only baseline GGT level, but also GGT variability may be an independent predictor of dementia, and might be used for risk stratification for future dementia.

MYC in Brain Development and Cancer.

The MYC family of transcriptional regulators play significant roles in animal development, including the renewal and maintenance of stem cells. Not surprisingly, given MYC's capacity to promote programs of proliferative cell growth, MYC is frequently upregulated in cancer. Although members of the MYC family are upregulated in nervous system tumours, the mechanisms of how elevated MYC promotes stem cell-driven brain cancers is unknown. If we are to determine how increased MYC might contribute to brain cancer progression, we will require a more complete understanding of MYC's roles during normal brain development. Here, we evaluate evidence for MYC family functions in neural stem cell fate and brain development, with a view to better understand mechanisms of MYC-driven neural malignancies.

Dipeptidyl peptidase-4 inhibitor compared with sulfonylurea in combination with metformin: cardiovascular and renal outcomes in a propensity-matched cohort study.

BACKGROUND: To determine the impact of dipeptidyl peptidase-4 inhibitor (DPP4i) on the risk of major cardiocerebrovascular and renal outcomes compared with sulfonylurea (SU) combined with metformin in patients with type 2 diabetes from a population-based cohort. METHODS: From a nationwide cohort in Korea (2008-2013), 23,674 patients with type 2 diabetes treated with DPP4i plus metformin or SU plus metformin were selected and matched by propensity score. Composite cardiocerebrovascular events including incident ischemic heart disease (IHD), ischemic stroke (IS), hospitalization for heart failure (HHF), and cardiocerebrovascular death, as well as renal events including incident end-stage renal disease or initiation of renal-replacement therapy were assessed by Cox proportional-hazards models. RESULTS: During a median follow-up of 19.6 months (interquartile range 7.2-36.4), 762 composite cardiocerebrovascular events and 17 end-stage renal events occurred. There was no significant difference in the risk of IHD (hazard ratio [HR], 1.00; 95% CI 0.81-1.23), IS (HR, 0.95; 95% CI 0.74-1.23), or cardiocerebrovascular death (HR, 0.74; 95% CI 0.46-1.18) in the DPP4i group compared to that in the SU group. Likewise, DPP4i therapy was not associated with the risk of end-stage renal outcomes (HR, 1.23; 95% CI 0.41-3.62). However, the risk of HHF was significantly higher in the DPP4i group than in the SU group (HR, 1.47; 95% CI 1.07-2.04). CONCLUSIONS: This real-world database analysis showed that DPP4i therapy did not increase the overall risk of major cardiovascular and renal outcomes compared to SU therapy. However, the DPP4i-associated risk of HHF remained significant.

Chronic renal dysfunction, proteinuria, and risk of Parkinson's disease in the elderly.

BACKGROUND: The roles of chronic kidney disease and proteinuria in the development of Parkinson's disease have not been widely studied. The objective of this study was to examine the associations of chronic renal dysfunction and proteinuria with the risk of PD in older adults using cohort data of the whole South Korean population. METHODS: We included 3,580,435 individuals aged ≥65 years who had undergone health checkups provided by the National Health Insurance Service of South Korea between 2009 and 2012 and were followed until 2015. Multivariable Cox proportional hazards regression models were performed. RESULTS: During a mean follow-up of 5.2 ± 1.3 years, 30,813 individuals (0.86% of the total population) developed PD. Lower estimated glomerular filtration rate and a higher degree of proteinuria on a dipstick test were associated with higher incidence probability of PD (log-rank P < 0.001). In Cox regression models, chronic renal dysfunction graded by estimated glomerular filtration rate (mL/min/1.73 m2 ) was associated with increased risk of PD after adjusting for potential confounding variables; hazard ratio (95% confidence interval) was 1.13 (1.10-1.17) for estimated glomerular filtration rate 60-90, 1.36 (1.31-1.42) for estimated glomerular filtration rate 30-60, and 1.47 (1.32-1.63) for estimated glomerular filtration rate <30 (P for trend <0.001). Proteinuria ≥1+ was also associated with increased risk of PD development (hazard ratio, 1.12; 95% confidence interval, 1.06-1.18). Coexistence of chronic kidney disease and proteinuria showed an increased hazard ratio of 1.33 (95% confidence interval, 1.23-1.45) for PD occurrence. CONCLUSIONS: Our findings suggest that chronic renal dysfunction and dipstick-positive proteinuria may be independent risk factors for the development of PD in older adults. © 2019 International Parkinson and Movement Disorder Society.