Comparison between a tubeless, on-body automated insulin delivery system and a tubeless, on-body sensor-augmented pump in type 1 diabetes: a multicentre randomised controlled trial.

AIMS/HYPOTHESIS: This study compares the efficacy and safety of a tubeless, on-body automated insulin delivery (AID) system with that of a tubeless, on-body sensor-augmented pump (SAP). METHODS: This multicentre, parallel-group, RCT was conducted at 13 tertiary medical centres in South Korea. Adults aged 19-69 years with type 1 diabetes who had HbA1c levels of <85.8 mmol/mol (<10.0%) were eligible. The participants were assigned at a 1:1 ratio to receive a tubeless, on-body AID system (intervention group) or a tubeless, on-body SAP (control group) for 12 weeks. Stratified block randomisation was conducted by an independent statistician. Blinding was not possible due to the nature of the intervention. The primary outcome was the percentage of time in range (TIR), blood glucose between 3.9 and 10.0 mmol/l, as measured by continuous glucose monitoring. ANCOVAs were conducted with baseline values and study centres as covariates. RESULTS: A total of 104 participants underwent randomisation, with 53 in the intervention group and 51 in the control group. The mean (±SD) age of the participants was 40±11 years. The mean (±SD) TIR increased from 62.1±17.1% at baseline to 71.5±10.7% over the 12 week trial period in the intervention group and from 64.7±17.0% to 66.9±15.0% in the control group (difference between the adjusted means: 6.5% [95% CI 3.6%, 9.4%], p<0.001). Time below range, time above range, CV and mean glucose levels were also significantly better in the intervention group compared with the control group. HbA1c decreased from 50.9±9.9 mmol/mol (6.8±0.9%) at baseline to 45.9±7.4 mmol/mol (6.4±0.7%) after 12 weeks in the intervention group and from 48.7±9.1 mmol/mol (6.6±0.8%) to 45.7±7.5 mmol/mol (6.3±0.7%) in the control group (difference between the adjusted means: -0.7 mmol/mol [95% CI -2.0, 0.8 mmol/mol] (-0.1% [95% CI -0.2%, 0.1%]), p=0.366). No diabetic ketoacidosis or severe hypoglycaemia events occurred in either group. CONCLUSIONS/INTERPRETATION: The use of a tubeless, on-body AID system was safe and associated with superior glycaemic profiles, including TIR, time below range, time above range and CV, than the use of a tubeless, on-body SAP. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) KCT0008398 FUNDING: The study was funded by a grant from the Korea Medical Device Development Fund supported by the Ministry of Science and ICT; the Ministry of Trade, Industry and Energy; the Ministry of Health and Welfare; and the Ministry of Food and Drug Safety (grant number: RS-2020-KD000056).

Stratification of Nontuberculous Mycobacterial Disease Risk in Type 2 Diabetes Based on Metformin Use: a Population-Based Cohort Study in South Korea.

In a 1:4 case-control matched analysis of data from a nationwide population-based cohort in South Korea, we evaluated whether metformin use mitigates the risk of nontuberculous mycobacterial disease in patients with type 2 diabetes. Multivariable analysis revealed no significant association of metformin use with a diminished risk for incident nontuberculous mycobacterial disease in patients with type 2 diabetes.

Association of the atherogenic index of plasma with cardiovascular risk beyond the traditional risk factors: a nationwide population-based cohort study.

BACKGROUND: The atherogenic index of plasma (AIP) is composed of triglycerides and high-density lipoprotein cholesterol and is a novel marker for assessing the risk of atherogenicity and cardiometabolic health. An association between AIP and greater frequency of major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus and high cardiovascular (CV) disease risk has been reported. However, only few studies have examined the correlation between AIP and CV risk in general populations. We thus aimed to evaluate the relationship between AIP and CV diseases using a large-scale population dataset from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). METHODS: A total of 514,866 participants were enrolled from the NHIS-HEALS and classified according to the AIP quartiles. We performed univariate and multivariate Cox proportional hazards regression analyses to determine the association between AIP and MACEs, CV events, and CV mortality. RESULTS: During follow-up, we documented 12,133, 11,055, and 1942 cases of MACEs, CV events, and CV mortality, respectively. The multivariate-adjusted hazard ratios [HRs; 95% confidence interval (CI)] for MACEs gradually and significantly increased with the AIP quartiles [1.113 (1.054-1.175) in Q2, 1.175 (1.113-1.240) in Q3, and 1.278 (1.209-1.350) in Q4], following an adjustment for the conventional CV risk factors, including age, sex, body mass index, smoking, alcohol drinking, physical activities, household income, fasting glucose, systolic blood pressure, low-density lipoprotein cholesterol, and estimated glomerular filtration rate. In subgroup analyses, the association of AIP with MACEs and CV events was particularly outstanding in patients with diabetes. CONCLUSIONS: AIP was significantly associated with CV risks after adjusting for the traditional risk factors. Therefore, it may be used as an effective mass screening method to identify patients at a high risk of CV events.

Pathogenesis, Murine Models, and Clinical Implications of Metabolically Healthy Obesity.

Although obesity is commonly associated with numerous cardiometabolic pathologies, some people with obesity are resistant to detrimental effects of excess body fat, which constitutes a condition called "metabolically healthy obesity" (MHO). Metabolic features of MHO that distinguish it from metabolically unhealthy obesity (MUO) include differences in the fat distribution, adipokine types, and levels of chronic inflammation. Murine models are available that mimic the phenotype of human MHO, with increased adiposity but preserved insulin sensitivity. Clinically, there is no established definition of MHO yet. Despite the lack of a uniform definition, most studies describe MHO as a particular case of obesity with no or only one metabolic syndrome components and lower levels of insulin resistance or inflammatory markers. Another clinical viewpoint is the dynamic and changing nature of MHO, which substantially impacts the clinical outcome. In this review, we explore the pathophysiology and some murine models of MHO. The definition, variability, and clinical implications of the MHO phenotype are also discussed. Understanding the characteristics that differentiate people with MHO from those with MUO can lead to new insights into the mechanisms behind obesity-related metabolic derangements and diseases.

Switching from insulin to dulaglutide therapy in patients with type 2 diabetes: A real-world data study.

AIM: Patients with type 2 diabetes (T2DM) who require injectable therapy have been conventionally treated with insulin. A glucagon-like peptide 1 receptor agonist was recently recommended as first-line injectable treatment, but few studies have investigated the effects of switching from insulin to dulaglutide. This study investigated the clinical efficacy and parameters affecting responses to dulaglutide as an alternative to insulin in patients with T2DM in a real-world clinical setting. METHODS: Ninety-eight patients with T2DM who were switched from insulin to dulaglutide therapy were retrospectively evaluated. Changes in HbA1c concentrations were assessed after 6 months of consistent treatment with dulaglutide. Multiple linear regression analysis was performed to evaluate parameters affecting the response to dulaglutide treatment. RESULTS: After treatment with dulaglutide for 6 months, patients experienced changes in HbA1c of -0.95% (95% confidence interval [CI]: -1.30% to -0.59%, P < 0.001) and in body weight of -1.75 kg (95% CI: -2.42 to -1.08 kg, P < 0.001). Multiple linear regression analysis showed that higher baseline HbA1c was significantly associated with a greater reduction in HbA1c. The most frequent adverse events were gastrointestinal symptoms. CONCLUSION: Switching from insulin to dulaglutide can lead to significant improvement in HbA1c levels and body weight ​reduction in T2DM patients over 6 months. Higher baseline HbA1c is associated with a better clinical response to dulaglutide.

Oral Semaglutide, the First Ingestible Glucagon-Like Peptide-1 Receptor Agonist: Could It Be a Magic Bullet for Type 2 Diabetes?

The gastrointestinal tract secretes gut hormones in response to food consumption, and some of these stimulate insulin secretion. Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone released from the lower digestive tract that stimulates insulin secretion, suppresses glucagon secretion, and decreases hunger. GLP-1 receptor agonist (GLP-1RA) mimics the action of endogenous GLP-1, consequently reversing hyperglycemia and causing weight reduction, demonstrating its efficacy as an antidiabetic and antiobesity agent. Previously restricted to injection only, the invention of the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate resulted in the development of oral semaglutide, the first ingestible GLP-1RA. Oral semaglutide demonstrated its efficacy in glycemic management and body weight loss with a low risk of hypoglycemia as a monotherapy and in combination with other hypoglycemic medications in its clinical trial programs named Peptide Innovation for Early Diabetes Treatment. Consistent with other injectable GLP-1RAs, gastrointestinal side effects were often reported. Additionally, cardiovascular safety was established by demonstrating that oral semaglutide was not inferior to a placebo in terms of cardiovascular outcomes. Thus, oral semaglutide represents a novel treatment option that is particularly well-suited for patients with type 2 diabetes and/or obesity.

The Role of Anti-Inflammatory Adipokines in Cardiometabolic Disorders: Moving beyond Adiponectin.

The global burden of obesity has multiplied owing to its rapidly growing prevalence and obesity-related morbidity and mortality. In addition to the classic role of depositing extra energy, adipose tissue actively interferes with the metabolic balance by means of secreting bioactive compounds called adipokines. While most adipokines give rise to inflammatory conditions, the others with anti-inflammatory properties have been the novel focus of attention for the amelioration of cardiometabolic complications. This review compiles the current evidence on the roles of anti-inflammatory adipokines, namely, adiponectin, vaspin, the C1q/TNF-related protein (CTRP) family, secreted frizzled-related protein 5 (SFRP5), and omentin-1 on cardiometabolic health. Further investigations on the mechanism of action and prospective human trials may pave the way to their clinical application as innovative biomarkers and therapeutic targets for cardiovascular and metabolic disorders.

Protective role of skeletal muscle mass against progression from metabolically healthy to unhealthy phenotype.

OBJECTIVE: Metabolically healthy individuals are known to be resistant to cardiovascular disease development. However, a considerable fraction of those individuals shows deteriorated metabolic health over time. Although skeletal muscle is the primary insulin-responsive target organ, a longitudinal investigation of the skeletal muscle mass in relation to the development of metabolically unhealthy phenotype has not been performed. We aimed to evaluate whether greater skeletal muscle mass is an independent protective factor for the development of metabolically unhealthy phenotype. DESIGN, PARTICIPANTS AND MEASUREMENTS: We conducted a retrospective cohort study with 9033 metabolically healthy volunteers who underwent routine health examinations in 2012 and a follow-up examination in 2016. Obesity was defined as Asian-Pacific body mass index criterion ≥25 kg/m2 . Subjects with fewer than two risk factors (elevated blood pressure, triglyceride, glucose, high-sensitivity C-reactive protein, insulin resistance and decreased high-density lipoprotein cholesterol levels) were characterized as metabolically healthy using Wildman criteria. RESULTS: At the 4-year follow-up, approximately one-fourth of the nonobese participants and half of the participants with obesity showed metabolic deterioration. In nonobese men and women, higher appendicular skeletal muscle mass (ASM)/weight at baseline was significantly associated with decreased risk of metabolic deterioration. Compared to the lowest quartile of ASM/weight, the adjusted odds ratios (95% confidence intervals) of the highest quartile were 0.68 (0.52-0.89) in nonobese men and 0.64 (0.46-0.90) in nonobese women. However, this association was not observed in obese subjects. CONCLUSIONS: Greater skeletal muscle mass at baseline is significantly associated with maintenance of metabolically healthy status, especially in nonobese individuals.

The haemoglobin glycation index is associated with nonalcoholic fatty liver disease in healthy subjects.

OBJECTIVES: The hemoglobin glycation index (HGI) quantifies interindividual variations in glycated hemoglobin (HbA1c) and is associated with diabetic complications and metabolic diseases. However, information on the association between HGI and non-alcoholic fatty liver disease (NAFLD) in healthy subjects is limited, particularly in Asian populations. This study aimed to investigate the association between HGI and NAFLD in a healthy Korean cohort. DESIGN: Subjects were stratified in quartiles according to their HGI level. NAFLD was diagnosed by hepatic ultrasonography, hepatic steatosis index and fatty liver index. Multiple logistic regression analysis was performed to evaluate the association between HGI quartiles and the risk of NAFLD. PATIENTS: Data from subjects without diabetes who underwent liver ultrasonography during routine health examinations were retrospectively reviewed. RESULTS: Data from 14 465 subjects were included in the analysis. The prevalence of NAFLD increased significantly with each HGI quartile (24.8%, 29.7%, 32.6% and 40.6% in quartiles 1-4, respectively; P < 0.001). In comparison with the lowest HGI quartile group, the highest quartile exhibited worse metabolic parameters, including body weight, waist circumference, body mass index and lipid profiles. Multiple logistic regression analysis adjusted for multiple factors showed that the odds ratio of having NAFLD was 1.564 (95% CI: 1.350-1.813, P < 0.001) in the highest HGI quartile. CONCLUSIONS: Elevated HGI levels are independently associated with NAFLD in a healthy Asian population.

Comparison of outcomes after carotid endarterectomy between type 2 diabetic and non-diabetic patients with significant carotid stenosis.

BACKGROUND: We aimed to compare early and late outcomes after carotid endarterectomy (CEA) between Korean type 2 diabetic and non-diabetic patients and to investigate the impact of diabetes on the overall incidence of cardiovascular events after CEA. METHODS: We retrospectively analyzed 675 CEAs, which were performed on 613 patients with significant carotid stenosis between January 2007 and December 2014. The CEAs were divided into a type 2 diabetes mellitus (DM) group (n = 265, 39.3%) and a non-DM group (n = 410, 60.7%). The study outcomes included the incidence of major adverse events (MAEs), defined as fatal or nonfatal stroke or myocardial infarction or all-cause mortality, during the perioperative period and within 4 years after CEA. RESULTS: Patients in the DM and non-DM groups did not differ significantly in the incidence of MAEs or any of the individual MAE manifestations during the perioperative period. However, within 4 years after CEA, the difference in the MAE incidence was significantly greater in the DM group (P = 0.040). Analysis of the individual MAE manifestations indicated a significantly higher risk of stroke in the DM group (P = 0.006). Multivariate analysis indicated that diabetes was not associated with MAEs or individual MAE manifestations during the perioperative period, whereas within 4 years after CEA, diabetes was an independent risk factor for MAEs overall (hazard ratio [HR], 1.62; 95% confidence interval [CI] 1.06-2.48; P = 0.026) and stroke (HR, 2.55; 95% CI 1.20-5.41; P = 0.015) in particular. CONCLUSIONS: Diabetic patients were not at greater risk of perioperative MAEs after CEA; however, the risk of late MAE occurrence was significantly greater in these patients. Within 4 years after CEA, DM was an independent risk factor for the occurrence of MAEs overall and stroke in particular.

Effect of SFRP5 (Secreted Frizzled-Related Protein 5) on the WNT5A (Wingless-Type Family Member 5A)-Induced Endothelial Dysfunction and Its Relevance With Arterial Stiffness in Human Subjects.

OBJECTIVE: SFRP5 (secreted frizzled-related protein 5) is an endogenous inhibitor of WNT5A (wingless-type family member 5a), which has been implicated in atherosclerosis. However, contradictory results have been reported about the role of SFRP5 in atherosclerosis. We aimed to investigate whether SFRP5 could restore WNT5A-induced endothelial dysfunction in vitro and ex vivo. In addition, we sought to determine whether the serum concentration of SFRP5 is associated with atherosclerosis in humans. APPROACH AND RESULTS: We measured endothelium-dependent vasorelaxation in the isolated thoracic aorta of Sprague-Dawley rats. In addition, we measured intracellular nitric oxide (NO) in human endothelial cells. The protein abundance of total and phosphorylated JNK (c-Jun N-terminal kinase), AKT (protein kinase B), and endothelial NO synthase was analyzed in human endothelial cells. Circulating SFRP5 and WNT5A levels and brachial-ankle pulse wave velocity were measured in 282 human subjects with type 2 diabetes mellitus. SFRP5 dose dependently restored Wnt5-induced impaired vasorelaxation in rat thoracic aorta by an endothelial NO synthase-dependent mechanism. SFRP5 treatment restored the WNT5A-induced reduction of NO production via endothelial NO synthase in human endothelial cells. WNT5A-induced changes in the phosphorylation of JNK, AKT, and endothelial NO synthase were ameliorated with SFRP5 administration. In humans with type 2 diabetes mellitus, the serum SFRP5 concentration positively correlated with brachial-ankle pulse wave velocity (r=0.146; P=0.024). Multivariate linear regression analysis demonstrated that the serum SFRP5 concentration was independently associated with brachial-ankle pulse wave velocity after adjustment for potential confounders [B (SE)=7.40 (3.35); P=0.028]. CONCLUSIONS: Our data suggest the possible compensatory action of SFRP5 against atherosclerosis under conditions of metabolic dysfunction.

Efficacy and safety of ipragliflozin as an add-on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: A randomized controlled trial.

AIM: To evaluate the efficacy and safety of ipragliflozin vs placebo as add-on therapy to metformin and sitagliptin in Korean patients with type 2 diabetes mellitus (T2DM). METHODS: This double-blind, placebo-controlled, multi-centre, phase III study was conducted in Korea in 2015 to 2017. Patients were randomized to receive either ipragliflozin 50 mg/day or placebo once daily for 24 weeks in addition to metformin and sitagliptin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to end of treatment (EOT). RESULTS: In total, 143 patients were randomized and 139 were included in efficacy analyses (ipragliflozin: 73, placebo: 66). Baseline mean (SD) HbA1c levels were 7.90 (0.69)% for ipragliflozin add-on and 7.92 (0.79)% for placebo. The corresponding mean (SD) changes from baseline to EOT were -0.79 (0.59)% and 0.03 (0.84)%, respectively, in favour of ipragliflozin (adjusted mean difference -0.83% [95% CI -1.07 to -0.59]; P < .0001). More ipragliflozin-treated patients than placebo-treated patients achieved HbA1c target levels of <7.0% (44.4% vs 12.1%) and < 6.5% (12.5% vs 1.5%) at EOT (P < .05 for both). Fasting plasma glucose, fasting serum insulin, body weight and homeostatic model assessment of insulin resistance decreased significantly at EOT, in favour of ipragliflozin (adjusted mean difference -1.64 mmol/L, -1.50 µU/mL, -1.72 kg, and -0.99, respectively; P < .05 for all). Adverse event rates were similar between groups (ipragliflozin: 51.4%; placebo: 50.0%). No previously unreported safety concerns were noted. CONCLUSIONS: Ipragliflozin as add-on to metformin and sitagliptin significantly improved glycaemic variables and demonstrated a good safety profile in Korean patients with inadequately controlled T2DM.

Improved trends in cardiovascular complications among subjects with type 2 diabetes in Korea: a nationwide study (2006-2013).

BACKGROUND: Representative data on the secular trends in cardiovascular disease (CVD) are limited in Asian populations with diabetes. We aimed to estimate the temporal trends in cardiovascular complications using Korean nationwide whole population-based claims data in subjects with and without diabetes. METHODS: Type 2 diabetes was defined as a current medication history of anti-diabetic drugs and the presence of International Classification of Diseases (ICD)-10 codes (E11-E14) as diagnosis. We compared the 8-year rates of six cardiovascular complications [i.e., ischemic heart disease, acute myocardial infarction (AMI), ischemic stroke, hemorrhagic stroke, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG)] in Korean adults aged 30 years and older using data from four consecutive nationwide databases (2006-2007, 2008-2009, 2010-2011, and 2012-2013) of Korean national health insurance service. RESULTS: A total of 1,645,348, 1,971,559, 2,291,247, and 2,562,612 subjects with type 2 diabetes were found in the year of 2006-2007, 2008-2009, 2010-2011, and 2012-2013, respectively. Age and gender standardized rates of the six predefined cardiovascular complications decreased in Korean adults with type 2 diabetes during the study period. The greatest relative reductions were observed for hospitalization due to AMI (-37.28%), followed by hospitalizations due to ischemic stroke (-36.98%). In the overall population without type 2 diabetes, the greatest relative reductions were observed for hospitalization for hemorrhagic stroke (-29.47%), followed by hospitalization due to ischemic stroke (-28.92%). Relative decreases in all six predefined cardiovascular complications were generally more profound in adults with diabetes than in those without diabetes, which led to significant decrease in the relative risks of all six cardiovascular complications in subjects with diabetes over the past 8 years. However, people with diabetes still had a two- to sixfold higher risk of hospitalization for major CVD events and interventions than people without diabetes. CONCLUSIONS: Our findings suggest a significant reduction in the rate of people affected by CVD within the diabetic population. However, as the number of people with diabetes rises, the absolute burden of CVD will still be high in Korea.

Impact of diabetes duration and degree of carotid artery stenosis on major adverse cardiovascular events: a single-center, retrospective, observational cohort study.

BACKGROUND: We aimed to investigate the impact of diabetes duration and carotid artery stenosis (CAS) on the occurrence of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) without clinical cardiovascular disease. METHODS: A total of 2006 patients with T2DM, without clinical cardiovascular disease, aged >50 years, and who underwent baseline carotid Doppler ultrasound screening with regular follow-ups at the outpatient clinic of our diabetes center, were stratified into four subgroups according to diabetes duration and CAS degree. The primary outcomes included the occurrence of MACE, defined as fatal or nonfatal stroke and myocardial infarction, and all-cause mortality. RESULTS: The difference in the MACE incidence was significantly greater in patients with a longer diabetes duration (≥10 years) and significant CAS (50-69% luminal narrowing) (p < 0.001). Analysis of individual MACE components indicated a trend towards an increased incidence of stroke (p < 0.001), parallel to a longer diabetes duration and significant CAS. In contrast, the risk of myocardial infarction was significantly higher in patients with a diabetes duration <10 years and significant CAS (p = 0.039). Multivariate regression analysis showed that patients with both a longer diabetes duration and significant CAS demonstrated additive and very high risks of MACE (hazard ratio [HR], 2.07; 95% confidence interval [CI] 1.17-3.66; p = 0.012) and stroke (HR, 3.38; 95% CI 1.54-7.44; p = 0.002). CONCLUSIONS: The risk of MACE is significantly greater in patients with T2DM, without clinical cardiovascular disease, who have both a longer diabetes duration and significant CAS, compared with those who have a shorter duration and/or nonsignificant CAS.

Differential association of body mass index on glycemic control in type 1 diabetes.

BACKGROUND: In contrast to type 2 diabetes, the association of body mass index (BMI) with glycemic control in type 1 diabetes (T1D) remains unclear. We investigated the relationship between BMI and average HbA1c levels in subjects with T1D. METHOD: In this multi-centre observational study, we analysed 719 subjects with T1D aged ≥18 years. Average HbA1c levels over 18 months and other clinical and laboratory parameters were evaluated. RESULTS: The mean age and duration of diabetes at baseline were 41.5 ± 13.9 and 11.3 ± 8.7 years, respectively. A U-shaped correlation between BMI and 18-month average HbA1c levels was documented by a spline curve. Based on this finding, subjects were divided into three groups according to BMI (group I, <21; group II, 21-23; and group III, ≥23 kg/m2 ). In group I, the BMI negatively correlated with average HbA1c (r = -0.172, p = 0.011), while a positive relationship was observed (r = 0.162, p = 0.012) in group III. Average HbA1c levels were lower and the proportion of individuals with well-controlled glycemia (HbA1c <7%) were increased in the higher BMI tertile group among subjects with group I as well as in the lower BMI tertile group among subjects with group III BMI. After adjustment with additional covariates in the multiple regression model, these associations between BMI and HbA1c levels according to the different BMI ranges remained significant. CONCLUSIONS: In Korean subjects with T1D, an inverse relationship of BMI with HbA1c levels was observed in the low BMI group, while a positive correlation was shown in the high BMI group. Copyright © 2016 John Wiley & Sons, Ltd.

The association of incident hypertension with metabolic health and obesity status: definition of metabolic health does not matter.

OBJECTIVE: Metabolically healthy obese (MHO) phenotype refers to obese individuals with a favourable metabolic profile. Its prognostic value remains controversial and may partly depend on differences in how the phenotype is defined. We aimed to investigate whether the MHO phenotype is associated with future development of incident hypertension in a Korean population according to various definitions of metabolic health. SUBJECTS AND METHODS: The study population comprised 31 033 Koreans without hypertension. Participants were stratified into metabolically healthy nonobese (MHNO), metabolically unhealthy nonobese (MUNO), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) by body mass index (cut-off value, 25·0 kg/m(2) ) and metabolic health state, using four different definitions: Adult Treatment Panel (ATP)-III, Wildman, Karelis and the homoeostasis model assessment (HOMA) criteria. RESULTS: Over the median follow-up period of 35·0 months (range, 4·5-81·4 months), 4589 of the 31 033 individuals (14·8%) developed incident hypertension. Compared with the MHNO group, the MHO group showed increased association with incident hypertension with multivariate-adjusted odds ratios of 1·56 (95% confidence interval [CI], 1·41-1·72), 1·58 (95% CI 1·42-1·75), 1·52 (95% CI 1·35-1·71) and 1·46 (95% CI 1·33-1·61), when defined by ATP-III, Wildman, Karelis and HOMA criteria, respectively. CONCLUSION: MUO individuals showed the highest association with the incident hypertension (adjusted odds ratios up to 2·00). MHO subjects showed an approximately 1·5-fold higher association with incident hypertension than their nonobese counterpart regardless of the definition of metabolic health used. Thus, considering both metabolic health and obesity is important for the assessment of potential cardiovascular outcomes.

Mortality and causes of death in a national sample of type 2 diabetic patients in Korea from 2002 to 2013.

BACKGROUND: We aimed to investigate the mortality rate (MR), causes of death and standardized mortality ratio (SMR) in Korean type 2 diabetic patients from 2002 to 2013 using data from the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC). METHODS: From this NHIS-NSC, we identified 29,807 type 2 diabetic subjects from 2002 to 2004. Type 2 diabetes was defined as a current medication history of anti-diabetic drugs and the presence of International Classification of Diseases (ICD)-10 codes (E11-E14) as diagnosis. Specific causes of death were recorded according to ICD-10 codes as the following: diabetes, malignant neoplasm, disease of the circulatory system, and other causes. RESULTS: A total of 7103 (23.8 %) deaths were recorded. The MR tended to increase with age. In particular, the ratio of MR for men versus women was the highest in their 40s-50s. The overall SMR was 2.32 and the SMRs attenuated with increasing age. The causes of death ascribed to diabetes, malignant neoplasm, ischemic heart disease, cerebrovascular disease, and other causes were 22.0, 24.8, 6.2, 11.2 and 31.3 %, respectively. The SMRs according to each cause of death were 9.73, 1.76, 2.60, 2.04 and 1.89, respectively. CONCLUSIONS: The MRs among type 2 diabetic subjects increased with age, and diabetic men exhibited a higher mortality risk than diabetic women in Korea. Subjects with type 2 diabetes exhibited an excess mortality when compared with the general population. Approximately 78.0 % of the diabetes-related deaths was not ascribed to diabetes, and malignant neoplasm was the most common cause of death among those not recorded as diabetes.

The risk of chronic kidney disease in a metabolically healthy obese population.

Obesity has become an important risk factor for chronic kidney disease (CKD). The metabolically healthy obese (MHO) phenotype refers to obese individuals with a favorable metabolic profile. However, its prognostic value remains controversial and may depend on the health outcome being investigated. To assess this, we examined the risk of MHO phenotype with incident CKD in a Korean population of 41,194 people without CKD. Individuals were stratified by body mass index (cutoff value, 25.0 kg/m(2)) and metabolic health state (assessed using Adult Treatment Panel-III criteria). Incident CKD was defined as a glomerular filtration rate of <60 ml/min per 1.73 m(2) calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Over the median follow-up period of 38.7 months, 356 of the individuals developed incident CKD. Compared with the metabolically healthy nonobese (MHNO) group, the MHO group showed increased risk of incident CKD with a multivariate-adjusted hazard ratio of 1.38 (95% CI, 1.01-1.87). Nonobese but metabolically unhealthy individuals were at an increased risk of incident CKD (multivariate-adjusted hazard ratio, 1.37 (95% CI, 1.02-1.93)) than the MHNO group. Metabolically unhealthy obese individuals were at the highest risk of incident CKD. Thus, a healthy metabolic profile does not protect obese adults from incident CKD. Hence, it is important to consider metabolic health along with obesity when evaluating CKD risk.

Association of serum angiopoietin-like protein 2 with carotid intima-media thickness in subjects with type 2 diabetes.

BACKGROUND: Although recent animal studies have suggested that angiopoietin-like protein 2 (ANGPTL2), a novel inflammatory adipokine, is likely to be involved in the pathogenesis of atherosclerosis, in rodents, little is known regarding whether serum ANGPTL2 level is also associated with atherosclerosis in humans, especially in patients with type 2 diabetes. The aim of this study was to investigate whether serum ANGPTL2 concentration is associated with atherosclerosis by measuring carotid intima-media thickness (IMT) in subjects with type 2 diabetes without previous history of cardiovascular diseases. In addition, we examined the clinical and biochemical variables associated with serum ANGPLT2 concentration. METHODS: We measured the circulating ANGPTL2 level in 166 subjects (92 men and 74 women; mean age of 60.0 years) with type 2 diabetes. Measurements of carotid IMT were performed in all subjects. RESULTS: Serum ANGPTL2 concentration was positively correlated with carotid IMT (r = 0.220, p = 0.004). In multiple linear regression, serum ANGPTL2 concentration was independently associated with increased carotid IMT along with older age, male gender, and higher systolic blood pressure. Higher levels of hemoglobin A1c and high-sensitivity C-reactive protein were significantly associated with elevated serum ANGPTL2 concentration in subjects with type 2 diabetes. CONCLUSIONS: Serum ANGPTL2 concentration was significantly and positively associated with carotid atherosclerosis in patients with type 2 diabetes, suggesting that ANGPTL2 may be important in the atherosclerosis in humans.

A randomized, double-blind, placebo-controlled, phase II clinical trial to investigate the efficacy and safety of oral DA-1229 in patients with type 2 diabetes mellitus who have inadequate glycaemic control with diet and exercise.

BACKGROUND: DA-1229 is a novel, potent and selective dipeptidyl peptidase-4 (DPP-IV) inhibitor that is orally bioavailable. We aimed to evaluate the optimal dose, efficacy and safety of DA-1229, in Korean subjects with type 2 diabetes mellitus suboptimally controlled with diet and exercise. METHODS: We enrolled 158 patients (mean age, 53 years and a mean BMI, 25.6 kg/m(2) ). The mean baseline fasting plasma glucose level, HbA1c and duration of diabetes were 8.28 mmol/L, 7.6% (60 mmol/mol) and 3.9 years, respectively. After 2 or 6 weeks of an exercise and diet program followed by 2 weeks of a placebo period, the subjects were randomized into one of four groups for a 12-week active treatment period: placebo, 2.5, 5 or 10 mg of DA-1229. RESULTS: All three doses of DA-1229 significantly reduced HbA1c from baseline compared to the placebo group (-0.09 in the placebo group vs. -0.56, -0.66 and -0.61% in 2.5, 5 and 10-mg groups, respectively) but without any significant differences between the doses. Insulin secretory function, as assessed by homeostasis model assessment ß-cell, the insulinogenic index, 2-h oral glucose tolerance test (OGTT) C-peptide and post-OGTT C-peptide area under the curve (AUC)0-2h, significantly improved with DA-1229 treatment. The incidence of adverse events was similar between the treatment groups and DA-1229 did not affect body weight or induce hypoglycaemic events. CONCLUSIONS: DA-1229 monotherapy (5 mg for 12 weeks) improved HbA1c, fasting plasma glucose level, OGTT results and ß-cell function. This drug was well tolerated in Korean subjects with type 2 diabetes mellitus.