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Background: The potential preventive effect of fenofibrate on lower extremity amputation (LEA) and peripheral arterial disease (PAD) in patients with type 2 diabetes (T2D) is not fully elucidated., Methods: We selected adult patients ≥ 20 years of age with T2D from the Korean National Health Insurance Service Database (2009-2012). The fenofibrate users were matched in a 1:4 ratio with non-users using propensity scores (PS). The outcome variables were a composite of LEA and PAD and the individual components. The risks of outcomes were implemented as hazard ratio (HR) with 95% confidence intervals (CI). For safety issues, the risks of acute kidney injury, rhabdomyolysis and resulting hospitalization were analyzed., Results: A total of 114,920 patients was included in the analysis with a median follow-up duration of 7.6 years (22,984 and 91,936 patients for the fenofibrate user and non-user groups, respectively). After PS matching, both groups were well balanced. The fenofibrate group was associated with significantly lower risks of composite outcome of LEA and PAD (HR 0.81; 95% CI 0.70-0.94), LEA (HR 0.76; 95% CI 0.60-0.96), and PAD (HR 0.81; 95% CI 0.68-0.96). The risk of acute kidney injury, rhabdomyolysis, or hospitalization for these events showed no significant difference between the two groups. Subgroup analyses revealed consistent benefits across age groups, genders, and baseline lipid profiles., Conclusions: This nationwide population-based retrospective observational study suggests that fenofibrate can prevent LEA and PAD in patients with T2D who are on statin therapy., (© 2024. The Author(s).)

Backgruound: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia., Methods: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment., Results: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events., Conclusion: The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

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., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: We evaluated the accuracy and safety of the CareSens Air, a novel real-time continuous glucose monitoring system (CGMS), during 15 days of use in adults with diabetes. Methods: Adults with either type 1 diabetes or type 2 diabetes requiring intensive insulin therapy participated at four sites in South Korea. All participants wore the sensor for 15 days. Participants were scheduled for four 8-h clinic sessions on Day 1, 5 ± 1, 10 ± 1, and 15. Accuracy was evaluated based on the proportion of continuous glucose monitoring (CGM) values within 15% of YSI values ≥100 mg/dL or within 15 mg/dL of YSI values <100 mg/dL (%15/15), along with the %20/20, %30/30, and %40/40 agreement rates. The mean absolute relative difference (MARD) between the CGM and YSI values was calculated. Results: Data from 83 participants (83 sensors, 10,029 CGM-YSI matched pairs) were analyzed. The overall MARD was 10.42%, and the overall %15/15, %20/20, %30/30, and %40/40 accuracy were 78.55%, 89.04%, 96.47%, and 98.87%, respectively. The consensus error grid analysis showed that 99.92% of CGM values fell into Zone A or B (Zone A: 89.83%, Zone B: 10.09%). The %20/20 accuracy of CGMS was 88.11% on Day 1, 90.11% on Day 3-5, 92.09% on Day 8-10, and 85.63% on Day 15. No serious adverse events were reported. Conclusions: The CareSens Air demonstrated accurate performance across the wide glycemic range and was well tolerated during the 15-day sensor use period.

Backgruound: Recent diabetes management guidelines recommend that sodium-glucose cotransporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1RAs) with proven cardiovascular benefits should be prioritized for combination therapy in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD). This study was aimed at evaluating SGLT2i or GLP-1RA usage rates and various related factors in patients with T2DM and established CVD., Methods: We enrolled adults with T2DM aged ≥30 years who were hospitalized due to established CVD from January 2019 to May 2020 at 13 secondary and tertiary hospitals in Korea in this retrospective observational study., Results: Overall, 2,050 patients were eligible for analysis among 2,107 enrolled patients. The mean patient age, diabetes duration, and glycosylated hemoglobin level were 70.0 years, 12.0 years, and 7.5%, respectively. During the mean follow-up duration of 9.7 months, 25.7% of the patients were prescribed SGLT2is after CVD events. However, only 1.8% were prescribed GLP-1RAs. Compared with SGLT2i non-users, SGLT2i users were more frequently male and obese. Furthermore, they had a shorter diabetes duration but showed worse glycemic control and better renal function at the time of the event. GLP-1RA users had a longer duration of diabetes and worse glycemic control at the time of the event than GLP-1RA non-users., Conclusion: The SGLT2i or GLP-1RA prescription rates were suboptimal in patients with T2DM and established CVD. Sex, body mass index, diabetes duration, glycemic control, and renal function were associated with the use of these agents.

Aims: Glucagon-like peptide-1 receptor agonist (GLP-1 RA) is used to treat obesity or type 2 diabetes mellitus (DM). We compared weight loss and side-effects between patients with and without DM using GLP-1 RA., Methods: This was a retrospective cohort study based on electronic medical records. Patients were categorized into three groups: liraglutide without DM (LiRa&#95;NL), liraglutide with DM (LiRa&#95;DM), and lixisenatide with DM (LiXi&#95;DM). Six-month outcomes were evaluated for weight loss, side-effect types, and onset discontinuation of GLP-1 RA., Results: We enrolled 356 (190 LiRa&#95;NL, 95 LiRa&#95;DM, and 71 LiXi&#95;DM) patients (women, 72.5 %; mean age, 43.7 ± 12.7 years; mean body mass index, 30.7 ± 5.2 kg/m 2 ). The mean glycated hemoglobin (HbA1c) participants were 7.7 ± 2.1 %. Average weight loss was 2.9 ± 0.3 kg. The change in HbA1c was lower in the LiXi&#95;DM group than in the LiRa&#95;DM group (- 1.1 ± 0.2 % vs. - 0.4 ± 0.1 %, P < 0.05). The LiRa&#95;DM group showed a more effective weight loss (- 3.0 ± 0.4 kg) than the LiXi&#95;DM group (- 0.9 ± 0.4 kg) (P < 0.05). Approximately 30 % of the patients reported experiencing side-effects, with gastrointestinal side-effects being the most frequent (20.5 %). The median side-effect onset was 1.9 ± 0.1 months from first treatment. The rate of GLP-1 RA discontinuation was 72.8 %. Discontinuation rates due to side-effects were 75.7 %, 68.9 %, and 64.4 % in the LiRa&#95;NL, LiRa&#95;DM, and LiXi&#95;DM groups, respectively., Conclusions: The LiRa&#95;NL group showed the most weight loss, although the discontinuation rate was high. Most side-effects occurred at 1-2 months. When prescribing GLP-1 RA, education concerning side-effects and discontinuation is needed to enhance treatment adherence., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

We investigated the risk of developing chronic kidney disease (CKD) in patients with young-onset Type 2 diabetes (YOD, diagnosed age < 40 years). We enrolled 84,384 patients aged 20-64 who started anti-diabetic medication between 2010 and 2011 from the Korea National Health Insurance Sharing Service; patients with Type 1 diabetes or a history of CKD were excluded. Multivariate logistic regression analyses were performed to adjust for YOD-distinct variables and compare the incidence of CKD between YOD and late-onset diabetes (LOD, diagnosed age ≥ 40 years). During the median observation period of 5.16 years (interquartile range: 4.58-5.77 years), 1480 out of 77,039 LOD patients and 34 out of 7345 YOD patients developed CKD. Patients with YOD had distinct baseline characteristics compared with the patients with LOD. The odds ratio of developing CKD in patients with YOD over LOD was 1.70 (95% CI 1.15-2.51) after adjusting clinically distinct variables. The increased CKD odds in YOD compared with LOD was greater in the non-smoking group (OR 2.03, 95% CI 1.26-3.26) than in the smoking group (OR 1.49, 95% CI 0.74-2.98, p = 0.0393 for interaction). Among YOD patients, hypertension (34.76% vs. 64.71%, p = 0.0003), dyslipidemia (46.87% vs. 73.53%, p = 0.0019), and sulfonylurea use (35.54% vs. 52.94%, p = 0.0345) were associated with CKD development. YOD patients have a greater risk of developing CKD than LOD patients after adjusting clinically distinct variables., (© 2023. The Author(s).)

Background: Many have the rising coincidence of diabetes mellitus (DM) and endemic tuberculosis (TB). We evaluated whether the severity of diabetes is associated with an increased risk of active TB infection., Methods:  Using a nationally representative database from the Korean National Health Insurance System, 2, 489, 718 people with type 2 DM who underwent a regular health checkup during 2009-2012 were followed up until the end of 2018. The diabetes severity score parameters included the number of oral hypoglycemic agents (≥ 3), insulin use, diabetes duration (≥ 5 years), and the presence of chronic kidney disease (CKD) or cardiovascular disease. Each of these characteristics was scored as one point, and their sum (0-5) was used as the diabetes severity score., Results: We identified 21, 231 cases of active TB during a median follow-up of 6.8 years. Each parameter of the diabetes severity score was associated with an increased risk of active TB (all P < 0.001). Insulin use was the most significant factor related to the risk of TB, followed by CKD. The risk of TB increased progressively with increasing diabetes severity score. After adjusting for possible confounding factors, the hazard ratio (95% confidence interval) for TB were 1.23 (1.19-1.27) in participants with one parameter, 1.39 (1.33-1.44) in those with two parameters, 1.65 (1.56-1.73) in those with three parameters, 2.05 (1.88-2.23) in those with four parameters, and 2.62 (2.10-3.27) in those with five parameters compared with participants with no parameters., Conclusion: Diabetes severity was strongly associated in a dose-dependent manner with the occurrence of active TB. People with a higher diabetes severity score may be a targeted group for active TB screening., (© 2023. The Author(s).)

Background: It remains unclear whether a combination of glycemic variability and glycated hemoglobin (HbA1c) status leads to a higher incidence of cardiovascular disease (CVD). Therefore, to investigate CVD risk according to the glucose control status during early diabetes, we examined visit-to-visit HbA1c variability among patients with type 2 diabetes (T2DM)., Methods: In this 9-year retrospective study, we measured HbA1c levels at each visit and tracked the change in HbA1c levels for 3 years after the first presentation (observation window) in newly diagnosed T2DM patients. We later assessed the occurrence of CVD in the last 3 years (target outcome window) of the study period after allowing a 3-year buffering window. The HbA1c variability score (HVS; divided into quartiles, HVS&#95;Q1-4) was used to determine visit-to-visit HbA1c variability., Results: Among 4,817 enrolled T2DM patients, the mean HbA1c level was < 7% for the first 3 years. The group with the lowest HVS had the lowest rate of CVD (9.4%; 104/1,109 patients). The highest incidence of CVD of 26.7% (8/30 patients) was found in HVS [≥ 9.0%]&#95;Q3, which was significantly higher than that in HVS [6.0-6.9%]&#95;Q1 ( P = 0.006), HVS [6.0-6.9%]&#95;Q2 ( P = 0.013), HVS [6.0-6.9%]&#95;Q3 ( P = 0.018), and HVS [7.0-7.9%]&#95;Q3 ( P = 0.040)., Conclusion: To our knowledge, this is the first long-term study to analyze the importance of both HbA1c change and visit-to-visit HbA1c variability during outpatient visits within the first 3 years. Lowering glucose levels during early diabetes may be more critical than reducing visit-to-visit HbA1c variability., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Purpose: Liraglutide is known to have much lower weight loss effects in real clinical fields than in randomized clinical trials because of its side effects (SE) and discomfort associated with injections. This study is aimed at determining whether the side effects of liraglutide affect weight reduction and its maintenance in real-world practice., Methods: Endocrinologists conducted a retrospective chart review of data from two tertiary university hospitals. All patients who had been prescribed liraglutide at least once between January 2014 and December 2019 were included. For an average of 3 and 6 months, weight changes due to the presence or absence of SE and discontinuation (MAIN or STOP) of liraglutide were checked., Results: Only 40.8% (64/157) of the patients remained on liraglutide for 6 months; 14.7% (23/157) maintained the drug despite SEs (MAIN&#95;SE(+)), and 40.1% (63/157) discontinued the drug despite not having SEs (STOP&#95;SE(-)). At 3 months, there was -5.9 ± 0.6%, -7.9 ± 0.9%, -4.5 ± 0.5%, and -3.4 ± 0.6% weight reduction in the MAIN&#95;SE(-), MAIN&#95;SE(+), STOP&#95;SE(-), and STOP&#95;SE(+) groups, respectively (all p < 0.001 compared to the baseline). However, there were no significant differences in the weight loss between the MAIN ( p = 0.062) and STOP ( p = 0.204) groups. At 6 months, the weight reduction was -2.0 ± 0.5% ( p < 0.001) in MAIN&#95;SE(-), -2.2 ± 0.7% ( p < 0.005) in MAIN&#95;SE(+), -1.7 ± 0.7% ( p < 0.01) in STOP&#95;SE(-), and -2.0 ± 0.6% ( p = 0.01) in STOP&#95;SE(+), compared to baseline. SEs also caused no significant differences in weight loss between the MAIN ( p = 0.787) and STOP ( p = 0.694) groups., Conclusions: Our study confirmed that the side effects of liraglutide did not affect weight reduction. Moreover, in the real world, the continuous rate of liraglutide use is not high, and the weight gradually increases after 3 months. Therefore, in addition to the side effects of liraglutide, the medical staff should consider various factors that affect drug adherence, consider ways to increase compliance, and continue to ensure management so that patients can maintain their weight., Competing Interests: No potential conflict of interest relevant to this article is reported by the authors., (Copyright © 2022 Jin Yu et al.)

Background: We evaluated patients visiting a tertiary university hospital due to a diagnosis of diabetes with a goal of achieving blood glucose control and evaluated blood glucose persistence over 7 years according to the change in blood glucose evident at 3 months after the first visit., Methods: Patients treated from 2009 to 2013 were categorized into four groups according to the change in HbA1c levels during the first 3 months of follow-up (Best&#95;group, ≥ 1.6% decrease; Better&#95;group, 0.5-1.5% decrease; Neutral&#95;group, maintained at -0.4% to +0.4%; Worse&#95;group, ≥ 0.5% increase). Each patient's blood glucose control status was then monitored for 7 years. The incidence of stroke and acute coronary syndrome during this period was confirmed., Results: Overall, 9,776 patients were included. HbA1c values were lower in the Best&#95;group than in the other groups at all time points (all P < 0.001). The rate of reaching targets of < 6.5% or < 7.0% HbA1c decreased over time; the rate at which the estimated glomerular filtration rate decreased to < 30 or < 60 mL/min/1.73m² increased over time (all trends, P < 0.01)., Conclusion: Blood glucose control status in the first 3 months after initiating hospital care enabled estimation of the patient's glycemic control status for the next 7 years. In cases with poor initial blood glucose control, a new or more active method of blood glucose control should be sought., Competing Interests: No potential conflict of interest relevant to this article is reported., (© 2022 The Korean Academy of Medical Sciences.)

Background: Elevated γ-glutamyl transferase (γ-GTP) level is associated with metabolic syndrome, impaired glucose tolerance, and insulin resistance, which are risk factors for type 2 diabetes. We aimed to investigate the association of cumulative exposure to high γ-GTP level with risk of diabetes., Methods: Using nationally representative data from the Korean National Health Insurance system, 346,206 people who were free of diabetes and who underwent 5 consecutive health examinations from 2005 to 2009 were followed to the end of 2018. High γ-GTP level was defined as those in the highest quartile, and the number of exposures to high γ-GTP level ranged from 0 to 5. Hazard ratio (HR) and 95% confidence interval (CI) for diabetes were analyzed using the multivariable Cox proportional-hazards model., Results: The mean follow-up duration was 9.2±1.0 years, during which 15,183 (4.4%) patients developed diabetes. There was a linear increase in the incidence rate and the risk of diabetes with cumulative exposure to high γ-GTP level. After adjusting for possible confounders, the HR of diabetes in subjects with five consecutive high γ-GTP levels were 2.60 (95% CI, 2.47 to 2.73) in men and 3.05 (95% CI, 2.73 to 3.41) in women compared with those who never had a high γ-GTP level. Similar results were observed in various subgroup and sensitivity analyses., Conclusion: There was a linear relationship between cumulative exposure to high γ-GTP level and risk of diabetes. Monitoring and lowering γ-GTP level should be considered for prevention of diabetes in the general population.

Guidelines for the management of patients with diabetes have become an important part of clinical practice that improve the quality of care and help establish evidence-based medicine in this field. With rapidly accumulating evidence on various aspects of diabetes care, including landmark clinical trials of treatment agents and newer technologies, timely updates of the guidelines capture the most current state of the field and present a consensus. As a leading academic society, the Korean Diabetes Association publishes practice guidelines biennially and the American Diabetes Association does so annually. In this review, we summarize the key changes suggested in the most recent guidelines. Some of the important updates include treatment algorithms emphasizing comorbid conditions such as atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease in the selection of anti-diabetic agents; wider application of continuous glucose monitoring (CGM), insulin pump technologies and indices derived from CGM such as time in range; more active screening of subjects at high-risk of diabetes; and more detailed individualization in diabetes care. Although there are both similarities and differences among guidelines and some uncertainty remains, these updates provide a good approach for many clinical practitioners who are battling with diabetes.

Aims/introduction: Increased blood glucose or increased weight is often observed in patients who are prescribed sodium-glucose cotransporter 2 inhibitors (SGLT2i). The aim of this study was to determine in advance which patients, among those prescribed a SGLT2i, would be likely to have improved or worsened blood glucose levels and gain or loss of weight through the use of real-world data-based prescriptions., Materials and Methods: After 3 months of dapagliflozin prescription, patients were divided into four groups: H(+)W(+) for improved glucose and weight loss; H(+)W(-) for improved blood glucose and weight gain; H(-)W(+) for worsened glucose and weight loss; and H(-)W(-) for worsened glucose and weight gain., Results: The proportion of patients in the H(+)W(+) group was 53.5% (325/608 patients), H(+)W(-) was 19.7% (120/608), H(-)W(+) was 26.8% (114/608) and H(-)W(-) was 8.1% (49/608). The odds of proceeding to H(+)W(-) compared with H(+)W(+), which served as the reference, were 144% in baseline hemoglobin A1c (HbA1c) 7.0-8.0%, 233% in baseline HbA1c 8.0-9.0% and 359% in baseline HbA1c ≥ 9.0% (odds ratio 3.59, P < 0.05) compared with the reference. The odds of proceeding to H(-)W(+) were 29, 13 and 8%, respectively (all P < 0.05), and to H(-)W(-) were 17, 15 and 8%, respectively (all P < 0.05), compared with the reference. The results were expected to vary individually, because changes in blood glucose and bodyweight are more affected by diet and exercise than by drugs., Conclusions: When first prescribing dapagliflozin, a physician should be aware of the weight gain rather than glucose change if the baseline HbA1c is high, and might concentrate on weight-related lifestyle training, such as diet and exercise., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Glycemic variability is associated with the development of diabetic complications and hypoglycemia. However, the effect of sodium-glucose transporter 2 (SGLT2) inhibitors on glycemic variability is controversial. We aimed to examine the effect of dapagliflozin as an add-on therapy to insulin on the glycemic variability assessed using continuous glucose monitoring (CGM) in subjects with type 2 diabetes mellitus., Methods: In this multicenter, placebo-controlled, double-blind, randomized study, 84 subjects received 10 mg of dapagliflozin (n=41) or the placebo (n=43) for 12 weeks. CGM was performed before and after treatment to compare the changes in glycemic variability measures (standard deviation [SD], mean amplitude of glycemic excursions [MAGEs])., Results: At week 12, significant reductions in glycosylated hemoglobin (-0.74%±0.66% vs. 0.01%±0.65%, P<0.001), glycated albumin (-3.94%±2.55% vs. -0.67%±2.48%, P<0.001), and CGM-derived mean glucose (-41.6±39.2 mg/dL vs. 1.1±46.2 mg/dL, P<0.001) levels were observed in the dapagliflozin group compared with the placebo group. SD and MAGE were significantly decreased in the dapagliflozin group, but not in the placebo group. However, the difference in ΔSD and ΔMAGE failed to reach statistical significance between two groups. No significant differences in the incidence of safety endpoints were observed between the two groups., Conclusion: Dapagliflozin effectively decreased glucose levels, but not glucose variability, after 12 weeks of treatment in participants with type 2 diabetes mellitus receiving insulin treatment. The role of SGLT2 inhibitors in glycemic variability warrants further investigations.

Background: Most of the widely used prediction models for cardiovascular disease are known to overestimate the risk of this disease in Asians. We aimed to generate a risk model for predicting myocardial infarction (MI) in middle-aged Korean subjects with type 2 diabetes., Methods: A total of 1,272,992 subjects with type 2 diabetes aged 40 to 64 who received health examinations from 2009 to 2012 were recruited from the Korean National Health Insurance database. Seventy percent of the subjects (n=891,095) were sampled to develop the risk prediction model, and the remaining 30% (n=381,897) were used for internal validation. A Cox proportional hazards regression model and Cox coefficients were used to derive a risk scoring system. Twelve risk variables were selected, and a risk nomogram was created to estimate the 5-year risk of MI., Results: During 7.1 years of follow-up, 24,809 cases of MI (1.9%) were observed. Age, sex, smoking status, regular exercise, body mass index, chronic kidney disease, duration of diabetes, number of anti-diabetic medications, fasting blood glucose, systolic blood pressure, total cholesterol, and atrial fibrillation were significant risk factors for the development of MI and were incorporated into the risk model. The concordance index for MI prediction was 0.682 (95% confidence interval [CI], 0.678 to 0.686) in the development cohort and 0.669 (95% CI, 0.663 to 0.675) in the validation cohort., Conclusion: A novel risk engine was generated for predicting the development of MI among middle-aged Korean adults with type 2 diabetes. This model may provide useful information for identifying high-risk patients and improving quality of care.

Background: Some patients admitted to hospitals for glycemic control experience hypoglycemia despite regular meals and despite adhering to standard blood glucose control protocols. Different factors can have a negative impact on blood glucose control and prognosis after discharge. This study investigated risk factors for hypoglycemia and its effects on glycemic control during the hospitalization of patients in the general ward., Methods: This retrospective study included patients who were admitted between 2009 and 2018. Patients were provided regular meals at fixed times according to ideal body weights during hospitalization. We categorized the patients into two groups: those with and those without hypoglycemia during hospitalization., Results: Of the 3,031 patients, 379 experienced at least one episode of hypoglycemia during hospitalization (HYPO group). Hypoglycemia occurred more frequently particularly in cases of premixed insulin therapy. Compared with the control group, the HYPO group was older (61.0±16.8 years vs. 59.1±16.5 years, P =0.035), with more females (60.4% vs. 49.6%, P <0.001), lower body mass index (BMI) (23.5±4.2 kg/m² vs. 25.1±4.4 kg/m², P <0.001), and higher prevalence of type 1 diabetes mellitus (6.1% vs. 2.6%, P <0.001), They had longer hospital stay (11.1±13.5 days vs. 7.6±4.6 days, P <0.001). After discharge the HYPO group had lower glycosylated hemoglobin reduction rate (-2.0%±0.2% vs. -2.5%±0.1%, P =0.003) and tended to have more frequent cases of cardiovascular disease., Conclusion: Hypoglycemia occurred more frequently in older female patients with lower BMI and was associated with longer hospital stay and poorer glycemic control after discharge. Therefore, clinicians must carefully ensure that patients do not experience hypoglycemia during hospitalization., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2020 Korean Diabetes Association.)

Aims: The incidence of stroke differs between Asians and Caucasians, and between people with or without diabetes mellitus (DM). This study aimed to develop a model to predict the risk of stroke in middle-aged patients with type 2 DM., Methods: Using the National Health Insurance Database in Korea, data from patients aged 40-64 years with type 2 DM who received a health examination from 2009 to 2012 (n = 1,297,131) were analyzed as development (n = 907,992) and validation (n = 389,139) cohorts. Cox proportional-hazards regression model was used to derive a risk-scoring system, and 13 predictive variables were selected. A risk score nomogram based on the risk prediction model was created to estimate the 5-year risk of stroke., Results: In patients with type 2 DM, significant predictors for the development of stroke were older age, being male or a current smoker, lack of exercise, low body mass index, low estimated glomerular filtration rate, presence of coronary heart disease, longer duration of DM, insulin or multiple oral hypoglycemic agents use, low (<100 mg/dL) or high (≥140 mg/dL) fasting blood glucose, high systolic blood pressure, high total cholesterol, and presence of atrial fibrillation. The concordance indexes for stroke prediction were 0.703 (95% confidence interval [CI] 0.700-0.707) in the development cohort and 0.703 (95% CI 0.698-0.708) in the validation cohort., Conclusions: We developed a risk model using various clinical parameters to predict stroke in patients with type 2 DM. This model may provide helpful information for identifying high-risk patients and guide prevention of stroke in this specific population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: MLR-1023, called Tolimidone when evaluated unsuccessfully by Pfizer for gastric ulcer disease, has been repurposed as a novel oral insulin sensitizer with its effects mediated by selective activation of Lyn kinase. We aimed to evaluate the optimal dose, efficacy and safety of MLR-1023 in patients with type 2 diabetes., Methods: Type 2 diabetes patients (18-75 years) on diet/exercise therapy were randomized and double-blinded to receive MLR-1023 (100-mg or 200-mg, once-daily [qd] or twice-daily [bid]) or matching placebo for 28 days. The primary endpoint was postprandial glucose (PPG) area under the curve (AUC 0 - 3h ) in a mixed meal tolerance test (MMTT) at day 29. Secondary endpoints included changes in fasting plasma glucose (FPG), insulin, HbA1c, lipids and body weight and adverse events. ANCOVA model was used for efficacy analysis., Results: The placebo-corrected least-squares mean differences (ΔLSM) in MMTT PPG AUC0-3 h (mmol/L) were -5.96 and -5.6 (both p = 0.03) in the MLR-1023 100-mg qd and 100-mg bid groups, respectively. The placebo-corrected ΔLSM in FPG (mmol/L) was -2.34 (p = 0.003) in the MLR-1023 100-mg qd group. Triglycerides improved with MLR-1023 (ΔLSM, -0.56 mmol/L, p = 0.07 and -0.59 mmol/L, p = 0.05) in the 200mgqd and 200 mg bid groups, respectively. Reductions in fasting insulin, HbA1c and body weight were not statistically significant. Most common adverse events with MLR-1023 treatment were headache (4.2%) and somnolence (2.5%)., Conclusions: MLR-1023 100-mg once-daily for 4 weeks was the most effective dose with significant reduction in PPG AUC following a MMTT. MLR-1023 was safe and well-tolerated in patients with type 2 diabetes. Clinical Trials Registration Number: NCT02317796., Competing Interests: Declaration of competing interest All other authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Recent evidence of the effectiveness of mobile phone-based diabetes management systems is generally based on studies conducted in tertiary hospitals or professional diabetes clinics., Objective: This study aimed to evaluate the clinical efficacy and applicability of a mobile phone-based glucose-monitoring and feedback system for the management of type 2 diabetes mellitus (T2DM) in multiple primary care clinic settings., Methods: In this multicenter, cluster-randomized controlled, open trial, 13 primary care clinics in Seoul and other large cities in South Korea were voluntarily recruited. Overall, 150 (9 clinics) and 97 (4 clinics) participants with T2DM were assigned to the intervention and control groups, respectively (2:1 allocation). Every month, participants in both groups attended face-to-face physicians' consultation for the management of diabetes in the clinic. For the intervention group, participants were required to upload their daily self-monitoring of blood glucose (SMBG) results using the mobile phone app in addition to outpatient care for 3 months. The results were automatically transmitted to the main server. Physicians had to check their patients' SMBG results through an administrator's website and send a short feedback message at least once a week. At baseline and 3 months, both groups had anthropometry and blood tests, including hemoglobin A 1c (HbA 1c ), and responded to questionnaires about treatment satisfaction and compliance., Results: At 3 months, participants in the intervention group showed significantly more improvement in HbA 1c (adjusted mean difference to control -0.30%, 95% CI -0.50 to -0.11; P=.003) and fasting plasma glucose (-17.29 mg/dL, 95% CI -29.33 to -5.26; P=.005) than those in the control group. In addition, there was significantly more reduction in blood pressure, and the score regarding treatment satisfaction and motivation for medication adherence increased more in the intervention group than in the control group. In the subgroup analyses, the effect on glycemic control was more significant among younger patients and higher baseline HbA 1c levels., Conclusions: The mobile phone-based glucose-monitoring and feedback system was effective in glycemic control when applied in primary care clinic settings. This system could be utilized effectively with diverse institutions and patients., Trial Registration: Clinical Research Information Service (CRIS) https://tinyurl.com/tgqawbz., (©Yeoree Yang, Eun Young Lee, Hun-Sung Kim, Seung-Hwan Lee, Kun-Ho Yoon, Jae-Hyoung Cho. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 26.02.2020.)

Context: The bidirectional relationship between low high-density lipoprotein cholesterol (HDL-C) and glucose intolerance is well established. Recent studies suggested an association of lipid variability with various health outcomes., Objective: To investigate the combined effect of HDL-C levels and their variability on the risk of diabetes., Design: A population-based cohort study., Setting and Participants: In all, 5,114,735 adults without known diabetes in the Korean National Health Insurance System cohort who underwent three or more health examinations from 2009 to 2013 were included. Visit-to-visit HDL-C variability was calculated using variability independent of the mean (VIM) and the coefficient of variation (CV). Low mean and high variability groups were defined as the lowest and highest quartiles of HDL-C mean and variability, respectively., Main Outcome Measures: Newly developed diabetes., Results: There were 122,192 cases (2.4%) of incident diabetes during the median follow-up of 5.1 years. Lower mean or higher variability of HDL-C was associated with higher risk of diabetes in a stepwise manner, and an additive effect of the two measures was noted. In the multivariable-adjusted model, the hazard ratios and 95% CIs for incident diabetes were 1.20 (1.18 to 1.22) in the high mean/high VIM group, 1.35 (1.33 to 1.37) in the low mean/low VIM group, and 1.40 (1.38 to 1.42) in the low mean/high VIM group compared with the high mean/low VIM group. Similar results were observed when modeling the variability using CV and in various subgroup analyses., Conclusions: Low mean and high variability in HDL-C were independent predictors of diabetes with an additive effect. Both elevating and stabilizing HDL-C may be important goals for reducing diabetes risk., (Copyright © 2019 Endocrine Society.)

Background: We aimed to investigate the effectiveness and safety of adding basal insulin to initiating dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin and/or sulfonylurea (SU) in achieving the target glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM)., Methods: This was a single-arm, multicenter, 24-week, open-label, phase 4 study in patients with inadequately controlled (HbA1c ≥7.5%) T2DM despite the use of DPP-4 inhibitor and metformin. A total of 108 patients received insulin glargine while continuing oral antidiabetic drugs (OADs). The primary efficacy endpoint was the percentage of subjects achieving HbA1c ≤7.0%. Other glycemic profiles were also evaluated, and the safety endpoints were adverse events (AEs) and hypoglycemia., Results: The median HbA1c at baseline (8.9%; range, 7.5% to 11.1%) decreased to 7.6% (5.5% to 11.7%) at 24 weeks. Overall, 31.7% subjects ( n =33) achieved the target HbA1c level of ≤7.0%. The mean differences in body weight and fasting plasma glucose were 1.2±3.4 kg and 56.0±49.8 mg/dL, respectively. Hypoglycemia was reported in 36 subjects (33.3%, 112 episodes), all of which were fully recovered. There was no serious AE attributed to insulin glargine. Body weight change was significantly different between SU users and nonusers (1.5±2.5 kg vs. -0.9±6.0 kg, P =0.011)., Conclusion: The combination add-on therapy of insulin glargine, on metformin and DPP-4 inhibitors with or without SU was safe and efficient in reducing HbA1c levels and thus, is a preferable option in managing T2DM patients exhibiting dysglycemia despite the use of OADs., Competing Interests: Sponsorship for this study and article processing charges was funded by Sanofi-Aventis Korea. Dol Mi Kim is an employee at Sanofi-Aventis Korea. No potential conflict of interest relevant to this article was reported except for her., (Copyright © 2019 Korean Diabetes Association.)

Background: We evaluated the efficacy and safety of acarbose add-on therapy in Korean patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled with metformin and sitagliptin., Methods: A total of 165 subjects were randomized to metformin and sitagliptin (Met+Sita, n =65), metformin, sitagliptin, and acarbose (Met+Sita+Acarb, n =66) and sitagliptin and acarbose (Sita+Acarb, exploratory assessment, n =34) therapy in five institutions in Korea. After 16 weeks of acarbose add-on or metformin-switch therapy, a triple combination therapy was maintained from week 16 to 24., Results: The add-on of acarbose (Met+Sita+Acarb group) demonstrated a 0.44%±0.08% (P<0.001 vs. baseline) decrease in glycosylated hemoglobin (HbA1c) at week 16, while changes in HbA1c were insignificant in the Met+Sita group (-0.09%±0.10%, P =0.113). After 8 weeks of triple combination therapy, HbA1c levels were comparable between Met+Sita and Met+Sita+Acarb group (7.66%±0.13% vs. 7.47%±0.12%, P =0.321). Acarbose add-on therapy demonstrated suppressed glucagon secretion (area under the curve of glucagon, 4,726.17±415.80 ng·min/L vs. 3,314.38±191.63 ng·min/L, P =0.004) in the absence of excess insulin secretion during the meal tolerance tests at week 16 versus baseline. The incidence of adverse or serious adverse events was similar between two groups., Conclusion: In conclusion, a 16-week acarbose add-on therapy to metformin and sitagliptin, effectively lowered HbA1c without significant adverse events. Acarbose might be a good choice as a third-line therapy in addition to metformin and sitagliptin in Korean subjects with T2DM who have predominant postprandial hyperglycemia and a high carbohydrate intake., Competing Interests: This study was supported by a grant from Bayer Korea, Co. Ltd. (Grant number: 15938)., (Copyright © 2019 Korean Diabetes Association.)

Aims: To evaluate the association between impaired heart rate variability (HRV) and cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM)., Methods: A total of 655 patients with T2DM who underwent cardiovascular autonomic function testing were consecutively recruited and followed up prospectively. Time- and frequency-domain HRV were assessed for 5 min by beat-to-beat heart rate recording. We estimated the development of CVD events during a follow-up period., Results: During a median follow-up of 7.8 years, 9.6% (n = 49) of patients developed CVD (10.6 per 1000 patient-years). The mean age and diabetes duration were 54.9 ± 8.6 years and 9.4 ± 7.3 years, respectively. Patients who had cardiovascular autonomic neuropathy (CAN) had decreased HRV compared with those with normal autonomic function. Multivariable cox hazard regression analysis revealed the lowest 10th percentile of the SD of the normal-to-normal interval (HR 2.62; 95% CI 1.30-5.31), total power (HR 2.81; 95% CI 1.37-5.79), low-frequency power (HR 2.68; 95% CI 1.28-5.59), and high-frequency power (HR 2.24; 95% CI 1.09-4.59) were significant predictors for developing CVD in patients with T2DM., Conclusions: Time- and frequency-domain measures of HRV independently predicted cardiovascular outcome in patients with T2DM., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Obesity is a well-known risk factor for type 2 diabetes, but few data exist on the association between weight changes and diabetes risk in non-obese subjects. This study aimed to investigate the effect of weight changes on the incidence of type 2 diabetes in Korea, using 51,405 non-diabetic subjects. Individuals who developed type 2 diabetes were more likely to be older and male, to have high body mass index (BMI), blood pressure, fasting blood glucose, and total cholesterol, to be current smokers and frequent drinkers, to be hypertensive and hyperlipidemic, and to have a family history of diabetes, compared to those without type 2 diabetes. Compared with the consistently non-obese group, there was a higher hazard ratio for incident diabetes (95% confidence interval) in subjects becoming obese [1.49 (1.26-1.77)] and remaining obese [2.56 (2.34-2.81)] after adjustment for confounding factors. Decreased BMI was significantly associated with lower risks for incident diabetes and the trends were more evident in the non-obese group. However, overall there was no significant association of increased BMI with incident diabetes. In conclusion, weight loss was significantly associated with lower risk for diabetes both in non-obese and obese Koreans, but particularly in the non-obese.

Background: Type 2 diabetes (T2D) is a progressive disease that often requires a patient to use multiple antihyperglycemic agents to achieve glycemic control with disease progression. Omarigliptin is a once-weekly dipeptidyl peptidase-4 inhibitor. The purpose of this trial was to assess the efficacy and safety of adding omarigliptin to the treatment regimen of patients with T2D inadequately controlled by dual therapy with metformin and glimepiride., Methods: Patients with T2D and HbA1c ≥7.5% and ≤10.5% while on metformin (≥1500 mg/day) and glimepiride (≥4 mg/day) were randomized to omarigliptin 25 mg once-weekly (N = 154) or placebo (N = 153) for 24 weeks. The primary objective was to assess whether omarigliptin was superior to placebo in reducing HbA1c at Week 24. Secondary objectives were to assess the effects of omarigliptin vs. placebo on FPG and the proportion of subjects attaining HbA1c goals of <7% and <6.5%., Results: From a mean baseline HbA1c of 8.5% (omarigliptin) and 8.6% (placebo), the least squares (LS) mean change from baseline in HbA1c at Week 24 was -0.67% in the omarigliptin group and -0.06% in the placebo group, with a between-group difference (95% CI) of -0.61% (-0.85, -0.38). Treatment with omarigliptin resulted in a significantly greater reduction in FPG relative to placebo (LS mean difference [95% CI] -0.9 mmol/L [-1.4, -0.4]; p < 0.001). The proportion of patients achieving glycemic goals of <7.0% and <6.5% was higher in the omarigliptin group relative to the placebo group. The overall incidences of adverse events (AEs), serious AEs, drug-related AEs and discontinuations were generally similar between treatment groups. The incidence of symptomatic hypoglycemia was 10.5% in the omarigliptin group and 8.5% in the placebo group. Relative to baseline, omarigliptin and placebo treatments were associated with LS mean changes in body weight of -0.1 kg and -0.9 kg, respectively., Conclusion: In patients with T2D and inadequate glycemic control on dual therapy with metformin and glimepiride, compared with placebo, once-weekly omarigliptin provided greater improvement in glycemic control and was generally well tolerated., Trial Registration: ClinicalTrials.gov: NCT01704261 , EudraCT Number: 2012-002612-10. Trial Registration Date: October 8, 2012.

Background: Insulin resistance is one of the most important contributing factors to cardiovascular disease. This study aimed to investigate the association between coronary artery stenosis (CAS) and triglyceride glucose index (TyG index), a simple insulin resistance marker, in asymptomatic subjects with type 2 diabetes., Methods: We recruited asymptomatic adults with type 2 diabetes but without previous history of coronary heart disease (n = 888). Significant CAS was defined as maximum intraluminal stenosis ≥70 % by coronary CT angiography. TyG index was calculated as log [fasting triglycerides (mg/dl) x fasting glucose (mg/dl)/2]., Results: Mean age was 63.8 ± 9.5 and 58.9 % of the subjects were men. We analyzed the participants according to the tertile of TyG index. The TyG index was correlated with HOMA-IR (r = 0.397, P < 0.001), and subjects with higher tertile of TyG index were younger but showed worse clinical and metabolic parameters. The prevalence of CAS was higher in subjects with higher tertile of TyG compared with those with lower tertile of TyG (14 % vs. 7.8 %, P = 0.022). On multiple regression analysis, the highest tertile of TyG index was an independent risk factor for CAS after adjustment for other confounders (odds ratio, 3.19 [95 % CI, 1.371-7.424]). Subgroup analysis showed that TyG index showed more significant association with CAS in patients with risk factors such as old age, longer duration of diabetes, poor glycemic control, no statin use, and male gender., Conclusion: Higher TyG index is associated with increased risk of CAS in asymptomatic subjects with type 2 diabetes, particularly when they have risk factors for cardiovascular disease., Trial Registration: This study was retrospectively registered in ClinicalTrials. gov with the registration number of NCT02070926 in Feb 23, 2014.

Metabolic health and obesity are not stable conditions, and changes in the status of these conditions might lead to different clinical outcomes. We aimed to determine whether changes in metabolic health status or obesity over time have any effect on the risk of future diabetes. Nondiabetic individuals (n = 2692) from a population-based prospective cohort study with baseline and 2 follow-up examinations at 4-year intervals were included. Being "metabolically obese" (MO) was defined as being in the highest quartile of the TyG index (ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]), whereas falling into the lower 3 quartiles was regarded as being "metabolically healthy" (MH). Individuals were classified as "obese" (O) or "nonobese" (NO) using a body mass index of 25 kg/m2 as a cut-off. The risk of diabetes at year 8 was assessed according to changes of metabolic health status between year 0 and 4. Multivariate-adjusted relative risks (RRs) (95% confidence interval [CI]) of diabetes were significantly higher in individuals who retained the MONO phenotype (RR 3.72, 95% CI 2.10, 6.60) or who had progressed to MONO from the MHNO phenotype (RR 1.96, 95% CI 1.06, 3.61), whereas it was not significant in individuals who had improved to MHNO from the MONO phenotype (RR 0.67, 95% CI 0.26, 1.74) compared with individuals who retained the MHNO phenotype. In contrast, obese individuals had significantly higher RRs for diabetes, independent of changes in metabolic health status, whereas weight reduction resulted in a decreased risk of diabetes. Sensitivity analysis using the presence or absence of the metabolic syndrome as a definition of metabolic health revealed similar results. Changes in metabolic health status were an independent risk factor for future diabetes in nonobese individuals, whereas general obesity had a greater contribution to the risk of obese individuals developing diabetes. These observations might imply a different intervention strategy for diabetes prevention according to obesity status.

Aims: We examined the association between hemoglobin A1c (HbA1c) variability and subclinical coronary atherosclerosis in subjects with type 2 diabetes., Methods: We used the multidetector coronary computed tomography data collected from subjects with type 2 diabetes who did not have a history of cardiovascular disease or angina symptoms. HbA1c measurements preceding the date of cardiac imaging were retrospectively collected, and intraindividual SD (HbA1c-SD), CV and adjusted SD of HbA1c measurements were calculated. Subclinical coronary atherosclerosis was defined as calcium score >400 without any cardiac symptoms., Results: A total of 595 subjects were categorized according to the median value of each HbA1c variability indicators. The prevalence of subclinical coronary atherosclerosis was higher in higher HbA1c variability group compared with lower HbA1c variability group. Multivariable logistic regression analysis showed that higher HbA1c-SD and -CV were associated with the presence of subclinical coronary atherosclerosis, independent of mean HbA1c level in subjects with diabetes duration ≤10 years (OR [95% CI]; HbA1c-SD, 2.894 [1.105-7.584]; HbA1c-CV, 2.540 [1.022-6.316])., Conclusions: Long-term stabilization of blood glucose level might be important in preventing subclinical coronary atherosclerosis in subjects with earlier period of type 2 diabetes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This study assessed the associations between microalbuminuria in asymptomatic patients with type 2 diabetes and the presence, extent, and severity of coronary atherosclerosis, as measured by coronary computed tomography angiography (CCTA), and the long-term clinical outcomes. In total, the study enrolled 284 consecutive eligible asymptomatic patients with type 2 diabetes and without known coronary artery disease (CAD), who then underwent CCTA and 24 h urine albumin measurements. Microalbuminuria was defined as 30-300 mg/day urinary albumin excretion. Obstructive CAD, as measured by CCTA, was defined as maximum intra-luminal stenosis ≥50 %. Patients with and without microalbuminuria were compared in terms of obstructive CAD prevalence, and the extent and severity of coronary atherosclerosis. They were evaluated using the following data: coronary artery calcium score (CACS), atheroma burden obstructive score (ABOS), segment involvement score (SIS) and segment stenosis score (SSS). All-cause mortality within a follow-up period of 5 years was also compared. Compared to patients without microalbuminuria, patients with microalbuminuria were more likely to have obstructive CAD (p = 0.004). Microalbuminuria was associated with higher ABOS (p = 0.010), SIS (p = 0.029), and SSS (p = 0.011), except for CACS (p = 0.058). Multivariable analyses adjusted for conventional cardiovascular risk factors revealed that microalbuminuria was an independent predictor of obstructive CAD [odds ratio 2.255, confidence intervals (CI) 1.121-4.538, p = 0.023] and all-cause mortality (hazard ratio 3.469, CI 1.319-9.121, p = 0.012). In asymptomatic patients with type 2 diabetes, microalbuminuria was associated with increased risk of CAD and poorer clinical outcomes.

Background: Limited data exist regarding the prevalence of coronary artery disease (CAD) as well as clinical outcomes in asymptomatic diabetic patients with normotension, controlled hypertension, and uncontrolled hypertension., Methods: We enrolled 935 consecutive asymptomatic type 2 diabetic patients without known CAD. Coronary computed tomography angiography was used to evaluate the prevalence and severity of CAD. Blood pressure was measured at baseline. Patients were assigned to one of the three groups: normotension (n=314), controlled hypertension (systolic blood pressure (SBP)< 140 mm Hg with treatment, n=458), or uncontrolled hypertension (SBP ≥ 140 mm Hg with or without treatment, n=163)., Results: Obstructive CAD (≥ 50% stenosis) increased from the prevalence in normotensive patients (33%) to that in patients with controlled (40%) or uncontrolled hypertension (52%) (p=0.003). The incidence of obstructive CAD in multivessel or left main CAD also increased across the three groups (13%, 21%, 32%, respectively, p<0.001). A multivariate logistic regression analysis showed that uncontrolled hypertension was an independent predictor of obstructive CAD (adjusted odds ratio, 2.13; 95% confidence interval (CI), 1.42 to 3.21, p<0.001). During a median follow-up of 3.1 years, uncontrolled hypertension was associated with increased risk of cardiac death or myocardial infarction compared to the risk in normotensive patients (hazard ratio, 6.11; 95% CI, 1.65 to 22.6, p=0.007)., Conclusion: In asymptomatic type 2 diabetic patients, uncontrolled hypertension was associated with increased risk of CAD and poor clinical outcomes., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Chemerin, a recently identified adipokine, has been linked to adiposity, insulin resistance, metabolic syndrome risk factors and inflammation. Here, we evaluated whether a 12-week lifestyle intervention in overweight and obese adults with type 2 diabetes could significantly affect the average blood glucose and serum chemerin levels over time., Design: Thirty-five overweight or obese subjects with type 2 diabetes were randomized to receive intensive lifestyle modification including supervised exercise sessions or usual care for 12 weeks. Anthropometric and clinical data were collected before the intervention and after 12 weeks., Results: Lifestyle intervention induced a significant decrease in HbA1c (-1·0 ± 0·5 vs 0·1 ± 0·6%, P < 0·001), BMI, total body fat content, serum lipocalin-2 and chemerin levels (-8·1 ± 21·6 vs + 8·2 ± 15·9 ng/ml, P = 0·021) and a significant increase in VO2 max after 12 weeks compared to the usual care group. Baseline chemerin levels were positively correlated with the homoeostasis model of assessment of insulin resistance (HOMA-IR), fasting insulin and the high-sensitivity C-reactive protein (hsCRP) and negatively correlated with insulin sensitivity index (ISI). Changes in the chemerin concentration during 12 weeks were independently negatively correlated with changes in ISI and positively correlated with changes in fasting plasma glucose, total cholesterol and lipocalin-2 levels., Conclusions: A 12-week intensive lifestyle intervention significantly decreased serum chemerin level compared to usual care. Decrease in serum chemerin level was associated with improved insulin sensitivity, and this may be involved in the beneficial effects of lifestyle intervention in overweight and obese type 2 diabetic patients., (© 2013 John Wiley & Sons Ltd.)

Background: To determine whether the TyG index, a product of the levels of triglycerides and fasting plasma glucose (FPG) might be a valuable marker for predicting future diabetes., Methods: A total of 5,354 nondiabetic subjects who had completed their follow-up visit for evaluating diabetes status were selected from a large cohort of middle-aged Koreans in the Chungju Metabolic Disease Cohort study. The risk of diabetes was assessed according to the baseline TyG index, calculated as ln[fasting triglycerides (mg/dL) × FPG (mg/dL)/2]. The median follow-up period was 4.6 years., Results: During the follow-up period, 420 subjects (7.8%) developed diabetes. The baseline values of the TyG index were significantly higher in these subjects compared with nondiabetic subjects (8.9 ± 0.6 vs. 8.6 ± 0.6; P<0.0001) and the incidence of diabetes increased in proportion to TyG index quartiles. After adjusting for age, gender, body mass index, waist circumference, systolic blood pressure, high-density lipoprotein (HDL)-cholesterol level, a family history of diabetes, smoking, alcohol drinking, education level and serum insulin level, the risk of diabetes onset was more than fourfold higher in the highest vs. the lowest quartile of the TyG index (relative risk, 4.095; 95% CI, 2.701-6.207). The predictive power of the TyG index was better than the triglyceride/HDL-cholesterol ratio or the homeostasis model assessment of insulin resistance., Conclusions: The TyG index, a simple measure reflecting insulin resistance, might be useful in identifying individuals at high risk of developing diabetes.

Background: This study aimed to compare the effects of sitagliptin on glycemic change and 24-h blood glucose variability with those of the sulfonylurea glimepiride., Subjects and Methods: A 4-week randomized double blind-labeled prospective design was used. We recruited 33 patients who had been treated with metformin for at least 2 months. Each participant prescribed with metformin was randomly assigned to either the sitagliptin (100 mg) or the glimepiride (2 mg) group. Continuous glucose monitoring (CGM) was used to monitor glycemic changes for 3 successive days in both groups at baseline and at the 4-week follow-up. Glycemic changes and glucose variability were obtained using CGM, and these data were averaged over all subjects., Results: The comparison of glycated hemoglobin (HbA1c) between baseline and the 4-week follow-up showed that HbA1c was significantly reduced in the sitagliptin group (7.0 ± 0.5% to 6.6 ± 0.4%, P<0.001) and the glimepiride group (7.3 ± 0.4% to 6.9 ± 0.4%, P<0.001). The sitagliptin and glimepiride groups had similar HbA1c levels after 4 weeks, and there were no significant differences between the two groups. The mean amplitude of glycemic excursions (MAGE) decreased significantly in the sitagliptin group (4.9 ± 1.0 to 3.7 ± 0.9 mmol/L, P<0.001), but no significant difference was observed in the glimepiride group (5.7 ± 1.5 to 5.0 ± 1.4 mmol/L, P=0.175). The SD and oxidative stress markers did not differ significantly between the two groups., Conclusions: When sitagliptin was combined with metformin, the patients showed much more efficient blood glucose controlling effects, not only the three indexes of fasting blood glucose, postprandial blood glucose, and glycated hemoglobin, but also MAGE.

Background: Gut hormones play a role in diabetes remission after a Roux-en-Y gastric bypass (RYGB). Our aim was to investigate differences in gut hormone secretion according to diabetes remission after surgery. Second, we aimed to identify differences in insulin secretion and sensitivity according to diabetes remission after RYGB., Methods: Twenty-two severely obese patients with type 2 diabetes underwent RYGB. A meal tolerance test (MTT) was performed 12 months after RYGB. The secretions of active glucagon-like peptide-1 (active GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY, C-peptide and insulin during the MTT test were calculated using total area under the curve values (AUC). Remission was defined as glycated haemoglobin (A(1C)) of <6.5% and a fasting glucose concentration of <126 mg/dL for 1 year or more without active pharmacological therapy., Results: Of the 22 patients, 16 (73%) had diabetes remission (remission group). The secretion CURVES of active GLP-1, GIP and peptide YY were not different between the groups. AUC of insulin and C-peptide were also not different. Homeostasis model assessment estimate of insulin resistance was significantly lower (1.26 ± 1.05 versus 2.37 ± 1.08, p = 0.006), and Matsuda index of insulin sensitivity was significantly higher in the remission group (10.5 ± 6.2 versus 5.8 ± 2.1, p = 0.039). The disposition index (functional reserve of beta cells) was significantly higher in the remission group compared with that in the non-remission group (5.34 ± 2.74 versus 1.83 ± 0.70, p < 0.001)., Conclusions: Remission of diabetes after RYGB is not associated with a difference in gut hormone secretion. Patients remaining diabetic had higher insulin resistance and decreased β cell functional reserve., (Copyright © 2012 John Wiley & Sons, Ltd.)

Improved glucose tolerance following a sequential meal is known as the second-meal phenomenon. We aimed to investigate its extent and underlying mechanisms in patients with type 2 diabetes. Metabolic responses after lunch in 12 diabetic patients were compared on two separate days: one with (Day BL) and another without (Day FL) breakfast. The responses of hormones were calculated by the incremental area under the curve (iAUC) values for 180 min after each meal. Indexes of early-phase insulin secretion were assessed, and β-cell function was estimated by mathematical modeling. [iAUC(glucose(180-360 min))] was significantly lower on Day BL than on Day FL (181 ± 43 vs. 472 ± 29 mmol·liter(-1)·min, P = 0.0005). The magnitude of the The second-meal phenomenon [iAUC(glucose(180-360 min)) on Day BL/Day FL] was 35 ± 9%. The peak levels of insulin and C-peptide were attained 45 min earlier after the second meal than after the first meal. iAUC(glucose(180-360 min)) correlated negatively with iAUC(insulin(180-210 min)) (r = -0.443, P = 0.0300), insulinogenic index (r = -0.769, P < 0.0001), acute C-peptide response (r = -0.596, P = 0.0021), and potentiation factor [i.e., potentiation effect on insulin secretion] ratio (180-360)/(0-20) (r = -0.559, P = 0.0045), while correlated positively with free fatty acid level before lunch (r = 0.679, P = 0.0003). The second-meal phenomenon was evident in patients with type 2 diabetes. Potentiation of the early-phase insulin response by a prior meal contributes to this phenomenon in type 2 diabetes.

Aims: To determine the relationship between serum uric acid, metabolic syndrome (MetS), and albuminuria in type 2 diabetic patients., Methods: A total of 504 Korean patients with type 2 diabetes aged 57.3 years were retrospectively evaluated for clinical histories, anthropometric measurements, and biochemical studies. Urinary albumin excretion (UAE) was measured by a 24-h urine collection., Results: Prevalence of MetS increased according to the quartiles of uric acid levels (≤3.7, 3.8 to 4.5, 4.6 to 5.5, and >5.5 mg/dl; 52.1%, 52.1%, 57.5%, and 71.6%, respectively, P<.001). Individual components of MetS (abdominal obesity, hypertriglyceridemia, low HDL-cholesterol, high blood pressure) were also significantly associated with the highest quintile of uric acid levels. Serum uric acid levels had significantly increased risk of albuminuria [odds ratio (OR) 1.425, 95% confidence interval (CI) 1.085-1.873] after adjusting for age, gender, and conventional risk factors. Uric acid level remains a significant predictor for abnormal albuminuria after adjusting for MetS presence as well as the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) (OR 1.414, 95% CI 1.071-1.868)., Conclusion: An elevated uric acid level was significantly associated with MetS and was an independent predictor of albuminuria after adjusting for conventional risk factors and MetS. Regular measurements of uric acid level could give information for predicting the presence of MetS and albuminuria in Korean type 2 diabetic patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aims: To determine whether short-term strict glycaemic control could restore incretin secretion in type 2 diabetic patients. The factors associated with incretin levels were also investigated., Methods: A meal tolerance test (MTT) was performed in eighteen poorly controlled (pDM) and fifteen well controlled (wDM) diabetic patients. Fourteen patients in the pDM group underwent follow-up MTT after strict glycaemic control. The secretions of intact glucagon-like peptide-1 (iGLP-1) and total glucose-dependent insulinotropic polypeptide (tGIP) during MTT were calculated by total and incremental area under the curve (TAUC and IAUC) values., Results: Posttreatment HbA1c level was significantly improved in the pDM group (11.2±0.9 to 7.9±0.9%). However, the secretion of incretin hormones was not increased in the posttreatment pDM group (TAUCiGLP-1, 3612±587 to 2916±405 pmol/L min; TAUCtGIP, 9417±1099 to 8338±903 pmol/L min). IAUCiGLP-1 was negatively correlated (r=-0.446, P=0.011) and independently associated (β=-137.2, P=0.027) with insulin resistance assessed by homeostasis model assessment., Conclusions: Incretin secretion is not restored by short-term strict glycaemic control. Decreased incretin secretion seems to develop early in the course of type 2 diabetes with increasing insulin resistance, but not to be influenced by glycaemic status., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Recent studies suggest that serum cystatin C level is not only a sensitive marker for renal dysfunction but also a predictive marker for cardiovascular disease (CVD). However, the mechanism of this connection is not fully understood. We aimed to determine whether insulin resistance or various biomarkers of cardiovascular risk have a role in the link between cystatin C and CVD in type 2 diabetes mellitus patients. Anthropometric measurements and biochemical studies including inflammatory biomarkers were performed in 478 patients with type 2 diabetes mellitus. The degree of insulin resistance was assessed by homeostasis model assessment (HOMA-IR) and indicators of metabolic syndrome. Estimated glomerular filtration rate (eGFR) was derived from the Modification of Diet in Renal Disease study equation. After adjusting for age, sex, body mass index, and eGFR, the cystatin C level increased significantly in proportion to the number of metabolic syndrome components present (1.08 +/- 0.06, 1.19 +/- 0.04, 1.20 +/- 0.04, 1.23 +/- 0.04, and 1.37 +/- 0.06 mg/L; P < .0001); and HOMA-IR increased significantly in proportion to cystatin C quartiles (1.16 +/- 0.15, 1.40 +/- 0.13, 1.49 +/- 0.13, and 2.00 +/- 0.17; P < .0001) (means +/- SE). Albumin-creatinine ratio, fibrinogen, uric acid, homocysteine, high-sensitivity C-reactive protein, and lipoprotein(a) all showed significant correlations with cystatin C that were generally higher than those with eGFR. Cystatin C level was independently associated with HOMA-IR (beta = 0.0380, P = .0082), albumin-creatinine ratio (beta = 0.0004, P < .0001), uric acid (beta = 0.0666, P < .0001), and homocysteine (beta = 0.0087, P = .0004). In conclusion, cystatin C level was significantly associated with insulin resistance and biomarkers reflecting inflammation independent of renal function. These components may have a role in addition to that of eGFR in explaining the link between cystatin C and CVD in type 2 diabetes mellitus patients., (Copyright 2010 Elsevier Inc. All rights reserved.)

We studied 65 adult patients without a history of diabetes who were diagnosed with diabetic ketoacidosis. Ketosis-prone type 2 diabetes was common (42%) among this group of Korean patients with new-onset diabetes presenting with diabetic ketoacidosis. These patients were younger, showed a greater defect in insulin secretion.

Recent morphologic analyses of human pancreases strongly suggest that a decreased beta-cell mass is observed from the early stages of diabetes and is caused by accelerated apoptosis of the beta-cells. In this article, we propose that fibrotic islet destruction might be one of the important pathogenic mechanisms of the limited capacity of beta-cell proliferation and accelerated apoptosis in diabetic patients. We have found that pancreatic stellate cells (PSCs) are involved in the progression of islet fibrosis in type 2 diabetes. High concentrations of glucose and insulin in islets contribute to PSC activation and proliferation through angiotensin II type 2 (ATII) signaling pathway, although the exact mechanisms remain to be confirmed. Angiotensin-converting enzyme inhibitors attenuate fibrotic islet destructions and that these have some beneficial effects on glucose tolerance. We suggest that PSCs might play a major role for the fibrotic islet destruction in patients with type 2 diabetes, and suppression of PSCs activation and proliferation might be one of the reasonable target to prevent and delay the progression of the type 2 diabetes mellitus.