Efficacy and safety of enavogliflozin, a novel SGLT2 inhibitor, in Korean people with type 2 diabetes: A 24-week, multicentre, randomized, double-blind, placebo-controlled, phase III trial.

AIMS: To evaluate the efficacy and safety of a novel sodium-glucose cotransporter 2 inhibitor, enavogliflozin 0.3 mg monotherapy, in Korean people with type 2 diabetes mellitus (T2DM) inadequately controlled with diet and exercise. MATERIALS AND METHODS: This study was a randomized, double-blind, placebo-controlled trial conducted in 23 hospitals. Individuals with haemoglobin A1c (HbA1c) of 7.0%-10.0% after at least 8 weeks of diet and exercise modification were randomized to receive enavogliflozin 0.3 mg (n = 83) or placebo (n = 84) for 24 weeks. The primary outcome was a change in HbA1c at week 24 from baseline. Secondary outcomes included the proportion of participants achieving HbA1c <7.0%, change in fasting glucose, body weight and lipid levels. Adverse events were investigated throughout the study. RESULTS: At week 24, the placebo-adjusted mean change in HbA1c from baseline in the enavogliflozin group was -0.99% (95% confidence interval -1.24%, -0.74%). The proportions of patients achieving HbA1c <7.0% (71% vs. 24%) at week 24 was significantly higher in the enavogliflozin group (p < .0001). Placebo-adjusted mean changes in fasting plasma glucose (-40.1 mg/dl) and body weight (-2.5 kg) at week 24 were statistically significant (p < .0001). In addition, a significant decrease in blood pressure, low-density lipoprotein cholesterol, triglyceride, and homeostasis model assessment of insulin resistance were observed, along with a significant increase in high-density lipoprotein cholesterol. No significant increase in treatment-related adverse events was observed for enavogliflozin. CONCLUSIONS: Monotherapy with enavogliflozin 0.3 mg improved glycaemic control in people with T2DM. Enavogliflozin therapy also exerted beneficial effects on body weight, blood pressure and lipid profile.

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

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

Efficacy and safety of monotherapy with enavogliflozin in Korean patients with type 2 diabetes mellitus: Results of a 12-week, multicentre, randomized, double-blind, placebo-controlled, phase 2 trial.

AIMS: The study aimed to evaluate and compare the efficacy and safety of enavogliflozin, a newly developed sodium-glucose cotransporter 2 inhibitor, with placebo in Korean patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Patients with glycated haemoglobin (HbA1c) of 7.0-10.0%, entered a 2-week placebo run-in period, and were randomized to receive once-daily enavogliflozin (0.1, 0.3 or 0.5 mg) or placebo for 12 weeks. The primary efficacy endpoint was the change in HbA1c from baseline at week 12. RESULTS: Overall, 194 patients were included in the full analysis set [placebo, n = 46; enavogliflozin (0.1 mg, n = 49; 0.3 mg, n = 50; 0.5 mg, n = 49)]. Patients receiving 0.1, 0.3 and 0.5 mg enavogliflozin showed significantly reduced HbA1c compared with those receiving placebo at week 12 (-0.79%, -0.89%, -0.92% and -0.08%, respectively; p < .001 vs. placebo). Mean changes in fasting plasma glucose from baseline at week 12 were -30.5, -31.1, -35.0 and 4.9 mg/dl in patients receiving enavogliflozin doses and placebo, respectively. The proportion of patients achieving HbA1c <7.0% at week 12 was significantly higher in the three enavogliflozin groups than in the placebo group (42.9%, 44.0%, 61.2% and 17.4%, respectively). A higher proportion of patients showed HbA1c reduction by >0.5% after receiving enavogliflozin doses than those receiving placebo (61.2%, 72.0%, 65.3% and 26.1%, respectively). There were no significant differences in incidences of adverse events of hypoglycaemia and genital infection between the groups. CONCLUSIONS: Once-daily enavogliflozin monotherapy for 12 weeks is an effective, safe, and well-tolerated treatment for Korean patients with type 2 diabetes mellitus.

Pharmacological disruption of the Notch transcription factor complex.

Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.

Overexpression of VEGF in the MOPC 315 Plasmacytoma Induces Tumor Immunity in Mice.

Vascular endothelial growth factor (VEGF) has important effects on hematopoietic and immune cells. A link between VEGF expression, tumor progression, and metastasis has been established in various solid tumors; however, the impact of VEGF expression by hematopoietic neoplasias remains unclear. Here, we investigated the role of VEGF in plasma cell neoplasia. Overexpression of VEGF in MOPC 315 tumor cells (MOPCSVm) had no effect on their growth in vitro. However, constitutive ectopic expression of VEGF dramatically reduced tumorigenicity of MOPC 315 when implanted subcutaneously into BALB/c mice. Mice implanted with MOPCSVm effectively rejected tumor grafts and showed strong cytotoxic T lymphocyte (CTL) activity against parental MOPC 315 cells. MOPCSVm implants were not rejected in nude mice, suggesting the process is T-cell-dependent. Adoptive transfer of splenocytes from recipients inoculated with MOPCSVm cells conferred immunity to naïve BALB/c mice, and mice surviving inoculation with MOPCSVm rejected the parental MOPC 315 tumor cells following a second inoculation. Immunohistochemical analysis showed that MOPCSVm induced a massive infiltration of CD3+ cells and MHC class II+ cells in vivo. In addition, exogenous VEGF induced the expression of CCR3 in T cells in vitro. Together, these data are the first to demonstrate that overexpression of VEGF in plasmacytoma inhibits tumor growth and enhances T-cell-mediated antitumor immune response.

The Anti-Atherosclerosis Effect of Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, in Apolipoprotein E Knockout Mice.

Interleukin (IL)-1ß plays an important role in atherosclerosis pathogenesis. We aimed to investigate the effect of anakinra, a recombinant human IL-1 receptor antagonist, on the progression of atherosclerosis in apolipoprotein E knockout (ApoE−/−) mice. ApoE−/− mice (8-week male) were treated with saline (control), anakinra 10, 25, and 50 mg/kg, respectively (n = 10 in each group). Mice were fed a standard chow (4 weeks) followed by an atherogenic diet (35kcal% fat, 1.25% cholesterol, 12 weeks). Atheromatous plaques in ApoE−/− mice and the expression of inflammatory genes and signaling pathways in human umbilical vein endothelial cells (HUVECs), rat aortic smooth muscle cells (RAOSMCs), and 3T3-L1 adipocytes were assessed. Anakinra reduced the plaque size of the aortic arch (30.6% and 25.2% at the 25 mg/kg and 50 mg/kg doses, both p < 0.05) and serum triglyceride in ApoE−/− mice and suppressed inflammatory genes (IL-1ß and IL-6) expressions in HUVECs and RAOSMCs (all p < 0.05). In RAOSMCs, anakinra reduced metalloproteinase-9 expression in a dose-dependent manner and inhibited cell migration. Anakinra-treated mice exhibited trends of lower CD68+ macrophage infiltration in visceral fat and monocyte chemoattractant protein-1 expression was reduced in 3T3-L1 adipocytes. Anakinra could be a useful component for complementary treatment with a standard regimen to reduce the residual cardiovascular risk.

Immature platelets as a biomarker for disease severity and mortality in COVID-19 patients.

COVID-19, caused by SARS-CoV-2, is a contagious life-threatening viral disease that has killed more than three million people worldwide to date. Attempts have been made to identify biomarker(s) to stratify disease severity and improve treatment and resource allocation. Patients with SARS-COV-2 infection manifest with a higher inflammatory response and platelet hyperreactivity; this raises the question of the role of thrombopoiesis in COVID-19 infection. Immature platelet fraction (IPF, %) and immature platelet counts (IPC, ×109 /l) can be used to assess thrombopoiesis. This study investigates whether the level of thrombopoiesis correlates with COVID-19 severity. A large cohort of 678 well-characterized COVID-19 patients was analyzed, including 658 (97%) hospitalized and 139 (21%) admitted to the intensive care unit (ICU). Elevated percentage IPF at presentation was predictive of length of hospitalization (P < 0·01) and ICU admission (P < 0·05). Additionally, percentage IPF at the peak was significantly higher among ICU patients than non-ICU patients (6·9 ± 5·1 vs 5·3 ± 8·4, P < 0·01) and among deceased patients than recovered patients (7·9 ± 6·3 vs 5·4 ± 7·8, P < 0·01). Furthermore, IPC at the peak was significantly higher among ICU patients than non-ICU patients (18·5 ± 16·2 vs. 13·2 ± 8·3, P < 0·05) and among patients on a ventilator than those not (22·1 ± 20·1 vs.13·4 ± 8·4, P < 0·05). Our study demonstrated that elevated initial and peak values of percentage IPF and IPC might serve as prognostic biomarkers for COVID-19 progression to severe conditions.

Safety and effectiveness of linagliptin in Korean patients with type 2 diabetes: A postmarketing surveillance study.

We designed a postmarketing surveillance study of linagliptin for patients with type 2 diabetes (T2D) in Korea. This prospective, observational, multicentre study investigated the safety and glycaemic effectiveness of linagliptin as monotherapy or combination therapy with other antidiabetic drugs in routine clinical practice. Endpoints were the incidence of adverse drug reactions (ADRs) and the change in HbA1c. Overall, 3119 and 2171 patients were included in the safety and effectiveness analysis sets, respectively. A total of 56 patients (1.8%) experienced ADRs. The most common ADR was gastrointestinal disorders (0.7%), followed by metabolism and nutrition disorders (0.5%). ADRs of special interest, including pancreatic diseases, cardiac diseases and hypoglycaemia, occurred in 12 patients, 11 of whom had hypoglycaemia, while one had a skin lesion. Mean HbA1c change during the study period was -0.8%. Lower body mass index, shorter diabetes duration and higher baseline HbA1c were independently associated with a better effectiveness, while the presence of diabetic complications, dyslipidaemia and the use of sulphonylureas were associated with a poor response. In conclusion, linagliptin showed an excellent safety profile and glycaemic effectiveness in Korean patients with T2D.

Early combination versus initial metformin monotherapy in the management of newly diagnosed type 2 diabetes: An East Asian perspective.

Type 2 diabetes (T2D) in the East Asian population is characterized by phenotypes such as low body mass index, an index of ß-cell dysfunction, and higher percentage of body fat, an index of insulin resistance. These phenotypes/pathologies may predispose people to early onset of diabetes with increased risk of stroke and renal disease. Less than 50% of patients with T2D in East Asia achieve glycaemic targets recommended by national or regional guidelines, which may be attributable to knowledge and/or implementation gaps. Herein, we review the latest evidence with special reference to East Asian patients with T2D and present arguments for the need to use early combination therapy to intensify glycaemic control. This strategy is supported by the 5-year worldwide VERIFY study, which reported better glycaemic durability in newly diagnosed patients with T2D with a mean HbA1c of 6.9% treated with early combination therapy of vildagliptin plus metformin versus those treated with initial metformin monotherapy followed by addition of vildagliptin only with worsening glycaemic control. This paradigm shift of early intensified treatment is now recommended by the American Diabetes Association and the European Association for the Study of Diabetes. In order to translate these evidence to practice, increased awareness and strengthening of the healthcare system are needed to diagnose and manage patients with T2D early for combination therapy.

Effect of increased levothyroxine dose on depressive mood in older adults undergoing thyroid hormone replacement therapy.

OBJECTIVE: Depressive mood consequent to hypothyroidism can be reversed with levothyroxine (LT4) replacement therapy. However, it is unclear whether increasing LT4 dose confers additional mood benefits. DESIGN AND PATIENTS: A single-blinded before-and-after study of 24 patients with hypothyroidism who were aged 65 years or older and undergoing LT4 replacement therapy with stable doses. MEASUREMENTS: Geriatric Depression Scale (GDS-K) and Hyperthyroid Symptom Scale (HSS-K) were assessed at baseline, 3 months after increasing LT4 dose by an additional 12.5 µg/d, and finally 3 months after returning to the baseline dose. RESULTS: Serum thyroid-stimulating hormone (TSH) concentrations decreased at the higher LT4 dose (1.95 ± 2.16 vs 0.47 ± 1.09 mIU/L, P < .001) and recovered after returning to the baseline dose. Serum-free thyroxine levels and HSS-K scores were unchanged during the study period. GDS-K scores improved on the increased dose (9.5 ± 6.6 vs 7.5 ± 4.7, P = .029), and this improvement was maintained after returning to the baseline dose (9.5 ± 6.6 vs 7.4 ± 5.4, P = .010). Higher serum TSH was independently associated with both higher GDS-K and depression risk among those with depressive mood (GDS-K > 10) at baseline. CONCLUSIONS: Depressive mood improves with increased LT4 dose, without significant hyperthyroid symptoms or signs, in older adults undergoing thyroid hormone replacement. These findings suggest the potential for varying the treatment target for hypothyroidism based on mood status and that low-dose LT4 treatment might be an ancillary treatment for depression.

Low-density lipoprotein cholesterol goal attainment rates in high-risk patients with cardiovascular diseases and diabetes mellitus in Korea: a retrospective cohort study.

BACKGROUND: Real-world evidence of low-density lipoprotein cholesterol (LDL-C) goal attainment rates for Asian patients is deficient. The objective of this study was to assess the status of dyslipidemia management, especially in high-risk patients with cardiovascular disease (CVD) including stroke and acute coronary syndrome (ACS). METHODS: This was a retrospective cohort study of 514,866 subjects from the National Health Insurance Service-National Health Screening Cohort database in Korea. Participants were followed up from 2002 to 2015. Subjects with a high-risk of CVD prior to LDL-C measurement and subjects who were newly-diagnosed for high-risk of CVD following LDL-C measurement were defined as known high-risk patients (n = 224,837) and newly defined high-risk patients (n = 127,559), respectively. Data were analyzed by disease status: stroke, ACS, coronary heart disease (CHD), peripheral artery disease (PAD), diabetes mellitus (DM) and atherosclerotic artery disease (AAD). RESULTS: Overall, less than 50% of patients in each disease category achieved LDL-C goals (LDL-C < 70 mg/dL in patients with stroke, ACS, CHD and PAD; and LDL-C < 100 mg/dL in patients with DM and AAD). Statin use was observed in relatively low proportions of subjects (21.5% [known high-risk], 34.4% [newly defined high-risk]). LDL-C goal attainment from 2009 to 2015 steadily increased but the goal-achiever proportion of newly defined high-risk patients with ACS remained reasonably constant (38.7% in 2009; 38.1% in 2015). CONCLUSIONS: LDL-C goal attainment rates in high-risk patients with CVD and DM in Korea demonstrate unmet medical needs. Proactive management is necessary to bridge the gap between the recommendations of clinical guidelines and actual clinical practice.

Effect of cilostazol, a phosphodiesterase-3 inhibitor, on coronary artery stenosis and plaque characteristics in patients with type 2 diabetes: ESCAPE study.

AIM: To perform a prospective study to evaluate the effect of cilostazol (CTZ) compared with aspirin (acetylsalicylic acid; ASA) in Korean people with diabetes and subclinical coronary atherosclerosis. MATERIALS AND METHODS: A total of 100 people with diabetes who had mild to moderate coronary atherosclerosis, assessed by coronary computed tomographic angiography (CCTA), were randomly assigned to either 200 mg/d CTZ or 100 mg/d ASA (n = 50 each group). The primary outcome was change in coronary artery stenosis assessed by CCTA after 12 months of treatment. Secondary outcomes included changes in plaque composition, coronary artery calcium score and cardiac markers. RESULTS: The mean age, body mass index and glycated haemoglobin concentration were 61.5 years, 25.0 kg/m2 and 56.8 mmol/mol, respectively, and were well matched between the two groups. Coronary artery stenosis decreased in the CTZ group (from 44.0 ± 2.1% to 40.4 ± 2.5%) but remained unchanged in the ASA group (from 38.9 ± 2.1% to 40.6 ± 2.1%). In the CTZ group, the non-calcified portion of plaques decreased significantly (from 20.6 ± 3.0 to 17.3 ± 3.0 mm3 ), whereas it did not change significantly in the ASA group (15.2 ± 2.8 vs 16.6 ± 2.9 mm3 ). Increases in HDL cholesterol, decreases in triglycerides, liver enzyme and high-sensitivity C-reactive protein levels, and reductions in abdominal visceral fat area and insulin resistance were observed only in the CTZ group. CONCLUSION: CTZ treatment for 12 months decreased coronary artery stenosis and the non-calcified plaque component. These results suggest that CTZ treatment may be an option for preventing the progression of coronary atherosclerosis in people with diabetes.

Potent suppression of both spontaneous and carcinogen-induced colitis-associated colorectal cancer in mice by dietary celastrol supplementation.

Celastrol is an anti-inflammatory natural triterpenoid, isolated from the herb Tripterygium wilfordii or thunder god vine. Here, we define mechanisms mediating anti-inflammatory activity of celastrol and demonstrate efficacy of a dietary celastrol supplement for chemoprevention of inflammation-driven carcinogenesis in mice. Dietary celastrol (31.25 ppm in rodent diet from 8 weeks to 25 weeks of age) is well tolerated and protects against LPS-induced acute inflammation in C57BL/6 mice, potently suppressing LPS-induction of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, Interleukin (IL)-6 and IL-1ß. To test whether dietary celastrol suppresses inflammation-driven colorectal cancer (CRC), we employed a unique model of spontaneous, inflammation-driven CRC in mice harboring a germ line deletion of the p27Kip1 gene and a T cell-specific deletion of Smad4 gene (Smad4co/co;Lck-crep27Kip1-/-or DKO), which develop severe intestinal inflammation and carcinogenesis as early as 3 months of age. Exposure of DKO mice to daily dietary celastrol (12.5 ppm in diet) from 6 weeks of age significantly suppressed development of colitis-associated CRC (CAC). Celastrol chemoprevention of CAC in this new model of intestinal neoplasia was associated with significant suppression of iNOS at 4 months of age, and iNOS, COX-2 and NFκB at 6 months of age, with significant reduction in inflammatory cytokines, IL-6 and IL-1ß. Chemoprevetion of CAC by dietary celastrol was further confirmed in the model of azoxymethane (AOM) plus dextran sodium sulfate (DSS)-induced carcinogenesis in C57BL/6 mice. These data suggest the potential for celastrol as a safe and effective dietary supplement in the chemoprevention of CAC in humans.

Suppression of Nrf2 attenuates adipogenesis and decreases FGF21 expression through PPAR gamma in 3T3-L1 cells.

Adipogenesis is the process of differentiation from preadipocytes to adipocytes and is orchestrated by various transcription factors, such as the peroxisome proliferator-activated receptor gamma (PPARγ) and the CCAAT-enhancer-binding protein alpha (C/EBPα). Oxidative stress is also a crucial factor in adipogenesis, and adipocyte differentiation is affected by the cellular redox status. The nuclear factor E2-related factor 2 (Nrf2), which is a basic leucine zipper (bZIP) transcription factor, acts as a regulator of cellular oxidative stress. Although several previous studies examined the function of Nrf2 in adipogenesis, their results were controversial. In this study, we investigated whether the suppression of Nrf2 in 3T3-L1 cells affected adipogenesis. We found that adipogenesis master regulator genes, such as PPARγ and C/EBPα, were downregulated during the differentiation stage in Nrf2-knockdown 3T3-L1 cells. Moreover, the fibroblast growth factor 21 (FGF21) and manganese superoxide dismutase (MnSOD) were markedly downregulated in Nrf2-knockdown 3T3-L1 cells. Taken together, the results of the present study suggest that the suppression of Nrf2 attenuates adipogenesis and decreases FGF21 expression through PPARγ in 3T3-L1 cells.

Effect of Rosuvastatin on Cholesterol Efflux Capacity and Endothelial Function in Type 2 Diabetes Mellitus and Dyslipidemia.

BACKGROUND: Quality and quantity of high-density lipoprotein cholesterol (HDL-C) may be associated with cardiovascular risk. We investigated the effect of rosuvastatin on cholesterol efflux (CE) for HDL function and vascular health.Methods and Results:We enrolled 30 dyslipidemic patients with type 2 diabetes mellitus and 20 healthy subjects as controls. Vascular health was assessed on flow-medicated dilation (FMD), nitroglycerin-induced dilatation of the brachial artery and carotid artery intima-media thickness (cIMT). These parameters were compared between patients and controls, and between baseline and at 12 weeks of treatment with rosuvastatin 20 mg. Age and body mass index were 49.8±11.3 years and 25.8±3.7 kg/m2in the patients, and 28.8±3.2 years and 22.4±2.4 kg/m2in the controls, respectively. The biomarkers related to lipid and glucose metabolism and lipoprotein (a), high-sensitivity C-reactive protein, and cIMT were significantly higher, and CE and FMD were significantly lower in the patients than in the controls. In the patients, rosuvastatin 20 mg decreased low-density lipoprotein cholesterol by 54.1% and increased HDL-C by 4.8%. The CE increased significantly after rosuvastatin treatment (12.26±2.72% vs. 14.05±4.14%). FMD also increased, and lipoprotein (a) and cIMT decreased significantly and were associated with changes of CE. CONCLUSIONS: Rosuvastatin-induced changes in HDL function are significantly associated with cardiovascular benefit.

The Cut-off Values of Surrogate Measures for Insulin Sensitivity in a Healthy Population in Korea according to the Korean National Health and Nutrition Examination Survey (KNHANES) 2007-2010.

BACKGROUND: This study aimed to identify the gender-specific characteristics of the surrogate measures of insulin resistance and to establish valid cut-off values for metabolic abnormalities in a representative sample in Korea. METHODS: Data were collected from the datasets of the Korean National Health and Nutrition Examination Survey between 2007 and 2010. The total number of eligible participants was 10,997. We used three measures of insulin resistance: the homeostasis model assessment-insulin resistance (HOMA-IR), McAuley index, and triglyceride and glucose (TyG) index. The estimated cut-off values were determined using the highest score of the Youden index. RESULTS: The area under the curve (AUC) of the HOMA-IR, McAuley index, and TyG index were 0.737 (95% confidence interval [CI], 0.725-0.750), 0.861 (95% CI, 0.853-0.870), and 0.877 (95% CI, 0.868-0.885), respectively. The cut-off values of the HOMA-IR were 2.20 in men, 2.55 in premenopausal women, and 2.03 in postmenopausal women, and those of the McAuley index were 6.4 in men and 6.6 in premenopausal and postmenopausal women. For the TyG index, the cut-off values were 4.76 in men and 4.71 in premenopausal and postmenopausal women. CONCLUSION: In conclusion, the present study provides the valid cut-off values of the indirect surrogate measures of insulin sensitivity. These values may be used as reference for insulin sensitivity in a clinical setting and may provide a simple and supplementary method for identifying populations at risk of insulin resistance.

The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE -/- mice fed a western diet.

AIMS/HYPOTHESIS: A recent large clinical study has shown that empagliflozin has a lower rate of cardiovascular and all-cause mortality when compared with placebo in patients with type 2 diabetes. We investigated the effect of empagliflozin (compared with glimepiride) on the progression of atherosclerosis, and its possible mechanisms of action. METHODS: Forty-eight 5-week-old male ApoE -/- mice were fed a western diet for 20 weeks and divided into four groups: control (saline, 154 mmol/l NaCl), glimepiride 0.1 mg/kg, empagliflozin 1 mg/kg and empagliflozin 3 mg/kg (n = 12/group). Plaque size and composition in the aortic arch/valve areas and cardiovascular risk variables in the blood and tissues were evaluated. Insulin resistance was estimated by HOMA and adiponectin levels. Body composition was determined using dual-energy x-ray absorptiometry. RESULTS: After 8 weeks of treatment, the empagliflozin and glimepiride groups exhibited decreased blood glucose levels. Atherosclerotic plaque areas in the aortic arch/valve were significantly smaller in the empagliflozin groups than in the control or glimepiride groups. Insulin resistance and circulating concentrations of TNF-α, IL-6, monocyte chemoattractant protein-1 (MCP-1), serum amyloid A and urinary microalbumin decreased after empagliflozin treatment, and this significantly correlated with plaque size. Empagliflozin treatment reduced weight and fat mass, lipid droplets in the liver, fat cell size, mRNA expression of Tnf, Il6 and Mcp-1 (also known as Ccl2) and the infiltration of inflammatory cells in plaque and adipose tissue compared with the control or glimepiride group. Empagliflozin treatment increased adiponectin levels. CONCLUSIONS/INTERPRETATION: Improvements in inflammation and insulin resistance seem to be mechanisms involved in the mitigation of atherosclerosis by empagliflozin.

One-hour postload plasma glucose concentration in people with normal glucose homeostasis predicts future diabetes mellitus: a 12-year community-based cohort study.

OBJECTIVE: In Caucasians, plasma glucose concentration at 1 h during an oral glucose tolerance test (OGTT) may be a better predictor of future diabetes mellitus than the fasting or 2-h postload glucose concentration. We investigated whether the 1-h glucose concentration could be used to predict future diabetes mellitus in Asian ethnicity. MEASUREMENTS: A total of 5703 Koreans with normal glucose tolerance were enrolled from the Korean Genome and Epidemiology Study. Indices of insulin sensitivity and ß-cell function estimated from standard 75-g OGTTs performed every 2 years for 12 years were used to identify whether the 1-h glucose concentration could predict future diabetes mellitus. RESULTS: The mean age and body mass index at baseline were 51·3 ± 8·7 years and 24·2 ± 3·0 kg/m2 , respectively. During the 12-year follow-up, 593 subjects (10·3%) developed diabetes mellitus. The area under the receiver-operating characteristic curve for incident diabetes mellitus was higher for the 1-h postload glucose concentration than for the fasting or postload 2-h glucose concentration (0·74 vs 0·61 or 0·63). The cut-off value of ≥8·0 mmol/l identified incident diabetes mellitus with 70% sensitivity and 68% specificity. After adjusting for typical risk factors, subjects with a 1-h postload glucose concentration ≥8·0 mmol/l had lower ß-cell function and a 2·84-fold increased risk of incident diabetes mellitus compared with their counterparts. CONCLUSIONS: In this community-based 12-year prospective cohort study, 1-h postload plasma glucose concentration was an independent predictor of future diabetes mellitus and 8·0 mmol/l was suggested as a cut-off value.

Circulating sortilin level as a potential biomarker for coronary atherosclerosis and diabetes mellitus.

CONTEXT: A previous genome-wide association study showed that a genetic variant of sortilin was associated with the risk of coronary artery disease (CAD). However, the role of circulating sortilin is still unknown. We investigated the potential role of plasma sortilin as a biomarker for CAD and diabetes mellitus. METHODS: We enrolled statin-naïve subjects with CAD (n = 31) who underwent coronary artery bypass surgery and control subjects (n = 116) who were free from CAD as evaluated by coronary CT angiography. The presence of diabetes mellitus was evaluated and plasma sortilin levels were measured with a commercial ELISA kit. RESULTS: Plasma sortilin levels were higher in subjects with CAD and subjects with diabetes mellitus than in those without CAD or diabetes mellitus. Subjects in the highest sortilin tertile group were older and had higher glucose and HbA1c levels, but lipid profiles in the three tertile groups were comparable. Multivariable logistic regression analysis revealed that sortilin levels were independently associated with CAD. In addition, the receiver operating characteristic curve analysis showed that plasma sortilin levels could identify the presence of CAD or diabetes mellitus. CONCLUSIONS: Elevated circulating sortilin levels are associated with CAD and diabetes mellitus and can be used as a biomarker of both diseases in statin-naïve subjects.

Probucol in Albuminuric Type 2 Diabetes Mellitus Patients on Renin-Angiotensin System Blockade: A 16-Week, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To determine the effect of probucol on urine albumin excretion in type 2 diabetes mellitus patients with albuminuria using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. APPROACH AND RESULTS: This was a 16-week, phase II, randomized, placebo-controlled, parallel-group study in type 2 diabetes mellitus patients with a urinary albumin/creatinine ratio of ≥300 mg/g using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, conducted in 17 tertiary referral hospitals. Eligible patients were randomized to probucol 250 mg/d (n=44), probucol 500 mg/d (n=41), and placebo (n=41) groups in a ratio of 1:1:1 after block randomization procedures, keeping the treatment assignment blinded to the investigators, patients, and study assistants. The primary end point was change in the geometric mean of urinary albumin/creatinine ratio from baseline to week 16 (ClinicalTrials.gov identifier NCT01726816). The study was started on November 8, 2012, and completed on March 24, 2014. The least squares mean change±SE from baseline in urinary albumin/creatinine ratio at week 16 was -7.2±639.5 mg/g in the probucol 250 mg/d group (n=43; P=0.2077 versus placebo group), 9.3±587.4 mg/g in the probucol 500 mg/d group (n=40; P=0.1975 versus placebo group), and 259.0±969.1 mg/g in the placebo group (n=41). Although the majority of subjects were on statins, probucol treatment significantly lowered total cholesterol and low-density lipoprotein cholesterol levels. QT prolongation occurred in one and two subjects in control and probucol 250 mg/d groups, respectively. CONCLUSIONS: Four months of probucol up to 500 mg/d failed to reduce urinary albumin excretion.