Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i Meta-analysis Cardio-Renal Trialists Consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across 3 patient populations (patients with diabetes at high risk for atherosclerotic cardiovascular disease, heart failure [HF], or chronic kidney disease). The outcomes of interest were MACE (composite of cardiovascular death, myocardial infarction , or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established atherosclerotic cardiovascular disease, previous myocardial infarction, diabetes, previous HF, albuminuria, chronic kidney disease stages, and risk groups). RESULTS: A total of 78 607 patients across 11 trials were included: 42 568 (54.2%), 20 725 (26.4%), and 15 314 (19.5%) were included from trials of patients with diabetes at high risk for atherosclerotic cardiovascular disease, HF, or chronic kidney disease, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ration [HR], 0.91 [95% CI, 0.87-0.96], P<0.0001) with a consistent effect across all 3 patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in cardiovascular death (HR, 0.86 [95% CI, 0.81-0.92], P<0.0001), with no significant effect for myocardial infarction in the overall population (HR, 0.95 [95% CI, 0.87-1.04], P=0.29), and no effect on stroke (HR, 0.99 [95% CI, 0.91-1.07], P=0.77). The benefit for cardiovascular death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [95% CI, 0.46-1.02] and HR, 0.86 [95% CI, 0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pinteraction=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of atherosclerotic cardiovascular disease, diabetes, kidney function, or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of cardiovascular death, particularly HF death and sudden cardiac death, without a significant effect on myocardial infarction in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.

Functional characterization of plant specific Indeterminate Domain (IDD) transcription factors in tomato (Solanum lycopersicum L.).

Plant-specific transcription factors (TFs) are responsible for regulating the genes involved in the development of plant-specific organs and response systems for adaptation to terrestrial environments. This includes the development of efficient water transport systems, efficient reproductive organs, and the ability to withstand the effects of terrestrial factors, such as UV radiation, temperature fluctuations, and soil-related stress factors, and evolutionary advantages over land predators. In rice and Arabidopsis, INDETERMINATE DOMAIN (IDD) TFs are plant-specific TFs with crucial functions, such as development, reproduction, and stress response. However, in tomatoes, IDD TFs remain uncharacterized. Here, we examined the presence, distribution, structure, characteristics, and expression patterns of SlIDDs. Database searches, multiple alignments, and motif alignments suggested that 24 TFs were related to Arabidopsis IDDs. 18 IDDs had two characteristic C2H2 domains and two C2HC domains in their coding regions. Expression analyses suggest that some IDDs exhibit multi-stress responsive properties and can respond to specific stress conditions, while others can respond to multiple stress conditions in shoots and roots, either in a tissue-specific or universal manner. Moreover, co-expression database analyses suggested potential interaction partners within IDD family and other proteins. This study functionally characterized SlIDDs, which can be studied using molecular and bioinformatics methods for crop improvement.

Exploring the impact of number and type of comorbidities on the risk of severe COPD exacerbations in Korean Population: a Nationwide Cohort Study.

BACKGROUND: It is difficult to assess the impact of multiple comorbidities on clinical outcomes in chronic obstructive pulmonary disease (COPD). In this study, we aimed to investigate exacerbation-associated comorbidities, determine whether the number of comorbidities is an independent risk factor for exacerbation, and identify other exacerbation-associated factors in a Korean COPD population using a nationwide population-based cohort. This study focused on severe exacerbations that required hospitalisation or emergency room visits. METHODS: The National Health Insurance Service-National Sample Cohort, version 2.0, data sampled between 2002 and 2015 were analysed. Data from two years after the diagnosis of COPD were analysed for each participant (N = 12,554, entire cohort). Moreover, 42% of the participants underwent additional health examinations (N = 5306, health-screening cohort). Fifteen comorbidities that were previously reported as risk factors for exacerbations were examined. A logistic regression model was used to analyse association with exacerbations. RESULTS: Asthma (1.57 [1.39-1.76] and 1.24 [1.06-1.44]), lung cancer (1.84 [1.30-2.59] and 2.28 [1.54-3.37]), and heart failure (1.39 [1.16-1.67] and 1.52 [1.18-1.97]) were associated with exacerbation in both cohorts (odds ratio [95% confidence interval] in the entire cohort and health-screening cohort, respectively). The number of comorbidities was an independent risk factor, and old age, male sex, low body mass index, and current smoking were also independent risk factors. High cholesterol levels and body mass index exerted protective effects against exacerbation. CONCLUSIONS: The number of comorbidities, certain comorbidities such as asthma, lung cancer and heart failure, and low BMI were associated with an increased risk of severe exacerbation in COPD patients.

Ralstonia solanacearum Type III Effector RipJ Triggers Bacterial Wilt Resistance in Solanum pimpinellifolium.

Ralstonia solanacearum causes bacterial wilt disease in solanaceous crops. Identification of avirulence type III-secreted effectors recognized by specific disease resistance proteins in host plant species is an important step toward developing durable resistance in crops. In the present study, we show that R. solanacearum effector RipJ functions as an avirulence determinant in Solanum pimpinellifolium LA2093. In all, 10 candidate avirulence effectors were shortlisted based on the effector repertoire comparison between avirulent Pe_9 and virulent Pe_1 strains. Infection assays with transgenic strain Pe_1 individually carrying a candidate avirulence effector from Pe_9 revealed that only RipJ elicits strong bacterial wilt resistance in S. pimpinellifolium LA2093. Furthermore, we identified that several RipJ natural variants do not induce bacterial wilt resistance in S. pimpinellifolium LA2093. RipJ belongs to the YopJ family of acetyltransferases. Our sequence analysis indicated the presence of partially conserved putative catalytic residues. Interestingly, the conserved amino acid residues in the acetyltransferase catalytic triad are not required for effector-triggered immunity. In addition, we show that RipJ does not autoacetylate its lysine residues. Our study reports the identification of the first R. solanacearum avirulence protein that triggers bacterial wilt resistance in tomato. We expect that our discovery of RipJ as an avirulence protein will accelerate the development of bacterial wilt-resistant tomato varieties in the future.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

The Impact of NAFLD and Waist Circumference Changes on Diabetes Development in Prediabetes Subjects.

The aim of this study was to investigate the association of nonalcoholic fatty liver disease (NAFLD) with diabetes and the impact of waist circumference (WC) changes in subjects with prediabetes. We enrolled 6240 subjects with prediabetes who underwent health check-ups in 2007 and revisited our hospital at least once for a follow-up examination between 2008 and 2013. Subjects were stratified by WC changes into three groups. The relative risks (RRs) for diabetes according to the NAFLD status and WC change were evaluated. The prevalence of NAFLD was 45.4% (2830/6240). During follow-up, the incidence of diabetes was 8.1% (505/6240). Subjects with NAFLD had a higher incidence of diabetes and the adjusted RRs were 1.81 (95% confidence interval [CI], 1.47 to 2.21), after adjustment for potential confounding factors. The adjusted RRs were related to WC changes. The adjusted RRs for diabetes according to tertiles of WC change (first, second, and third tertile) were 1.64 (95% CI, 1.08 to 2.49), 1.73 (95% CI, 1.28 to 2.34), and 2.04 (95% CI, 1.42 to 2.93), respectively. NAFLD has significantly increased risk of incident diabetes in subjects with prediabetes. The risk for diabetes is gradually increased with tertiles of WC change.

Clinical parameters affecting the therapeutic efficacy of empagliflozin in patients with type 2 diabetes.

We aimed to investigate the clinical factors affecting the therapeutic effectiveness of the sodium-glucose cotransporter-2 inhibitor empagliflozin in patients with type 2 diabetes mellitus (T2DM). We reviewed the medical records of 374 T2DM patients aged between 20 and 75 years who were prescribed empagliflozin 10 mg or 25 mg as add-on therapy for more than 90 consecutive days. Changes in hemoglobin A1c (HbA1c) from baseline levels and the reduction in body weights of the study participants were assessed. We found that younger patients (≤ 50 years), patients with the highest levels of HbA1c (>9%) at baseline, patients with an estimated glomerular filtration rate (eGFR) of >90 mL/min/1.73 m2, and patients with a shorter duration of T2DM (< 10 years) were more likely to exhibit a better glycemic response. Multivariate linear regression analysis revealed that a shorter duration of T2DM, higher baseline levels of HbA1c, and higher eGFR were positively associated with HbA1c reduction. Higher BMI and lower HbA1c levels were predictors of a more significant reduction in body weight among patients taking empagliflozin. The glucose-lowering effect of empagliflozin was more evident in T2DM patients with higher baseline HbA1c levels, better renal function, and shorter duration of T2DM.

Effectiveness and Safety of Adding Basal Insulin Glargine in Patients with Type 2 Diabetes Mellitus Exhibiting Inadequate Response to Metformin and DPP-4 Inhibitors with or without Sulfonylurea.

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.

Clinical Efficacy and Parameters Affecting the Response to Dulaglutide Treatment in Patients with Type 2 Diabetes: A Retrospective, Real-World Data Study.

INTRODUCTION: This study aimed to investigate the efficacy and clinical factors affecting the glycemic response to dulaglutide in type 2 diabetes (T2D) in a real-world clinical setting. METHODS: We conducted a retrospective study of 234 patients at the Asan Medical Center, Republic of Korea, who had T2D and initiated dulaglutide from June 2016 to December 2017. The primary outcome was the change in glycated hemoglobin (HbA1c) concentration between baseline and 6 months after the initiation of therapy. Multivariate regression analysis was used to determine the clinical parameters contributing to a superior glycemic response to dulaglutide. RESULTS: The mean age of the patients was 53, and 50% were male. Their mean baseline HbA1c, body mass index and duration of diabetes were 8.8%, 27.6 kg/m2 and 10.2 years, respectively. The change in HbA1c between baseline and 6 months was - 0.92% (95% CI: - 1.1% to - 0.74%, p < 0.001). The reduction in body weight over the same period was -2.1 kg (95% CI: - 2.9 to - 1.3 kg, p < 0.001). Using multivariate regression analysis, baseline HbA1c was found to be a significant predictor of superior glycemic response to dulaglutide. CONCLUSION: The use of dulaglutide was associated with a significant reduction in HbA1c and body weight over a 6-month period in a real-world clinical setting. T2D patients with higher baseline HbA1c concentrations were more likely to demonstrate good clinical responses to dulaglutide.

Implications of the dynamic nature of metabolic health status and obesity on risk of incident cardiovascular events and mortality: a nationwide population-based cohort study.

AIMS: We hypothesized that transitions in metabolic health status and obesity affect the cardiovascular (CV) risk and mortality in population with metabolically healthy obesity (MHO). METHODS: This study enrolled 514,866 participants from the Korean National Health Insurance Service-National Sample Cohort. Changes in metabolic health status and obesity from the baseline examination in 2009-2010 to the next biannual health examination in 2011-2012 were determined. Study participants were categorized into four groups: (1) metabolically healthy, non-obese (MHNO), defined as BMI < 25 kg/m2 and no or one metabolic risk factor; (2) metabolically unhealthy, non-obese (MUNO), defined as BMI < 25 kg/m2 and ≥2 metabolic risk factors; (3) MHO, defined as BMI ≥ 25 kg/m2 and no or one metabolic risk factor; and (4) metabolically unhealthy, obese (MUO), defined as BMI ≥ 25 kg/m2 and ≥2 metabolic risk factors. The study subjects were followed-up from 2011 to 2015 for cardiovascular events, CV mortality and all-cause mortality. RESULTS: Among the subjects classified as MHO in 2009-2010, 45.6% were classified as MHO in 2011-2012, whereas 11.6%, 6.0%, and 36.8% were classified as MHNO, MUNO, and MUO, respectively. The risk of CV events was higher in baseline MHO group than MHNO group (HR, 1.14; 95% CI, 1.05-1.24). However, in baseline MHO group, CV mortality was not increased (HR, 0.85; 95% CI, 0.69-1.06) and all-cause mortality was even lower than that of MHNO group (HR, 0.86; 95% CI, 0.79-0.93). Compared to the stable MHO subjects, the risk of CV events was significantly higher in the subjects who transitioned from MHO to MUO with multivariate-adjusted HRs of 1.24 (95% CI: 1.00-1.54). When weight loss and progression to metabolic unhealthy phenotype occur simultaneously in the MHO population, the all-cause mortality was increased compared to the stable MHO group (HR, 1.96; 95% CI, 1.45-2.65). CONCLUSIONS: Subjects with MHO constitute a heterogeneous group. Our finding supports that evolving to a metabolically unhealthy status and losing weight simultaneously is associated with the adverse outcome in the MHO population.

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

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

Asian Subpopulations May Exhibit Greater Cardiovascular Benefit from Long-Acting Glucagon-Like Peptide 1 Receptor Agonists: A Meta-Analysis of Cardiovascular Outcome Trials.

BACKGROUND: Based on reported results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major adverse cardiovascular events (MACEs) and to identify subpopulations exhibiting the greatest cardiovascular (CV) benefit. METHODS: Three CVOTs reporting effects of long-acting GLP-1 RAs were included: LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide once weekly). In all studies, the primary endpoint was three-point MACE, comprising CV death, non-fatal myocardial infarction, and non-fatal stroke. Overall effect estimates were calculated as hazard ratios and 95% confidence intervals (CIs) using the random-effects model; subgroup analyses reported in the original studies were similarly analyzed. RESULTS: Overall, statistically significant risk reductions in MACE and CV death were observed. Subgroup analysis indicated a significant racial difference with respect to CV benefit (P for interaction <0.001), and more substantial risk reductions were observed in subjects of African origin (relative risk [RR], 0.78; 95% CI, 0.60 to 0.99) and in Asians (RR, 0.35; 95% CI, 0.09 to 1.32). However, post hoc analysis (Bonferroni method) revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with white subjects (P<0.0001). CONCLUSION: Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in high-risk patients with type 2 diabetes mellitus. Our findings of a particularly effective reduction in CV events with GLP-1 RA in Asian populations merits further exploration and dedicated trials in specific populations.

Transplantation of human mobilized mononuclear cells improved diabetic neuropathy.

Rodent stem cells demonstrated regenerative effects in diabetic neuropathy via improvement in nerve perfusion. As a pre-clinical step, we explored if human mobilized mononuclear cells (hMNC) would have the same effects in rats. hMNC were injected into Rt. hind-limb muscles of streptozotocin-induced diabetic nude rats, and the grafts were monitored using with MRI. After 4 weeks, the effects were compared with those in the vehicle-injected Lt. hind limbs. Nerve conduction, muscle perfusion and gene expression of sciatic nerves were assessed. Induction of diabetes decreased nerve function and expression of Mpz and Met in the sciatic nerves, which are related with myelination. hMNC injection significantly improved the amplitude of compound muscle action potentials along with muscle perfusion and sciatic nerve Mpz expression. On MRI, hypointense signals were observed for 4 weeks at the graft site, but their correlation with the presence of hMNC was detectable for only 1 week. To evaluate paracrine effects of hMNC, IMS32 cells were tested with hepatocyte growth factor (HGF), which had been reported as a myelination-related factor from stem cells. We could observe that HGF enhanced Mpz expression in the IMS32 cells. Because hMNC secreted HGF, IMS32 cells were co-cultured with hMNC, and the expression of Mpz increased along with morphologic maturation. The hMNC-induced Mpz expression was abrogated by treatment of anti-HGF. These results suggest that hMNC could improve diabetic neuropathy, possibly through enhancement of myelination as well as perfusion. According to in vitro studies, HGF was involved in the hMNC-induced myelination activity, at least in part.

The impact of non-alcoholic fatty liver disease and metabolic syndrome on the progression of coronary artery calcification.

It is unclear whether non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease. We examined the independent impact of NAFLD on the progression of the coronary artery calcification (CAC) score, a well-known marker of atherosclerosis progression. We examined 1,173 asymptomatic participants who underwent repeated CAC score measurement during routine health examinations. The subjects were categorised into four groups based on the presence (+) or absence (-) of NAFLD and metabolic syndrome (MetS). The progression of CAC score was defined as either incident CAC in a CAC-free population at baseline or an increase of ≥2.5 units between the baseline and the final square roots of the CAC scores of participants with detectable CAC at baseline. CAC progression was seen in 18.6% (98/526), 28.3% (77/272), 29.1% (30/103) and 32.0% (87/272) of the subjects with NAFLD(-)/MetS(-), NAFLD(+)/MetS(-), NAFLD(-)/MetS(+) and NAFLD(+)/MetS(+), respectively. The subjects with NAFLD(+)/MetS(+) and NAFLD(+)/MetS(-) had a significantly higher risk of CAC progression than those with NAFLD(-)/MetS(-) (multivariate-adjusted odds ratio [OR]: 1.76; 95% confidence interval [CI]: 1.18-2.62 and multivariate-adjusted OR: 1.53, 95% CI: 1.05-2.23, respectively). NAFLD is an independent risk factor for CAC progression, irrespective of the presence of MetS.

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

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

Trends in the prevalence of metabolic syndrome and its components in South Korea: Findings from the Korean National Health Insurance Service Database (2009-2013).

BACKGROUND: The prevalence of metabolic syndrome has markedly increased worldwide. However, studies in the United States show that it has remained stable or slightly declined in recent years. Whether this applies to other countries is presently unclear. OBJECTIVES: We examined the trends in the prevalence of metabolic syndrome and its components in Korea. METHODS: The prevalence of metabolic syndrome and its components was estimated in adults aged >30 years from the Korean National Health Insurance Service data from 2009 to 2013. The revised National Cholesterol Education Program criteria were used to define metabolic syndrome. RESULTS: Approximately 10 million individuals were analyzed annually. The age-adjusted prevalence of metabolic syndrome increased from 28.84% to 30.52%, and the increasing trend was more prominent in men. Prevalence of hypertriglyceridemia, low HDL-cholesterol, and impaired fasting plasma glucose significantly increased. However, the prevalence of hypertension decreased in both genders. The prevalence of abdominal obesity decreased in women over 50 years-of-age but significantly increased in young women and men (<50 years). CONCLUSIONS: The prevalence of metabolic syndrome is still increasing in Korea. Trends in each component of metabolic syndrome are disparate according to the gender, or age groups. Notably, abdominal obesity among young adults increased significantly; thus, interventional strategies should be implemented particularly for this age group.

Comparison between sodium-glucose cotransporter 2 inhibitors and pioglitazone as additions to insulin therapy in type 2 diabetes patients: A systematic review with an indirect comparison meta-analysis.

AIMS/INTRODUCTION: We aimed to evaluate the efficacy and safety of pioglitazone (PIO) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) as additions to insulin therapy for the management of type 2 diabetes mellitus. MATERIALS AND METHODS: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through December 2016. Randomized controlled trials published in English that compared SGLT2i plus insulin (SGLT2i/INS) or PIO plus insulin (PIO/INS) with placebo plus insulin (PCB/INS) in type 2 diabetes mellitus patients were included. We compared the efficacy and safety between SGLT2i/INS and PIO/INS indirectly. RESULTS: A total of 14 randomized controlled trials comparing 7,226 participants were included (8 SGLT2i and 6 PIO studies). SGLT2i/INS achieved similar reductions in hemoglobin A1c (weighted mean difference [WMD] -0.01% [-0.1 mmol/mol], 95% confidence interval [CI] -0.25 to 0.22% [-2.7 to -2.4 mmol/mol]; P = 0.896) and fasting plasma glucose (WMD -0.90 mg/dL, 95% CI: -15.50 to 13.71 mg/dL; P = 0.904), and a similar proportion of participants achieved hemoglobin A1c <7.0% (<53.0 mmol/mol; relative risk 0.98, 95% CI: 0.73 to 1.33; P = 0.917) as compared with the PIO/INS group, with greater weight reduction (WMD -4.54 kg, 95% CI: -5.67 to -3.41 kg; P < 0.001). PIO/INS showed non-significant trends toward a higher risk of hypoglycemia (relative risk 1.15, 95% CI: 0.97 to 1.35; P = 0.102) and higher reduction of total daily insulin doses (WMD -2.45 IU/day, 95% CI: -7.30 to 2.40 IU/day; P = 0.438). CONCLUSIONS: Both PIO and SGLT2i are feasible adjunctive oral agents to pre-existing insulin therapy in individuals with inadequately controlled type 2 diabetes mellitus.

Cardiovascular Diseases and Life Expectancy in Adults With Type 2 Diabetes: A Korean National Sample Cohort Study.

Objective: Although type 2 diabetes is a strong risk factor for cardiovascular disease and mortality, information on its association with mortality and life expectancy according to cardiovascular comorbidities is limited, especially in Asia. Thus, this study assessed mortality and reductions in life expectancy associated with cardiometabolic multimorbidity. Design and Methods: A total of 569,831 participants older than 30 years from Korean National Health Insurance Service-National Sample Cohort were enrolled between 2002 and 2006 and followed for a median of 12.0 years. They were categorized into five mutually exclusive groups according to baseline disease status, as follows: none (reference group); diabetes only; diabetes and stroke; diabetes and myocardial infarction (MI); and diabetes, stroke, and MI. Mortality rates and hazard ratios (HRs), reductions of life expectancy, and age-specific contributions to life expectancy were calculated by constructing life tables. Results: The mortality rates per 1000 person-years were 6.85, 19.86, 67.17, 66.34, and 115.52 in the reference, diabetes only; diabetes and stroke; diabetes and MI; and diabetes, stroke, and MI groups, respectively. The corresponding HRs for all-cause mortality were 1.70 [95% confidence interval (CI), 1.66 to 1.75], 3.66 (95% CI, 3.32 to 4.03), 3.56 (95% CI, 3.06 to 4.14), and 4.79 (95% CI, 3.05 to 7.50) compared with the reference group. The estimated reductions in life expectancy were greater at younger ages and markedly increased with more cardiometabolic comorbidities. Conclusion: Young Asians with type 2 diabetes, especially those with cardiovascular comorbidity, did not live as long than their nondiabetic equivalents. Thus, these individuals require special attention to prevent further reductions in life expectancy.

Effects of Incretin-Based Therapies on Diabetic Microvascular Complications.

The morbidity and mortality associated with diabetic complications impose a huge socioeconomic burden worldwide. Therefore, the ultimate goal of managing diabetes mellitus (DM) is to lower the risk of macrovascular complications and highly morbid microvascular complications such as diabetic nephropathy (DN) and diabetic retinopathy (DR). Potential benefits of incretin-based therapies such as glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on the diabetic macrovascular complications have been recently suggested, owing to their pleiotropic effects on multiple organ systems. However, studies primarily investigating the role of these therapies in diabetic microvascular complications are rare. Nevertheless, preclinical and limited clinical data suggest the potential protective effect of incretin-based agents against DN and DR via their anti-inflammatory, antioxidative, and antiapoptotic properties. Evidence also suggests that these incretin-dependent and independent beneficial effects are not necessarily associated with the glucose-lowering properties of GLP-1 RAs and DPP-4 inhibitors. Hence, in this review, we revisit the preclinical and clinical evidence of incretin-based therapy for DR and DN, the two most common, morbid complications in individuals with DM. In addition, the review discusses a few recent studies raising concerns of aggravating DR with the use of incretin-based therapies.

Visceral adiposity index predicts the conversion of metabolically healthy obesity to an unhealthy phenotype.

OBJECTIVE: Some individuals with metabolically healthy obesity (MHO) convert to metabolically unhealthy obesity (MUO) phenotype, and visceral adiposity is one of proposed mechanisms underlying such conversion. Visceral adipose index (VAI) is a novel mathematical model which estimates visceral adiposity based on anthropometric and lipid profiles. We aimed to determine the association of VAI-estimated visceral adiposity with the MHO-to-MUO conversion and the predictive value of VAI in estimating such unfavorable outcomes. METHODS: A total of 2,204 Korean subjects with the MHO phenotype were enrolled and stratified by body mass index and metabolic health state according to Wildman criteria at baseline and last follow-up examinations. VAI was calculated at baseline. RESULTS: Over a median follow-up period of 41.1 months, 46.0% of subjects converted to MUO phenotype. Higher VAI quartiles were associated with a greater proportion of subjects who underwent MHO-to-MUO conversion, and also with increased odds ratios for such conversion even after multivariate analyses. The optimal VAI cut off value was around 1.00, and VAI had a greater power in the prediction of MHO-to MUO conversion than waist circumference in both genders. CONCLUSION: MHO phenotypes with high VAI values are associated with poor future metabolic outcomes. VAI-estimated visceral adiposity is well correlated with the prognosis of MHO subjects, and VAI has a good predictive value in determining the MHO-to-MUO conversion.

Role of NO/VASP Signaling Pathway against Obesity-Related Inflammation and Insulin Resistance.

Obesity has quickly become a worldwide pandemic, causing major adverse health outcomes such as dyslipidemia, type 2 diabetes mellitus, cardiovascular disease and cancers. Obesity-induced insulin resistance is the key for developing these metabolic disorders, and investigation to understand the molecular mechanisms involved has been vibrant for the past few decades. Of these, low-grade chronic inflammation is suggested as a critical concept in the development of obesity-induced insulin resistance, and the anti-inflammatory effect of nitric oxide (NO) signaling has been reported to be linked to improvement of insulin resistance in multiple organs involved in glucose metabolism. Recently, a body of evidence suggested that vasodilatory-stimulated phosphoprotein (VASP), a downstream mediator of NO signaling plays a crucial role in the anti-inflammatory effect and improvement of peripheral insulin resistance. These preclinical studies suggest that NO/VASP signaling could be an ideal therapeutic target in the treatment of obesity-related metabolic dysfunction. In this review, we introduce studies that investigated the protective role of NO/VASP signaling against obesity-related inflammation and insulin resistance in various tissues.