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Background: Type 2 diabetes (T2D) and hypertension (HTN) are well-known modifiable risk factors for dementia, but their intricate attributes accounting for dementia development has not been clearly delineated. Objective: We conducted this study to investigate and compare the effects of T2D and HTN on dementia risk. Methods: We screened data of matched pairs of patients with T2D or HTN between January 1, 2000 and December 31, 2017 from Taiwan’s National Health Insurance Research Database. Fine and Gray’s subdistribution hazard models were used for calculating the risk of dementia. Results: Patients with T2D and subsequent HTN were associated with significantly higher risks of all-cause dementia (aHR 1.51, 95% CI 1.25–1.83) and vascular dementia (aHR 2.30, 95% CI 1.71–3.13) compared with those without subsequent HTN. Patients with HTN and subsequent T2D were associated with significantly higher risks of all-cause dementia (aHR 1.15, 95% CI 1.08–1.21), vascular dementia (aHR 1.25, 95% CI 1.62–1.34), and other dementia (aHR 1.31, 95% CI 1.03–1.66) compared with those without subsequent HTN. The subgroups of male and female patients, age of 50–69 and 70–90 years with subsequent comorbidity were associated with significantly higher risks of all-cause dementia and vascular dementia than those without subsequent comorbidity. Conclusion: This nationwide cohort study demonstrated that patients with T2D and subsequent HTN had association with higher risks of all-cause dementia and vascular dementia, and those with HTN and subsequent T2D were associated with higher risks of all-cause dementia, vascular dementia, and other dementia.

This study compared the efficacy of two statin treatments (simvastatin vs rosuvastatin) in achieving the combined goal of low-density lipoprotein cholesterol (LDL-C)2.6 mmol/L and non-high-density lipoprotein cholesterol (non-HDL-C)3.4 mmol/L in patients with type 2 diabetes and dyslipidemia.After a 5-week run-in, 89 patients with type 2 diabetes having fasting triglyceride (TG) levels of 1.7 to 5.7 mmol/L or non-HDL-C levels of 3.4 to 5.2 mmol/L were randomized to receive simvastatin 20 mg daily for 4 weeks followed by 40 mg for 8 weeks or rosuvastatin 10 mg for 4 weeks followed by 20 mg for 8 weeks. The primary end-point was the percentage of patients achieving the combined goal at week 12.Although significant between-group differences were observed in changes in LDL-C and non-HDL-C levels, both study treatments were sufficiently intensive for a 40% to 55% LDL-C reduction. At the end of the study, the two groups had similar percentages of patients who achieved the combined lipid goal (84% vs 89%, p = 0.66). All patients who attained the combined lipid goal also met the apolipoprotein B (Apo-B) target of0.9 g/L. No between-group differences were noted in changes in HDL-C and TG levels at week 12. The patients tolerated both treatments well.In our study, ≈85% of patients with type 2 diabetes and dyslipidemia could achieve the combined lipid goal with statin monotherapy. The two statin treatments could sufficiently control diabetic dyslipidemia (NCT00506961).

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756

We conducted this study to investigate the long-term outcomes of sulfonylurea (SU) use in patients with chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D). We used propensity-score matching to identify 6008 pairs of SU users and nonusers from Taiwan’s National Health Insurance Research Database from 1 January 2000 to 31 December 2017. Cox proportional hazard models were used to compare the risks of mortality, cardiovascular events, non-invasive positive pressure ventilation, invasive mechanical ventilation, bacterial pneumonia, lung cancer, and hypoglycemia between SU users and nonusers. In the matched cohorts, the mean follow-up time for SU users and nonusers was 6.57 and 5.48 years, respectively. Compared with nonusers, SU users showed significantly lower risks of mortality [aHR 0.53(0.48–0.58)], cardiovascular events [aHR 0.88(0.81–0.96)], non-invasive positive pressure ventilation [aHR 0.74(0.6–0.92)], invasive mechanical ventilation [aHR 0.57(0.5–0.66)], and bacterial pneumonia [aHR 0.78(0.7–0.87)]. A longer cumulative duration of SU use was associated with a lower risk of these outcomes. This nationwide cohort study demonstrated that SU use was associated with significantly lower risks of cardiovascular events, ventilation use, bacterial pneumonia, and mortality in patients with COPD and T2D. SU may be a suitable option for diabetes management in these patients.

Optimal control of diabetes and relevant risk factors substantially reduce the risks of chronic complications and mortality. We investigated all-cause mortality rate and major causes of death between 2007 and 2018 in patients with diabetes in Taiwan. This study was conducted using data from Taiwan National Health Insurance Research Database. We selected patients with diabetes diagnosed between 2007 and 2017 (grouped according to the year of diabetes diagnosis 2007-2010 vs. 2011-2017). Information on mortality and causes of death by the end of 2018 was confirmed through linking to the National Death Registry. Standardized mortality rate (SMR) were calculated by weighting the World Health Organization (WHO) standard population (WHO 2000-2025). More than 2.7 million of patients with diabetes were analyzed and a total of 566121 deaths were identified. Overall, the SMR was 11.72 per 1000 person-years. Patients with diabetes diagnosed in 2011-2017 had a lower SMR (8.42 vs. 12.92 per 1000 person-years) than those diagnosed in 2007-2010. Similar finding were noted regarding the major causes of death (cancer, diabetes, heart disease, hypertensive disease, and cerebrovascular disease). Compared with patients who were diagnosed in 2008-2010, those who were diagnosed in 2011-2014 and 2015-2018 had a higher 3-year survival rate (0.9356 vs. 0.9438 vs. 0.946, log-rank test p

IntroductionWe investigated health service utilization, including hospitalizations and emergency department visits, for women with hyperglycemia in pregnancy between 2008 and 2017 in Taiwan.MethodsData from the Health and Welfare Data Science Center were used to conduct this nationwide population-based study. We identified pregnant women and the date of childbirth according to Birth Certificate Applications from 2007 to 2018. The study population was divided into four groups: known DM, newly diagnosed DM, GDM, and no DM/GDM. To assess quality of healthcare during the gestation period, trends in 30-day readmission rate, number of emergency department visits/hospitalizations per 100 childbirths, and length of hospital stay from 2008 to 2017 were examined.ResultsA total of 1830511 childbirths and 990569 hospitalizations were identified for analyses. Between 2008 and 2017, women with hyperglycemia in pregnancy (known DM, newly diagnosed DM, and GDM) had a higher rate of hospitalization, a longer length of hospital stay, and higher rates of various maternal and fetal outcomes, compared with women with no DM/GDM. Nevertheless, the differences between women with GDM and those with no DM/GDM in the aforementioned outcome measures were modest. Women with GDM had a modest decrease in the 30-day readmission rate (p for trend 0.046) with no significant difference in the number of emergency department visits during the study period.DiscussionOur findings provide evidence of the quality of healthcare for women with GDM between 2008 and 2017 in Taiwan.

The global incidence of adolescents with type 2 diabetes mellitus is increasing. This cohort study was conducted aiming to describe the characteristics, drug-use condition, and long-term outcomes of adolescents with type 2 diabetes mellitus.Two thousand seven hundred fifty-five newly diagnosed adolescents with type 2 diabetes mellitus (using ICD-9-CM: 250.x and having ≥3 clinic visits) were identified from the national health insurance dataset during 2000-2014. Treatments were classified into four groups: metformin, sulfonylurea (SU), metformin plus SU, and insulin with or without oral antidiabetic drugs. The multiple Cox regression model was used to compare the risks of mortality and hospitalization among these four groups.The mean follow-up period was 5.4 years. After 1 year of antidiabetic treatment, they gradually needed intensified therapy, and at 3 years, half of them showed treatment failure. The mortality rate was 2.08 per 1,000 person-years. Respiratory diseases (36.2%) and dysglycemia (16.4%) were the most common causes of hospitalization among these adolescents. Compared with persons taking metformin plus SU, metformin users were associated with a lower risk of all-cause hospitalization [0.82 (0.67-0.99)]; insulin users were associated with a higher risk of dysglycemia [4.38 (2.14-8.96)], cancer [3.76 (1.39-10.1)], and respiratory hospitalization [1.66 (1.14-2.41)]; and SU users were associated with a higher risk of hospitalization for respiratory diseases [1.91 (1.13-3.23)].This nationwide cohort study demonstrated that adolescents with type 2 diabetes mellitus were prone to treatment failure. Furthermore, respiratory diseases and dysglycemia were the most common causes of hospitalization.

Although type 1 diabetes mellitus (T1DM) is recognized as a catastrophic disease among the different types of diabetes, it is often confusedly diagnosed in clinical practice and difficult in care. The objective of this study is to reach a multidisciplinary consensus for the establishment of clinical recommendations on T1DM to optimize its undoubtedly diagnostic evaluation and transitional care.Scientific evidence was reviewed by a committee of researchers, based on which recommendations related to T1DM diagnosis were formulated. A two-round method was conducted to compare the opinions of a panel of 32 specialists (adult endocrinologists [53.1%], pediatric endocrinologists [43.8%], a diabetes educator for child and adolescent [3.1%]) on these issues.The panel reached consensus on two of the six items discussed. The four items on which no consensus was reached were related to autoantibody detection and age of onset. Up to 80% of the panelists favored items related to the glucagon test and diabetic ketoacidosis history for T1DM diagnosis. Consensus regarding transitional care through diabetes educators was established.The assessment conducted by experts on T1DM showed a high level of professional agreement regarding the proposed diagnostic and transitional care recommendations. A comprehensive analysis of the latest evidence is warranted for the items on which consensus was not established.

We conducted this study to compare the risks of asthma development and exacerbation between metformin users and nonusers. Overall, 57,743 propensity score-matched metformin users and nonusers were identified from Taiwan’s National Health Insurance Research Database between 1 January 2000, and 31 December 2017. We used the Cox proportional hazards model with robust standard error estimates to compare the risks of asthma onset, exacerbation, and hospitalization for asthma in participants with type 2 diabetes (T2D). Compared with metformin nonuse, the aHRs (95% CI) for metformin use in asthma development, exacerbation, and hospitalization for asthma were 1.13 (1.06–1.2), 1.62 (1.35–1.95), and 1.5 (1.22–1.85), respectively. The cumulative incidences of asthma development, exacerbation, and hospitalization for asthma were significantly higher in metformin users than nonusers (p < 0.001). A longer cumulative duration of metformin use for more than 728 days was associated with significantly higher risks of outcomes than metformin nonuse. Our study demonstrated that metformin users showed significantly higher risks of asthma development, exacerbation, and hospitalization for asthma than metformin nonusers. Moreover, metformin use for more than 728 days was associated with higher risks of outcomes. A randomized control study is warranted to verify our results.

Objectives: Chronic kidney disease (CKD) has emerged as a global health concern. Many studies have identified an association between hyperuricemia and CKD, and some studies have revealed that urate-lowering therapy (ULT) can attenuate CKD progression. However, only a few studies have explored the role of ULT in the prevention of new onset CKD. Methods: To compare the risk of incident CKD between users and nonusers of ULT in patients with gout, we conducted a 13-year population-based retrospective cohort study. Overall incidence of CKD was compared between 7126 ULT users and 7126 matched ULT nonusers. Results: The CKD incidence rate for both the users and nonusers of ULT was 1.7 per 100 person-years, after adjusting for sex, age, region of residence, comorbidities, and medications used. No significant difference in CKD risk (adjusted hazard ratio [aHR]: 0.97; 95% confidence interval [CI]: 0.88-1.07) was noted between the ULT users and nonusers. In the subgroup of patients with diabetes mellitus (DM) and without hypertension (HT), ULT tended to be associated with lower risk of incident CKD (aHR: 0.52; 0.95% CI: 0.28-0.97). Compared with the risk of new onset CKD in patients receiving xanthine oxidase inhibitors, those receiving uricosuric agents seemed to have a lower risk of developing CKD (aHR: 0.81, 95% CI: 0.67-0.99). Conclusion: This population-based cohort study indicated that ULT is not associated with lower risk of CKD development. However, in the subgroup of patients with DM and without HT, ULT is associated with significantly lower risk of incident CKD.

Pregnant and lactating women are vulnerable to iodine deficiency. This study was conducted to evaluate the iodine nutritional status of lactating women in northern Taiwan.Women recruited from Taipei Veterans General Hospital (TVGH) in 2019 provided a spot urine sample and completed a Food Frequency Questionnaire. The urinary iodine concentration (UIC) was measured by inductively coupled plasma mass spectrometry.The overall median UIC in 198 women was 120.4 μg/L, indicating a sufficient iodine status. Univariate analysis revealed a lower median UIC in women of younger age (p = 0.004), who were not taking multivitamins (p = 0.004), not on a postpartum nourishment diet (p = 0.04), and whose infant received more breast milk (p = 0.004). The median UIC was100 μg/L in the group aged 20 to 29 years (UIC: 74.4 μg/L) and in women whose infants' diet was composed of50% breast milk (UIC: 86.1 μg/L). A postpartum nourishment diet was followed by 73.7% (n = 146) of the women. Nevertheless, a significant decrease in the intake frequency of iodine-containing foods, including seaweeds (p0.001), seafood (p0.001), dairy products (p = 0.009), and multivitamins (p0.001) was observed compared with the intake noted in a previous survey of pregnant women in TVGH. Following multivariate analysis, only younger age (20-29 vs ≥30 years; odds ratio [OR]: 3.38; 95% confidence interval [CI]: 1.49-7.65), no use of multivitamin (OR: 1.89; 95% CI: 1.03-3.48), and infant diet composition (50% breast milk vs50% breast milk; OR: 2.93; 95% CI: 1.37-6.25) were independently associated with UIC100 μg/L.The results suggest that the iodine status in lactating women in northern Taiwan is adequate. However, iodine deficiency may continue to be present in certain subgroups, such as women of younger age and those who do not take multivitamins.

Aims/Introduction Studies assessing the long‐term outcomes of insulin persistence are scant. We compared the risk of all‐cause mortality among patients with different degrees of insulin persistence. Materials and Methods In total, 293,210 patients with type 2 diabetes mellitus undergoing insulin therapy were enrolled during 2002–2014. Insulin persistence was defined as continual insulin treatment without a 90‐day gap of discontinuation in the 2‐year observation period. Mortality rates were compared between 111,220 patients with ≥90% insulin persistence and 111,220 matched patients with, Patients with high insulin persistence as compared with low insulin persistence decreased the risk of mortality by 20%.

Background & Aims Studies have described prominent histologic improvement in patients with nonalcoholic steatohepatitis (NASH) using thiazolidinedione (TZD); however, these were all short term with moderate sample size, no liver‐related long‐term outcomes could be noted. Methods This retrospective cohort study enrolled patients with newly diagnosed type 2 diabetes mellitus (T2DM) from Taiwan's National Health Insurance Research Database between 1 January 2000 and 31 December 2013. We matched TZD users and nonusers at a 1:1 ratio through propensity score matching. This study included 5095 paired TZD users and nonusers. Cox proportional hazard models were used to compare the risks of cirrhosis, hepatic decompensation, hepatic failure and all‐cause mortality between TZD users and nonusers. The Kaplan‐Meier method was used to compare the cumulative incidence of these main outcomes. Results The incidence rates of cirrhosis, hepatic decompensation, hepatic failure and all‐cause mortality during follow‐up were 0.77 vs 1.95, 1.43 vs 1.75, 0.36 vs 0.70, and 4.89 vs 3.78 per 1000 person‐years between TZD users and nonusers. The adjusted hazard ratios of cirrhosis, hepatic decompensation, hepatic failure and all‐cause mortality were 0.39 (95% confidence interval [CI]: 0.21‐0.72), 0.86 (95% CI: 0.52‐1.44), 0.46 (95% CI: 0.18‐1.17) and 1.18 (95% CI: 0.87‐1.61) respectively. Conclusions Our study demonstrated that TZD use could significantly lower the risk of cirrhosis. In clinical settings, TZD use might be able to improve liver‐related long‐term outcomes.

The natural history of youth-onset type 2 diabetes between the West and the East seems similar, with a high proportion of comorbidities (obesity, hypertension and dyslipidemia), increased risk of microvascular complications and high treatment failure rates.

Background In this study, we investigated whether serum levels of advanced glycation end products (AGEs) independently correlated with relative muscle strength after adjustment for clinical variables including diabetic peripheral neuropathy in patients with type 2 diabetes. Relative muscle strength was defined as muscle strength (in decinewtons, dN) divided by total muscle mass (in kg). Methods We enrolled 152 ambulatory patients with type 2 diabetes. Each participant underwent measurements of muscle strength and total muscle mass. Serum levels of AGEs were determined. The Michigan Neuropathy Screening Instrument Physical Examination (MNSI-PE) was performed to assess diabetic peripheral neuropathy. Results The participants were divided into three groups on the basis of tertiles of serum AGEs levels. Significant differences were observed among the three groups in relative handgrip strength (71.03 ± 18.22, 63.17 ± 13.82, and 61.47 ± 13.95 dN/kg in the low-tertile, mid-tertile, and high-tertile groups, respectively, P = 0.005). The relative muscle strength of the ankle plantar flexors was higher in the low-tertile group than in the mid-tertile and high-tertile groups (107.60 ± 26.53, 94.97 ± 19.72, and 94.18 ± 16.09 dN/kg in the low-tertile, mid-tertile, and high-tertile groups, respectively, P = 0.002). After adjustment for MNSI-PE score and other clinical variables in partial correlation analysis, the correlations between serum levels of AGEs and the relative muscle strength of handgrip, ankle dorsiflexor, and ankle plantar flexor remained significant. Serum AGEs level was the only variable that remained significantly related to the relative muscle strength of handgrip, ankle dorsiflexor, and ankle plantar flexor when AGEs level, fasting plasma glucose, and glycated hemoglobin (HbA1c) were entered into multiple regression models simultaneously. Conclusions After adjustment for multiple factors including diabetic peripheral neuropathy, this study demonstrated that increased serum levels of AGEs were independently associated with decreased relative muscle strength in patients with type 2 diabetes. Compared with fasting plasma glucose and HbA1c, serum level of AGEs is more strongly associated with relative muscle strength.

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

To investigate the long-term outcomes of Pay-for-Performance (P4P) care in patients with young-onset (20-40 years of age) diabetes (YOD).We recruited 3088 pairs of propensity-score matched patients with and without P4P care from the National Health Insurance Research Database between January 1, 2001, and December 31, 2017. The study used a multivariable Cox regression model to compare the risks of mortality, hospitalization for cardiovascular events, and major microvascular outcomes in YOD patients with and without P4P care.The multivariable-adjusted model showed that patients with P4P care had significantly lower risks of mortality (aHR 0.31, 95% CI 0.25-0.38) and hospitalization for cardiovascular events (aHR 0.63, 95% CI 0.5-0.79) but a significantly higher risk of major microvascular outcomes (aHR 1.31, 95% CI 1.07-1.6). Patients with a longer cumulative duration of P4P and complete P4P care showed further lower risks of mortality, hospitalization for cardiovascular events, and major microvascular outcomes than those without P4P care.This nationwide cohort study showed that young-onset diabetes patients with P4P care had lower risks of death and cardiovascular events but a higher risk of major microvascular outcomes. However, patients with a longer duration of P4P care showed lower risks of these outcomes.

Persons with type 2 diabetes (T2D) have neutrophil dysfunction with a higher risk of infection than those without diabetes. We conducted this study aiming to compare the risk of pneumonia between metformin use and nonuse in persons with T2D. We identified 49,012 propensity score-matched metformin users and nonusers from Taiwan’s National Health Insurance Research Database between January 1, 2000, and December 31, 2017. We used the Cox proportional hazards model to compare the risks of pneumonia and respiratory death. The mean (SD) age of the participants was 57.46 (12.88) years, and the mean follow-up time for metformin users and nonusers was 5.47 (3.71) years and 5.15 (3.87) years, respectively. Compared with the nonuse of metformin, the adjusted hazard ratios (95% CI) for metformin use in bacterial pneumonia, invasive mechanical ventilation, and respiratory cause of death were 0.89 (0.84–0.94), 0.77 (0.73–0.82), and 0.64 (0.56–0.74), respectively. A longer cumulative duration of metformin use had further lower adjusted hazard ratios in these risks compared with nonuse. In patients with T2D, metformin use was associated with significantly lower risks of bacterial pneumonia, invasive mechanical ventilation, and respiratory cause of death; moreover, longer metformin use duration was associated with lower hazard ratios of these risks.

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Sarcopenia is a common and progressive skeletal muscle condition, often described as an intermediate stage in the development of frailty and disability in patients with diabetes. This can be improved through physical activity and exercise. This descriptive phenomenological study explored the exercise experiences of older adults with diabetes and sarcopenia. Individual interviews were conducted following semi-structured interview guidelines, and narratives were analyzed using Giorgi’s method. Data saturation was achieved after interviewing 14 purposively sampled older patients with diabetes and sarcopenia. The study identified three main themes: encountering difficulty during exercise, recognizing the advantages of exercise, and constructing a suitable exercise model. While older adults with diabetes and sarcopenia may encounter difficulty during exercise, they also experience positive feedback from exercise. Understanding the limitations of older adults, individualizing exercise models based on their exercise experiences, and providing appropriate interventions and necessary emotional support can effectively prevent diabetes and sarcopenia.

PurposeTo compare the risks of chronic kidney disease (CKD), end-stage renal disease (ESRD), sight-threatening retinopathy, and leg amputation between patients with diabetes or hypertension.MethodsFrom January 1, 2000, to December 31, 2015, we identified 28943 matched pairs of patients with diabetes with and without subsequent hypertension, 89102 pairs of patients with hypertension with and without subsequent diabetes, and 145294 pairs of patients with coexisting diabetes and hypertension with a previous history of diabetes or hypertension from Taiwan’s National Health Insurance Research Database. Cox proportional-hazard models were used for calculating the risks of CKD, sight-threatening retinopathy, and leg amputation.ResultsThe mean follow-up time of this study in different cohorts was between 3.59 and 4.28 years. In diabetes patients with vs. without subsequent hypertension, hypertension patients with vs. without subsequent diabetes, and comorbid diabetes and hypertension patients with previous diabetes vs. with previous hypertension, the adjusted HRs (95% CIs) for CKD were 2.77 (2.61-2.94), 1.73 (1.68-1.77), and 1.04 (1.02-1.07); for ESRD were 42.38 (22.62-79.4), 2.76 (2.43-3.13), and 0.72 (0.66-0.79); for sight-threatening retinopathy were 2.07 (1.85-2.3), 3.41 (3.14-3.71), and for leg amputation were 1.51 (1.43-1.58); and 4.74 (3.02-7.43), 6.27(4.72-8.31), and 1.19(1.03-1.38).ConclusionsThis study demonstrated that both diabetes and hypertension are risk factors for the development of CKD, retinopathy, and amputation. Tracing subsequent diabetes for patients with hypertension, and hypertension for patients with diabetes are important in clinical settings.

Isolated postchallenge hyperglycemia (IPH) is a type of diabetes mellitus defined as 2-h glucose ≥200 mg/dL but fasting glucose126 mg/dL. The purpose of the study was to assess impacts of IPH on 10-year atherosclerotic cardiovascular disease (ASCVD) risk scores in postmenopausal women. This study analyzed data from 428 postmenopausal women who underwent oral glucose tolerance test at a medical center. Ten-year ASCVD risk was evaluated by using Pooled Cohort Equations. Logistic regression analysis was performed to estimate odds ratios for having high 10-year ASCVD risk scores (≥5%) among these women. The subjects with IPH had higher systolic blood pressure and worse lipid profile than those without IPH. Ten-year ASCVD risk scores for postmenopausal women with IPH were calculated under 2 scenarios: the IPH women were considered non-diabetic, they were designated as patients with DM. The median ASCVD risk score of the participants with IPH increased significantly from 3.7% under scenario 1 to 7.1% under scenario 2. Approximately 20% women with IPH were re-categorized from risk category of5% to ≥7.5% once they were identified as patients with DM (scenario 2). The results of logistic regression analyses showed that IPH was independently positively associated with 10-year ASCVD risk scores ≥5% under both scenarios. Postmenopausal women with IPH were characterized by unfavorable cardiovascular risk profile and high predicted 10-year ASCVD risk. Knowing the women's hidden DM status would significantly alter their risk categorization.

We conducted this study to determine the effect of metformin use on the risk of new-onset chronic urticaria in patients with type 2 diabetes (T2D). In total, 24,987 pairs of metformin users and nonusers were identified with propensity score-matching from Taiwan’s National Health Insurance Research Database from 1 January 2000, to 31 December 2017. Multivariable Cox proportional hazards models were used to compare the risks of chronic urticaria development, severe chronic urticaria, and hospitalization for chronic urticaria between metformin users and nonusers. Compared with metformin nonuse, the aHRs (95% CI) for metformin use in chronic urticaria development, severe chronic urticaria, and hospitalization for chronic urticaria were 1.56 (1.39–1.74), 0.40 (0.12–1.30), and 1.45 (0.82–2.56), respectively. The cumulative incidence of chronic urticaria development was significantly higher in metformin users than in nonusers (p < 0.0001). A longer average cumulative duration of metformin use was associated with higher risks of new-onset and hospitalization for chronic urticaria than metformin nonuse. This nationwide cohort study showed that metformin use was associated with a significantly higher risk of chronic urticaria development. A longer average cumulative duration of metformin use was associated with a higher risk of outcomes. More prospective studies are needed to verify our results.

Aim To compare long-term outcomes among three groups with different ages of diabetes onset. Method 66,520 paired age-, and sex-matched persons with and without type 2 diabetes were selected from the Taiwan National Health Insurance Research Database from 2000 to 2012. Cox proportional hazards models were used to compare the outcomes. Using late-onset diabetes as a reference, adjusted difference in differences analyses were performed to assess excessive odds comparing diabetes versus non-diabetes for young-onset diabetes (YOD) and early-onset diabetes in the risks of mortality and vascular complications. Results Persons with type 2 diabetes, irrespective of the onset age, had higher associated risks of all-cause mortality and vascular complications than their matched counterparts without diabetes. Compared to the odds of complications between those with diabetes and non-diabetes in the late-onset diabetes group, the excess odds in YOD are generally greater than in the early-onset diabetes (for stroke: 1.90 vs. 1.32; heart failure: 2.03 vs. 1.58; myocardial infarction: 3.02 vs. 1.56; and microvascular complications: 3.52 vs. 3.01). Conclusions Diabetes with different ages of onset may imply distinct long-term health outcomes. The persons with young-onset and early-onset diabetes seem to bear excess risk for mortality and vascular complications.

Diabetes remains a global epidemic and a tremendous health challenge, especially in the Asian population. Dramatic increases in the prevalence of diabetes across different countries or areas in Asia have been reported in recent epidemiological studies. Although clinical guidelines have strengthened appropriate antihyperglycemic medications and lifestyle modifications for optimal diabetes management, inadequate glycemic control still occurs in many patients with an increased risk of developing microvascular and macrovascular complications. Insulin administration is the main therapy for diabetes in response to the inability to secrete insulin, and is recommended in current guidelines to treat patients with type 2 diabetes after failure of oral antidiabetic drugs. Clinical studies have shown that long‐acting insulin analogs improve basal glycemic control with reduced risk of hypoglycemia. In the present review, we discuss previous challenges with basal insulin therapy in Asia, the pharmacological development of insulin analogs to overcome the unmet medical needs and recent clinical studies of the new ultra‐long‐acting insulin analog, insulin glargine U300. Furthermore, relevant findings of current real‐world evidence are also included for the comparison of the efficacy and safety of different insulin formulations. Based on the accumulating evidence showing a low incidence of hypoglycemia and technical benefits of dose titration, treatment with glargine U300 can be a promising strategy for Asian diabetes patients to achieve glycemic targets with favorable safety.

To compare the risks of all-cause mortality, hepatic outcomes, major adverse cardiovascular events between metformin users and nonusers for patients with diabetes and cirrhosis.From the Taiwan's National Health Insurance Research Database, we selected propensity-score matched metformin users and nonusers from the cohorts of type 2 diabetes mellitus with compensated (n = 26 164) or decompensated liver cirrhosis (n = 15 056) between 1 January 2000 and 31 December 2009, and followed them until 31 December 2010. Cox proportional hazards models with robust sandwich standard error estimates were used to assess risk of investigated outcomes for metformin users.The incidence rates of mortality during follow-up were 3.8 and 3.3 per 100 patient-years (adjusted hazard ratio [aHR] 1.13, 95% confidence interval 1.01-1.25) for metformin users and nonusers, respectively. The incidence rates of cirrhotic decompensation during follow-up were 5.9 and 4.9 per 100 patient-years (aHR 1.15, 95% confidence interval 1.04-1.27) for metformin users and nonusers. The risk of death (P for trend.01) and cirrhotic decompensation (P for trend.0001) associated with metformin use was significant for those taking metformin for40 defined daily doses in 90 days or1000 mg/d. The outcomes of metformin use vs nonuse for type 2 diabetes mellitus with decompensated liver cirrhosis were not statistically different, except that metformin users had higher risk of mortality (aHR 1.15).Metformin use was associated with higher risks of mortality and cirrhotic decompensation in patients with compensated liver cirrhosis. Prospective studies are required to confirm our results.

BACKGROUND We investigated the uses and frequency of self-monitoring of blood glucose (SMBG) with glycemic control and hypoglycemia in two groups of type 2 diabetes (T2D) (recently diagnosed and long-term follow-up) using real-world data in Taiwan (the Taiwan Diabetes Registry). METHODS Patients with T2D recently diagnosed within 6 months (n = 3297, mean age 54.4 ± 13.9 years) and T2D patients with long-term follow-up (n = 1201, mean age 65.5 ± 12.1 years, mean diabetes duration 14.3 ± 7.8 years) from the Taiwan Diabetes Registry were analysed. All patients were interviewed by certified diabetes educators. Information about SMBG and hypoglycemia was recorded. Demography, personal history, and laboratory data were obtained from electronic medical records. Logistic regression analyses were used to examine the associations of SMBG with glycated haemoglobin (HbA1c)

Background In insulin-treated patients with type 2 diabetes mellitus (T2DM), glycemic control is usually suboptimal. Methods This study compared the risks of mortality and cardiovascular events in insulin-treated patients adding or not adding alpha-glucosidase inhibitors (AGIs). Results This cohort study included data from the Taiwan National Health Insurance Research Database. In total, 17,417 patients newly diagnosed as having T2DM and undergoing insulin therapy during 2000–2012 were enrolled. Overall incidence rates of all-cause mortality, hospitalized coronary artery disease (CAD), stroke, and heart failure were compared between 4165 AGI users and 4165 matched nonusers. The incidence rates of all-cause mortality were 17.10 and 19.61 per 1000 person-years in AGI nonusers and users, respectively. Compared with nonusers, AGI users had a higher mortality risk [adjusted hazard ratio (aHR) = 1.21, 95% confidence interval (CI) = 1.05–1.40; p = 0.01]. Regarding AGI use, aHRs (95% CI) for cardiovascular death, non-cardiovascular death, hospitalized CAD, stroke, and heart failure were 1.20 (0.83–1.74), 1.27 (1.07–1.50), 1.12 (0.95–1.31), 0.98 (0.85–1.14), and 1.03 (0.87–1.22) respectively. Conclusion AGI use was associated with higher risks of all-cause mortality and non-cardiovascular death in insulin-treated patients with T2DM. Therefore, adding AGIs in insulin-treated patients may not be appropriate.

Objectives Some patients with type 2 diabetes mellitus (T2DM) experience decreased mobility associated with lower relative muscle strength (normalized with muscle mass). This study aimed to identify factors predicting relative muscle strength of patients with T2DM assessed at regular clinical visits. Methods A total of 144 T2DM patients underwent fasting blood drawing (determining white blood cell count [WBC], diabetic kidney disease [DKD], and glycated hemoglobin [HbA1c]) and the assessment of body composition, diabetic peripheral neuropathy (DPN), activity level, and muscle strength (grip, knee extensor, and ankle plantar flexor strength). One-way ANOVA and multiple regression models were used to identify factors associated with the relative muscle strength. Results Our data showed that age, diabetes duration, fat percentage, WBC, DPN, and DKD were negatively associated with the relative muscle strength. Specifically, a greater WBC was associated with lower relative muscle strength of both distal and proximal muscle groups of extremities after the adjustment of other associated factors. DPN was associated with lower relative strength of the distal muscle groups of extremities. Conclusions WBC may be used as a marker of inflammation, and greater count, even within the normal range, is negatively associated with the relative muscle strength in patients with T2DM.

Background Chronic low-grade inflammation is considered one of the major mechanisms for the progression of diabetic kidney disease. We investigated the prognostic value of circulating soluble tumor necrosis factor receptor 2 (sTNFR2) for early nephropathy in patients with type 2 diabetes. Materials and methods A total of 364 patients with type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2 were followed up for a median of 4 years. Renal outcomes were defined as a composite of either or both a >30% decline in the eGFR and/or albuminuria stage progression determined with consecutive tests. Results Seventy-three patients developed renal composite events. Serum concentrations of sTNFR2 were strongly associated with the risk of renal function decline and progressive changes in albuminuria. Through a receiver operating characteristic curve analysis, a serum sTNFR2 level of 1.608 ng/mL was adopted as the discriminator value for predicting renal outcomes (area under the curve 0.63, 95% confidence interval 0.57–0.70, p < 0.001), yielding a sensitivity of 75.3% and a specificity of 51.2%. The association of sTNFR2 levels ≥1.608 ng/mL to renal outcomes was significant after adjusting for relevant variables (hazard ratio 2.27, 95% confidence interval 1.23–4.20, p = 0.009) and remained consistent across subgroups stratified by age, sex, systolic blood pressure, eGFR, albuminuria, and the use of renin-angiotensin system blockers. Conclusions Higher circulating levels of sTNFR2 are independently associated with an eGFR decline and progressive albuminuria in patients with type 2 diabetes.

Diabetic kidney disease (DKD) and its comorbidities can be prevented by treating multiple targets. Technology-assisted team-based care with regular feedback and patient empowerment can improve the attainment of multiple targets and clinical outcomes in patients with type 2 diabetes, but the effects of this intervention on patients with DKD are unclear.To evaluate the effect of the Joint Asia Diabetes Evaluation (JADE) web portal, nurse reminders, and team-based care on multiple risk factors in patients with DKD.This 12-month multinational, open-label randomized clinical trial was conducted between June 27, 2014, and February 19, 2019, at 13 hospital-based diabetes centers in 8 countries or regions in Asia. All patients who participated had DKD. The intention-to-treat data analysis was performed from April 7 to June 30, 2020.Patients were randomized in a 1:1:1 ratio at each site to usual care, empowered care, or team-based empowered care. All patients underwent a JADE web portal-guided structured assessment at baseline and month 12. Patients in the usual care and empowered care groups received a medical follow-up. Patients in the empowered care group also received a personalized JADE report and nurse telephone calls every 3 months. Patients in the team-based empowered care group received additional face-to-face reviews every 3 months from a physician-nurse team.The primary outcome was the proportion of patients who attained multiple treatment targets (defined as ≥3 of 5 targets: HbA1c level7.0% [53 mmol/mol], blood pressure130/80 mm Hg, low-density lipoprotein cholesterol level1.8 mmol/L, triglyceride level1.7 mmol/L, and/or persistent use of renin-angiotensin-aldosterone system inhibitors).A total of 2393 patients (mean [SD] age, 67.7 [9.8] years; 1267 men [52.9%]) were randomized to the usual care group (n = 795), empowered care group (n = 802), and team-based empowered care group (n = 796). At baseline, 34.7% patients (n = 830) were on 3 treatment targets. On intention-to-treat analysis, the team-based empowered care group had the highest proportion of patients who had further increase in attainment of multiple treatment targets (within-group differences: usual care group, 3.9% [95% CI, 0.0%-7.8%]; empowered care group, 1.3% [95% CI, -2.8% to 5.4%]; team-based empowered care group, 9.1% [95% CI, 4.7%-13.5%]). The team-based empowered care group was more likely to attain multiple treatment targets than the usual care group (risk ratio [RR], 1.17; 95% CI, 1.00-1.37) and the empowered care group (RR, 1.25; 95% CI, 1.06-1.48) after adjustment for site. Compared with the group that did not attain multiple treatment targets, the group that attained multiple treatment targets reported a lower incidence of cardiovascular, kidney, and cancer events (8.4% [n = 51] vs 14.5% [n = 134]; P = .004). Analysis of the per-protocol population yielded similar results.This trial found that technology-assisted team-based care for 12 months improved the attainment of multiple treatment targets as well as empowerment in patients with DKD.ClinicalTrials.gov Identifier: NCT02176278.

An elevated fasting glucose level in non-diabetic individuals is a key predictor of type 2 diabetes. Genome-wide association studies (GWAS) have identified hundreds of SNPs for fasting glucose but most of their functional roles in influencing the trait are unclear. This study aimed to identify the mediation effects of DNA methylation between SNPs identified as significant from GWAS and fasting glucose using Mendelian randomisation (MR) analyses.We first performed GWAS analyses for three cohorts (Taiwan Biobank with 18,122 individuals, the Healthy Aging Longitudinal Study in Taiwan with 1989 individuals and the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance with 416 individuals) with individuals of Han Chinese ancestry in Taiwan, followed by a meta-analysis for combining the three GWAS analysis results to identify significant and independent SNPs for fasting glucose. We determined whether these SNPs were methylation quantitative trait loci (meQTLs) by testing their associations with DNA methylation levels at nearby CpG sites using a subsample of 1775 individuals from the Taiwan Biobank. The MR analysis was performed to identify DNA methylation with causal effects on fasting glucose using meQTLs as instrumental variables based on the 1775 individuals. We also used a two-sample MR strategy to perform replication analysis for CpG sites with significant MR effects based on literature data.Our meta-analysis identified 18 significant (p 5 × 10Our analysis results suggest that rs2232326 and rs2232328 in G6PC2 may affect DNA methylation at CpGs near the gene and that the methylation may have downstream effects on fasting glucose. Therefore, SNPs in G6PC2 and CpGs near G6PC2 may reside along the pathway that influences fasting glucose levels. This is the first study to report CpGs near G6PC2, an important gene for regulating insulin secretion, mediating the effects of GWAS-significant SNPs on fasting glucose.

Management of type 2 diabetes mellitus (T2DM) in patients with liver cirrhosis is complex and suboptimal, but no clinical trial has adequately investigated antidiabetic drug use for such patients. We evaluate the risk of mortality, cardiovascular events, and hepatic outcomes between dipeptidyl peptidase-4 (DPP-4) inhibitor users and nonusers in patients with type 2 diabetes mellitus (T2DM) and cirrhosis.We selected 2828 paired propensity score matched DPP-4 inhibitor users and nonusers from a cohort of T2DM with compensated liver cirrhosis between January 1, 2007, and December 31, 2012. Cox proportional hazards models were used to assess the risk of main outcomes for DPP-4 inhibitor users.The incidence rate of decompensated cirrhosis during follow-up was 2.20 and 1.53 per 100 patient-years (adjusted hazard ratio [aHR] 1.35, 95% confidence interval [CI] 1.03-1.77) for DPP-4 inhibitor users and nonusers, respectively. The aHRs (95% CI) of variceal bleeding and hepatic failure were 1.67 (1.11-2.52) and 1.35 (1.02-1.79), respectively, for DPP-4 inhibitor users over nonusers. The risk of all-cause mortality, hepatocellular carcinoma, and major cardiovascular events between DPP-4 inhibitor users and nonusers were not statistically different.This study found that DPP-4 inhibitor users were associated with higher risks of decompensated cirrhosis and hepatic failure than did nonusers among patients with T2DM and compensated liver cirrhosis. We must continue to search for appropriate antidiabetic drugs for patients with liver cirrhosis.

Few studies investigated the respiratory outcomes of metformin use in patients with coexistent type 2 diabetes mellitus (T2DM) and chronic obstructive pulmonary disease (COPD). We want to compare the long-term respiratory endpoints of metformin use and nonuse in patients with T2DM and COPD. This retrospective cohort study enrolled patients with T2DM and COPD from Taiwan’s National Health Insurance Program between January 1, 2000, and December 31, 2012. Main outcomes were hospitalized bacterial pneumonia, hospitalization for COPD, noninvasive positive pressure ventilation (NIPPV), invasive mechanical ventilation (IMV), and lung cancer. In total, 20,644 propensity score-matched metformin users and nonusers were assessed. The adjusted hazard ratios (95% confidence intervals) of metformin use relative to nonuse for bacterial pneumonia, hospitalization for COPD, NIPPV, IMV, and lung cancer were 1.17 (1.11–1.23), 1.34 (1.26–1.43), 0.99 (0.89–1.10), 1.10 (1.03–1.17), and 1.12 (0.96–1.30). Metformin use also exhibited significant dose–response relationship with respect to the risks of bacterial pneumonia, hospitalization for COPD and IMV. Consistent results were found in the sensitivity test. This nationwide cohort study demonstrated that in patients with T2DM and COPD, metformin use was associated with higher risks of pneumonia, hospitalization for COPD, and IMV. If patients with COPD use metformin, vigilance with regard to their pulmonary condition may be required.

ObjectivesAlthough studies have demonstrated the association of hyperuricemia with cardiovascular (CV) diseases, few have explored the effect of urate-lowering therapy (ULT) on the incidence of CV diseases. Therefore, we compared the risks of hospitalized coronary artery disease (CAD), stroke, heart failure (HF), and all-cause mortality between ULT users and nonusers among patients with gout.MethodsWe performed this retrospective cohort study using Taiwan's population-based National Health Insurance Research Database. In total, 5218 patients with gout were included from 2000 to 2012. We compared the incidence rates (IRs) of hospitalized CAD, stroke, HF, and all-cause mortality between ULT users and matched nonusers.ResultsThe IRs of hospitalized stroke were 0.6 and 1.0 per 100 person-years for ULT users and nonusers, respectively, after adjusting for age, sex, residence, comorbidities, and medications. ULT users showed lower adjusted hazard ratios (aHR) for hospitalized stroke (aHR: 0.52, p < 0.001) and all-cause mortality (aHR: 0.6, p = 0.02) than nonusers. Subgroup analyses revealed that uricosuric agents and xanthine oxidase inhibitors were significantly associated with lower risks of hospitalized stroke and all-cause mortality, respectively. The effect of uricosuric agents on the decrease in hospitalized stroke risk indicated a dose-response relationship.ConclusionsOur study showed lower risks of hospitalized stroke and all-cause mortality in ULT users than in nonusers among patients with gout. Therefore, patients with gout may receive ULT to mitigate the risks of hospitalized stroke and mortality.

Background Insulin is highly recommended for diabetes management in persons with liver cirrhosis. However, few studies have evaluated its long-term effects in these persons. We conducted this study to compare the risks of mortality, liver-related complications, and cardiovascular events in persons with type 2 diabetes mellitus (T2DM) and compensated liver cirrhosis. Methods From January 1, 2000, to December 31, 2012, we selected 2047 insulin users and 4094 propensity score-matched nonusers from Taiwan’s National Health Insurance Research Database. Cox proportional hazard models were used to assess the risks of outcomes. Results The mean follow-up time was 5.84 years. The death rate during the follow-up period was 5.28 and 4.07 per 100 person-years for insulin users and nonusers, respectively. In insulin users, the hazard ratios and 95% confidence intervals (CIs) of all-cause mortality, hepatocellular carcinoma, decompensated cirrhosis, hepatic failure, major cardiovascular events, and hypoglycemia were 1.31 (1.18–1.45), 1.18 (1.05–1.34), 1.53 (1.35–1.72), 1.26 (1.42–1.86), 1.41 (1.23–1.62), and 3.33 (2.45–4.53), respectively. Conclusions This retrospective cohort study indicated that among persons with T2DM and compensated liver cirrhosis, insulin users were associated with higher risks of death, liver-related complications, cardiovascular events, and hypoglycemia compared with insulin nonusers.

Background& aims Type 2 diabetes mellitus (T2DM) management in patients with cirrhosis is complicated. No clinical trials have investigated appropriate antidiabetic drug use in these patients. This study compared the risks of all-cause mortality, major adverse cardiovascular events (MACE) and hepatic outcomes between patients with T2DM and cirrhosis using and not using thiazolidinedione (TZD). Methods We selected 1,705 propensity score-matched TZD users and nonusers from a Taiwan National Health Insurance Research Database cohort of T2DM patients with compensated cirrhosis between January 1, 2000, and December 31, 2012 and followed them until December 31, 2013. Cox proportional hazards models with robust sandwich standard error estimates were used to assess risks of investigated outcomes for TZD users. Results MACE incidence rates during follow-up were 2.14 and 1.30 per 100 patient-years for TZD users and nonusers, respectively (adjusted hazard ratio [aHR] 1.70; 95% confidence interval [CI], 1.32-2.19). On the basis of TZD use, the aHRs (95% CIs) for stroke, ischemic heart disease and heart failure were 1.81 (1.28-2.55), 1.59 (1.03-2.44) and 2.09 (1.22-3.60) respectively. Compared with TZD nonusers, rosiglitazone users had significantly higher aHR [1.67 (1.26-2.20)] and pioglitazone users had no significant difference of aHR [1.12 (0.90-1.64)]. All-cause mortality, hepatocellular carcinoma, decompensated cirrhosis and hepatic failure risks did not differ significantly between TZD users and nonusers. Conclusions Compared with nonuser, TZD users demonstrated significantly higher MACE risks. Therefore, the risks of cardiovascular complications should be considered when prescribing TZDs to patients with T2DM and cirrhosis.

Implementation of insulin therapy among those with diabetes is often suboptimal as a result of non-adherence or non-persistence. Studies regarding factors leading to insulin nonpersistence are limited. Therefore, we conducted this retrospective cohort study to determine the factors affecting insulin nonpersistence.A total of 274,852 persons with type 2 diabetes mellitus under insulin therapy during the period 2000-2014 were enrolled. Persons who stopped insulin therapy for90 days were defined as having insulin nonpersistence. We searched for factors associated with insulin nonpersistence during the long-term follow-up period.According to the multiple Cox regression model with a mean follow-up of 13.9 years, the factors associated with higher risk of insulin nonpersistence were age40 years, men, residing in a rural area, Charlson comorbidity index score = 4, use of two or more oral antidiabetic drugs, and hypoglycemia during follow-up. The Kaplan-Meier graph showed that patients aged40 years had significantly less insulin persistence.This nationwide cohort study indicated that persons with young-onset type 2 diabetes, less medical resources, and more comorbidities are at risk of insulin nonpersistence. Healthcare providers should regularly assess insulin persistence and help patients who are having difficulty with insulin-taking.

Objective Associations between albuminuria and renal outcomes are inconsistent in patients with type 2 diabetes (T2D). Soluble tumor necrosis factor receptor type 1 (sTNFR1) is involved in declined kidney function and poor renal outcomes but this has not been confirmed among Chinese T2D patients. This study aimed to examine the association of sTNFR1 and renal outcomes in a cohort of these patients. Methods Two hundred and eighty-three Chinese T2D patients were enrolled in a prospective observational study which excluded individuals with estimated glomerular filtration rates (eGFR) 30% decline in eGFR and worsening albuminuria from consecutive tests of blood/urine during a 3.5-year follow-up. Results Higher sTNFR1 levels were associated with impaired renal outcomes. sTNFR1 levels of ≥ 979 pg/mL yielded the most sensitivity and specific predictions of renal outcomes according to the receiver operating curve (area under the curve 0.68, p< 0.001; sensitivity 78.3%, specificity 48.9%). Renal events occurred more frequently in subjects with sTNFR1 ≥ 979 pg/mL than in others (sTNFR1 < 979 pg/mL; 29% vs. 10%, p

Many studies have demonstrated that hyperuricemia is associated with hypertension (HTN) development, but few studies have explored whether urate-lowering therapy (ULT), which reverses hyperuricemia, decreases the risk of incident HTN. In this retrospective cohort study, we compared the risk of incident HTN of gout patients between those undergoing and not undergoing ULT. Risks of new-onset diabetes mellitus (DM) and chronic kidney disease (CKD) were also examined. In total, 2712 gout patients from 2000 to 2012 were enrolled. Overall incidence rates of HTN, DM, and CKD were compared between 1356 patients undergoing ULT recipients and 1356 matched control patients. After adjustment for sex, age, area, comorbidities, and drugs used, the incidence rates of HTN were 4.8 and 3.0 per 100 person years for non-ULT and ULT patients, respectively. ULT patients had a lower adjusted hazard ratio (aHR) of HTN (aHR: 0.64, 95% confidence interval [CI]: 0.54–0.75, p

This study aimed to investigate the long-term outcomes of sulfonylurea (SU) use in patients with T2DM and compensated liver cirrhosis. From January 1, 2000, to December 31, 2012, we selected the data of 3781 propensity-score-matched SU users and nonusers from Taiwan’s National Health Insurance Research Database. The mean follow-up time for this study was 5.74 years. Cox proportional hazards models with robust sandwich standard error estimates were used to compare the risks of main outcomes between SU users and nonusers. The incidence of mortality during follow-up was 3.24 and 4.09 per 100 person-years for SU users and nonusers, respectively. The adjusted hazard ratios and 95% confidence intervals for all-cause mortality, major cardiovascular events, and decompensated cirrhosis in SU users relative to SU nonusers were 0.79 (0.71–0.88), 0.69 (0.61–0.80), and 0.82 (0.66–1.03), respectively. The SU-associated lower risks of death and cardiovascular events seemed to have a dose–response trend. This population-based cohort study demonstrated that SU use was associated with lower risks of death and major cardiovascular events compared with SU non-use in patients with T2DM and compensated liver cirrhosis. SUs may be useful for glycemic management for patients with liver cirrhosis.

Background/Purpose: We investigated hospitalization rates of patients with type 2 diabetes mellitus (T2DM) and individuals without diabetes mellitus (non-DM) in a disease-specific manner from 2005 to 2014 in Taiwan. Methods: This population-based study was conducted using data from the National Health Insurance Research Database. We analyzed the hospitalization rates of patients with and without T2DM. We collected up to five diagnostic codes given at discharge for each hospitalization, and the first one was considered the main diagnosis. Odds ratios were determined to assess the risk of hospitalization according to disease-specific classifications in patients with T2DM compared with those without T2DM. Results: The hospitalization rates of non-DM patients was stable from 2005 to 2014. By contrast, the rate of hospitalization among patients with T2DM decreased from 395.4 (per 1000 person-years) in 2005 to 336.9 (per 1000 person-years) in 2014. An increase in hospitalization rates for malignancies and sepsis/infection (other than pneumonia) was observed from 2005 to 2014 in both patients with and without T2DM. Although patients with T2DM had a higher hospitalization risk for all the disease-specific classifications than non-DM patients, this difference in risk decreased from 2005 to 2014 for all diseases except pneumonia. Conclusion: Hospitalization rates for malignancies and sepsis/infection (other than pneumonia) continually increased from 2005 to 2014 in Taiwan. Although patients with T2DM had a greater risk of disease-specific hospitalization than those without, this difference in risk decreased from 2005 to 2014 for all diseases except for pneumonia. Keywords: Hospitalization, National Health Insurance, Taiwan, Type 2 diabetes mellitus

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans., Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

Aim People with young-onset diabetes (YOD) exhibit a higher risk of morbidity and mortality than those with late-onset diabetes. Few studies have explored the preferred management of diabetes in such patients. We compared the risks of hospitalization and mortality among people with YOD to whom second-line oral antidiabetic drugs (OADs) were administered. Methods 7257 people taking second-line OADs after initial metformin therapy were enrolled during 2009–2014. Using add-on sulfonylureas (SUs) as a reference, the multivariable Cox regression model was used to compare the hospitalization and mortality risks among 5 categories of second-line OADs: alpha-glucosidase inhibitors, meglitinide, dipeptidyl peptidase-4 (DPP-4) inhibitors, SUs, and thiazolidinediones. Results After baseline characteristics, comorbidities, duration of diabetes, and drug use were controlled, the adjusted hazard ratios and 95% confidence interval for all-cause, cardiovascular, and non-infection hospitalization and all-cause mortality for metformin plus DPP-4 inhibitors were 0.62 (0.52–0.73), 0.49 (0.29–0.85), 0.64 (0.54–0.76), and 0.50 (0.27–0.92), respectively, when compared with the data for metformin plus SUs. Conclusions Among people with YOD, taking add-on DPP-4 inhibitors was associated with lower risks of all-cause hospitalization and mortality than taking add-on SUs. DPP-4 inhibitors thus seem to be a suitable second-line OAD for such patients.

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

Objective: Upstroke time per cardiac cycle (UTCC) in the lower extremities has been found to be predictive of cardiovascular mortality in the general population. Therefore, the purpose of the study was to test the associations between increasing UTCC and outcomes in patients with type 2 diabetes. Methods: A total of 452 patients with type 2 diabetes (age, 67.5 ± 8.6 years; male, 54%) registered in a share-care program participated in the study at an outpatient clinic in Taipei Veterans General Hospital across a mean of 5.8 years. Primary outcomes were all-cause mortality hospitalization for coronary artery disease, stroke, revascularization, amputation, and diabetic foot syndrome. Secondary end-point outcome was all-cause mortality. Results: Increment of UTCC associations with primary and secondary outcomes were undertaken prior to baseline characteristic adjustments. A UTCC of 20.1% exhibited the greatest area under curve (AUC), sensitivity, and specificity balance to predict composite events in receiver operating curves (AUC, 0.63 [P = .001]; sensitivity, 67.7%; specificity, 54.9%). Sixty-four composite events and 17 deaths were identified from medical records. UTCC ≥20.1% was associated with the occurrence of composite events and an increased risk of mortality. For composite events, an adjusted hazard ratio (HR) of 2.45 and 95% confidence interval (CI) of 1.38 to 4.35 (P = .002) were calculated. For all-cause mortality, an adjusted HR of 1.91 and 95% CI of 0.33 to 10.99 (P = .467) were calculated. Conclusion: Increasing UTCC was associated with cardiovascular outcomes in patients with type 2 diabetes. Therefore, UTCC is advocated as a noninvasive screening tool for ambulatory patients with type 2 diabetes. Abbreviations: CAD = coronary artery disease; CI = confidence interval; eGFR = estimated glomerular filtration rate; HR = hazard ratio; PAD = peripheral artery disease; UTCC = upstroke time per cardiac cycle.

Context The long-term safety and benefit of pioglitazone use in combination with insulin are still uncertain. Objective This study compared the risks of all-cause mortality and major cardiovascular (CV) events between pioglitazone users and nonusers receiving insulin therapy. Design, Setting and Patients We conducted a 13-year retrospective cohort study by using data from the population-based National Health Insurance Research Database in Taiwan. A total of 20 376 patients with type 2 diabetes mellitus (T2DM) receiving insulin therapy were enrolled during 2000 to 2012. Overall, the incidence rates of all-cause mortality and CV events were compared between 2579 pioglitazone users and 2579 matched nonusers. Results After adjustment for age, sex, comorbidities, Diabetes Complications Severity Index scores, and drugs used, mortality rates were 30.26 and 15.02 per 1000 person-years for pioglitazone nonusers and users, respectively. The adjusted hazard ratio (aHR) of mortality was 0.47 (95% confidence interval [CI]: 0.38–0.58, P < 0.001) for pioglitazone users compared with nonusers. The aHRs of CV and non-CV deaths were 0.78 (95% CI: 0.51–1.19) and 0.50 (95% CI: 0.38–0.66), respectively. The aHRs of hospitalized coronary artery disease, hospitalized stroke, and incident heart failure were not significantly different between pioglitazone users and nonusers. Conclusions This nationwide cohort study demonstrated that pioglitazone use reduced the risks of all-cause mortality and non-CV death for patients with T2DM undergoing insulin therapy.