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1.  Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and bayesian network meta-analysis 
Objective To assess the effects of different classes of antihypertensive treatments, including monotherapy and combination therapy, on survival and major renal outcomes in patients with diabetes.
Design Systematic review and bayesian network meta-analysis of randomised clinical trials.
Data sources Electronic literature search of PubMed, Medline, Scopus, and the Cochrane Library for studies published up to December 2011.
Study selection Randomised clinical trials of antihypertensive therapy (angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), α blockers, β blockers, calcium channel blockers, diuretics, and their combinations) in patients with diabetes with a follow-up of at least 12 months, reporting all cause mortality, requirement for dialysis, or doubling of serum creatinine levels.
Data extraction Bayesian network meta-analysis combined direct and indirect evidence to estimate the relative effects between treatments as well as the probabilities of ranking for treatments based on their protective effects.
Results 63 trials with 36 917 participants were identified, including 2400 deaths, 766 patients who required dialysis, and 1099 patients whose serum creatinine level had doubled. Compared with placebo, only ACE inhibitors significantly reduced the doubling of serum creatinine levels (odds ratio 0.58, 95% credible interval 0.32 to 0.90), and only β blockers showed a significant difference in mortality (odds ratio 7.13, 95% credible interval 1.37 to 41.39). Comparisons among all treatments showed no statistical significance in the outcome of dialysis. Although the beneficial effects of ACE inhibitors compared with ARBs did not reach statistical significance, ACE inhibitors consistently showed higher probabilities of being in the superior ranking positions among all three outcomes. Although the protective effect of an ACE inhibitor plus calcium channel blocker compared with placebo was not statistically significant, the treatment ranking identified this combination therapy to have the greatest probability (73.9%) for being the best treatment on reducing mortality, followed by ACE inhibitor plus diuretic (12.5%), ACE inhibitors (2.0%), calcium channel blockers (1.2%), and ARBs (0.4%).
Conclusions Our analyses show the renoprotective effects and superiority of using ACE inhibitors in patients with diabetes, and available evidence is not able to show a better effect for ARBs compared with ACE inhibitors. Considering the cost of drugs, our findings support the use of ACE inhibitors as the first line antihypertensive agent in patients with diabetes. Calcium channel blockers might be the preferred treatment in combination with ACE inhibitors if adequate blood pressure control cannot be achieved by ACE inhibitors alone.
doi:10.1136/bmj.f6008
PMCID: PMC3807847  PMID: 24157497
2.  Pitavastatin and Atorvastatin Double-Blind Randomized ComPArative Study among HiGh-Risk Patients, Including ThOse with Type 2 Diabetes Mellitus, in Taiwan (PAPAGO-T Study) 
PLoS ONE  2013;8(10):e76298.
Background
Evidence about the efficacy and safety of statin treatment in high-risk patients with hypercholesterolemia is available for some populations, but not for ethnic Chinese. To test the hypothesis that treatment with pitavastatin (2 mg/day) is not inferior to treatment with atorvastatin (10 mg/day) for reducing low-density lipoprotein cholesterol (LDL-C), a 12-week multicenter collaborative randomized parallel-group comparative study of high-risk ethnic Chinese patients with hypercholesterolemia was conducted in Taiwan. In addition, the effects on other lipid parameters, inflammatory markers, insulin-resistance-associated biomarkers and safety were evaluated.
Methods and Results
Between July 2011 and April 2012, 251 patients were screened, 225 (mean age: 58.7 ± 8.6; women 38.2% [86/225]) were randomized and treated with pitavastatin (n = 112) or atorvastatin (n = 113) for 12 weeks. Baseline characteristics in both groups were similar, but after 12 weeks of treatment, LDL-C levels were significantly lower: pitavastatin group = −35.0 ± 14.1% and atorvastatin group = −38.4 ± 12.8% (both: p < 0.001). For the subgroup with diabetes mellitus (DM) (n = 125), LDL-C levels (−37.1 ± 12.9% vs. −38.0 ± 13.1%, p = 0.62) were similarly lowered after either pitavastatin (n = 63) or atorvastatin (n = 62) treatment. Triglycerides, non-high density lipoprotein cholesterol, and apoprotein B were similarly and significantly lower in both treatment groups. In non-lipid profiles, HOMA-IR and insulin levels were higher to a similar degree in both statin groups. Hemoglobin A1C was significantly (p = 0.001) higher in the atorvastatin group but not in the pitavastatin group. Both statins were well tolerated, and both groups had a similar low incidence of treatment-emergent adverse events.
Conclusion
Both pitavastatin (2 mg/day) and atorvastatin (10 mg/day) were well tolerated, lowered LDL-C, and improved the lipid profile to a comparable degree in high-risk Taiwanese patients with hypercholesterolemia.
Trial Registration
ClinicalTrials.gov NCT01386853 http://clinicaltrials.gov/ct2/show/NCT01386853?term=NCT01386853&rank=1
doi:10.1371/journal.pone.0076298
PMCID: PMC3788128  PMID: 24098467
3.  A Taiwanese food frequency questionnaire correlates with plasma docosahexaenoic acid but not with plasma eicosapentaenoic acid levels: questionnaires and plasma biomarkers 
Background
Little evidence is available for the validity of dietary fish and polyunsaturated fatty acid intake derived from interviewer-administered questionnaires and plasma docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentration.
Methods
We estimated the correlation of DHA and EPA intake from both questionnaires and biochemical measurements. Ethnic Chinese adults with a mean (± SD) age of 59.8 (±12.8) years (n = 297) (47% women) who completed a 38-item semi-quantitative food-frequency questionnaire and provided a plasma sample were enrolled. Plasma fatty acids were analyzed by capillary gas chromatography.
Results
The Spearmen rank correlation coefficients between the intake of various types of fish and marine n-3 fatty acids as well as plasma DHA were significant, ranging from 0.20 to 0.33 (P < 0.001). In addition, dietary EPA, C22:5 n-3 and DHA were significantly correlated with the levels of marine n-3 fatty acids and DHA, with the Spearman rank correlation coefficients ranging from 0.26 to 0.35 (P < 0.001). Moreover, compared with those in the lowest fish intake quintile, participants in the highest quintile had a significantly higher DHA level (adjusted mean difference, 0.99 ± 0.10%, test for trend, P < 0.001). Similar patterns between dietary DHA intake and plasma DHA levels were found. However, the association between dietary fish intake and plasma EPA was not significant (test for trend, P = 0.69).
Conclusions
The dietary intakes of fish and of long chain n-3 fatty acids, as determined by the food frequency questionnaire, were correlated with the percentages of these fatty acids in plasma, and in particular with plasma DHA. Plasma DHA levels were correlated to dietary intake of long-chain n-3 fatty acids.
doi:10.1186/1471-2288-13-23
PMCID: PMC3598308  PMID: 23414574
N-3 fatty acid; Biomarker; Food frequency questionnaire
4.  Common sequence variants in CD36 gene and the levels of triglyceride and high-density lipoprotein cholesterol among ethnic Chinese in Taiwan 
Background
Evidence of the genetic association between CD36 candidate gene and the risk of metabolic syndrome and its components has been inconsistent. This case–control study assessed the haplotype-tagged SNPs from CD36 on the risk of metabolic syndrome and components.
Methods and results
We recruited 1,000 cases and age, gender-matched controls were randomly selected from the participants with metabolic syndrome defined by International Diabetes Federation. Overall, the haplotype tagged SNPs of CD36 gene were not related to the risk of metabolic syndrome. For individuals with normal lipid levels, several SNPs were significantly associated with the triglycerides and HDL-cholesterol levels: Subjects with rs3211848 homozygote had a higher triglyceride level (99.16 ± 2.61 mg/dL), compared with non-carriers (89.27 ± 1.45 mg/dL, P = 0.001). In addition, compared with non-carriers, individuals with rs1054516 heterozygous and homozygous genotypes had a significantly lower HDL-cholesterol (46.6 ± 0.46 mg/dL for non-carrier, 44.6 ± 0.36 mg/dL for heterozygous, and 44.3 ± 0.56 mg/dL for homozygous, P = 0.0008).
Conclusion
The CD36 gene variants were significantly associated with triglycerides and HDL-cholesterol concentrations among ethnic Chinese in Taiwan.
doi:10.1186/1476-511X-11-174
PMCID: PMC3575328  PMID: 23249574
Metabolic syndrome; CD 36 gene polymorphism
5.  Identification of the HDL-ApoCIII to VLDL-ApoCIII ratio as a predictor of coronary artery disease in the general population: The Chin-Shan Community Cardiovascular Cohort (CCCC) study in Taiwan 
Background
Apolipoprotein (Apo) levels are considered more reliable than plasma lipoprotein levels for predicting coronary artery disease (CAD). However, a unanimous Apo marker for CAD has not been identified. In the Chin-Shan Community Cardiovascular Cohort (CCCC), we sought to identify a common Apo marker for predicting CAD in the general population.
Methods
We examined the cross-sectional association between Apo markers and CAD in the CCCC from 1990 to 2001. Among 3,602 subjects, 90 had angiographically proven CAD (>50% stenosis in ≥1 vessel), and 200 did not have CAD. These subjects were divided into the following 4 groups for analysis: normolipidemic (total cholesterol [TC] <200 mg/dL, triglyceride [TG] <150 mg/dL), hypertriglyceridemic (TC <200 mg/dL, TG ≥150 mg/dL), hypercholesterolemic (TC ≥200 mg/dL, TG <150 mg/dL), and hyperlipidemic (TC ≥200 mg/dL, TG ≥150 mg/dL).
Results
Compatible with findings in other populations, our results showed that CAD patients in the CCCC had higher ApoB and lower high-density lipoprotein (HDL) cholesterol and ApoAI concentrations than non-CAD subjects, but the differences were not significant in all groups. Plasma concentrations of ApoE and lipoprotein (a) were not consistently correlated with CAD. In contrast, the ratio of HDL-ApoCIII to very-low-density lipoprotein (VLDL)-ApoCIII was the only universal determinant for CAD in the normolipidemic group (P=0.0018), the hypertriglyceridemic group (P=0.0001), the hypercholesterolemic group (P=0.0001), and the hyperlipidemic group (P=0.0001). Overall, a high HDL-ApoCIII/VLDL-ApoCIII ratio was observed in all CAD patients, including those with a normal lipid profile. In multivariate analyses, the HDL-ApoCIII/VLDL-ApoCIII ratio was the strongest predictor for CAD among all lipid factors investigated (odds ratio, 2.04; 95% confidence interval, 1.46–2.84; P<0.0001).
Conclusions
A high HDL-ApoCIII to VLDL-ApoCIII ratio is a better marker for predicting CAD than are the conventional lipid markers or ApoAI and ApoB. High HDL-ApoCIII and low VLDL-ApoCIII values in CAD, irrespective of lipid variations, suggest that ApoCIII is markedly transported from VLDL to HDL in this disease. Measurement of plasma ApoCIII may improve CAD prediction in the general population.
doi:10.1186/1476-511X-11-162
PMCID: PMC3543287  PMID: 23173569
Apolipoproteins; Coronary artery disease; Lipoproteins; Cardiovascular risk factors; Chin-Shan Community Cardiovascular Cohort (CCCC) Study; High-density lipoprotein (HDL); Very-low-density lipoprotein (VLDL); Apolipoprotein CIII (ApoCIII)
6.  Differential effects of the changes of LDL cholesterol and systolic blood pressure on the risk of carotid artery atherosclerosis 
Background
The effects of baseline and changes in blood pressure and low density lipoprotein (LDL) cholesterol on the carotid intima media thickness (IMT) have not been well documented.
Methods
A total of 2572 adults (mean age 53.8 years, 54.6% women) in a Taiwanese community undertook three blood pressure and LDL cholesterol examinations over 6 years. Latent growth curve modeling was used to investigate the effects of baseline and change in blood pressure and LDL cholesterol on IMT.
Results
Greater baseline LDL and blood pressure were associated with an increase in IMT (0.005 ± 0.002 mm per 1 mg/dL [p = 0.006] and 0.041 ± 0.004 mm mmHg [p <0.0001], respectively. Change in blood pressure was associated with a significant increase in IMT (0.047±0.016, P = 0.004), whilst the association between change in LDL and change in IMT was not statistically significant (0.008±0.006, P = 0.20).
Conclusions
Carotid IMT was associated with baseline blood pressure and LDL cholesterol, yet only changes of blood pressure, not LDL cholesterol, were related to carotid IMT during the 6-year observation.
doi:10.1186/1471-2261-12-66
PMCID: PMC3445849  PMID: 22900906
Latent growth curve modeling; Carotid intima media thickness; Blood pressure; LDL cholesterol
7.  Lipid-related residual risk and renal function for occurrence and prognosis among patients with first-event acute coronary syndrome and normal LDL cholesterol 
Background
We investigated relationship of low levels of high density lipoprotein cholesterol (HDL-C), high levels of triglycerides, and renal function for the odds, prognosis and survival following acute coronary events among patients with a first event and normal low density lipoprotein cholesterol levels.
Results
A case-control study based on 557 patients and 1086 matched control subjects was conducted. Case patients were followed up for survival with a median of 1.9 years. Participants in the higher quintiles of HDL-C had lower odds to develop acute coronary events (the adjusted odds ratios were 0.24 for the second, 0.24 for the third, 0.10 for the fourth and 0.05 for the fifth quintile). Patients with normal glomerular filtration rate were at a lower risk for all-cause death. However, a reverse association between triglycerides and death risk was found: patients with higher triglycerides were at a lower risk for all-cause death (adjusted relative risk, 0.38 for triglycerides ranging from 82 to 132.9 mg/dL, and 0.14 for triglycerides > = 133 mg/dL).
Conclusions
Low HDL-C was significantly associated with acute coronary events, and triglyceride levels as well as renal function were inversely related to all-cause deaths after the coronary event.
doi:10.1186/1476-511X-10-215
PMCID: PMC3235983  PMID: 22099211
acute coronary syndrome; residual risk; dyslipidemia
8.  The relation of aminoterminal propeptide of type III procollagen and heart rate variability parameters in heart failure patients: A potential serum marker to evaluate cardiac autonomic control and sudden cardiac death 
Background
Cardiac extra-cellular matrix (ECM) fibrosis plays an important role in the pathophysiology of heart failure (HF). It may provide electrical heterogeneity and substrate for arrhythmogenicity, which may cause sudden cardiac death (SCD).
Methods
Twenty-one Patients with HF manifestations, and left ventricular ejection fraction (LVEF) ≤ 50% were enrolled. The median age was 62 years and median LVEF was 33 %. Time- and frequency-domain analysis of heart rate variability (HRV) on 24-hour ambulatory electrocardiography recording was assessed. Serum markers of ECM turnover including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2 and 9 (MMP-2 and MMP-9), and tissue inhibitor of metalloproteinase 1 (TIMP-1) were analyzed.
Results
The serum PIIINP level was significantly correlated with standard deviation of all normal RR intervals (SDNN) (r=−0.722, p=<0.001), percentage of adjacent NN interval differences >50 ms (pNN50) (r=−0.528, p=0.014), percentage of adjacent NN interval differences >20 ms (pNN20) (r=−0.545, p=0.002), very low frequency (VLF) (r=−0.490, p=0.024), low frequency (LF) (r=−0.491, p=0.024), high frequency (HF) (r=−0.513, p=0.018). PINP, MMP-2, 9, TIMP-1 were not correlated with time- and frequency-domain analysis of HRV.
Conclusions
PIIINP was significantly correlated with time- and frequency-domain analysis of HRV in HF patients. PIIINP is a potential serological marker to evaluate cardiac autonomic control and risk of SCD in HF patients.
doi:10.1515/CCLM.2010.348
PMCID: PMC3141296  PMID: 20846104
extra-cellular matrix; heart failure; collagen; HRV
9.  Plasma fatty acids and the risk of metabolic syndrome in ethnic Chinese adults in Taiwan 
Background
Evidence of predictive power of various fatty acids on the risk of metabolic syndrome was scanty. We evaluated the role of various fatty acids, including saturated fat, monounsaturated fat, transfat, n-6 fatty acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for the risk of the metabolic syndrome in Taiwan.
Results
A nested case-control study based on 1000 cases of metabolic syndrome and 1:1 matched control subjects. For saturated fat, monounsaturated fat and transfat, the higher the concentration the higher the risk for metabolic syndrome: participants in the highest quintile had a 2.22-fold (95% confidence interval [CI], 1.66 to 2.97) higher risk of metabolic syndrome. In addition, the participants in higher EPA quintiles were less likely to have the risk of metabolic syndrome (adjusted risk, 0.46 [0.34 to 0.61] for the fifth quintile). Participants in the highest risk group (low EPA and high transfat) had a 2.36-fold higher risk of metabolic syndrome (95% CI, 1.38 to 4.03), compared with those in the lowest risk group (high EPA and low transfat). For prediction power, the area under ROC curves increased from 0.926 in the baseline model to 0.928 after adding fatty acids. The net reclassification improvement for metabolic syndrome risk was substantial for saturated fat (2.1%, P = 0.05).
Conclusions
Plasma fatty acid components improved the prediction of the metabolic syndrome risk in Taiwan.
doi:10.1186/1476-511X-10-33
PMCID: PMC3056817  PMID: 21333029
10.  Prediction model for high glycated hemoglobin concentration among ethnic Chinese in Taiwan 
Background
This study aimed to construct a prediction model to identify subjects with high glycated hemoglobin (HbA1c) levels by incorporating anthropometric, lifestyle, clinical, and biochemical information in a large cross-sectional ethnic Chinese population in Taiwan from a health checkup center.
Methods
The prediction model was derived from multivariate logistic regression, and we evaluated the performance of the model in identifying the cases with high HbA1c levels (> = 7.0%). In total 17,773 participants (age > = 30 years) were recruited and 323 participants (1.8%) had high HbA1c levels. The study population was divided randomly into two parts, with 80% as the derivation data and 20% as the validation data.
Results
The point-based clinical model, including age (maximal 8 points), sex (1 point), family history (3 points), body mass index (2 points), waist circumference (4 points), and systolic blood pressure (3 points) reached an area under the receiver operating characteristic curve (AUC) of 0.723 (95% confidence interval, 0.677- 0.769) in the validation data. Adding biochemical measures such as triglycerides and HDL cholesterol improved the prediction power (AUC, 0.770 [0.723 - 0.817], P = < 0.001 compared with the clinical model). A cutoff point of 7 had a sensitivity of 0.76 to 0.96 and a specificity of 0.39 to 0.63 for the prediction model.
Conclusions
A prediction model was constructed for the prevalent risk of high HbA1c, which could be useful in identifying high risk subjects for diabetes among ethnic Chinese in Taiwan.
doi:10.1186/1475-2840-9-59
PMCID: PMC2955643  PMID: 20875098
11.  Postprandial Glucose Improves the Risk Prediction of Cardiovascular Death Beyond the Metabolic Syndrome in the Nondiabetic Population 
Diabetes Care  2009;32(9):1721-1726.
OBJECTIVE
With increasing evidence about the cardiovascular risk associated with postprandial nonfasting glucose and lipid dysmetabolism, it remains uncertain whether the postprandial glucose concentration increases the ability of metabolic syndrome to predict cardiovascular events.
RESEARCH DESIGN AND METHODS
This was an observational study of 15,145 individuals aged 35–75 years without diabetes or cardiovascular diseases. Postprandial glucose was obtained 2 h after a lunch meal. Metabolic syndrome was diagnosed using the criteria of the U.S. National Cholesterol Education Program Adult Treatment Panel III. Cardiovascular and all-cause deaths were primary outcomes.
RESULTS
During a median follow-up of 6.7 years, 410 individuals died, including 82 deaths from cardiovascular causes. In a Cox model adjusting for metabolic syndrome status as well as age, sex, smoking, systolic blood pressure, LDL, and HDL cholesterol levels, elevated 2-h postprandial glucose increased the risk of cardiovascular and all-cause death (per millimole per liter increase, hazard ratio 1.26 [95% CI 1.11–1.42] and 1.10 [1.04–1.16], respectively), with significant trends across the postprandial glucose quintiles. Including 2-h postprandial glucose into a metabolic syndrome–included multivariate risk prediction model conferred a discernible improvement of the model in discriminating between those who died of cardiovascular causes and who did not (integrated discrimination improvement 0.4, P = 0.005; net reclassification improvement 13.4%, P = 0.03); however, the improvement was only marginal for all-cause death.
CONCLUSIONS
Given the risk prediction based on metabolic syndrome and established cardiovascular risk factors, 2-h postprandial glucose improves the predictive ability to identity nondiabetic individuals at increased risk of cardiovascular death.
doi:10.2337/dc08-2337
PMCID: PMC2732157  PMID: 19502543
12.  Cell therapy generates a favourable chemokine gradient for stem cell recruitment into the infarcted heart in rabbits 
European Journal of Heart Failure  2009;11(3):238-245.
Aims
Stem cell recruitment into the heart is determined by a concentration gradient of stromal-derived factor 1 (SDF-1) from bone marrow to peripheral blood and from blood to injured myocardium. However, this gradient is decreased in chronic myocardial infarction (MI). This study evaluated the effect of cell therapy using bone marrow stromal cells (BMSCs) on an SDF-1 gradient in post-infarction rabbits.
Methods and results
Myocardial infarction was induced in male New Zealand white rabbits (2.5–3 kg) by ligation of the left anterior descending coronary artery. Two months later, the rabbits were randomized to either saline or BMSC (2 × 106 autologous BMSCs injected into the left ventricular cavity) treatment. Four weeks after therapy, the SDF-1 gradients from bone marrow to blood and from blood to myocardium increased in the BMSC group compared with the saline group. This was accompanied by an increase in cells positive for CD34, CD117, and STRO-1 in the myocardium, resulting in more capillary density, better cardiac function, and a decrease in infarct size.
Conclusion
Generation of an SDF-1 gradient towards the heart is a novel effect of BMSC-based cell therapy. This effect facilitates stem cell recruitment into remodelled myocardium and supports improvement in cardiac function.
doi:10.1093/eurjhf/hfn035
PMCID: PMC2645052  PMID: 19147447
Stromal-derived factor 1; Bone marrow stromal cell; Myocardial infarction; Ventricular remodelling

Results 1-12 (12)