Siyan Zhan

Association between angiotensinogen, angiotensin II receptor genes, and blood pressure response to an angiotensin-converting enzyme inhibitor.

Background— To identify the genetic contribution to the variation in blood pressure (BP) response to angiotensin-converting enzyme inhibitors (ACEIs), single-nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT), angiotensin receptor 1 (AGTR1), and angiotensin receptor 2 (AGTR2) genes were evaluated for their association with BP response to ACEI in Chinese patients with hypertension in a 2-stage design. Methods and Results— We selected 1447 hypertensive patients from a 3-year benazepril postmarket surveillance trial and genotyped them for 14 SNPs in the AGT, AGTR1, and AGTR2 genes. The AGT rs7079 (C/T) SNP (3′-untranslated region) was significantly associated with the response of diastolic BP to benazepril (diastolic BP response: −7.4 mm Hg for subjects with the CC genotype, −8.9 mm Hg for CA, and −10.1 mm Hg for AA; P=0.001). Although there was no association of individual SNPs in the AGTR1 gene, there was a graded response between common haplotypes and systolic BP reduction in the order of haplotype 2 (H2)/lack of haplotype 3 (non-H3) (−13.6 mm Hg) > non-H2/non-H3 (−10.9 mm Hg) > H3/non-H2 (−6.6 mm Hg) (P=0.004). The total variations in response to ACEI therapy that were explained by the AGT SNP and AGTR1 haplotype groups were 13% for systolic and 9% to 9.6% for diastolic BP, respectively. Conclusion— AGT SNP rs7079 and AGTR1 haplotypes were associated with BP reduction in response to ACEI therapy in hypertensive Chinese patients. This will be useful in future studies, providing genetic markers to predict the hypertensive response to ACEI therapy.

Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: A systematic review and network meta-analysis

AIMS To evaluate current evidence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on blood pressure, heart rate, and hypertension in patients with type 2 diabetes. METHODS Medline, Embase, the Cochrane library, and the website www.clinicaltrials.gov were searched on April 5th, 2014. Randomized-controlled trials with available data were included if they compared GLP-1RAs with placebo and traditional antidiabetic drugs in patients with type 2 diabetes with duration ≥ 12 weeks. Weighted mean difference for blood pressure and heart rate, odds ratio (OR) for hypertension were calculated by random-effect model. Network meta-analysis was performed to supplement direct comparisons. RESULTS Sixty trials with 14 treatments were included. Compared with placebo, insulin, and sulfonylureas, GLP-1RAs decreased systolic blood pressure with range from -1.84 mmHg (95% CI: -3.48 to -0.20) to -4.60 mmHg (95% CI: -7.18 to -2.03). Compared with placebo, a reduction in diastolic blood pressure was detected significantly only for exenatide-10 μg-twice-daily (-1.08 mmHg, 95% CI: -1.78 to -0.33). Exenatide (2 mg once weekly), liraglutide 1.2 mg once daily), and liraglutide (1.8 mg once daily) increased heart rate by 3.35 (95% CI: 1.23-5.50), 2.06 (95% CI: 0.43, 3.74), and 2.35 (95% CI: 0.94-3.76) beats/min versus placebo. This effect was evident compared with active control (range: 2.22-3.62). No significant association between incident hypertension and GLP-1RAs was detected, except for the association between exenatide-10 μg-twice-daily and sulfonylureas (OR, 0.40, 95% CI: 0.16, 0.82). CONCLUSIONS GLP-1RAs were associated with modest reduction on blood pressure, a slight increase in heart rate, yet no significant association with hypertension. Further investigation to explore mechanisms is warranted.

An accurate risk score for estimation 5-year risk of type 2 diabetes based on a health screening population in Taiwan

This study aimed to provide the epidemiological model evaluating the risk of developing type 2 diabetes (T2DM) in Taiwan periodic health-check population. We derived risk functions using multivariate Cox regression in a random half of the sample. Rules based on these risk functions were evaluated in another half. Model coefficients were used to assign each variable a score. 73,961 subjects aged 35-74, were included and followed up with a median 3.15 years. Six predictive models (PMs) were developed. PM1 contained simple clinical information, while PM2 contained fasting plasma glucose (FPG) based on PM1, and PM3 further added variables indicating lipid level, liver and kidney. PM4 only included FPG. The capability of published ARIC score model was also evaluated. Eventually we considered score defined nine predictors by PM2. The area under the ROC curve (AUC) was 0.848 (95% CI, 0.829-0.868) predicting diabetes within 5 years, and also had adequate performance in validation subsample (AUC=0.833, 95% CI, 0.811-0.855). The 5-year T2DM probability can be calculated by: 1-0.9743960037 exp((score points -15.0281284)). We concluded that this diabetes risk score, derived from clinical information combined with FPG is a simple, effective tool to identify individuals at high risk for undiagnosed T2DM.

Metabolic syndrome and the development of chronic kidney disease among 118 924 non‐diabetic Taiwanese in a retrospective cohort

Aim:  Metabolic syndrome (MetS) is a common risk factor for cardiovascular and chronic kidney disease (CKD) in Western populations; however, no prospective studies have examined MetS as a risk factor for CKD in Chinese adults.

Effect of Glucagon-like Peptide-1 Receptor Agonists on Lipid Profiles Among Type 2 Diabetes: A Systematic Review and Network Meta-analysis

PURPOSE The goal of this study was to assess the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on lipid profiles in patients with type 2 diabetes. METHODS The MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched from inception through October 31, 2013. Randomized controlled trials with available data were selected if they compared GLP-1 RAs with placebo and traditional antidiabetic drugs with a duration ≥8 weeks. The weighted mean difference for changes in lipid profiles was estimated by using the random effects model, and a network meta-analysis was performed to supplement direct comparisons. FINDINGS Thirty-five trials with 13 treatments were included in the analysis. GLP-1 RAs decreased HDL-C with a range of -0.06 mmol/L (95% CI, -0.11 to -0.01) to -0.13 mmol/L (95% CI, -0.17 to -0.10) compared with thiazolidinediones, whereas thiazolidinediones were associated with a significant increase in HDL-C compared with placebo (0.09 mmol/L [95% CI, 0.06 to 0.12]). A significant reduction in LDL-C was detected for all GLP-1 RAs versus placebo (range, -0.08 to -0.16 mmol/L), insulin (range, -0.10 to -0.19 mmol/L), and thiazolidinediones (range, -0.16 to -0.24 mmol/L). Exenatide, liraglutide 1.8 mg once daily, and taspoglutide decreased total cholesterol with a range of -0.16 mmol/L (95% CI, -0.26 to -0.06) to -0.27 mmol/L (95% CI, -0.41 to -0.12) versus placebo and thiazolidinediones (range, -0.26 to -0.37 mmol/L). The decreased effect was more evident in exenatide long-acting release and liraglutide 1.8 mg once daily. A significant reduction in triglyceride levels was observed with liraglutide 1.8 mg once daily (-0.30 mmol/L [95% CI, -0.49 to -0.11]) and taspoglutide 20 mg once weekly (-0.17 mmol/L [95% CI, -0.31 to -0.01]) versus placebo. IMPLICATIONS GLP-1 RAs were associated with modest reductions in LDL-C, total cholesterol, and triglycerides but no significant improvement in HDL-C. Further evidence is needed to determine if improvements in lipid profiles might translate into reductions in cardiovascular outcomes.

Incidence, Clinical Features and Impact on Anti-Tuberculosis Treatment of Anti-Tuberculosis Drug Induced Liver Injury (ATLI) in China

Background Anti-tuberculosis drug induced liver injury (ATLI) is emerging as a significant threat to tuberculosis control in China, though limited data is available about the burden of ATLI at population level. This study aimed to estimate the incidence of ATLI, to better understand its clinical features, and to evaluate its impact on anti-tuberculosis (TB) treatment in China. Methodology/Principal Findings In a population-based prospective study, we monitored 4,304 TB patients receiving directly observed treatment strategy (DOTS) treatment, and found that 106 patients developed ATLI with a cumulative incidence of 2.55% (95% Confidence Interval [CI], 2.04%–3.06%). Nausea, vomiting and anorexia were the top three most frequently observed symptoms. There were 35 (33.02%) ATLI patients with no symptoms, including 8 with severe hepatotoxicity. Regarding the prognosis of ATLI, 84 cases (79.25%) recovered, 18 (16.98%) improved, 2 (1.89%) failed to respond to the treatment with continued elevation of serum alanine aminotransferase, and 2 (1.89%) died as result of ATLI. Of all the ATLI cases, 74 (69.81%) cases changed their anti-TB treatment, including 4 (3.77%) cases with medication administration change, 21 (19.81%) cases with drugs replacement, 54 (50.94%) cases with therapy interruption, and 12 (11.32%) cases who discontinued therapy. In terms of treatment outcomes, 53 (51.46%) cases had TB cured in time, 48 (46.60%) cases had therapy prolonged, and 2 (1.94%) cases died. Compared with non-ATLI patients, ATLI patients had a 9.25-fold (95%CI, 5.69–15.05) risk of unsuccessful anti-TB treatment outcomes and a 2.11-fold (95%CI,1.23–3.60) risk of prolonged intensive treatment phase. Conclusions/Significance ATLI could considerably impact the outcomes of anti-TB treatment. Given the incidence of ATLI and the size of TB population in China, the negative impact is substantial. Therefore, more research and efforts are warranted in order to enhance the diagnosis and the prevention of ATLI.

Effects of Glucagon-Like Peptide-1 Receptor Agonists on Weight Loss in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis

To evaluate the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on weight reduction in patients with Type 2 diabetes mellitus (Type 2 DM), a network meta-analysis was conducted. MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched from 1950 to October 2013. Randomized controlled trials (RCTs) involving GLP-1 RAs were included if they provided information on body weight. A total of 51 RCTs were included and 17521 participants were enrolled. The mean duration of 51 RCTs was 31 weeks. Exenatide 10 μg twice daily (EX10BID) reduced weight compared with exenatide 5 μg twice daily (EX5BID), liraglutide 0.6 mg once daily (LIR0.6QD), liraglutide—1.2 mg once daily (LIR1.2QD), and placebo treatment, with mean differences of −1.07 kg (95% CI: −2.41, −0.02), −2.38 kg (95% CI: −3.71, −1.06), −1.62 kg (95% CI: −2.79, −0.43), and −1.92 kg (95% CI: −2.61, −1.24), respectively. Reductions of weight treated with liraglutide—1.8 mg once daily (LIR1.8QD) reach statistical significance (−1.43 kg (95% CI: −2.73, −0.15)) versus LIR1.2QD and (−0.98 kg (95% CI: −1.94, −0.02)) versus placebo. Network meta-analysis found that EX10BID, LIR1.8QD, and EX2QW obtained a higher proportion of patients with weight loss than other traditional hypoglycemic agents. Our results suggest GLP-1 RAs are promising candidates for weight control in comparison with traditional hypoglycemic drugs, and EX10BID, LIR1.8QD, and EX2QW rank the top three drugs.

Cardiovascular safety and glycemic control of glucagon-like peptide-1 receptor agonists for type 2 diabetes mellitus: A pairwise and network meta-analysis

AIMS Integrating evidence from all randomized controlled trials (RCTs) of glucagon-like peptide-1 receptor agonists (GLP-1s) to assess the safety of cardiovascular disease (CVD) and efficacy of glycemic control. METHODS Besides performing pairwise meta-analysis, network meta-analysis of all RCTs was used to combine direct and indirect estimates of the effect of GLP-1 with placebo, active comparator drugs (ACD), or another GLP-1 agent with treatment duration ≥8 weeks in T2DM patients, 15,883 for CVD safety from 45 RCTs and 14,136 for glycemic control from 36 RCTs. RESULTS For CVD safety, both of the results from pairwise and network meta-analysis failed to demonstrate significant difference between any two comparators. For glycemic control, the effect of any GLP-1 was better than placebo, but no difference was found between GLP-1s. We also found that liraglutide was the only GLP-1 drug shown to be more effective on improving glycemic control than ACD and exenatide. The results based on direct or indirect estimates were similar for two outcomes. CONCLUSION Our network meta-analysis provides a complete picture of the associations between GLP-1s, ACD and placebo on CVD safety and glycemic control. The GLP-1s are promising candidates for the treatment of T2DM, but more long-term trials are needed to confirm potential CVD safety.

Impact of GLP-1 Receptor Agonists on Major Gastrointestinal Disorders for Type 2 Diabetes Mellitus: A Mixed Treatment Comparison Meta-Analysis

Aim. We aimed to integrate evidence from all randomized controlled trials (RCTs) and assess the impact of different doses of exenatide or liraglutide on major gastrointestinal adverse events (GIAEs) in type 2 diabetes (T2DM). Methods. RCTs evaluating different doses of exenatide and liraglutide against placebo or an active comparator with treatment duration ≥4 weeks were searched and reviewed. A total of 35, 32 and 28 RCTs met the selection criteria evaluated for nausea, vomiting, and diarrhea, respectively. Pairwise random-effects meta-analyses and mixed treatment comparisons (MTC) of all RCTs were performed. Results. All GLP-1 dose groups significantly increased the probability of nausea, vomiting and diarrhea relative to placebo and conventional treatment. MTC meta-analysis showed that there was 99.2% and 85.0% probability, respectively, that people with exenatide 10 μg twice daily (EX10BID) was more vulnerable to nausea and vomiting than those with other treatments. There was a 78.90% probability that liraglutide 1.2 mg once daily (LIR1.2) has a higher risk of diarrhea than other groups. A dose-dependent relationship of exenatide and liraglutide on GIAEs was observed. Conclusions. Our MTC meta-analysis suggests that patients should be warned about these GIAEs in early stage of treatment by GLP-1s, especially by EX10BID and LIR1.2, to promote treatment compliance.

Uric acid and incident chronic kidney disease in a large health check-up population in Taiwan.

Aim:  Uric acid (UA) is strongly associated with the confirmed chronic kidney disease (CKD) risk factors, such as hypertension, diabetes and metabolic syndrome (MS); however, whether higher UA is independently associated with CKD is still debatable. Other studies found that low UA level may reflect inadequate protection against oxidant‐mediated stress; it is also unknown whether hypouricemia may have a harmful effect on the kidney. No studies have examined whether there is a J‐shaped relationship between UA and incident CKD.