Xianhui Qin

Efficacy of folic acid supplementation in stroke prevention: a meta-analysis

BACKGROUND The efficacy of treatments that lower homocysteine concentrations in reducing the risk of cardiovascular disease remains controversial. Our aim was to do a meta-analysis of relevant randomised trials to assess the efficacy of folic acid supplementation in the prevention of stroke. METHODS We collected data from eight randomised trials of folic acid that had stroke reported as one of the endpoints. Relative risk (RR) was used as a measure of the effect of folic acid supplementation on the risk of stroke with a random effect model. The analysis was further stratified by factors that could affect the treatment effects. FINDINGS Folic acid supplementation significantly reduced the risk of stroke by 18% (RR 0.82, 95% CI 0.68-1.00; p=0.045). In the stratified analyses, a greater beneficial effect was seen in those trials with a treatment duration of more than 36 months (0.71, 0.57-0.87; p=0.001), a decrease in the concentration of homocysteine of more than 20% (0.77, 0.63-0.94; p=0.012), no fortification or partly fortified grain (0.75, 0.62-0.91; p=0.003), and no history of stroke (0.75, 0.62-0.90; p=0.002). In the corresponding comparison groups, the estimated RRs were attenuated and insignificant. INTERPRETATION Our findings indicate that folic acid supplementation can effectively reduce the risk of stroke in primary prevention.

Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China: The CSPPT Randomized Clinical Trial

IMPORTANCE Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data. OBJECTIVE To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension. DESIGN, SETTING, AND PARTICIPANTS The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20,702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study. INTERVENTIONS Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10,348) or a tablet containing enalapril, 10 mg, alone (n = 10,354). MAIN OUTCOMES AND MEASURES The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death. RESULTS During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events. CONCLUSIONS AND RELEVANCE Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00794885.

Efficacy of folic acid supplementation in stroke prevention: new insight from a meta-analysis

Aims:  There are growing data and a continuing controversy over the efficacy of folic acid supplementation in stroke prevention. We conducted a meta‐analysis based on relevant, up‐to‐date published randomised trials to further examine this issue.

Folic Acid Therapy and Cardiovascular Disease in ESRD or Advanced Chronic Kidney Disease: A Meta-Analysis

BACKGROUND AND OBJECTIVES The efficacy of folic acid therapy to lower homocysteine (Hcy) levels in an effort to reduce cardiovascular disease (CVD) risk in patients with ESRD or advanced chronic kidney disease (ACKD; creatinine clearance, <30 ml/min) remains inconclusive. We conducted a meta-analysis of relevant randomized trials to further examine this issue. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This meta-analysis included 3886 patients with ESRD/ACKD from seven qualified randomized trials using folic acid therapy and with CVD reported as one of the end points. RESULTS When pooling the seven trials, folic acid therapy reduced the risk of CVD by 15% (RR, 0.85; 95% CI, 0.76 to 0.96; P = 0.009). A greater beneficial effect was observed among those trials with a treatment duration >24 months (RR, 0.84; 95% CI, 0.72 to 0.98; P = 0.02), a decrease in Hcy level >20% (RR, 0.83; 95% CI, 0.73 to 0.95; P = 0.007), and no or partial folic acid fortification (RR, 0.80; 95% CI, 0.65 to 0.99; P = 0.04). The beneficial effect also was seen when Hcy levels decreased >20%, even in the presence of folic acid fortification (RR, 0.85; 95% CI, 0.73 to 0.99; P = 0.04). In the corresponding comparison groups, the estimated RRs were attenuated and insignificant. CONCLUSIONS Folic acid therapy can reduce CVD risk in patients with ESRD/ACKD by 15%. A greater beneficial effect was observed among those trials with no or partial folic acid fortification or a decrease in Hcy level >20% regardless of folic acid fortification.

Folic acid supplementation and cancer risk: A meta-analysis of randomized controlled trials

There are growing data and a continuing controversy over the effect of folic acid supplementation on cancer risk. We conducted a meta‐analysis based on up‐to‐date published relevant randomized trials to further examine this issue. Relative risk (RR) was used to measure the effect of folic acid supplementation on risk of cancer using a random‐effects model. Overall, folic acid supplementation had no significant effect on total cancer incidence (13 trials, n = 49,406, RR = 1.05; 95% CI: 0.99–1.11, p = 0.13), colorectal cancer (seven trials, n = 33,824, 1.01; 0.82–1.23, p = 0.95), other gastrointestinal cancer (two trials, n = 20,228, 1.00; 0.75–1.33, p = 0.99), prostate cancer (five trials, n = 27,065, 1.17; 0.84–1.62, p = 0.35), other genitourinary cancer (two trials, n = 20,228, 0.97; 0.75–1.27, p = 0.84), lung cancer (five trials, n = 31,864, 1.00; 0.84–1.21, p = 0.97), breast cancer (four trials, n = 19,800, 0.82; 0.63–1.07, p = 0.15), hematological malignancy (three trials, n = 25,670, 0.87; 0.64–1.17, p = 0.35) and total cancer mortality (six trials, n = 31,930, 1.02; 0.90–1.15, p = 0.81). However, a significantly reduced risk was observed for melanoma (three trials, n = 19,128, 0.47; 0.23–0.94, p = 0.03). Furthermore, higher total cancer incidence risk was observed among those trials with a higher percent use of lipid‐lowering drugs (>60%, 1.10; 1.00–1.20, p = 0.04), or with lower percent baseline hypertension (≤70%, 1.08; 1.00–1.16, p = 0.057).Consistently, meta‐regression analyses suggested that the similar trend between percent use of lipid‐lowering drugs (p = 0.084) or percent baseline hypertension (p = 0.056) and log‐RR for total cancer incidence associated with folic acid supplementation. Our findings indicate that folic acid supplementation has no significant effect on total cancer incidence, colorectal cancer, prostate cancer, lung cancer, breast cancer or hematological malignancy, but reduces the risk of melanoma.

Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease: The Renal Substudy of the China Stroke Primary Prevention Trial

Importance The efficacy of folic acid therapy on renal outcomes has not been previously investigated in populations without folic acid fortification. Objective To test whether treatment with enalapril and folic acid is more effective in slowing renal function decline than enalapril alone across a spectrum of renal function at baseline from normal to moderate chronic kidney disease (CKD) among Chinese adults with hypertension. Design, Setting, and Participants In this substudy of eligible China Stroke Primary Prevention Trial (CSPPT), 15 104 participants with an estimated glomerular filtration rate (eGFR) 30 mL/min/1.73 m2 or greater, including 1671 patients with CKD, were recruited from 20 communities in Jiangsu province in China. Interventions Participants were randomized to receive a single tablet daily containing 10 mg enalapril and 0.8 mg folic acid (n = 7545) or 10 mg enalapril alone (n = 7559). Main Outcomes and Measures The primary outcome was the progression of CKD, defined as a decrease in eGFR of 30% or more and to a level of less than 60 mL/min/1.73 m2 if the baseline eGFR was 60 mL/min/1.73 m2 or more, or a decrease in eGFR of 50% or more if the baseline eGFR was less than 60 mL/min/1.73 m2; or end-stage renal disease. Secondary outcomes included a composite of the primary outcome and all-cause death, rapid decline in renal function, and rate of eGFR decline. Results Overall, 15 104 Chinese adults with a mean (range) age of 60 (45-75) years were recruited; median follow-up was 4.4 years. There were 164 and 132 primary events in the enalapril group and the enalapril-folic acid group, respectively. Compared with the enalapril group, the enalapril-folic acid group had a 21% reduction in the odds of the primary event (odds ratio [OR], 0.79; 95% CI, 0.62-1.00) and a slower rate of eGFR decline (1.28% vs 1.42% per year; P = .02). Among the participants with CKD at baseline, folic acid therapy resulted in a significant reduction in the risks for the primary event (OR, 0.44; 95% CI, 0.26-0.75), rapid decline in renal function (OR, 0.67; 95% CI, 0.47-0.96) and the composite event (OR, 0.62; 95% CI, 0.43-0.90), and a 44% slower decline in renal function (0.96% vs 1.72% per year, P < .001). Among those without CKD at baseline, there was no between-group difference in the primary end point. Conclusions and Relevance Enalapril-folic acid therapy, compared with enalapril alone, can significantly delay the progression of CKD among patients with mild-to-moderate CKD. Trial Registration clinicaltrials.gov Identifier: NCT00794885.

MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults

BackgroundThis study aimed to investigate if the homocysteine-lowering efficacy of two commonly used physiological doses (0.4 mg/d and 0.8 mg/d) of folic acid (FA) can be modified by individual methylenetetrahydrofolate reductase (MTHFR) C677T and/or methionine synthase (MTR) A2756G polymorphisms in hypertensive Chinese adults.MethodsA total of 480 subjects with mild or moderate essential hypertension were randomly assigned to three treatment groups: 1) enalapril only (10 mg, control group); 2) enalapril-FA tablet [10:0.4 mg (10 mg enalapril combined with 0.4 mg of FA), low FA group]; and 3) enalapril-FA tablet (10:0.8 mg, high FA group), once daily for 8 weeks.ResultsAfter 4 or 8 weeks of treatment, homocysteine concentrations were reduced across all genotypes and FA dosage groups, except in subjects with MTR 2756AG /GG genotype in the low FA group at week 4. However, compared to subjects with MTHFR 677CC genotype, homocysteine concentrations remained higher in subjects with CT or TT genotype in the low FA group (P < 0.05 for either of these genotypes) and TT genotype in the high FA group (P < 0.05). Furthermore, subjects with TT genotype showed a greater homocysteine-lowering response than did subjects with CC genotype in the high FA group (mean percent reduction of homocysteine at week 8: CC 10.8% vs. TT: 22.0%, P = 0.005), but not in the low FA group (CC 9.9% vs. TT 11.2%, P = 0.989).ConclusionsThis study demonstrated that MTHFR C677T polymorphism can not only affect homocysteine concentration at baseline and post-FA treatment, but also can modify therapeutic responses to various dosages of FA supplementation.

Effect of folic acid supplementation on the progression of carotid intima-media thickness: A meta-analysis of randomized controlled trials

OBJECTIVES We conducted a meta-analysis of relevant randomized trials to assess whether folic acid supplementation reduces the progression of atherosclerosis as measured by carotid intima-media thickness (CIMT). METHODS This analysis included 2052 subjects from ten folic acid randomized trials with the change in CIMT reported as one of the end points. Summary estimates of weighted mean differences (WMDs) and 95% CIs were obtained by using random-effect models. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. RESULTS Our analysis showed that folic acid supplementation significantly reduces the progression of CIMT (WMD: -0.04 mm; 95%CI: -0.07, -0.02; P<0.001), particularly in subjects with chronic kidney disease (CKD) (WMD: -0.16 mm; 95%CI: -0.26, -0.07; P=0.0006) or high cardiovascular disease (CVD) risk (WMD: -0.05 mm; 95%CI: -0.11, 0.00; P=0.06) but not in subjects who were generally healthy with only elevated homocysteine concentrations (WMD:0.00 mm; 95%CI: -0.01, 0.01; P=0.35). Furthermore, meta-regression analysis of the data showed that the baseline CIMT levels (P=0.011) and the percent reduction of homocysteine (P<0.001) were positively related to the effect size. Consistently, a greater beneficial effect was seen in those trials with baseline CIMT levels ≥0.8 mm (WMD: -0.14 mm; 95%CI: -0.19, -0.08; P<0.0001), and a reduction in the homocysteine concentration ≥30% (WMD: -0.22 mm; 95%CI: -0.38, -0.06; P=0.009). In the corresponding comparison groups, the effect sizes were attenuated and insignificant. CONCLUSIONS Our findings indicate that folic acid supplementation is effective in reducing the progression of CIMT, particularly in subjects with CKD or high CVD risk and among trials with higher baseline CIMT levels or a larger homocysteine reduction.

Prevalence and Associated Factors of Diabetes and Impaired Fasting Glucose in Chinese Hypertensive Adults Aged 45 to 75 Years

Objective This study examined the prevalence of impaired fasting glucose (IFG) and diabetes and their associated factors in 17,184 Chinese hypertensive adults aged 45–75 years. Methods A cross-sectional investigation was carried out in a rural area of Lianyungang, China. Previously undiagnosed diabetes [fasting plasma glucose (FPG) ≥7.0mmol/l] and IFG (6.1–6.9mmol/l) were defined based on FPG concentration. Previously diagnosed diabetes was determined on the basis of self-report. Total diabetes included both previously diagnosed diabetes and previously undiagnosed diabetes. Results The prevalence of previously diagnosed diabetes, undiagnosed diabetes, and IFG were 3.4%, 9.8%, and 14.1%, respectively. About 74.2% of the participants with diabetes had not previously been diagnosed. In the multivariable logistic-regression model, older age, men, antihypertensive treatment, obesity (BMI ≥25kg/m2), abdominal obesity (waist circumference ≥90cm for men and ≥80cm for women), non-current smoking, a family history of diabetes, higher heart rate, lower physical activity levels, and inland residence (versus coastal) were significantly associated with both total diabetes and previously undiagnosed diabetes. Furthermore, methylene- tetrahydrofolate reductase (MTHFR) 677 TT genotype was an independent associated factor for total diabetes, and current alcohol drinking was an independent associated factor for previously undiagnosed diabetes. At the same time, older age, men, abdominal obesity, non-current smoking, current alcohol drinking, a family history of diabetes, higher heart rate, and inland residence (versus coastal) were important independent associated factors for IFG. Conclusion In conclusion, we found a high prevalence of diabetes in Chinese hypertensive adults. Furthermore, about three out of every four diabetic adults were undiagnosed. Our results suggest that population-level measures aimed at the prevention, identification (even if only based on the FPG evaluation), and treatment of diabetes should be urgently taken to overcome the diabetes epidemic in Chinese hypertensive adults.

Prevalence of hyperhomocysteinaemia and its major determinants in rural Chinese hypertensive patients aged 45–75 years

We aimed to investigate the prevalence of hyperhomocysteinaemia (total plasma homocysteine (tHcy) ≥ 10 μmol/l) and its major determinants in rural Chinese hypertensive patients. A cross-sectional investigation was carried out in Lianyungang of Jiangsu province, China. This analysis included 13 946 hypertensive adults. The prevalence of hyperhomocysteinaemia was 51.6 % (42.7 % in women and 65.6 % in men). The OR of hyperhomocysteinaemia were 1.52 (95 % CI 1.39, 1.67) and 2.32 (95 % CI 2.07, 2.61) for participants aged 55-65 and 65-75 v. 45-55 years; 1.27 (95 % CI 1.18, 1.37) for participants with a BMI ≥ 25 v. < 25 kg/m²; 1.14 (95 % CI 1.06, 1.23) for participants with v. without antihypertensive treatment; 1.09 (95 % CI 1.00, 1.18) for residents inland v. coastal; 0.89 (95 % CI 0.82, 0.97) and 0.83 (95 % CI 0.74, 0.92) for participants with moderate and high v. low physical activity levels; 1.54 (95 % CI 1.41, 1.68) and 2.47 (95 % CI 2.17, 2.81) for participants with a glomerular filtration rate 60-90 and < 60 v. ≥ 90 ml/min per 1.73 m²; and 1.20 (95 % CI 1.07, 1.35) and 3.81 (95 % CI 3.33, 4.36) for participants with CT and TT v. CC genotype at methylenetetrahydrofolate reductase 677C>T polymorphism, respectively. Furthermore, higher tHcy concentrations were observed in smokers of both sexes (men: geometric mean 12.1 (interquartile range (IQR) 9.2-14.5) v. 11.9 (IQR 9.-14.) μmol/l, P= 0.005; women: geometric mean 10·3 (IQR 8.3-13.0) v. 9.6 (IQR 7.8-11.6) μmol/l, P= 0.010), and only in males with hypertension grade 3 (v. grade 1 or controlled blood pressure) (geometric mean 12.1 (IQR 9.2-14.4) v. 11.7 (IQR 9.2-14.0), P= 0.016) and in male non-drinkers (yes v. no) (geometric mean 12.3 (IQR 9.4-14.8) v. 11.7 (IQR 9.1-13.9), P= 0.014). In conclusion, there was a high prevalence of hyperhomocysteinaemia in Chinese hypertensive adults, particularly in the inlanders, who may benefit greatly from tHcy-lowering strategies, such as folic acid supplementation and lifestyle change.