Folic Acid Therapy Reduces Serum Uric Acid in Hypertensive Patients: a Substudy of the China Stroke Primary Prevention Trial (CSPPT)1–3

See corresponding editorial on page 775.

Folic acid therapy reduces serum uric acid in hypertensive patients: a substudy of the China Stroke Primary Prevention Trial (CSPPT)1–3

Xianhui Qin,4,10 Youbao Li,4,10 Mingli He,5 Genfu Tang,7,8 Delu Yin,6 Min Liang,4 Binyan Wang,4 Jing Nie,4 Yong Huo,9 Xin Xu,4 and Fan Fan Hou4* Downloaded from https://academic.oup.com/ajcn/article/105/4/882/4638049 by guest on 30 September 2021 4National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Departments of 5Neurology and 6Cardiology, First People’s Hospital, Lianyungang, China; 7Institute for Biomedicine and 8School of Health Administration, Anhui Medical University, Hefei, China; and 9Department of Cardiology, Peking University First Hospital, Beijing, China

ABSTRACT long been considered the most important risk factor for gout Background: The effect of folic acid supplementation on uric acid because it causes the deposition of urate crystals (1). Fur- (UA) concentrations is still inconclusive. thermore, substantial and increasing evidence has suggested Objective: We aimed to test the efficacy of folic acid therapy in that elevated uric acid (UA)11 concentrations are closely as- reducing serum UA in hypertensive patients. sociated with risks of hypertension and diabetes (2, 3) as well Design: A total of 15,364 hypertensive patients were randomly as the risk of chronic kidney disease (CKD), stroke, and cor- assigned to a double-blind daily treatment with a single tablet that onary heart disease (4–6). contained 10 mg enalapril and 0.8 mg folic acid (n = 7685) or 10 mg A secondary prevention with a focus on the treatment of enalapril alone (n = 7679). The main outcome was the change in hyperuricemia in patients with gout is the goal of current clinical serum UA, which was defined as UA at the exit visit minus that at practice (1). Furthermore, long-term urate-lowering drugs usu- baseline. Secondary outcomes were as follows: 1) controlled hyper- ally involve both high costs and risks. For example, in patients , m uricemia (UA concentration 357 mol/L after treatment) and 2) with asymptomatic hyperuricemia, the use of allopurinol sig- new-onset hyperuricemia in participants with normal UA concen- nificantly increased risks of hypersensitivity reactions and , m trations ( 357 mol/L). mortality (7). Individuals who used allopurinol for a long du- Results: After a median of 4.4 y of treatment, the mean 6 SD UA concentration increased by 34.7 6 72.5 mmol/L in the enalapril- 1 Supported by the National Natural Science Foundation of China alone group and by 30.7 6 71.8 mmol/L in the enalapril–folic acid 2 m (81402735, 81473052), the Major State Basic Research Development Pro- group, which resulted in a mean group difference of 4.0 mol/L gram of China (973 program 2012CB517703), the National Key Technology 2 2 m (95% CI: 6.5, 1.6 mol/L; P = 0.001). Furthermore, compared Support Program of China (2013BAI09B06 and 2015BAI2B07), the Na- with enalapril alone, enalapril–folic acid treatment showed an in- tional Key Research and Development Program (2016YFC0903100), the crease in controlled hyperuricemia (30.3% compared with 25.6%; Major Scientific and Technological Planning Project of Guangzhou OR: 1.31; 95% CI: 1.01, 1.70) and a decrease in new-onset hy- (201505051532194 and 15020010), the Science, Technology and Innovation peruricemia (15.0% compared with 16.3%; OR: 0.89; 95% CI: Committee of Shenzhen (JCYL20130401162636527), the National Natural 0.79, 0.99). A greater beneficial effect was observed in subjects Science Foundation of China (Key Program) (81430016), the Special Project with hyperuricemia (P-interaction = 0.07) or higher concentrations on the Integration of Industry, Education and Research of Guangdong of total homocysteine (tHcy) (P-interaction = 0.02) at baseline. Province (2011A091000031), and the Guangzhou Clinical Research Center for Chronic Kidney Disease Program (7415695988305). Furthermore, there was a significant inverse relation (P , 0.001) 2 The funders had no role in the design and conduct of the study (data between the reduction of tHcy and the change in UA concentrations. collection, management, analysis, and interpretation); the preparation, re- Conclusions: Enalapril–folic acid therapy, compared with ena- view, or approval of the manuscript; or the decision to submit the manuscript lapril alone, can significantly reduce the magnitude of the in- for publication. crease of UA concentrations in hypertensive adults. This trial 3 Supplemental Figures 1–3 and Supplemental Tables 1–10 are available was registered at clinicaltrials.gov as NCT00794885. Am J from the “Online Supporting Material” link in the online posting of the ar- Clin Nutr 2017;105:882–9. ticle and from the same link in the online table of contents at http://ajcn. nutrition.org. 10 Keywords: controlled hyperuricemia, folic acid supplementation, These authors contributed equally to this work. *To whom correspondence should be addressed. E-mail: ffhouguangzhou@ new-onset hyperuricemia, total homocysteine, uric acid concentrations 163.com. 11 Abbreviations used: CKD, chronic kidney disease; CSPPT, China INTRODUCTION Stroke Primary Prevention Trial; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure; tHcy, total homocysteine; UA, uric acid. Hyperuricemia is a metabolic disorder that, in recent decades, Received August 2, 2016. Accepted for publication January 4, 2017. has become increasingly common worldwide. Hyperuricemia has First published online February 1, 2017; doi: 10.3945/ajcn.116.143131.

882 Am J Clin Nutr 2017;105:882–9. Printed in USA. Ó 2017 American Society for Nutrition FOLIC ACID THERAPY REDUCES SERUM URIC ACID 883 ration had higher occurrences of both bladder cancer and all- This study was approved by the Ethics Committee of the Institute cause cancers (8). Some clinical studies have shown that of Biomedicine, Anhui Medical University, Hefei, China. febuxostat could also lead to cutaneous adverse effects in w2% of patients and was associated with a higher incidence of hep- Intervention and follow-up atotoxicity (9, 10). Thus, both allopurinol and febuxostat are currently not recommended for the treatment of asymptomatic Eligible participants were randomly assigned in a 1:1 ratio to 1 hyperuricemia. Therefore, a safe, inexpensive, and effective of 2 treatment groups. The first group received a daily oral dose of strategy for the prevention of the elevation of UA concentrations 1 tablet that contained 10 mg enalapril and 0.8 mg folic acid is of clinical and public health importance. (single-tablet combination; i.e., the enalapril–folic acid group), The major function of xanthine oxidase is the oxidation of the and the second group received a daily oral dose of 1 tablet that purines xanthine and hypoxanthine to UA (11). Folic acid and its contained 10 mg enalapril only (i.e., the enalapril-alone group). derivatives have been reported to offer a potent inhibition of Other classes of antihypertensive medications, mostly dihydropyr- idine calcium channel blockers and hydrochlorothiazide, could be xanthine oxidase (12). Concurrently, there is a significant as- Downloaded from https://academic.oup.com/ajcn/article/105/4/882/4638049 by guest on 30 September 2021 sociation between hyperhomocysteinemia and hyperuricemia prescribed concomitantly if necessary. (13), with hyperhomocysteinemia being highly prevalent in gout Participants were followed up every 3 mo. At each visit, patients (14). A previous case-control study showed that high trained study personnel measured blood pressure and recorded folate intake may protect against gout (15); however, subsequent the number of pills that were taken between visits, concomitant intervention studies that used folic acid supplementation failed to medication use, and any adverse events for all participants. At the lower blood UA concentrations (16, 17). These contradictory conclusion of the study, an exit visit was conducted to collect findings may have been due in part to small sample sizes or short serum samples and to assess UA and renal outcomes. treatment durations. The CSPPT (China Stroke Primary Prevention Trial) Laboratory assays showed that the combined use of enalapril and folic acid, compared with the use of enalapril alone, significantly reduced Serum concentrations of UA, total homocysteine (tHcy), risk of first stroke by 21% in hypertensive Chinese adults (18). creatinine, lipids, and fasting glucose at both baseline and exit Furthermore, in the renal substudy of the CSPPT, enalapril– visits were measured with the use of automated analyzers folic acid therapy, compared with therapy with enalapril (Beckman Coulter) at the core laboratory of the National Clinical alone, delayed the progression of CKD in patients with mild Research Center for Kidney Disease, Guangzhou, China. Serum folate and vitamin B-12 were measured at a commercial labo- to moderate CKD (OR: 0.44; 95% CI: 0.26, 0.75) (19). The ratory with the use of a chemiluminescent immunoassay (New current, prespecified UA substudy of the CSPPT aimed to test Industrial). The eGFR was calculated with the use of the Chronic the effect of folic acid therapy on the change of serum UA in Kidney Disease Epidemiology Collaboration equation. hypertensive patients.

Major definitions METHODS Hyperuricemia was defined as a UA concentration $417 mmol/L $ m Study design and participants (7 mg/dL) in men or 357 mol/L (6 mg/dL) in women (1, 20). Controlled hyperuricemia was defined as a UA concentration The rationales and study designs for the CSPPT (clinicaltrials.gov; ,357 mmol/L after treatment (21). The change in the eGFR was NCT00794885) (18) and the renal substudy of the CSPPT (19) calculated as the eGFR at baseline minus that at the exit visit. have been described in detail previously. Briefly, the CSPPT was a randomized, double-blind, actively controlled trial that was conducted from May 2008 to August 2013 in 32 communities in Outcomes the Anhui and Jiangsu provinces of China. The study enrolled a The primary outcome was the change in the UA concentration, total of 20,702 hypertensive adults aged 45–75 y who did not which was defined as the UA concentration at the exit visit minus have a history of major cardiovascular diseases. Participants that at baseline. were randomly assigned to receive treatment with either a Secondary outcomes included the following: 1) controlled combination of enalapril and folic acid or with enalapril alone hyperuricemia and 2) new-onset hyperuricemia in patients with and were followed up for a median of 4.5 y. The renal substudy normal UA concentrations (,357 mmol/L) (19) at baseline. enrolled CSPPT participants from the 20 communities in the Jiangsu province with the exclusion of individuals with an estimated glomerular filtration rate (eGFR) ,30 mL $ min21 $ 1.73 m22 or a Statistical analysis missing eGFR at baseline. Of 15,364 eligible participants, 10 subjects (0.07%) who Detailed inclusion and exclusion criteria for the CSPPT have reported the use of UA-lowering drugs and 2191 subjects (14.3%) been described elsewhere (18). The UA substudy was initiated 3 y with unknown UA outcomes were excluded from the current after completion of the enrollment of the CSPPT. This substudy analysis. In addition, there were missing values on serum total enrolled CSPPT participants from the 20 communities in the cholesterol (n = 204), BMI (n = 2), smoking status (n = 4), Jiangsu province with the exclusion of individuals who used drinking status (n = 7), tHcy (n = 116), serum folate (n = 155), UA-lowering drugs or had missing UA concentrations at baseline. serum vitamin B-12 (n = 155), serum fasting glucose (n = 203), The flow of the participants is presented in Supplemental Figure 1. and eGFR (n = 206) at baseline as well as eGFR (n = 121) and 884 QIN ET AL. tHcy (n = 18) at exit. Multiple imputation was used to deal with Of these participants, the final UA measurement at the exit visit missing values in the outcome analyses. was obtained for 13,163 subjects (85.7%). Participants without UA Mean 6 SDs or medians (25th to 75th percentiles) and pro- concentrations at the exit visit did not differ in base- portions were calculated for population characteristics by line characteristics from those with UA concentrations (Supple- treatment group. The treatment effects, which are expressed as mental Table 1). During the treatment period, a total of 10 ORs for dichotomous outcomes and between-group differences participants (4 subjects in the enalapril-alone group and 6 for changes in UA concentrations, were estimated with the use subjects in the enalapril–folic acid group) who reported of generalized linear regression models with adjustment for age, physician-diagnosed gout and the use of UA-lowering drugs sex, 5,10-methylenetetrahydrofolate reductase C677T polymor- were excluded from the analysis. One participant in the ena- phisms, BMI, fasting glucose, UA, total cholesterol, tHcy, folate, lapril–folic acid group who reported physician-diagnosed vitamin B-12, eGFR, systolic blood pressure (SBP), smoking, gout but did not use UA-lowering drugs was included in the and drinking status at baseline, mean SBP during the treatment analysis. period, and the change in the eGFR. In further exploratory All baseline characteristics were comparable between the Downloaded from https://academic.oup.com/ajcn/article/105/4/882/4638049 by guest on 30 September 2021 analyses, possible modifications of the treatment effects on the enalapril-alone group and the enalapril–folic acid group in the primary outcome were also assessed for the variables age, sex, total population (Table 1) as well as in participants with hy- 5,10-methylenetetrahydrofolate reductase C677T genotype, peruricemia (Supplemental Table 2) or UA concentrations eGFR, tHcy, baseline SBP and hyperuricemia, and mean SBP ,357 mmol/L (Supplemental Table 3) at baseline. during the treatment period. A 2-tailed P , 0.05 was considered to be statistically signifi- Treatment adherence and blood pressure cant in all analyses. R software (version 3.2.0; The R Foundation, The median length of follow-up was 4.4 y (IQR: 4.2–4.6 y). http://www.R-project.org/) was used for all statistical analyses. The mean treatment compliance, which was defined as the percentage of the study treatment medication that was ac- RESULTS tually taken during the trial, was 76% in both treatment groups. Study participants and baseline characteristics The mean blood pressure during the trial was 140/84 mm Hg, As illustrated in the flowchart (Supplemental Figure 1), the which represented an average decrease of 28/12 mm Hg from substudy included a total of 15,364 participants of the CSPPT. baseline. During the entire trial period, there was no significant

TABLE 1 Characteristics of the study population in the uric acid substudy of the CSPPT (2008–2013)1 Enalapril (n = 7679) Enalapril and folic acid (n = 7685)

Age, y 59.5 6 7.62 59.5 6 7.5 Sex, M, n (%) 3041 (39.6) 3000 (39.0) BMI, kg/m2 25.6 6 3.6 25.7 6 3.6 MTHFR 677TT genotype, n (%) 2044 (26.6) 2034 (26.5) BP, mm Hg Baseline SBP 168.5 6 21.1 168.1 6 20.8 Baseline DBP 95.3 6 12.1 95.4 6 11.8 Mean SBP during treatment period 140.1 6 11.4 139.8 6 11.2 Mean DBP during treatment period 83.8 6 7.6 83.8 6 7.4 Cardiovascular disease risk factor, n (%) Current smoking 1739 (22.7) 1752 (22.8) Current alcohol drinking 1790 (23.3) 1750 (22.8) Self-reported hyperlipidemia 227 (3.0) 225 (2.9) Self-reported diabetes 297 (3.9) 275 (3.6) Laboratory result Total cholesterol, mmol/L 5.7 6 1.2 5.7 6 1.2 Triglycerides, mmol/L 1.7 6 1.0 1.7 6 1.5 HDL cholesterol, mmol/L 1.3 6 0.4 1.3 6 0.4 Fasting glucose, mmol/L 6.1 6 1.8 6.0 6 1.8 Uric acid, mmol/L 294.0 6 78.8 293.8 6 79.7 eGFR, mL $ min21 $ 1.73 m22 94.2 6 13.0 93.9 6 13.4 Vitamin B-12, pg/mL 409.3 6 167.1 403.7 6 151.9 Drug use, n (%) Antihypertensive drugs 3831 (49.9) 3761 (48.9) Lipid-lowing drugs 65 (0.9) 66 (0.9) Glucose-lowering drugs 131 (1.7) 147 (1.9) Antiplatelet drugs 314 (4.1) 277 (3.6) 1 BP, blood pressure; CSPPT, China Stroke Primary Prevention Trial; DBP, diastolic blood pressure; eGFR, estimated glomerular ﬁltration rate; MTHFR, 5,10-methylenetetrahydrofolate reductase; SBP, systolic blood pressure. 2 Mean 6 SD (all such values for continuous variables). FOLIC ACID THERAPY REDUCES SERUM URIC ACID 885 TABLE 2 concentrations increased by a mean of 5.1 and 15.4 ng/mL in the Serum total homocysteine and folate concentrations at baseline and after enalapril-alone group and the enalapril–folic acid group, re- 1 treatment in the uric acid substudy of the CSPPT (2008–2013) spectively. Accordingly, the enalapril–folic acid group had a Enalapril Enalapril and folic much greater reduction in serum tHcy than did the enalapril- Variable (n = 7679) acid (n = 7685) P alone group (P , 0.001) (Table 2). A similar trend was ob- m served in participants with or without hyperuricemia and with Total homocysteine, mol/L , $ m At baseline 14.7 6 9.2 14.7 6 8.9 0.910 UA concentrations 357 or 357 mol/L (Supplemental Ta- At exit 14.4 6 8.1 12.7 6 6.1 ,0.001 bles 4 and 5). Change 20.2 6 7.2 21.9 6 7.9 ,0.001 Folate, ng/mL Treatment effects on primary and secondary outcomes At baseline 7.7 6 3.3 7.6 6 3.2 0.424 At exit 12.7 6 5.9 23.1 6 17.2 ,0.001 Mean baseline UA concentrations were comparable between Change 5.1 6 5.9 15.4 6 17.3 ,0.001 the 2 groups (enalapril-alone group: 294.0 6 78.8 mmol/L;

6 m Downloaded from https://academic.oup.com/ajcn/article/105/4/882/4638049 by guest on 30 September 2021 1 All values are means 6 SDs. Change was deﬁned as the exit value enalapril–folic acid group: 293.8 79.7 mol/L; P = 0.865). minus the baseline value. Differences between treatment groups were com- After a median 4.4 y of treatment, the UA concentration in- pared with the use of 2-sample t tests. CSPPT, China Stroke Primary Pre- creased by 34.7 6 72.5 mmol/L in the enalapril-alone group and vention Trial. by 30.7 6 71.8 mmol/L in the enalapril–folic acid group, which resulted in a mean group difference of 24.0 mmol/L (95% CI: 26.5, 21.6 mmol/L; P = 0.001). Adjustment for changes in the difference in blood pressure between the 2 treatment groups eGFR and other important covariables at baseline attenuated but (Supplemental Figure 2). did not substantially change the results (mean difference: 23.3 mmol/L; 95% CI: 25.4, 21.1 mmol/L; P = 0.003) (Table 3). Furthermore, compared with the enalapril-alone group, the Treatment effects on serum folate and tHcy concentrations enalapril–folic acid group showed a signiﬁcant increase in the Baseline folate and tHcy concentrations were comparable adjusted odds of a reduction of UA concentrations .20 mmol/L between the 2 treatment groups. After treatment, folate (OR: 1.15; 95% CI: 1.04, 1.26) (Supplemental Table 6) and

TABLE 3 Effects of folic acid therapy on primary and secondary outcomes in hypertensive patients in the uric acid substudy of the CSPPT (2008–2013)1 Enalapril Enalapril and folic acid P

Primary outcome Change in uric acid concentration n 6600 6563 — Uric acid concentrations at baseline, mmol/L 294.0 6 78.82 293.8 6 79.7 0.865 Uric acid concentrations at exit, mmol/L 328.7 6 87.3 324.5 6 86.3 0.005 Change, mmol/L 34.7 6 72.5 30.7 6 71.8 0.001 Change by group3 — 24.0 (26.5, 21.6) 0.001 Multivariate adjusted3,4 — 23.3 (25.4, 21.1) 0.003 Secondary outcome, n (%) Controlled hyperuricemia (uric acid concentrations 196 (25.6) 224 (30.3) 0.043 ,357 mmol/L at exit visit)5,6 Sex adjusted 1.00 (reference) 1.31 (1.04, 1.66) 0.022 Age and sex adjusted 1.00 (reference) 1.31 (1.04, 1.66) 0.024 Multivariate adjusted4 1.00 (reference) 1.31 (1.01, 1.70) 0.042 New-onset hyperuricemia, n (%)5,7 869 (16.3) 795 (15.0) 0.065 Sex adjusted 1.00 (reference) 0.90 (0.81, 1.00) 0.049 Age and sex adjusted 1.00 (reference) 0.90 (0.81, 1.00) 0.042 Multivariate adjusted4 1.00 (reference) 0.89 (0.79, 0.99) 0.039 1 Change in uric acid concentrations was defined as the uric acid concentration at the exit visit minus that at baseline. Differences between treatment groups were compared with the use of 2-sample t tests, chi-square tests, and generalized linear regression models accordingly. CSPPT, China Stroke Primary Prevention Trial; eGFR, estimated glomerular filtration rate; MTHFR, 5,10-methylenetetrahydrofolate reductase; SBP, systolic blood pressure. 2 Mean 6 SD (all such values). 3 All values are bs; 95% CIs in parentheses. 4 Adjusted for age, sex, MTHFR C677T polymorphisms, BMI, fasting glucose, uric acid, total cholesterol, total homocysteine, folate, vitamin B-12, eGFR, SBP, smoking and drinking status at baseline, mean SBP during the treatment period, and the change in the eGFR (defined as the eGFR at baseline minus that at exit). 5 All values are ORs; 95% CIs in parentheses. 6 Hyperuricemia was defined as a uric acid concentration $417 mmol/L in men or $357 mmol/L in women. Partic- ipants with hyperuricemia at baseline were included in the analysis. 7 Participants with normal uric acid concentrations (,357 mmol/L) at baseline were included in the analysis. 886 QIN ET AL. of a UA reduction .10% (OR: 1.11; 95% CI: 1.00, 1.23) enalapril alone, enalapril and folic acid showed a significant (Supplemental Table 7). decrease in the adjusted odds of new-onset hyperuricemia (OR: In participants with hyperuricemia at baseline, UA concen- 0.89; 95% CI: 0.79, 0.99; P = 0.039) (Table 3). Similar bene- trations decreased by 215.6 6 89.4 and 228.0 6 91.3 mmol/L ficial results were observed when the outcome was defined as an in the enalapril-alone group and enalapril–folic acid group, re- increase in the UA concentration $60 mmol/L and to the spectively, which resulted in a mean group difference of amount of hyperuricemia [762 participants (14.3%) in the 28.7 mmol/L (95% CI: 215.2, 22.4 mmol/L; P = 0.007) enalapril-alone group and 686 participants (13.0%) in the ena- (Supplemental Table 8). The proportion of controlled hyper- lapril–folic acid group; OR: 0.88; 95% CI: 0.78, 0.99]. uricemia in the enalapril-alone group and enalapril–folic acid group was 25.6% and 30.3%, respectively, which resulted in a Concomitant medications significant increase in the adjusted odds of controlled hyper- The most common concomitant medications were dihy- uricemia (OR: 1.31; 95% CI: 1.01, 1.70; P = 0.042) (Table 3). dropyridine and hydrochlorothiazide, which were used in w79% Similar beneficial trends were observed in participants with UA and w58% of participants, respectively. There were no signifi- Downloaded from https://academic.oup.com/ajcn/article/105/4/882/4638049 by guest on 30 September 2021 concentrations $476 mmol/L (8 mg/dL) at baseline [12 partic- cant differences in concomitant medication use during the trial ipants (8.1%) in the enalapril-alone group and 27 participants between the 2 treatment groups (Supplemental Table 9). (15.9%) in the enalapril–folic acid group; OR: 2.28; 95% CI: 1.05, 4.93] or with UA concentrations $357 mmol/L at baseline [331 subjects (25.9%) compared with 376 subjects (29.6%), Stratified analyses by potential effect modifiers respectively; OR: 1.20; 95% CI: 0.99, 1.45]. Stratified analyses were performed to assess the treatment effect In participants with UA concentrations ,357 mmol/L at on the primary outcome in various subgroups (Figure 1). The baseline, UA increased by 43.1 6 66.0 and 40.4 6 63.9 mmol/L baseline tHcy positively modified the efficacy of folic acid therapy in the enalapril-alone and enalapril–folic acid groups, re- in UA reduction (P-interaction = 0.020). Other variables, including spectively, which resulted in a mean group difference of age (,60 compared with $60 y; P-interaction = 0.082), sex 22.4 mmol/L (95% CI: 24.6, 20.2 mmol/L; P = 0.036) (Sup- (P-interaction = 0.321), hyperuricemia (no compared with plemental Table 8). New-onset hyperuricemia occurred in 869 yes; P-interaction = 0.070), serum folate concentrations subjects (16.3%) and 795 subjects (15.0%) in the enalapril-alone (median: ,7.3 compared with $7.3 ng/mL; P-interaction = 0.835), and enalapril–folic acid groups, respectively. Compared with eGFR (,60, 60 to ,90, and $90 mL $ min21 $ 1.73 m22;

FIGURE 1 Stratified analyses by potential effect modifiers for the primary outcome in hypertensive patients in the uric acid substudy of the China Stroke Primary Prevention Trial (2008–2013). Generalized linear regression models were used with adjustment for age, sex, MTHFR C677T polymorphisms, BMI, fasting glucose, uric acid, total cholesterol, total homocysteine, folate, vitamin B-12, eGFR, SBP, smoking and drinking status at baseline, mean SBP during the treatment period, and the change in the eGFR (defined as the eGFR at baseline minus that at exit). Boxes denote bs, lines represent 95% CIs, and arrows indicate the lower and upper ends of 95% CI exceed limits. eGFR, estimated glomerular filtration rate; FA, folic acid; MTHFR, 5,10-methylenetetrahydrofolate reductase; SBP, systolic blood pressure. FOLIC ACID THERAPY REDUCES SERUM URIC ACID 887 P-interaction = 0.130), baseline SBP (,160 compared with inverse relation between the reduction of tHcy and the change in $160 mm Hg; P-interaction = 0.422), and mean SBP during the UA concentrations. A possible explanation for this result was that treatment period (,140 compared with $140 mm Hg; P-in- chronic elevation in tHcy results in parallel increases in interaction = 0.241), did not appear to significantly modify the tracellular S-adenosylhomocysteine (22). As a potent inhibitor treatment effect (Figure 1). Note that, at the existing sample sizes for most S-adenosylmethionine–dependent methyltransferases, of some subgroups, the power for detecting an interaction in the test S-adenosylhomocysteine may induce marked DNA damage and may have been limited such that a negative finding in the test would release purine nucleotides (23, 24). The catabolism of purine not necessarily have confirmed the absence of an interaction. nucleotides ultimately leads to the production of UA (11). As The largest UA reduction that was associated with higher tHcy such, the reduction of tHcy may be one possible pathway was observed in participants with different baseline UA con- through which folic acid exerts its hypouricemic effect. This centrations, although the comparisons were NS (Supplemental hypothesis could be further tested by observing change in UA in Table 10). Furthermore, there was a significant inverse relation patients who are treated for metabolic vitamin B-12 deficiency between the reduction of tHcy (baseline minus exit concentra- because vitamin B-12 deficiency elevates tHcy independent of Downloaded from https://academic.oup.com/ajcn/article/105/4/882/4638049 by guest on 30 September 2021 tions) and the change in the UA concentration (P , 0.001) folic acid (25). To our knowledge, our results offer new insights (Figure 2). into the role of elevated tHcy on the metabolism of UA. How- ever, it is possible that other mechanisms that are independent of tHcy lowering may also be involved. Further elucidation of DISCUSSION the exact mechanisms that underlie the beneficial effect of This study shows that enalapril and folic acid, compared with folate and the detrimental effect of tHcy on UA metabolism enalapril alone, could reduce the magnitude of the increase in UA may possibly provide new strategies for the control of concentrations, increase the proportion of controlled hyperuri- hyperuricemia. cemia, and decrease the incidence of new-onset hyperuricemia. Previous studies have shown a continuous relation between elevated UA concentrations and cardiovascular events (26–28). A Our study provides some clues to the possible UA-lowering m mechanisms of folic acid therapy. First, the UA reduction that was 10- mol/L increase in the UA concentration was significantly associated with folic acid therapy was independent of the baseline associated with a 2.4% increase (HR: 1.024; 95% CI: 1.017, eGFR and the changes in the eGFR. Second, folic acid therapy 1.032) in cardiovascular events (27, 28). In addition, the Re- resulted in a greater UA-lowering effect in participants with duction of Endpoints in Non-Insulin Dependent Diabetes Mel- higher tHcy at baseline. At the same time, there was a significant litus With the Angiotensin II Antagonist Losartan study showed that losartan, compared with placebo, lowered UA concentrations w9.5 mmol/L after a 6-mo treatment in patients with type 2 diabetes and nephropathy (baseline UA concentration: 400 mmol/L) (29, 30). Approximately 22% of the renoprotective effect (an absolute 4–5% risk reduction) (29) and 50% of the cardiovascular protective effect (an absolute 4.6% risk reduction) (30) of losartan are attributable to differences in the achieved UA concentrations. Furthermore, the study indicated that it was the reduction of UA per se that was important rather than the specific treatment strategy used. Nevertheless, we agree that, on average, the magnitude of UA reduction that was associated with folic acid therapy in our study was relatively small in the total participants. However, compared with the enalapril-alone group, the enalapril–folic acid group showed a significant increase in the adjusted odds of a reduction of UA concentrations .20 mmol/L (OR: 1.15; 95% CI: 1.04, 1.26) (Supplemental Table 6) and a UA reduction .10% (OR: 1.11; 95% CI: 1.00, 1.23) (Supplemental Table 7). More importantly, as shown in Supplemental Figure 3, the folic acid treatment clearly shifted the distribution of the change in UA concentrations toward the left tail in a subset of participants (i.e., a greater UA reduction was observed in subgroups with baseline tHcy concentrations $15 mmol/L or with baseline FIGURE 2 Relation between the reduction of total homocysteine (base- hyperuricemia). The clinical relevance of this left shift in UA line concentrations minus exit concentration) and the change in uric acid reduction was supported by our analyses that are presented in concentrations in hypertensive patients in the uric acid substudy of the China Table 3. The folic acid treatment significantly increased the Stroke Primary Prevention Trial (2008–2013). Generalized linear regression models were used with adjustment for age, sex, MTHFR C677T polymor- adjusted odds of controlled hyperuricemia by 31% and de- phisms, BMI, fasting glucose, uric acid, total cholesterol, total homocys- creased the adjusted odds of new-onset hyperuricemia by 11%. teine, folate, vitamin B-12, eGFR, SBP, smoking and drinking status at Consistently, the larger reduction in UA that was associated with baseline, mean SBP during the treatment period, and the change in eGFR folic acid therapy was observed in subjects with hyperuricemia (defined as the eGFR at baseline minus that at exit). eGFR, estimated glomerular filtration rate; MTHFR, 5,10-methylenetetrahydrofolate reductase; (mean UA concentration: 28.7 mmol/L), tHcy concentrations SBP, systolic blood pressure. $15 mmol/L (UA concentration: 27.0 mmol/L), hyperuricemia 888 QIN ET AL. combined with tHcy concentrations 10–15 mmol/L (UA con- A couple of limitations should be addressed. First, w14% of centration: 210.1 mmol/L), and hyperuricemia combined with randomly assigned participants (including 2.6% of participants tHcy $15 mmol/L (UA concentration: 214.9 mmol/L) at who died before the end of the CSPPT) did not have UA mea- baseline. In China, the prevalence of hyperuricemia is w13% surements available at the exit visit and were excluded from the (31), and the prevalence of tHcy concentrations $15 mmol/L is analysis. However, baseline characteristics were similar between 27–30% (32, 33), without the mandatory folic acid fortification participants who were included in the analysis and individuals of foods. In China, the estimated number of adults with hyper- who were not included in the analysis, which should have mini- uricemia is 170 million, and the number of adults with tHcy mize any bias. Second, mean folate concentrations in the enalapril- concentrations $15 mmol/L is 350 million. From a public health alone group also increased substantially during the course of the perspective, even a small reduction of the average UA concen- trial. The cause of this increase was unclear. During the course of tration in the general population may lead to substantial re- the study, subjects received nutritional health education, which duction in the number of individuals with hyperuricemia and may have led to improved dietary choices. However, we had no elevated UA-related diseases. Folic acid is appealing because it detailed food intake information at either at baseline or at the exit Downloaded from https://academic.oup.com/ajcn/article/105/4/882/4638049 by guest on 30 September 2021 is safe and inexpensive. The policy of mandatory fortification visit. Whatever the cause, this change likely attenuated the bene- with folic acid has been proved to be practicable and sustain- ficial effect of the study vitamin. Furthermore, the reduction in UA able (34). As such, we believe that our findings of the beneficial in subjects with a high baseline UA concentration may have effect of folic acid therapy on UA reduction may possibly have indicated a regression to the mean phenomenon. However, we some clinical and public health implications. adjusted the baseline UA and had the enalapril-alone group as the In a previous study (16), a total of 480 hypertensive patients control group. Overall, our findings remain to be confirmed in were randomly assigned to one of the following 3 treatment future studies, and underlying mechanisms by which folic acid groups: 10 mg enalapril (enalapril-alone group; n = 180), 10 mg reduces UA warrant future investigation. enalapril and 0.4 mg folic acid (low–folic acid group; n = 180) In conclusion, the combination of enalapril and folic acid, or 10 mg enalapril and 0.8 mg folic acid (high–folic acid group; compared with enalapril alone, reduces the magnitude of the n = 180) daily for 8 wk. In the total participants, there was no increase in UA concentrations in hypertensive adults. If validated, significant change in UA from baseline to the end of the treat- high folic acid or folate intake may be considered to be an ad- ment in any of the 3 treatment groups. Furthermore, compared juvant nutritional recommendation for preventing and treating with the enalapril-alone group, neither the high– nor low–folic hyperuricemia particularly in individuals with asymptomatic acid group had any significant effect on UA concentrations, hyperuricemia that is coupled with high tHcy. which was perhaps due in part to the small sample sizes. We thank J David Spence (Stroke Prevention and Atherosclerosis Research However, in participants with hyperuricemia at baseline, UA m Center, Robarts Research Institute, University of Western Ontario, London, concentrations decreased by a median of 28.2 and 57.0 mol/L Ontario, Canada) and Smith Liu (Departments of Epidemiology and Medi- in the enalapril-alone group and the high–folic acid group, re- cine, Warren Alpert Medical School, Brown University, Providence, Rhode spectively, which resulted in a significant group difference of Island) for their helpful comments. 28.8 mmol/L. Our current study had a larger sample size and The authors’ responsibilities were as follows—XQ and YL: analyzed the longer treatment duration with a mean age of 59.5 y at baseline data and wrote the manuscript; XQ, YL, MH, GT, DY, ML, BW, YH, and and a mean follow-up duration of 4.4 y. Previous studies have FFH: conducted the research; FFH: had primary responsibility for the final shown that UA concentrations increased with advancing age content of the manuscript; and all authors: designed the research and read and approved the final manuscript. XQ reports having received grants from (35). Consistently during our current trial, UA increased in both the National Science Foundation and consulting fees from the AUSA Re- of the treatment groups in the total participants perhaps because search Institute, Shenzhen AUSA. BW reports having received grants from of the reduction in the eGFR (the eGFR at the exit visit minus the National Science Foundation and the Special Project on the Integration 21 that at baseline resulted in a mean decline of 5 mL $ min $ of Industry, Education and Research of Guangdong Province, and consulting 2 1.73 m 2) over time and the concomitant use of diuretics fees from the AUSA Research Institute, Shenzhen AUSA. YH reports having (w58%) (Supplemental Table 7). However, this effect was received grants from the National Major Scientific and Technological Spe- significantly attenuated with the enalapril–folic acid treatment. cial Project and nonfinancial support from Shenzhen AUSA. XX reports More importantly, although our current study also showed a having received grants from the Major Scientific and Technological Planning Project of Guangzhou and the Science, Technology and Innovation Commit- greater UA reduction that was associated with folic acid therapy tee of Shenzhen and personal fees from the AUSA Research Institute, in participants with hyperuricemia, the group difference was Shenzhen AUSA. FFH reports having received grants from the Major State only a mean concentration of 8.7 mmol/L. Previous studies have Basic Research Development Program of China, the Ministry of Science and shown that, after 6–12 mo of folic acid treatment, decreasing Technology of the People’s Republic of China, the National Key Technology concentrations of tHcy reach a plateau (36, 37). We speculated Support Program of China, the Major Scientific and Technological Planning that the efficacy of folic acid therapy on UA reduction di- Project of Guangzhou, the National Natural Science Foundation of China, the minished during prolonged treatment once a new, steady ho- Guangzhou Clinical Research Center for Chronic Kidney Disease Program, and mocysteine concentration had been established. Consistently, it the State Key Laboratory for Organ Failure Research, Guangzhou, China. The remaining authors reported no conflicts of interest related to the study. has been shown that the effects of losartan on UA excretion waned over time once a new steady UA state was achieved (28, 29). 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