Table 1.
General outcome table
| Author, Year, Country | Sex | Total Sample Size | Duration Months | Folate Baseline |
Homocysteine | FA Plus Other Vit B | FA dose mg/day | Key points | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | Change | Change % | ||||||||
| Mehta K, 2005 [21], India | Both | 124 | 3 | NA | NA | NA | NA | No | 5 | 84 patients with documented CAD and 40 control subjects, primary outcome was reduction in t-HCY levels after folate therapy in patients with hyperhomocysteinemia, they found a significant reduction in t-HCY levels in patients with mild and moderate hyperhomocysteinemia but nts with severe no reduction in patients with severe |
| Zoungas S, 2006 [22], Australia/New Zealand | Both | 315 | 42 | NA | 27 | −4.7 | −17.4 | No | 15 | 156 patients with ESRD and 159 healthy controls were recruited, the aim of the study was to establish whether high-dose folic acid would slow the progression of atherosclerosis and reduce cardiovascular events in patients with chronic renal failure (CRF), acid therapy was shown to not slow atherosclerosis folic acid therapy was shown to not slow atherogression or improve cardiovascular morbidity or mortality in patients with CRF. |
| Bleie O, 2011 [23], Norway | Both | 40 | 24 | 12.2 | 10.7 | −3.3 | −30.8 | Yes | 0.8 | 40 patients with stable CAD were randomly assigned to folic acid + VB12 therapy or placebo, the objective of the study was to assess the effect of folic acid + VB12 on coronary vascular function, they found a significant increase in basal and adenosine-induced coronary blood flow in the folic acid + VB12 group. |
| Liu M, 2020 [24], China | Both | 99 | 3 | NA | 13.1 | −1.47 | −11.2 | Yes | 0.4 | 42 patients with CAD and 48 healthy subjects were studied, the objective of the study was to evaluate the effect of B vitamins supplementation on dyslipidemia and inflammatory cytokines, they found improvement in hcy levels, TG,TC, HDL-C, IL-10 and IL-1B. CC, |
| Shidfar F, 2009 [25], Iran | Both | 40 | 2 | 5.08 | 12.91 | −3.98 | −30.8 | No | 5 | 40 patients with hypercholesterolemia were randomly assigned to folate supplementation and placebo therapy for 8 weeks, the aim of this study was to assess the effect of folate therapy on hcy levels and total antioxidant capacity, they found a significant decrease in HCY levels and a significant increase in total antioxidant capacity in folate group. |
| Schnyder G, 2002 [26], Switzerland | Both | 553 | 11 | NA | 11.2 | −2.9 | −25.7 | Yes | 1 | 553 patients with h/o successful angioplasty of at least 1 significant coronary stenosis were randomly assigned to a Folic acid + Vit. B12 + Vit. B6 or placebo therapy for 6 months. Follow up of 11 months resulted on significantly reduced rate of target lesion revascularization, decreasing the incidence of major adverse events after percutaneous coronary intervention. |
| Vermeulen E, 2000 [27], Netherlands | Both | 158 | 24 | 12.1 | 14.7 | −4.6 | −31.3 | Yes | 5 | 158 Healthy siblings (siblings of 167 patients with h/o premature atherothrombotic disease) were assigned to Placebo or FA + Vit. B6 daily for 24 months (about 2 years). The results showed lowering of fasting HCY concentration and decreased risk of atherosclerotic coronary events |
| VITATOPS Trial, 2010 [28], Australia | Both | 8164 | 41 | NA | 14.3 | −4 | −30 | Yes | 2 | 8164 patients with history of recent stroke or TIA were randomly assigned to daily administration of FA + Vit. B6 + Vit. B12 or placebo. Results showed that B vitamins were safe but were not more effective than placebo in reducing major vascular events. |
| Van Dijk S, 2015 [29], Netherlands | Both | 2919 | 24 | 18.7 | 14.4 | −3.8 | −26.4 | Yes | 0.4 | 2919 patients were randomly assigned to FA + Vitamin B12 or placebo, compared to placebo b vitamin supplementation lowered serum homocysteine, but had no effect on PWV levels, or carotid IMT. |
| Doshi S, 2002 [30], UK | Both | 33 | 1.5 | 22.37 | 10.7 | −2.3 | −21.5 | No | 5 | 33 patients were randomly assigned to FA or placebo, after assessing the flow-mediated dilatation FMD. Data collected at 6 weeks (about 1 and a half months) showed that FA improves endothelial function in CAD |
| Bonaa K, 2006 [31], Norway | Both | 2815 | 36 | 12.4 | 13.1 | −3.8 | −27.5 | Yes | 0.8 | Patients were divided into groups of folic acid with vitamins B and placebo. Folic acid + B12, with or without vitamin B6, did not significantly reduce the risk of the primary outcome (MI, stroke, sudden death;risk ratio, 1.08; 95% confidence interval, 0.93 to 1.25; P = 0.31), as compared with placebo. Folic acid + B12 + B6 group, showed increased risk in primary outcome (relative risk, 1.22; 95% confidence interval, 1.00 to 1.50; P = 0.05), so it is not recommended by the study. |
| Toole J, 2004 [32], United States/Canada/Scotland | Women | 3680 | 24 | 26 | 13.4 | −2.3 | −17.2 | Yes | 2.5 | Mean reduction of total homocysteine was 2 µmol/L greater in the high- dose group than in the low-dose group, but there was no treatment effect on any end point. The unadjusted risk ratio for any stroke, CHD event, or death was 1.0 (95% confidence interval [CI], 0.8–1.1), with chances of an event within 2 years of 18.0% in the high-dose group and 18.6% in the low-dose group. The risk of ischemic stroke within 2 years was 9.2% for the high-dose and 8.8% for the low-dose groups (risk ratio, 1.0; 95% CI, 0.8–1.3;P = 0.8)0 by log-rank test of the primary hypothesis of difference in ischemic stroke between treatment groups). |
| Guo H, 2009 [33], China | Both | 82 | 2 | NA | NA | NA | NA | No | 5 | The plasma Hcy levels of 52 cases with UA and 30 control subjects were measured by using high-performance liquid chromatography (HPLC) with fluorescence detection, plasma folic acid and vitamin B12 levels were also measured. |
| Jonasson T, 2005 [33], Sweden | Both | 60 | 3 | NA | 17.5 | −10.5 | −60 | Yes | 5 | 60 patients randomized into 5 mg folic acid + pyridoxine + cyanocoobalamin and placebo. Folic acid therapy reduced plasma tHCY from 17.4 to 9.2 mmol/L (p-0.0001). |
| Rydlewicz A, 2001 [35], UK | Both | 368 | 1.5 | NA | 10.54 | −2.06 | −19.54 | No | 0.4 | Only the 400 µg and 600 µg groups had significantly lower homocysteine levels compared to placebo (p = 0.038 and p < 0.001, respectively).Using multiple linear regression and each individual’s total folic acid intake (diet plus supplement), a total daily folic acid intake of 926 µg per day would be required to ensure that 95% of the elderly population would be without cardiovascular risk from folate deficiency. |
| Huo Y, 2015 [35], China | Both | 20,702 | 54 | 8.1 | 12.5 | NA | NA | No | 0.8 | During a median treatment duration of 4.5years, 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). |
| Lange H, 2004 [37], Germany/Netherlands | Both | 636 | 6 | NA | 12.6 | −3.6 | −28.6 | Yes | 1.2 | 636 participants with history of coronary stent received 1.2 mg folic acid + B6 and B12 or placebo. Folate therapy increased risk of restenosis compared to placebo group (34.5% vs. 26.5%, P = 0.05), and a higher percentage required repeated target-vessel revascularization (15.8% vs. 10.6%, P = 0.05). |
| Liem A, 2004 [37], Netherlands | Both | 283 | 12 | NA | NA | NA | NA | No | 5 |
At 12 months, lipid parameters were similar for both groups; mean total cholesterol value was 5.5 mmol/l (S.D. 0.9) in the folic acid group and 5.7 mmol/l (S.D. 0.9) in the control group. Mean LDL values were 3.3 mmol/l (S.D. 0.8) and 3.4 mmol/l (S.D. 0.8), respectively. No significant changes in mean HDL or triglycerides were observed In this study, administration of folic acid, when added to statin therapy, did not have any beneficial effects on cardiovascular mortality or morbidity in a population of post-AMI patients with a relative high cholesterol value at admission |
| Wrone E, 2004 [38], United States | Both | 528 | 24 | 47.16 | 32.9 | −3.6 | −10.9 | Yes | 5 | 510 patients on chronic dialysis were randomized to 1, 5, or 15 mg of folic acid contained in a renal multivitamin. Mortality and cardiovascular events did not vary (43.7% in 1 mg group, 38.6% in 5 mg group, 47.1% in 15 mg group; lP = 0.47) Folic acid supplementation in ESRD is unlikely to produce benefit at doses between 1 and 15 mg/d. |
| Liem A, 2003 [40], Netherlands | Both | 593 | 24 | 17 | 12.1 | −2.6 | −21.4 | No | 0.5 | 593 patients on statins for a mean of 3.2 years were randomized into folic acid (n = 300) or placebo (n = 293). In folic acid group homocysteine levels decreased by 18%, from whilecontrol group was unaffected (p 0.001 between groups). The primary end point (all-cause mortality and a composite of vascular events) was seen in 31 (10.3%) patients in the folic acid group and in 28 (9.6%) patients in the control group (relative risk 1.05; 95% confidence interval: 0.63 to 1.75). |
| Liem A, 2005 [41], Netherlands | Both | 593 | 42 | 16 | 12.1 | −2.6 | −21.5 | No | 0.5 | There were no significant differences between the groups (log rank test, p = 0.53); the relative risk for total events was 0.85 (95% confidence interval 0.56 to 1.31). |
| Lonn E, 2006 [41], Canada | Both | 5522 | 60 | 27.4 | NA | −3.2 | −26.2 | Yes | 2.5 | Mean plasma homocysteine levels decreased by 2.4 µmol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 µmol per liter (0.1 mg per liter) in the placebo group. Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. |
| Righetti M, 2006 [43], Italy | Both | 88 | 28 | 6.8 | 37.2 | −15.1 | −43.6 | Yes | 5 | Homocysteine-lowering folate therapy decreases cardiovascular events in dialysis patients. It is necessary to perform large prospective studies to confirm results. |
| Jamison R, 2007 [43], United States | Both | 2056 | 38 | 15.6 | 24 | −5.9 | −24.5 | Yes | 40 | Treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced chronic kidney disease or end-stage renal disease. |
| Vianna A, 2007 [45], Brazil | Both | 186 | 24 | 10 | 23.5 | −13 | −55.3 | No | 4.29 | Folate treatment for only 2 years was not effective in modifying cardiovascular death and nonfatal cardiovascular events in this sample of patients with chronic uremia |
| Ebbing M, 2008 [45], Norway | Both | 2324 | 38 | NA | 10.8 | −3.2 | −29.6 | Yes | 0.8 | The article examines the effects of B-vitamin supplementation on homocysteine levels and its potential to reduce cardiovascular risk in 3096 adult participants undergoing coronary angiography. The study found no significant benefit in reducing mortality or cardiovascular events despite lowering homocysteine levels. |
| Severino M, 2009 [46], Philippines | Both | 243 | 6 | NA | 12.8 | NA | NA | Yes | 1 | The study comprised 240 patients with either unstable angina or non-ST-elevation myocardial infarction in the previous 2 weeks who were randomized to a folate group (n = 116) or a placebo group (n = 124). The composite endpoint of death, nonfatal acute coronary syndrome, and serious re-hospitalization was significantly higher in the folate group; serious re-hospitalization alone was significantly higher in this group. Folic acid-based supplementation is not beneficial and may even be harmful. |
| Armitage J, 2010 [48], UK | Both | 12,064 | 80 | 16.8 | 13.5 | −3.8 | −28 | Yes | 2 | Double-blind randomized controlled trial of 12,064 survivors of myocardial infarction. There were no apparent effects on major coronary events (vitamins, 1229 [20.4%], vs. placebo, 1185 [19.6%]; RR, 1.05; 95% CI, 0.97–1.13), stroke (vitamins, 269 [4.5%], vs. placebo. Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12) supplementation did not have beneficial effects on vascular outcomes |
| Heinz J, 2010 [49], Germany | Both | 650 | 24 | 14.3 | 29 | −8.6 | −30 | Yes | 5 | Randomly assigned 650 patients with end-stage renal disease. Increased intake of folic acid, vitamin B(12), and vitamin B(6) did not reduce total mortality and had no significant effect on the risk of cardiovascular events in patients with end-stage renal disease. |
| House A, 2010 [50], Canada | Both | 238 | 32 | 16 | 15.5 | −4.8 | −31 | Yes | 2.5 |
B-vitamin therapy (folic acid, B6, B12) resulted in a greater decrease in glomerular filtration rate (GFR) over 36 months in the treatment group compared to placebo, indicating faster progression of nephropathy in those receiving B vitamins. The B-vitamin group also experienced an increased risk of vascular events (hazard ratio: 2.0), suggesting that high-dose supplementation may worsen vascular outcomes in diabetic nephropathy patients. |
| Bostom A, 2011 [51], United States/Canada/Brazil | Both | 4110 | 48 | NA | 16.4 | −4.4 | −26.8 | Yes | 5 |
High-dose folic acid, vitamin B6, and B12 supplementation significantly reduced homocysteine levels, but this did not lead to a reduction in cardiovascular disease events or all-cause mortality in kidney transplant recipients. The study found no significant difference between the high-dose and low-dose multivitamin groups for the composite cardiovascular outcome, despite the homocysteine-lowering effect. |
| Righetti M, 2003 [52], Italy | Both | 81 | 12 | 5.98 | 50.3 | −26 | −51.7 | No | 5 |
Folic acid treatment reduced homocysteine levels in hemodialysis patients, but 88% of treated patients maintained higher-than-normal levels of homocysteine. A trend was observed towards reduced cardiovascular events in the treated group, but this reduction was not statistically significant. |
| Nand N, 2013 [53], India | Both | 100 | 6 | 11.93 | 31.06 | −17.84 | −57.44 | Yes | 2.5 |
Folic acid and vitamin B12 supplementation significantly reduced homocysteine levels in patients with chronic kidney disease (CKD) after 6 months (from 32.61 µmol/L to 19.69 µmol/L in the treatment group). Despite the reduction in homocysteine levels, supplementation did not lead to a significant decrease in cardiovascular disease mortality or other cardiovascular outcomes. |
| Bahmani F, 2018 [54], Iran | Women | 60 | 3 | NA | 19.9 | −3.5 | −17.6 | No | 5 | The study focused on a sample of 60 women diagnosed with endometrial hyperplasia (EH) for 3 months. The research examined the effects of folic acid supplementation at a daily dose of 5 mg, although no additional vitamin B12 was provided. After the intervention, folic acid supplementation significantly improved glycemic control, triglycerides, VLDL, cholesterol, and hs-CRP levels , but did not influence recurrence or other metabolic profiles. |
| Maurizi A, 2016 [55], Italy | Both | 26 | 6 | NA | NA | NA | NA | Yes/no | 0,4 | The study focused on a sample of 26 patients with type 1 diabetes who were overweight or obese, undergoing intensive insulin therapy for 6 months. The research examined the effects of folic acid supplementation at a daily dose of 0.4 mg, although no additional vitamin B12 but it was provided additional D-chiroinositol (DCI). After 3-month follow-up, a significant reduction in HbA1c levels was observed in DCI-treated group versus control group [7.5% (58 mmol/mol) ± 1.1 vs. 8.1% (65 mmol/mol) ± 1.9, respectively, p\0.05]. At the end of the study period (6 months), HbA1c reduction in DCI treated group vs. control group was statistically confirmed. |
| El-khodary N, 2022 [56], Egypt | Both | 100 | 3 | NA | 1,7 | −0,4 | 23,5 | No | 5 |
This clinical trial has been performed on 100 patients with T2DM randomly folic acid 5 mg/d for 3 months. although no additional vitamin B12 was provided. After the intervention, folic acid supplementation caused a significant decrease in homocysteine and sortilin serum levels (28.2% and 33.7%, P < 0.0001, respectively). After 3 months of intervention, 8.7% decrease in fasting blood glucose (P = 0.0005), 8.2% in HbA1c (P = 0.0002), 13.7% in serum insulin (P < 0.0001) and 21.7% in insulin resistance (P < 0.0001) were found in the folic acid group. |
| Satapathy S, 2020 [57], India | Both | 80 | 2 | NA | 4,9 | −2,45 | −50 | Yes | 5 | 80 patients with type 2 diabetes and oral antidiabetics were divided on 4 groups: folic acid, Methylcobalamin, Folic acid + methylcobalamin, or antidiabetic alone. Methylcobalamin and Folic acid + methylcobalamin groups showed improvement in HbA1c, plasma insulin, insulin resistance and serum adiponectin compared to antidiabetic alone. Homocysteine levels improved in all groups except antidiabetics alone, and there was no lipids improvement in any of the groups. |
| Araghi S, 2020 [58], Netherlands | Both | 1298 | 54 | 21.4 | 14.4 | −0.1 | −0.69 | Yes | 0.4 | 1,298 individuals (44.5%) participated in the second follow-up round, with a median follow-up of 54 months. The intervention with folic acid and vitamin B12 showed no significant effect on osteoporotic fracture risk or any fracture risk (HR: 0.99 and HR: 0.77, respectively). However, a potential interaction was noted with baseline homocysteine concentrations, indicating a lower risk of any fracture in the treatment group with higher homocysteine levels (> 15.1 mmol/l). No age-dependent effects were found. |
| Albert CM, 2008 [59], United States | Women | 5442 | 88 | NA | 12.3 | −2.3 | −18.5 | Yes | 2.5 | This study tested whether a combination of folic acid, vitamin B6, and vitamin B12 reduces cardiovascular disease (CVD) risk among high-risk women. Involving 5,442 female US health professionals, the trial followed participants for 88 months. Results showed that the treatment did not significantly reduce the risk of myocardial infarction, stroke, coronary revascularization, or CVD mortality compared to placebo, despite lowering homocysteine levels. The conclusion is that this vitamin combination does not reduce total cardiovascular events in high-risk women. |
| Cole B, 2007 [60], United States/Canada | Both | 1021 | 84 | 23.8 | 9.8 | NA | NA | No | 1 | 1021 participants were involved in an 84-month study that assessed folic acid’s effectiveness in preventing colorectal adenomas. It found no significant difference in adenoma incidence between the folic acid and placebo groups. Furthermore, folic acid was linked to higher risks of multiple adenomas and non-colorectal cancers leading to the conclusion that folic acid does not reduce colorectal adenoma risk and may increase colorectal neoplasia risk. |
| Mark S, 1996 [61], China | Both | 3318 | 72 | NA | NA | NA | NA | Multi-vitaminicuco | 0.8 | 3,318 participants were part of an RCT study that evaluated the effects of a multivitamin/mineral supplement on cancer and cerebrovascular disease. Over 72 months, the supplement group showed a slight reduction in overall mortality (RR = 0.93) and cerebrovascular disease deaths (RR = 0.63), particularly among men. Blood pressure elevations were less common in the supplement group. The findings suggest that such supplements may reduce mortality from cerebrovascular disease and hypertension in populations with micronutrient-poor diets. |
| Potena L, 2008 [62], Italy | Both | 51 | 12 | NA | 17.9 | NA | NA | No | 15 | 51 participants after heart transplantation were randomized into 15 mg/day of methyltetrahydrofolate or standard therapy were followed up for 7-year outcome. Survival was greater in recipients randomized to folate (88%± 6% vs. 61%±9%, P = 0.04) as well as lower mortality (relative risk [RR] 0.53, 95% confidence interval [CI] 0.25–0.97; P = 0.036), Also, decreased mortality was seen in High-risk subgroup which included participants >55 years old and patients transplanted because of coronary artery disease (RR 0.43, 95% CI 0.17–0.85) but not in the lower-risk subgroup (RR 1.11, 95% CI 0.22–5.61). |
| Hodis H, 2009 [63], United States | Both | 506 | 37 | 21.4 | 9.7 | −2.1 | −21.6 | Yes | 5 | 506 participants with initial tHcy ≥ 8.5 mol/L without diabetes and cardiovascular disease were randomized to high-dose B vitamin supplementation (5 mg folic acid + 0.4 mg vitamin B12 + 50 mg vitamin B6) or placebo for 3.1 years. In participants with baseline tHcy ≥ 9.1 mol/L, those randomized to B vitamin supplementation had a statistically significant lower average rate of carotid artery intima media thickness progression compared with placebo (P = 0.02) |
| Lamas G, 2013 [64], United States/Canda | Both | 1708 | 55 | NA | NA | NA | NA | Yes | 0.8 | 1708 patients aged ≥ 50 years who had MI at least 6 weeks earlier and serum creatinine levels of 176.8 mol/L (2.0 mg/dL) or less, were randomized into high-dose multivitamin and multiminerals or placebo. High-dose multivitamins group did not statistically significantly reduce cardiovascular events in patients after MI who received standard medications. Cardiovascular death, MI, or stroke occurred in 94 (11%) patients in the vitamin group and 115 (13%) in the placebo group (hazard ratio, 0.82 [CI, 0.62 to 1.07]; P 0.142). |
| Galan P, 2010 [65], France | Both | 2501 | 56 | 15.2 | 12.8 | −2.9 | −22.7 | Yes | 0.56 | 2501 patients with a history of myocardial infarction, unstable angina, or ischaemic stroke were randomized into dietary supplement containing 5-methyltetrahydrofolate (560 µg), vitamin B-6 (3 mg), and vitamin B-12 (20 µg, omega 3 fatty acid or placebo. B vitamins group lowered plasma homocysteine concentrations by 19% compared with placebo, but had no significant effects on major vascular events (75 vs. 82 patients, hazard ratio, 0.90 [95% confidence interval 0.66 to 1.23, P = 0.50]). Study does not support the routine use of dietary supplements containing B vitamins or omega 3 fatty acids for prevention of cardiovascular disease in patients with a history cardiovascular disease. |
RCT Randomized control trial, NA Not applicable, CAD Coronary artery disease, t-HCY Total homocysteine, HCY Homocysteine, ESRD End-stage renal disease, CRF Chronic renal failure, VB12 Vitamin B-12, TG Triglycerides, TC Total cholesterol, LDL-C Low-density lipoprotein cholesterol, HDL-C High-density lipoprotein cholesterol, IL-10 Interleukin 10, IL-1B Interleukin 1B, H/O History of, Vit. B12 Vitamin B12, Vit. B6 Vitamin B6, FA Folic acid, HX History, TIA Transient ischemic attack, PWV Pulse wave velocity, IMT Intima-media thickness, FMD Flow-mediated dilation, CHD Coronary heart disease, UA Unstable angina, HPLC High-performance liquid chromatography, mg Milligrams, g Grams, MI Myocardial infarction, HR Heart rate