Administration of B-group vitamins reduces circulating homocysteine in polycystic ovarian syndrome patients treated with metformin: a randomized trial. Weekly may be as efficacious as daily folic acid supplementation in improving folate status and lowering serum homocysteine concentrations in Guatemalan women. Effects of Metformin With or Without Supplementation With Folate on Homocysteine Levels and Vascular Endothelium of Women With Polycystic Ovary Syndrome Serum homocysteine, vitamin B 12 and folic acid levels in different types of glaucoma Hydroxocobalamin reduces hyperhomocysteinemia in end-stage renal disease. Reduction of the genomic damage level in haemodialysis patients by folic acid and vitamin B12 supplementation. Comparative effects of hydroxocobalamin and cyanocobalamin on plasma homocysteine concentrations in end-stage renal disease. Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment. Effect of folic acid in women with and without insulin resistance who have hyperhomocysteinemic polycystic ovary syndrome. Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer's disease: a 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients. Results of 2-year vitamin B treatment on cognitive performance Cobalamin dose regimen for maximum homocysteine reduction in end-stage renal disease. Effect of Vitamin B12 and Folic Acid Supplementation on Bone Mineral Density and Quantitative Ultrasound Parameters in Older People with an Elevated Plasma Homocysteine Level: B-PROOF, a Randomized Controlled Trial Comparative study of response to treatment with supraphysiologic doses of B-vitamins in hyperhomocysteinemic hemodialysis patients. Homocysteine Lowering by Folate-Rich Diet or Pharmacological Supplementations in Subjects with Moderate Hyperhomocysteinemia Effects of metformin plus gliclazide versus metformin plus glimepiride on cardiovascular risk factors in patients with type 2 diabetes mellitus. Decrease of carotid intima-media thickness in patients at risk to cerebral ischemia after supplementation with folic acid, Vitamins B6 and B12. High dose-B-vitamin treatment of hyperhomocysteinemia in dialysis patients. Effect of multivitamin supplementation
on the homocysteine and methylmalonic
acid blood concentrations in women
over the age of 60 years Effect of vitamin B-12 and n-3 polyunsaturated fatty acids on plasma homocysteine, ferritin, C-reaction protein, and other cardiovascular risk factors: a randomized controlled trial. Pharmacological Dose of Vitamin B12 Is as Effective as Low-Dose Folinic Acid in Correcting Hyperhomocysteinemia of Hemodialysis Patients Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease. Efficacy of folate and vitamin B12 in lowering homocysteine concentrations in hemodialysis patients.
BACKGROUND The aim of the current study was to assess the effects of B-group vitamins and folic acid administration on serum levels of homocysteine ( Hcy ) in patients with polycystic ovarian syndrome ( PCOS ) on short-term metformin treatment . METHODS Patients were r and omly assigned to one of three treatment groups . Group 1 patients ( n = 20 ) received metformin ( 850 mg twice daily ) ; group 2 patients ( n = 20 ) received metformin ( 850 mg twice daily ) and B-group vitamins ( vitamin B1 , 250 mg ; vitamin B6 , 250 mg ; vitamin B12 , 1000 microg twice daily ) ; and group 3 patients ( n = 20 ) received metformin ( 850 mg twice daily ) and folic acid ( 174 microg twice daily ) . In all groups , lipid profiles and plasma total Hcy , vitamin B12 , folic acid and glucose levels were recorded at baseline and at 3 months . RESULTS A 26.5 % increase in Hcy levels was seen after 12 weeks of metformin therapy , while 21.17 and 8.33 % decreases in Hcy levels were detected when B-group vitamins or folic acid plus metformin were given respectively . There were no statistically significant differences recorded in insulin sensitivity using homeostasis model assessment in the three groups . CONCLUSION These findings suggest that B-group vitamins and folic acid administration counteract the Hcy-increasing effect seen with metformin therapy Daily folic acid ( FA ) supplementation improves folate status , lowers circulating homocysteine ( Hcy ) concentrations , and reduces the risk of neural tube defects . Little is known about the efficacy of weekly FA supplementation . The objective of this study was to compare the efficacy of weekly and daily FA supplementations in improving folate and vitamin B-12 status and lowering Hcy concentrations in healthy reproductive-aged women . A r and omized , double-blind supplementation trial was conducted in Guatemala . A total of 459 women were assigned r and omly to 4 groups to receive weekly ( 5000 or 2800 microg ) or daily ( 400 or 200 microg ) FA for 12 wk . Daily and weekly iron , zinc , and vitamin B-12 were also provided . We determined serum and RBC folate by microbiological assays , but the latter was available only at baseline . Serum Hcy and vitamin B-12 were also measured . We used generalized linear regression models to assess the effects of treatment on biochemical indicators . Supplementation improved folate status similarly across all 4 groups . Overall , mean serum folate concentrations increased by 15.4 nmol/L ( 95 % CI : 13.8 , 16.9 ) and the geometric mean serum Hcy concentration decreased by 9.8 % ( 95 % CI : -12.3 , -7.1 ) . Daily supplementation improved serum vitamin B-12 by 20 % ( 95 % CI : 8 , 33.2 ) , whereas weekly supplementation had no effect . In conclusion , weekly FA ( either high or low dose ) plus vitamin B-12 may be as efficacious as daily supplementation in improving serum folate and lowering Hcy concentrations in healthy women of reproductive age OBJECTIVE To evaluate whether the administration of metformin exerts any effects on serum homocysteine ( Hcy ) levels in patients with polycystic ovary syndrome ( PCOS ) and whether supplementation with folate enhances the positive effects of metformin on the structure and function of the vascular endothelium . RESEARCH DESIGN AND METHODS A total of 50 patients affected by PCOS , without additional metabolic or cardiovascular diseases , were enrolled in a prospect i ve nonr and omized placebo-controlled double-blind clinical study . They were grouped into two treatment arms that were matched for age and BMI . Patients were treated with a 6-month course of metformin ( 1,700 mg daily ) plus folic acid ( 400 μg daily ; experimental group , n = 25 ) or placebo ( control group , n = 25 ) . Complete hormonal and metabolic patterns , serum Hcy , folate , vitamin B12 , endothelin-1 levels , brachial artery diameter at the baseline ( BAD-B ) and after reactive hyperemia ( BAD-RH ) , flow-mediated dilation , and intima-media thickness in both common carotid arteries were evaluated . RESULTS After treatment , a significant increase in serum Hcy levels was observed in the control group compared with the baseline values and the experimental group . A beneficial effect was observed in the concentrations of BAD-B , BAD-RH , flow-mediated dilation , intima-media thickness , and serum endothelin-1 in both groups . However , the results were improved more significantly in the experimental group than in the control subjects . CONCLUSIONS Metformin exerts a slight but significant deleterious effect on serum Hcy levels in patients with PCOS , and supplementation with folate is useful to increase the beneficial effect of metformin on the vascular endothelium Background This study was performed to compare levels of serum homocysteine ( Hcy ) , vitamin B12 and folic acid in patients with primary open-angle glaucoma ( POAG ) , pseudoexfoliative glaucoma ( PEXG ) , normotensive glaucoma ( NTG ) and healthy controls . Methods Twentyfive patients with POAG , 24 with PEXG , and 18 with NTG , along with 19 control healthy subjects were included this prospect i ve study . Levels of serum Hcy  were measured using immunoassay , and those of  serum vitamin B12 and folic acid were measured using competitive chemiluminescent enzyme immunoassay . Results The mean Hcy concentration in the PEXG group was significantly higher ( P < 0.001 ) as compared to the other groups . There were no significant differences with respect to the mean Hcy concentrations among other groups ( P > 0.05 ) . There were no statistical differences in serum vitamin B12 levels among POAG , PEXG , NTG and control subjects ( P > 0.05).The mean serum folic acid level was significantly lower in the subjects with PEXG ( P < 0.009 ) . However , the mean folic acid concentrations among the other groups did not differ significantly ( P > 0.05 ) . Conclusion Elevated levels of Hcy in PEXG may explain the role of endothelial dysfunction among patients with PEXG Renal failure causes hyperhomocysteinemia , an important risk factor for cardiovascular disease and venous access thrombosis in end-stage renal disease ( ESRD ) . Folic acid is necessary for homocysteine ( Hcy ) metabolism , and therapy with 1 mg/d or more of folic acid reduces plasma total Hcy ( tHcy ) concentrations in ESRD , although seldom to normal . In contrast to folic acid , the Hcy-lowering effect of vitamin B(12 ) has not been well studied in ESRD . We performed a prospect i ve r and omized controlled clinical trial involving 24 maintenance hemodialysis patients with normal or supranormal serum folate and vitamin B(12 ) concentrations who received either st and ard therapy , which included 5 to 6 mg folic acid , 5 to 10 mg pyridoxine , and 6 to 10 microg oral vitamin B(12 ) per day , or st and ard therapy plus 1 mg hydroxocobalamin  administered subcutaneously once per week after dialysis . Plasma tHcy and serum methylmalonic acid ( MMA ) concentrations were measured before and after 8 and 16 weeks of continuous treatment . Hydroxocobalamin reduced plasma tHcy by an average of 32 % ( P < .005 ) and serum MMA by an average of 19 % ( P < .001 ) . The Hcy-lowering effect of hydroxocobalamin was independent of baseline serum vitamin B(12 ) , folic acid , and MMA concentrations .  Patients with higher baseline plasma tHcy concentrations had the greatest response ( r = 0.80 ; P < .002 ) . These results show that parenteral hydroxocobalamin reduces plasma tHcy dramatically in vitamin B(12)-replete hemodialysis patients . Persons with considerable persisting hyperhomocysteinemia despite high-dose folic acid therapy are likely to respond to the addition of hydroxocobalamin , irrespective of their serum vitamin B(12 ) concentrations BACKGROUND Cancer incidence and genomic damage of peripheral lymphocytes are elevated in patients with end-stage renal failure . Among other uraemic toxins , homocysteine ( Hcy ) levels are increased in most of these patients . In healthy individuals , plasma Hcy correlates with the degree of genomic damage observed in peripheral blood lymphocytes ( PBL ) . The accumulation of Hcy can be reduced by supplementation with folic acid and vitamin B12 . The aim of this study was to analyse whether this supplementation can also lower the genomic damage in PBL of haemodialysis patients . This may ultimately help to reduce cancer incidence in renal patients . METHODS In a prospect i ve study with 27 patients , we analysed the genomic damage in dialysis patients before and at different time points after the initiation of folate/vitamin B12 supplementation .  Genomic damage was measured by the frequency of micronuclei , a subset of chromosomal aberrations , in PBL . RESULTS Supplementation with folic acid and vitamin B12 ( more markedly with both ) reduced the micronucleus frequency in PBL of dialysis patients . This was not mediated by altered lymphocyte proliferation capacity or changes in DNA cytosine-methylation . Plasma-Hcy was lowered more efficiently by the combined folic acid/vitamin B12 supplementation , and lymphocyte DNA of this group exhibited a nonsignificant trend for a reduction of 1,N(6)-etheno-2'-deoxyadenosine , a marker for oxidative stress . CONCLUSIONS A reduction of the genomic damage in PBL can be achieved in dialysis patients by supplementation with folic acid and vitamin B12 . This may be mediated by Hcy reduction End-stage renal disease ( ESRD ) is associated with marked hyperhomocysteinemia which is only partially corrected by folic acid and pyridoxine supplementation . We and others have reported that various forms of parenteral cobalamin reduce plasma total homocysteine ( tHcy ) concentrations of patients with ESRD substantially below the lowest levels attainable with folic acid . We here report a 16-week r and omized controlled crossover trial which directly compared the Hcy-lowering effect of intravenous hydroxocobalamin ( HC ) with that of cyanocobalamin ( CC ) .  Folic acid- and vitamin B12-replete maintenance hemodialysis patients were r and omly assigned to receive either 1 mg intravenous HC weekly for 8 weeks followed by CC for a further 8 weeks , or CC for 8 weeks followed by HC for 8 weeks . Hydroxocobalamin  increased serum cobalamin concentrations 40-fold , whereas CC increased them only 10-fold , but both treatments reduced plasma tHcy concentrations similarly by 33 % ( P < .001 ) . Crossover to the alternate form of the vitamin greatly affected the serum cobalamin concentration but was without further effect on the plasma tHcy concentration . These results confirm that weekly cobalamin injections lower plasma tHcy concentrations of hemodialysis patients well below the level attainable with folic acid . Hydroxocobalamin and CC are equipotent despite producing very different serum cobalamin concentrations AIM The aim of the study is to compare the effects of metformin and insulin treatment for gestational diabetes mellitus ( GDM ) on vitamin B12 and homocysteine ( Hcy ) status . METHODS Women with GDM , who met criteria for insulin treatment , were r and omly assigned to metformin ( n = 89 ) or insulin ( n = 91 ) in the Adelaide cohort of the metformin in gestational diabetes ( MiG ) trial .  Fasting serum total vitamin B12 ( TB12 ) , holotranscobalamin ( HoloTC ) , a marker of functional B12 status and plasma Hcy concentrations were measured at 20 - 34 weeks ( at r and omization ) and 36 weeks gestation , then at 6 - 8 weeks postpartum . RESULTS Circulating TB12 , HoloTC and Hcy were similar in both treatment groups at each time point . Women who were taking dietary folate supplements  at r and omization had higher serum TB12 and HoloTC at r and omization than those not taking folate . Overall , serum TB12 fell more between r and omization and 36 weeks gestation in the metformin group than in the insulin group ( metformin : -19.7 ± 4.7 pmol/l , insulin : -6.4 ± 3.6 pmol/l , p = 0.004 ) . The decrease in serum TB12 during treatment was greater with increasing treatment duration in metformin-treated ( p < 0.001 ) , but not in insulin-treated women . CONCLUSIONS Total , but not bioavailable , vitamin B12 stores were depleted during pregnancy to a greater extent in metformin-treated  than in insulin-treated women with GDM , but neither analyte differed between groups at any stage . This adds further evidence supporting metformin as a safe alternative treatment to insulin in GDM . Further investigation is needed to evaluate whether women treated with metformin for longer periods in pregnancy require additional B12 or other supplementation OBJECTIVE To study the effect of folic acid on homocysteine ( Hcy ) levels in women with insulin resistance and polycystic ovary syndrome ( PCOS ) in a prospect i ve clinical trial . METHOD Of 210 women with PCOS , 70 were hyperhomocysteinemic ; and of these , 32 were insulin resistant and 38 were not . The 70 women were treated with folic acid for 3 months .  Baseline and serum levels of Hcy and insulin were measured in both groups . RESULTS In both groups Hcy concentrations were significantly decreased following folic acid supplementation . The mean+/-SD levels before and after treatment were 14.03+/-1.5 micromol/L and 12.53+/-1.72 micromol/L in group 1 ( P<0.001 ) , and they were 12.07+/-0.87 micromol/L and 8.83+/-0.78 micromol/L in group 2 ( P<0.001 ) . CONCLUSION The Hcy levels of hyperhomocysteinemic women with PCOS were reduced after 3 months of folic acid supplementation , and the rate of reduction was higher among women without insulin resistance . No change was found in fasting insulin levels BACKGROUND Elevated serum homocysteine levels have been associated with the development of Alzheimer 's dementia ( AD ) . The combined use of a mecobalamin capsule preparation , which contains vitamin B12 0.5 mg with an active methyl base , and an over-the-counter nutritional supplement that contains folic acid 1 mg and pyridoxine hyperchloride 5 mg may be effective as a homocysteine-lowering vitamin regimen . OBJECTIVE The aim of this study was to determine whether oral multivitamin supplementation containing vitamins B6 and B12 and folic acid would improve cognitive function and reduce serum homocysteine levels in patients with mild to moderate AD . METHODS This r and omized , double-blind , placebocontrolled trial was conducted at En Chu Kong Hospital , Taipei , Taiwan . Male and female patients aged > 50 years with mild to moderate AD and normal folic acid and vitamin B12 concentrations were enrolled . All patients received treatment with an acetylcholinesterase inhibitor and were r and omized to receive add-on mecobalamin ( B12 ) 500 mg + multivitamin supplement , or placebos , PO QD for 26 weeks . The multivitamin contained pyridoxine ( B6 ) 5 mg , folic acid 1 mg , and other vitamins and iron .  Serum homocysteine level was measured and cognitive tests were conducted at baseline and after 26 weeks . The primary efficacy outcome was change in cognition , measured as the change in score from baseline to week 26 on the Alzheimer 's Disease Assessment Scale 11-item Cognition subscale . Secondary efficacy outcomes included changes in function in performance of activities of daily living ( ADLs ) and concentrations of homocysteine , B12 , and folic acid . Tolerability was assessed by comparing the 2 study groups with respect to physical examination findings , including changes in vital signs , laboratory test abnormalities , concomitant medication use , and compliance of study medication was assessed using an interview with the patient 's caregiver , as well as the monitoring of adverse events ( AEs ) throughout the study . RESULTS Eighty-nine patients ( 45 men , 44 women ; all Taiwanese ; mean [ SD ] age , 75 [ 7.3 ] years ) were enrolled and r and omized . Overall , there were no significant differences in cognition or ADL function scores between the 2 groups . At week 26 , the mean ( SD ) between-group difference in serum homocysteine concentration versus placebo was -2.25 ( 2.85 ) micromol/L ( P = 0.008 ) , and the mean serum concentrations of vitamin B12 and folic acid were significantly higher ( but within normal range ) in the multivitamin group compared with placebo ( . , + 536.9 [ 694.4 ] pg/mL [ P < 0.001 ] and + 13.84 ng/mL [ 11.17 ] [ P = 0.012 ] at 26 weeks , respectively ) . The 2 most common AEs were muscle pain ( 11.1 % and 6.8 % ) and insomnia ( 8.9 % and 9.1 % ) in the multivitamin and placebo groups , respectively . CONCLUSIONS In this population of patients with mild to moderate AD in Taiwan , a multivitamin supplement containing vitamins B(6 ) and B(12 ) and folic acid for 26 weeks decreased homocysteine concentrations . No statistically significant beneficial effects on cognition or ADL function were found between multivitamin and placebo at 26 weeks Objective : We investigated the effects of 2-year folic acid and vitamin B12 supplementation on cognitive performance in elderly people with elevated homocysteine ( Hcy ) levels . Methods : This multicenter , double-blind , r and omized , placebo-controlled trial included 2,919 elderly participants ( 65 years and older ) with Hcy levels between 12 and 50 µmol/L. Participants received daily either a tablet with 400 µg folic acid and 500 µg vitamin B12 ( B-vitamin group ) or a placebo tablet . Both tablets contained 15 µg vitamin D3 . Data were available for global cognitive functioning assessed by Mini-Mental State Examination ( n = 2,556 ) , episodic memory ( n = 2,467 ) , attention and working memory ( n = 759 ) , information processing speed ( n = 731 ) , and executive function ( n = 721 ) . Results : Mean age was 74.1 ( SD 6.5 ) years . Hcy concentrations decreased 5.0 ( 95 % confidence interval −5.3 to −4.7 ) µmol/L in the B-vitamin group and 1.3 ( −1.6 to −0.9 ) µmol/L in the placebo group . Cognitive domain scores did not differ over time between the 2 groups , as determined by analysis of covariance . Mini-Mental State Examination score decreased with 0.1 ( −0.2 to 0.0 ) in the B-vitamin group and 0.3 ( −0.4 to −0.2 ) in the placebo group ( p = 0.05 ) , as determined by an independent t test . Conclusions : Two-year folic acid and vitamin B12 supplementation did not beneficially affect performance on 4 cognitive domains in elderly people with elevated Hcy levels . It may slightly slow the rate of decline of global cognition , but the reported small difference may be attributable to chance . Classification of evidence : This study provides Class I evidence that 2-year supplementation with folic acid and vitamin B12 in hyperhomocysteinemic elderly people does not affect cognitive performance Plasma total homocysteine ( tHcy ) concentrations are markedly increased in end-stage renal disease and only partially corrected by folic acid supplementation . We and others have reported that cobalamin , administered parenterally , reduces plasma tHcy substantially below the lowest concentrations attainable with folic acid . We have now carried out a r and omized controlled clinical trial to compare the plasma Hcy-lowering effect of 3 intravenous cyanocobalamin dose regimens in maintenance hemodialysis patients : 1 mg postdialysis every 28 , 14 , and 7 days in addition to routine oral vitamin B supplementation .  All patients in the hemodialysis unit where the study was carried out routinely received 1 mg intravenous cyanocobalamin every month , so participants who were r and omized to receive the vitamin every 28 days simply continued with their existing treatment program . Serum cobalamin and plasma tHcy concentrations in the control group did not change over the course of the study . As measured after 8 weeks of therapy , intravenous cyanocobalamin every 14 days increased serum cobalamin approximately 2.5-fold and reduced plasma tHcy by 11.5 % ( P = .035 ) below the concentration previously attained with monthly administration , whereas treatment every 7 days increased serum cobalamin concentrations approximately 5-fold and reduced plasma tHcy by 11.0 % ( P = .013 ) . These results show that intravenous cyanocobalamin at 7- or 14-day intervals reduces plasma tHcy concentrations of hemodialysis patients below the levels brought about by prior long-term administration every 4 weeks and confirms that plasma tHcy lowering with parenteral cobalamin is a true pharmacological effect and not merely correction of a latent deficiency state High plasma homocysteine ( Hcy ) levels are associated with increased osteoporotic fracture incidence . However , the mechanism remains unclear . We investigated the effect of Hcy-lowering vitamin B12 and folic acid treatment on bone mineral density ( BMD ) and calcaneal quantitative ultrasound ( QUS ) parameters . This r and omized , double-blind , placebo-controlled trial included participants aged ≥65 years with plasma Hcy levels between 12 and 50 µmol/L. The intervention comprised 2-year supplementation with either a combination of 500 µg B12 , 400 µg folic acid , and 600 IU vitamin D or placebo with 600 IU vitamin D only . In total , 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS .  Femoral neck ( FN ) BMD , lumbar spine ( LS ) BMD , calcaneal broadb and ultrasound attenuation ( BUA ) , and calcaneal speed of sound ( SOS ) were assessed . After 2 years , FN-BMD and BUA had significantly decreased , while LS-BMD significantly increased ( all p < 0.01 ) and SOS did not change in either treatment arm . No statistically significant differences between the intervention and placebo group were present for FN-BMD ( p = 0.24 ) , LS-BMD ( p = 0.16 ) , SOS ( p = 0.67 ) , and BUA ( p = 0.96 ) . However , exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons > 80 years ( estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group , p = 0.04 for difference ) . In conclusion , this study showed no overall effect of treatment with vitamin B12 and folic acid on BMD or QUS parameters in elderly , mildly hyperhomocysteinemic persons , but suggests a small beneficial effect on BUA in persons > 80 years who were compliant in taking the supplement BACKGROUND Hyperhomocysteinemia is a well-recognized risk factor for accelerated atherosclerosis in hemodialysis patients . OBJECTIVES To examine the effects of two doses of vitamins B6 and B12 and folic acid on homocysteine levels in hemodialysis patients and assess the functional impact of the methylenetetrahydrofolate reductase genotype on the response to treatment . METHODS In a r and omized prospect i ve study , we assessed the effects of folic acid and two doses of B-vitamins in 50 hemodialysis patients with hyperhomocysteinemia . Patients were divided into two groups : 26 patients ( group A ) who received 25 mg of vitamin B6 daily and one monthly injection of 200 microg vitamin B12 , and 24 patients ( group B ) who received 100 mg of vitamin B6 daily and one monthly injection of 1,000 microg vitamin B12 . In addition , both groups received 15 mg folic acid daily . Patients were evaluated for homocysteine levels as well as for coagulation and a thorough lipid profile . Baseline Hcy levels were determined after at least 4 weeks washout from all folic acid and B-vitamins that were given . MFTHR alleles were analyzed , as were activated protein C resistance , von Willebr and factor and lupus anticoagulant . RESULTS Basal plasma Hcy levels were significantly elevated in hemodialysis patients compared with normal subjects ( 33.8 + /- 4.3 vs. 4.5 to 14.0 micromol/L ) . Following treatment , Hcy levels were significantly reduced to 21.2 + /- 1.6 in group A and 18.6 + /- 1.4 micromol/L in group B ( P < 0.01 ) . There was no difference in Hcy reduction following the administration of either high or low dosage of vitamins B6 and B12 utilized in the present study . There was no correlation between Hcy levels or thrombophilia and high incidence of thrombotic episodes in hemodialysis patients . Genotypic evaluation of MTHFR revealed that the presence of homozygous thermolabile MTHFR ( n = 5 ) was associated with higher Hcy levels and better response to treatment ( Hcy levels decreased by 58 % , from 46.2 + /- 14.6 to 19.48 + 4.1 micromol/ L following treatment ) . In patients with heterozygous thermolabile MTHFR ( n = 25 ) , Hcy levels decreased by 34 % , from 31.2 + /- 3.7 to 18.1 + /- 1.1 micromol/L following treatment . The efficacy of high and low doses of B-vitamins on the reduction of homocysteine levels was comparable . CONCLUSIONS Treatment with B-vitamins in combination with folic acid significantly decreased homocysteine levels in hemodialysis patients , independently of the tested doses . In addition , mutations in MTHFR were associated with elevated plasma levels of Hcy . Neither vascular access nor the presence of diabetes was associated with higher pre- or post-treatment homocysteine level Background / Objectives : To compare the efficacy of a diet rich in natural folate and of two different folic acid supplementation protocol s in subjects with “ moderate ” hyperhomocysteinemia , also taking into account C677 T polymorphism of 5,10-methylenetetrahydrofolate reductase ( MTHFR ) gene . Subjects/ Methods : We performed a 13 week open , r and omized , double blind clinical trial on 149 free living persons with mild hyperhomocyteinemia , with daily 200 μg from a natural folate-rich diet , 200 μg [6S]5-methyltetrahydrofolate ( 5-MTHF ) , 200 μg folic acid or placebo . Participants were stratified according to their MTHFR genotype . Results : Homocysteine ( Hcy ) levels were reduced after folate enriched diet , 5-MTHF or folic acid supplementation respectively by 20.1 % ( p < 0.002 ) , 19.4 % ( p < 0.001 ) and 21.9 % ( p < 0.001 ) , as compared to baseline levels and significantly as compared to placebo ( p < 0.001 , p < 0.002 and p < 0.001 , respectively for enriched diet , 5-MTHF and folic acid ) . After this enriched diet and the folic acid supplementation , Hcy in both genotype groups decreased approximately to the same level , with higher percentage decreases observed for the TT group because of their higher pre-treatment value . Similar results were not seen by genotype for 5-MTHF . A significant increase in RBC folate concentration was observed after folic acid and natural folate-rich food supplementations , as compared to placebo . Conclusions : Supplementation with natural folate-rich foods , folic acid and 5-MTHF reached a similar reduction in Hcy concentrations High blood glucose level , lipid profile disturbances and plasma homocysteine ( Hcy ) are important risk factors for cardiovascular diseases in patients with type 2 diabetes . This study was conducted to evaluate and compare effects of glimepiride/metformin combination versus gliclazide/metformin combination on cardiovascular risk factors in type-2 diabetes mellitus ( T2DM ) patients . One hundred and eighty T2DM patients were r and omly allocated for treatment with placebo ( control ) , metformin ( 500 mg twice daily ) , glimepiride ( 3 mg once daily ) , gliclazide ( 80 mg once daily ) , metformin plus glimepiride or metformin plus gliclazide for 3 months . We evaluated plasma levels of glucose ( PG ) , glycated hemoglobin ( HbA1C ) , Hcy , vitamin B12 , folic acid and lipid profile before treatment and 3 months post treatment . Compared to metformin treated patients , glimepiride plus metformin induced significant reductions in : fasting plasma glucose , postpr and ial PG level , HbA1C % and Hcy level . Conversely , plasma folic acid and vitamin B12 were significantly increased . The levels of total cholesterol and triglyceride were significantly decreased ; low-density lipoprotein was markedly decreased , whereas high-density lipoprotein was significantly increased and hence risk ratio was signiﬁcantly decreased . Similar results but with lower values were obtained using combination of metformin plus gliclazide on glycemic control only . Combination of glimepiride with metformin was superior to gliclazide plus metformin in alleviating the cardiovascular risk factors in type 2 diabetes mellitus patients OBJECTIVE Hyperhomocysteinemia is associated with atherosclerotic risk . Although vitamins can lower homocysteine ( Hcy ) , information about effects on atherosclerosis is scarce . METHODS We used carotid intima-media thickness ( IMT ) as an accepted marker of atherosclerotic changes .  Fifty patients ( 60 + /- 8 years ) with IMT > or = 1 mm were included . In a double blind , r and omized trial they received daily 2.5 mg folic acid , 25 mg Vitamin B6 , and 0.5 mg Vitamin B12 or placebo for 1 year . RESULTS In the treatment group , Hcy decreased from 10.50 + /- 3.93 to 6.56 + /- 1.53 micromol/l ( P < 0.0001 ) , whereas it remained unchanged in the placebo group ( 10.76 + /- 2.36 versus 10.45+/-3.30 micromol/l ) . IMT decreased from 1.50 + /- 0.44 to 1.42 + /- 0.48 mm ( P = 0.034 ) in the treatment group , whereas it increased from 1.47 + /- 0.57 to 1.54 + /- 0.71 mm in the placebo group . The mean individual changes of IMT between both groups differed significantly ( -0.08 + /- 0.17 versus 0.07 + /- 0.25 mm , P = 0.019 ) . Multiple regression analysis revealed that the observed effect on IMT depended only on medication . CONCLUSIONS Vitamin supplementation significantly reduces IMT in patients at risk . This effect is independent of Hcy concentration Hyperhomocysteinemia , an arteriosclerotic risk factor , persists in 75 % of dialysis patients despite routine low dose supplementation with the B-vitamin co-factors/substrates for homocysteine ( Hcy ) metabolism , and normal or supernormal plasma status of these vitamins ( Atherosclerosis 114:93 , 1995 ) . We conducted a placebo-controlled eight-week trial of the effect on plasma homocysteine of adding supraphysiologic dose folic acid ( 15 mg/day ) , B-6 ( 100 mg/day ) , and B-12 ( 1 mg/day ) to the usual daily dosing of 1 mg folic acid , 10 mg B-6 , and 12 micrograms B-12 , in 27 hyperhomocysteinemic dialysis patients .  Total plasma homocysteine was measured at baseline , and after four and eight weeks . Blinded analyses revealed no evidence of toxicity in the group r and omized to supraphysiologic dose B-vitamin supplementation . Plasma homocysteine was significantly reduced after both four weeks ( -29.8 % vs. -2.0 % ; P = 0.0024 ) and eight weeks ( -25.8 % vs. + 0.6 % ; P = 0.0009 ) of active versus placebo treatment . Also , 5 of 15 treated versus 0 of 12 placebo group patients had their plasma Hcy reduced to within the normative range ( < 15 mumol/liter ) . Supraphysiologic doses of B-vitamins may be required to correct hyperhomocysteinemia in dialysis patients Summary Background Deficiency of folic acid , vitamin B6 and /or vitamin B12 can result in elevated total plasma homocysteine concentrations ( tHcy ) , which are considered to be a risk factor for vascular disease . Studies have shown that supplementation of the three vitamins can lower tHcy even in subjects with tHcy in the normal range . Aim of the study The aim of this study was to evaluate the effect of a 6 month supplementation with vitamin B6 , B12 and folate on the concentrations of total plasma homocysteine and serum methylmalonic acid ( MMA ) of elderly women . Methods The study was design ed as a r and omized placebo controlled doubleblind trial , and 220 healthy women ( aged 60–91 years ) were involved .  The vitamin and mineral capsule contained pyridoxine ( 3.4 mg ) , folic acid ( 400 µg ) and cobalamin ( 9 µg ) in addition to other micronutrients  . Blood concentrations of folate , cobalamin , tHcy , MMA and the activity coefficient of erythrocyte alpha-aspartic aminotransferase ( alpha-EAST ) were measured at baseline and after 6 months of supplementation . Dietary intake was evaluated at the beginning and the end of the intervention by two 3–day diet records . Results Median concentrations of serum cobalamin , serum folate and erythrocyte folate increased significantly and tHcy and alpha – EAST activity ( indicative of improved status of vitamin B6 ) coefficient decreased significantly in the supplemented group . Median MMA concentration of the supplemented group was significantly lower than that of the placebo group after the intervention . The vitamin supplementation had a greater decreasing effect on the tHcy concentration of volunteers with lower vitamin and higher tHcy initial concentrations . In a linear regression model , baseline tHcy , serum folate , age and alpha – EAST activity coefficient were significantly correlated with the change in tHcy . The change in MMA in the supplement group was significantly associated to the baseline MMA values . Conclusions Our results show that a 6 month supplementation including physiological dosages of B vitamins improves the status of these nutrients and reduces tHcy in presumed healthy elderly women OBJECTIVES Vitamin B-12 and n-3 polyunsaturated fatty acids ( PUFA ) decrease blood homocysteine ( Hcy ) concentrations . However , the combined effect of these nutrients on Hcy and ferritin , and C-reactive protein is limited and inconclusive . The objective was to examine the synergistic effect of vitamin B-12 in combination of n-3 PUFA on plasma Hcy , ferritin , and other biochemical markers . METHODS In a r and omized controlled trial , thirty eligible subjects were r and omly divided into three groups , and assigned to receive 1000 μg of vitamin B-12 , 2 g fish oil , or 1000 μg vitamin B-12 and 2 g fish oil , respectively , for 8 weeks . Plasma phospholipids ( PL ) fatty acids and biochemical markers were determined . This study was registered under Clinical Trials.gov Identifier : NCT01762072 . RESULTS Plasma PL 20:5n-3 , 22:6n-3 and n-3 PUFA was increased after 4 and 8 week supplementation of fish oil , and vitamin B-12+fish oil . Plasma concentrations of triacylglycerol , uric acid , C-reactive protein , and ferritin were significantly decreased after 4 and 8 week supplementation of fish oil , and vitamin B-12+fish oil . In all groups , significant changes in plasma Hcy were observed during the study period . Vitamin B-12 , fish oil , and vitamin B-12+fish oil supplementation lowered plasma Hcy concentrations by 22 % , 19 % , and 39 % , respectively . CONCLUSIONS The combination of vitamin B-12 and fish oil has a synergistic effect on lowering plasma concentrations of Hcy Various regimens of folic acid-based and vitamin B12 ( Vit B12 ) supplementations have been tried for lowering plasma homocysteine ( Hcy ) levels in uremic patients . However , the therapeutic potency of low-dose folic acid and Vit B12 alone is not properly understood . In this study , seventy-five patients on chronic hemodialysis ( HD ) therapy were r and omized into three groups . The FNA group received intravenous ( IV ) supplementation with folinic acid 3 mg weekly ; the Vit B12 group received IV supplementation with vitamin B12 1 mg weekly ; and the combination group received IV supplementation with both agents weekly  . Blood levels of Hcy , folic acid , and Vit B12  were measured monthly for three months . After three months of treatment , plasma levels of Hcy decreased significantly in all three groups when compared with their baselines ( all p < 0.05 ) . The final Hcy level was significantly lower in the combination group ( 11.5 ± 2.3 μmol/L ) when compared with that of the FNA group ( 15.9 ± 5.6 μmol/L , p < 0.05 ) but not with the Vit B12 group ( 15.9 ± 11.6 μmol/L ) , although their baseline levels were similar . The percentage decreases of tHcy at the end of the treatment in the FNA group , Vit B12 group , and combination group were 16.4 % , 29.3 % , and 38.9 % respectively . Our study showed that IV pharmacologic dose of Vit B12 alone is as effective as low-dose folic acid in correcting hyperhomocysteinemia in chronic HD patients , and combining both drugs in low doses may have added effects It is known that the metabolism of homocysteine ( Hcy ) depends on the vitamins B6 , B12 and folate , and furthermore that metformin reduces serum vitamin B12 levels . In order to investigate whether metformin treatment affects serum total Hcy ( tHcy ) levels we performed an open , prospect i ve , r and omised study in 60 non-diabetic male patients with cardiovascular disease . After a 4-week run-in period with lovastatin 40 mg day-1 , and diet and lifestyle advice , patients were r and omised into two groups , both continuing the run-in treatment . One group received metformin up to 2000 mg day-1 , whereas the control group got no additional treatment . After 12 and 40 weeks of metformin treatment , tHcy levels increased moderately but significantly by 7.2 % ( p < 0.05 ) and 13.8 % ( p < 0.05 ) in the metformin group relative to the control group , whereas serum vitamin B12 levels decreased by 13.4 % ( p < 0.0005 ) and 17.7 % ( p < 0.0005 ) , respectively . Serum folate levels did not change after 12 weeks , but decreased by 8.0 % after 40 weeks ( p = 0.061 ) relative to the control group . Serum levels of total cysteine and methylmalonic acid ( MMA ) did not change . In conclusion , metformin treatment increased tHcy levels and decreased levels of vitamin B12 and folate . Since MMA levels were unchanged , it remains an open question whether the increase in tHcy levels is secondary to reduced vitamin B12 levels , folate levels or a combination of both To evaluate the efficacy of supplementation with high dose folic acid with and without vitamin B 12 in lowering plasma total homocysteine ( tHcy ) concentrations in hemodialysis ( HD ) patients , we studied 36 HD patients r and omized into four groups according to the received therapeutic regimen : group I ( only folic acid ( FA ) , 5 mg/day ) , group II ( FA , 5 mg/day + vitamin B 12 , 1 mg/day ) group III ( only FA , 15 mg/day ) , group IV ( FA , 15 mg/day , vitamin B 12 , 1 mg/day ) for a period of 8 weeks . Plasma tHcy and serum FA and vitamin B 12 levels were measured at baseline and after the supplementation period . Dietary intakes were assessed during the study period . At baseline , 27.8 % of the patients had normal levels of tHcy  and 72.2 % had hyperhomocysteinemia . After supplementation , plasma tHcy increased by 1.35 % in group I and decreased by 6.99 % , 14.54 % and 30.09 % in groups II , III and IV respectively , which was only significant in group IV ( P= 0.014 ) . The patients did not show any significant changes in serum folic acid , but a significant change in serum vitamin B 12 in group IV ( P= 0.006 ) . Percentage of patients reaching normal levels of plasma tHcy was 5.6 fold higher in group IV than in the reference group ( group I ) . No correlations were found between changes of plasma tHcy levels and dietary intakes . We conclude that oral supplementation with 15 mg/day folic acid together with 1 mg/day of vitamin B 12 is effective in reducing tHcy levels in HD patients . These supplements also have a desirable effect on serum folic acid and vitamin B12
Therefore , although the overall effect of metformin on the concentration of serum Hcy was neutral , our results suggested that metformin could increase the concentration of Hcy when exogenous B-group vitamins or folic acid supplementation was not given
The aim of this systematic review is to assess whether metformin could change the concentration of serum homocysteine ( Hcy ) with and without simultaneous supplementation of B-group vitamins or folic acid .