title: Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial Homocysteine levels are unaffected by metformin treatment in both nonpregnant and pregnant women with polycystic ovary syndrome Is Reducing Ovarian Volume in Polycystic Ovarian Syndrome Patients after Administration of Metformin Associated with Improving Cardiovascular Risk Factors? Association of Metformin, Elevated Homocysteine, and Methylmalonic Acid Levels and Clinically Worsened Diabetic Peripheral Neuropathy Comparison of effects of gliclazide, metformin and pioglitazone monotherapies on glycemic control and cardiovascular risk factors in patients with newly diagnosed uncontrolled type 2 diabetes mellitus. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. Plasma Homocysteine Predicts Mortality Independently of Traditional Risk Factors and C-Reactive Protein in Patients With Angiographically Defined Coronary Artery Disease Does metformin improve vascular heath in children with type 1 diabetes? Protocol for a one year, double blind, randomised, placebo controlled trial The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome. Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment. Does metformin decrease blood pressure in patients with Type 2 diabetes intensively treated with insulin? Serum uric acid concentration as non-classic cardiovascular risk factor in women with polycystic ovary syndrome: effect of treatment with ethinyl-estradiol plus cyproterone acetate versus metformin. Effects of metformin plus gliclazide versus metformin plus glimepiride on cardiovascular risk factors in patients with type 2 diabetes mellitus. Homocysteine levels in women with polycystic ovary syndrome treated with metformin versus rosiglitazone: a randomized study. Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease. Inadequacy of initiating rosuvastatin then metformin on biochemical profile of polycystic ovarian syndrome patients Effects of an antiandrogenic oral contraceptive pill compared with metformin on blood coagulation tests and endothelial function in women with the polycystic ovary syndrome: influence of obesity and smoking. Comparison of glycaemic control and cardiovascular risk profile in patients with type 2 diabetes during treatment with either repaglinide or metformin. Prospective, randomized trial of metformin and vitamins for the reduction of plasma homocysteine in insulin-resistant polycystic ovary syndrome.
abstract: Objectives To study the effects of metformin on the incidence of vitamin B-12 deficiency ( < 150 pmol/l ) , low concentrations of vitamin B-12 ( 150 - 220 pmol/l ) , and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin . Design Multicentre r and omised placebo controlled trial . Setting Outpatient clinics of three non-academic hospitals in the Netherl and s. Participants 390 patients with type 2 diabetes receiving treatment with insulin . Intervention 850 mg metformin or placebo three times a day for 4.3 years . Main outcome measures Percentage change in vitamin B-12 , folate , and homocysteine concentrations from baseline at4 , 17 , 30 , 43 , and 52 months . Results Compared with placebo , metformin treatment was associated with a mean decrease in vitamin B-12 concentration of −19 % ( 95 % confidence interval −24 % to −14 % ; P<0.001 ) and in folate concentration of −5 % ( 95 % CI −10 % to −0.4 % ; P=0.033 ) , and an increase in homocysteine concentration of 5 % ( 95 % CI −1 % to 11 % ; P=0.091 ) . After adjustment for body mass index and smoking , no significant effect of metformin  on folate concentrations was found . The absolute risk of vitamin B-12 deficiency ( < 150 pmol/l ) at study end was 7.2 percentage points higher in the metformin group than in the placebo group ( 95 % CI 2.3 to 12.1 ; P=0.004 ) , with a number needed to harm of 13.8 per 4.3 years ( 95 % CI 43.5 to 8.3 ) . The absolute risk of low vitamin B-12 concentration ( 150 - 220 pmol/l ) at study end was 11.2 percentage points higher in the metformin group ( 95 % CI 4.6 to 17.9 ; P=0.001 ) , with a number needed to harm of 8.9 per 4.3 years ( 95 % CI 21.7 to 5.6 ) . Patients with vitamin B-12 deficiency at study end had a mean homocysteine level of 23.7 µmol/l ( 95 % CI 18.8 to 30.0 µmol/l ) , compared with a mean homocysteine level of 18.1 µmol/l ( 95 % CI 16.7 to 19.6 µmol/l ; P=0.003 ) for patients with a low vitamin B-12 concentration and 14.9 µmol/l ( 95 % CI 14.3 to 15.5 µmol/l ; P<0.001 compared with vitamin B-12 deficiency ; P=0.005 compared with low vitamin B-12 ) for patients with a normal vitamin B-12 concentration ( > 220 pmol/l ) . Conclusions Long term treatment with metformin increases the risk of vitamin B-12 deficiency , which results in raised homocysteine concentrations . Vitamin B-12 deficiency is preventable ; therefore , our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered . Trial registration Clinical trials.gov NCT00375388 Background . Women with polycystic ovary syndrome have elevated homocysteine levels . Elevated homocysteine levels associate with pregnancy complications . Women with polycystic ovary syndrome are often treated with metformin , a drug that may increase homocysteine levels . Hence , we investigated the effect of metformin treatment on homocysteine levels in nonpregnant and pregnant women with polycystic ovary syndrome . Methods . Two prospect i ve r and omized placebo‐controlled studies included women with polycystic ovary syndrome in a university hospital setting . Sixty‐three infertile women were treated with metformin 1,000 mg bid or placebo for 16 weeks and 38 pregnant women with metformin 850 mg bid or placebo from the first trimester and throughout pregnancy . All the women had polycystic ovary syndrome and all participants received diet and lifestyle advice , and oral folate and vitamin B12 substitution , and a daily oral multivitamin tablet . The main outcome measures were serum levels of homocysteine , folate , and vitamin B12 . Results . Serum homocysteine levels were unaffected by metformin treatment both in nonpregnant and pregnant women with polycystic ovary syndrome . However , in nonpregnant women both serum folate and vitamin B12 levels decreased with treatment . At inclusion in nonpregnant women , serum homocysteine levels associated negatively with serum levels of folate and methyl malonic acid and positively with free testosterone index . No such associations were seen in pregnant women . Conclusions . Metformin treatment in women with polycystic ovary does not increase serum homocysteine levels in the nonpregnant or the pregnant state Background Women with polycystic ovary syndrome ( PCOS ) are at increased risk for cardiovascular ( CV ) and metabolic disorders . There is a close relationship between elevated and rogen plasma levels and the ultrasound findings of stromal hypertrophy . In r and omized trials , the administration of metformin has been shown to be followed by an improvement in insulin sensitivity and decrease in and rogen levels in most women . In the present study , we investigate the association between reduced ovarian volume in PCOS patients after administration of metformin with improvement in CV risk factors . Material s and Methods This was a r and omized clinical trial study . A total of 28 women diagnosed with PCOS who referred to the infertility clinic were selected .  Anthropometric characteristics of the patients , mean ovarian volume and plasma levels of fasting blood sugar ( FBS ) , lipid profile , luteinizing hormone ( LH ) , follicle stimulating hormone ( FSH ) , estradiol , testosterone , 17-α-OH progesterone ( 17OHP ) , dehydroepi and rosterone sulfate ( DHEAS ) , C-reactive protein ( CRP ) and homocysteine ( Hcy ) were evaluated before and after treatment with 500 mg metformin , three times daily for three months . Statistics were calculated with the aid of SPSS 16.0 with student ’s paired t- and Pearson ’s correlation coefficient tests . Significance was set at p<0.05 . Results There were significant reductions in mean ovarian volume and body mass index ( BMI ) , in addition to CRP , Hcy , testosterone , FBS , HDL and LDL levels . There was a positive correlation between mean ovarian volume and waist-to-hip ratio (WHR).After treatment , there correlation noted with reduction in mean ovarian volume and decreased BMI , in addition to reductions in CRP , LDL , Hcy and testosterone levels . Conclusion A positive correlation may exist between reduced mean ovarian volume and improvement in CV risk factors  after administration of metformin ( Registeration Number : I RCT 138903244176N1 ) OBJECTIVE The severity of peripheral neuropathy in diabetic patients varies for unclear reasons . Long-term use of metformin is associated with malabsorption of vitamin B12 ( cobalamin [ Cbl ] ) and elevated homocysteine ( Hcy ) and methylmalonic acid ( MMA ) levels , which may have deleterious effects on peripheral nerves . The intent of this study was to clarify the relationship among metformin exposure , levels of Cbl , Hcy , and MMA , and severity of peripheral neuropathy in diabetic patients . We hypothesized that metformin exposure would be associated with lower Cbl levels , elevated Hcy and MMA levels , and more severe peripheral neuropathy . RESEARCH DESIGN AND METHODS This was a prospect i ve case-control study of patients with type 2 diabetes and concurrent symptomatic peripheral neuropathy , comparing those who had received > 6 months of metformin therapy ( n = 59 ) with those without metformin exposure ( n = 63 ) . Comparisons were made using clinical ( Toronto Clinical Scoring System and Neuropathy Impairment Score ) , laboratory ( serum Cbl , fasting Hcy , and fasting MMA ) , and electrophysiological measures ( nerve conduction studies ) . RESULTS Metformin-treated patients had depressed Cbl levels and elevated fasting MMA and Hcy levels . Clinical and electrophysiological measures identified more severe peripheral neuropathy in these patients ; the cumulative metformin dose correlated strongly with these clinical and para clinical group differences . CONCLUSIONS Metformin exposure may be an iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes . Interval screening for Cbl deficiency and systemic Cbl therapy should be considered upon initiation of , as well as during , metformin therapy to detect potential secondary causes of worsening peripheral neuropathy OBJECTIVE The objective of this study was to evaluate and compare the effects of gliclazide-modified release ( gliclazide-MR ) , metformine ( MET ) and pioglitazone ( PIO ) monotherapies on glycemic control and conventional/non-conventional cardiovascular risk factors in patients with newly diagnosed type 2 diabetes mellitus ( T2DM ) . MATERIAL AND METHODS A single center , r and omized , 52-wk comparator-controlled clinical study was carried out in patients with newly diagnosed uncontrolled T2DM . A total of 57 patients were r and omized into gliclazide-MR , metformin and pioglitazone groups . Drugs were administered for 12 months . Anthropometric measurements , fasting plasma glucose ( FPG ) , postpr and ial plasma glucose ( PPG ) , HbA1c , insulin , HOMA-IR , lipid parameters , the markers of coagulation/fibrinolysis , inflammation and endothelial dysfunction were measured at baseline and at months 3 , 6 , and 12 . RESULTS In the gliclazide-MR group , HC , FPG , HbA1c , insulin , HOMA-IR , TC , trigylcerides , Lp ( a ) , E-selectin and Hcy were significantly decreased after treatment compared to baseline . In the MET group , BMI , WC , FPG , PPG , HbA1c , ICAM-1 and Hcy significantly decreased after treatment compared to baseline . In PIO group , WC , HC , FPG , PPG , HbA1c , C-peptid , HOMA-IR , trigylcerides , vWF , IL-6 , ICAM-1 , E-selectin and Hcy significantly decreased after treatment compared to baseline , whereas , HDL-C increased . At the end of the month 12 , the decreases in insulin and HOMA-IR score were more pronounced with PIO compared to gliclazide . CONCLUSIONS Gliclazide-MR , MET and PIO monotherapies , were equally effective in proving glycemic control in patients with newly diagnosed , oral antidiabetic (OAD)-naive T2DM . But , improvements in conventional/non-conventional cardiovascular risk factors were more pronounced in patients on PIO therapy compared to gliclazide and MET therapies . Also , all of the 3 drugs represent effective and safe first-line pharmacological treatment options in these patients OBJECTIVE Metformin is a key treatment option in type 2 diabetes . However , metformin may decrease vitamin B12 levels and increase levels of homocysteine , a cardiovascular risk factor . We investigated whether 16 weeks of treatment with metformin affects serum concentrations of homocysteine , folate and vitamin B12 in subjects with type 2 diabetes treated with insulin . DESIGN Placebo-controlled , r and omized trial . MEASUREMENTS at baseline and 16 weeks later . SETTING This trial was conducted in the outpatient clinics of three general hospitals in The Netherl and s. SUBJECTS A total of 745 patients with type 2 diabetes , treated with insulin and not known with a contraindication for the use of metformin , were approached ; 390 gave informed consent and entered the study . Thirty-seven subjects dropped out ( 12 placebo and 25 metformin users ) . INTERVENTION Addition of metformin or placebo to insulin therapy . PRIMARY OUTCOME PARAMETERS : Serum homocysteine , folate , vitamin B12 , indices of glycaemic control and body weight . RESULTS Amongst those who completed 16 weeks of treatment , metformin use , as compared with placebo , was associated with an increase in homocysteine of 4 % ( 0.2 to 8 ; P=0.039 ) and with decreases in folate [ -7 % ( -1.4 to -13 ) ; P=0.024 ] and vitamin B12 [ -14 % ( -4.2 to -24 ) ; P<0.0001 ] . In addition , the increase in homocysteine could be explained by the decreases in folate and vitamin B12 . CONCLUSION In patients with type 2 diabetes , 16 weeks of treatment with metformin reduces levels of folate and vitamin B12 , which results in a modest increase in homocysteine . The clinical significance of these findings remains to be investigated Background Plasma homocysteine ( tHCY ) has been associated with coronary artery disease ( CAD ) . We tested whether tHCY also increases secondary risk , after initial CAD diagnosis , and whether it is independent of traditional risk factors , C-reactive protein ( CRP ) , and methylenetetrahydrofolate reductase ( MTHFR ) genotype . Methods and Results Blood sample s were collected from 1412 patients with severe angiographically defined CAD ( stenosis ≥70 % ) . Plasma tHCY was measured by fluorescence polarization immunoassay . The study cohort was evaluated for survival after a mean of 3.0±1.0 years of follow-up ( minimum 1.5 years , maximum 5.0 years ) . The average age of the patients was 65±11 years , 77 % were males , and 166 died during follow-up . Mortality was greater in patients with tHCY in tertile 3 than in tertiles 1 and 2 ( mortality 15.7 % versus 9.6 % , P = 0.001 [ log-rank test ] , hazard ratio [ HR ] 1.63 ) . The relative hazard increased 16 % for each 5-&mgr;mol/L increase in tHCY ( P < 0.001 ) . In multivariate Cox regression analysis , controlling for univariate clinical and laboratory predictors , elevated tHCY remained predictive of mortality ( HR 1.64 , P = 0.009 ) , together with age ( HR 1.72 per 10-year increment , P < 0.0001 ) , ejection fraction ( HR 0.84 per 10 % increment , P = 0.0001 ) , diabetes ( HR 1.98 , P = 0.001 ) , CRP ( HR 1.42 per tertile , P = 0.004 ) , and hyperlipidemia . Homozygosity for the MTHFR variant was weakly predictive of tHCY levels but not mortality . Conclusions In patients with angiographically defined CAD  , tHCY is a significant predictor of mortality , independent of traditional risk factors , CRP , and MTHFR genotype . These findings increase interest in tHCY as a secondary risk marker and in secondary prevention trials ( ie , with folate/B vitamins ) to determine whether reduction in tHCY will reduce risk Background Cardiovascular disease is the leading cause of mortality in Type 1 diabetes ( T1D ) . Vascular dysfunction is an early and critical event in the development of cardiovascular disease . Children with T1D have vascular dysfunction therefore early interventions to improve vascular health are essential to reduce cardiovascular mortality in T1D . Metformin is an insulin sensitising agent which is known to improve vascular health outcomes in type 2 diabetes ( T2D ) and other individuals with insulin resistance . It has been used safely in children and adolescents with T2D for over 10 years . This study aims to assess the effect of metformin on vascular health in children with T1D . Methods / Design This study is a 12 month , double blind , r and omised , placebo controlled trial to determine the effect of metformin on vascular health in children ( age 8–18 ) with T1D . The sample size is 76 with 38 children in the metformin group and 38 children in the placebo group . Vascular health and biochemical markers will be measured at baseline , 3 , 6 and 12 months . Vascular function will be measured using flow mediated dilatation and glyceryl trinitrate mediated dilatation of the brachial artery and vascular structure will be measured with carotid and aortic intima media thickness , using st and ardised protocol s. Discussion This study will be the first to investigate the effect of metformin on vascular health in children with T1D . It will provide important information on a potential intervention to improve cardiovascular morbidity and mortality in this population at high risk from cardiovascular disease . Trial registration Australia New Zeal and Clinical Trials Registry BACKGROUND Oxidative stress and hyperhomocysteinaemia are risk factors for cardiovascular diseases . The aim of this study was to assess the effects of rosiglitazone and metformin on cardiovascular disease risk factors such as insulin resistance , oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome ( PCOS ) . METHODS Fifty lean patients ( BMI < 25 kg/m2 ) with PCOS and 35 healthy subjects were included this study . Serum homocysteine , sex steroids , fasting insulin , fasting glucose and lipid levels were measured . Total antioxidant status ( TAS ; combines concentrations of individual antioxidants ) and malonyldialdehyde concentration ( MDA ) were determined . Insulin resistance was evaluated by using the homeostasis model insulin resistance index ( HOMA-IR ) , quantitative insulin sensitivity check index ( QUICKI ) , Area under the curve insulin ( AUCI ) and the insulin sensitivity index ( ISI ) . Patients were divided into two groups . One group was treated with metformin ( n = 25 ) and the other received rosiglitazone ( n = 25 ) for 12 weeks . All measurements were repeated at the end of 12 weeks . RESULTS Compared with healthy women , those with PCOS had significantly elevated serum MDA , homocysteine , HOMA-IR , AUCI and lipoprotein a levels , and significantly decreased serum TAS , QUICKI and ISI . Serum free testosterone levels showed a significant positive correlation with MDA , AUCI and HOMA-IR , and a negative correlation with TAS , ISI and QUICKI in PCOS patients . HOMA-IR and AUCI significantly decreased , while QUICKI and ISI significantly increased after treatment in both groups . Serum TAS level increased and serum MDA level decreased after the rosiglitazone treatment , but these parameters did not change after the metformin treatment . Serum homocysteine and lipid levels did not change in either group , while serum and rogen levels and LH/FSH ratio significantly decreased after the treatment period in only the rosiglitazone-treated group . CONCLUSION Elevated insulin resistance , oxidative stress and plasma homocysteine levels and changes in serum lipid profile ( risk factors for cardiovascular disease ) were observed in lean PCOS patients .  Rosiglitazone seemed to decrease elevated oxidative stress when compared with metformin treatment in lean PCOS patients 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 AIMS We investigated in a double-blind study whether metformin reduces blood pressure ( BP ) in patients with Type 2 diabetes intensively treated with insulin . METHODS A total of 220 patients with Type 2 diabetes were asked to undergo 24-h ambulatory BP monitoring ( 24-h ABPM ) . One hundred and eighty-two gave informed consent . Eighty-nine were r and omized to metformin and 93 to placebo . Thirty-five subjects dropped out ( 13 placebo  , 22 metformin users ) ; 147 patients underwent a second  24-h ABPM , 16 weeks after r and omization . RESULTS Systolic BP ( SBP ) , diastolic BP ( DBP ) , pulse BP ( PP ) , mean BP ( MP ) and heart rate ( HR ) were measured as office BP measurements and as 24-h ABPM for 24-h , day and night . Office BP measurements did not differ significantly between the placebo- and metformin-treated groups for any BP measure , but showed a non-significant trend for SBP reduction with metformin use ( mean baseline-adjusted difference , metformin minus placebo : -4.2 mmHg , 95 % CI , -9.9 to + 1.5 ; P = 0.15 ) . The baseline-adjusted differences of the ambulatory measurements were -0.2 mmHg ( 95 % CI , -2.9 to + 2.6 ) for the 24-h SBP , and + 1.1 mmHg ( 95 % CI , -0.7 to + 2.8 ) for the 24-h DBP . On the whole , BP differences between metformin- and placebo-treated groups were not statistically significant . The only significant difference was for night-time PP ( baseline-adjusted difference : -2.2 mmHg ; 95 % CI , -4.2 to -0.2 ) . These results were not different after adjustment for age and diabetes duration , or for ( changes in ) body mass index , glycated haemoglobin , insulin dose or plasma homocysteine . CONCLUSION Metformin does not significantly affect BP in patients with Type 2 diabetes intensively treated with insulin BACKGROUND Serum uric acid levels have emerged as a cardiovascular risk factor , and interventions aim ed to decrease its level have been related with an improvement in clinical and non- clinical cardiovascular outcomes . METHODS Serum uric acid levels were measured in 40 polycystic ovary syndrome ( PCOS ) patients and 40 non-hyper and rogenic women matched for BMI and grade of obesity , and were followed-up in 34 PCOS patients who were r and omized to an oral contraceptive containing 35 mg ethinyl-estradiol plus 2 mg cyproterone acetate ( Diane(35 ) Diario ) or metformin ( 850 mg twice daily ) for 24 weeks . RESULTS There were no statistically significant differences in uric acid levels between PCOS and non-hyper and rogenic control women . Considering all PCOS and non-hyper and rogenic control women as a whole , obese women showed higher uric acid concentrations than lean and overweight women , and the main determinant of serum uric acid level was the BMI . In PCOS women , Diane(35 ) Diario treatment was related with a decrease in uric acid levels ( P = 0.018 ) , whereas no changes were observed with metformin . CONCLUSIONS Obesity is the main determinant of serum uric acid concentrations in PCOS patients , yet amelioration of and rogen excess with an anti and rogenic contraceptive pill results in a significant decrease in these levels , an effect that is not observed with metformin . Clinical Trials.gov NLM Identifier : NCT00428311 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 BACKGROUND Elevated levels of plasma homocysteine ( Hcy ) have been implicated as a significant risk factor for cardiovascular disease . Although long-term treatment with metformin can increase Hcy levels in patients with type II diabetes mellitus or coronary heart disease , it is becoming an increasingly accepted and widespread medication in polycystic ovary syndrome ( PCOS ) . In the literature , only one study has demonstrated that metformin increases Hcy levels in PCOS patients , but the effect of other insulin sensitizers on Hcy levels have not been reported previously in women with PCOS . We aim ed to assess the effects of metformin and rosiglitazone on plasma Hcy levels in patients with PCOS . METHODS Thirty women were r and omized to two groups : 15 women in group 1 received 850 mg of metformin twice daily for 3 months . In group 2 , 15 women received 4 mg of rosiglitazone for 3 months . In both groups , body mass index , menstrual pattern , and plasma total Hcy , insulin , glucose and lipid metabolism parameters were recorded at baseline and at 3 months . RESULTS Hcy levels increased from 8.93+/-0.49 to 11.26+/-0.86 micromol/l ( P = 0.002 ) and from 10.70+/-0.86 to 12.36+/-0.81 micromol/l ( P = 0.01 ) in the metformin and rosiglitazone groups , respectively . Apolipoprotein ( Apo ) A1 levels increased from 127.10+/-6.85 to 145.7+/-7.18 mg/dl ( P = 0.018 ) in the metformin group . Total cholesterol ( total-C ) , high-density lipoprotein cholesterol ( HDL-C ) , low-density lipoprotein cholesterol ( LDL-C ) , lipoprotein ( a ) and Apo B levels decreased in the metformin group , but the change was not significant . Total-C levels decreased from 161.15+/-8.94 to 150.23+/-8.73 mg/dl ( P = 0.026 ) , HDL-C decreased from 43.13+/-2.65 to 39.15+/-2.52 mg/dl ( P = 0.005 ) and LDL-C levels decreased from 93.83+/-6.06 to 80.7+/-2.30 mg/dl ( P = 0.021 ) in the rosiglitazone group . CONCLUSION Treatment with insulin sensitizers in women with PCOS may lead to increases in Hcy levels 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 Background Polycystic ovary syndrome ( PCOS ) afflicts at least 5 % of women . Both metformin and statin have been used as methods to ameliorate symptoms and improve prognosis . Aim To test the efficacy of concomitant usage of metformin and statins in PCOS patients . Material s and methods This is a prospect i ve , r and omized , double-blinded , placebo controlled study . 37 patients received rosuvastatin ( 10 mg/day ) for a period of 3 months , then the patients were r and omly allocated to one of two groups : the first group ( or intervention group ) received rosuvastatin ( 10 mg/day ) plus metformin ( 850 mg twice daily after meals ) , and the second group ( referred to as control group hereafter ) received rosuvastatin ( 10 mg/day ) plus placebo for a period of 3 months .  Biochemical and clinical data were collected at each time point . Results There were no significant differences between the intervention and control groups for baseline lipid profile ( LDL , HDL , triglycerides , total cholesterol ) , CRP , homocysteine , DHEAS , testosterone and insulin ( p > 0.05 for all variables ) . There were no significant differences in lipid profile , CRP , homocysteine , DHEAS , testosterone and insulin between the intervention and placebo groups at 3 and 6 months after treatment ( p > 0.05 for all ) . Significant differences in the outcome variables of LDL , total cholesterol and FBS emerged within the intervention group , with significantly higher levels at 6 months compared to 3 months . We also did not find any significant group differences in unit change of the outcome variables between baseline and 3 months . Conclusions We found that the combination of statin and metformin has no advantage in PCOS management . In fact , the increase of LDL , total cholesterol and FBS within the intervention group warrants re assessment of current regimens to avoid any patient harm OBJECTIVE To study the blood clotting tests and endothelial function of polycystic ovary syndrome ( PCOS ) patients and non-hyper and rogenic women , and their changes during PCOS treatment , as a function of the presence of obesity and smoking . DESIGN Case-control study followed by a r and omized clinical trial . METHODS Blood clotting and endothelial function were analyzed in 40 PCOS patients and 20 non-hyper and rogenic women . Thirty-four PCOS women were r and omized to an oral contraceptive containing 35 microg ethinyl-estradiol plus 2 mg cyproterone acetate ( Diane(35)Diario ) or metformin ( 850 mg twice daily ) , monitoring the changes on these parameters during 24 weeks of treatment . The influence of obesity and smoking was also analyzed . RESULTS Blood clotting and endothelial function tests were similar among PCOS patients and controls with the exception of a higher platelet count in the former . Obesity increased circulating fibrinogen levels , prothrombin activity and platelet counts , and reduced prothrombin and activated partial thromboplastin times . Smoking increased fibrinogen levels , platelet counts , and prothrombin activity , and reduced prothrombin time , in relation to the larger waist circumference of smokers . Irrespective of the treatment received , PCOS patients showed a decrease in prothrombin time and an increase in prothrombin activity , with a parallel increase in homocysteine levels in metformin users . The activated partial thromboplastin time decreased markedly in the patients treated with Diane(35)Diario . Finally , flow-mediated dilation improved in non-smokers irrespective of the drug received , but worsened in smokers . CONCLUSIONS Oral contraceptives and metformin may exert deleterious effects on blood clotting tests of PCOS women , yet the effects of metformin appear to be milder . Because smoking potentiates some of these effects and deteriorates endothelial function , smoking cessation should be promoted in PCOS patients OBJECTIVE To compare glycaemic control and cardiovascular risk profile in patients with type 2 diabetes following 12 months ' treatment with either repaglinide or metformin . STUDY DESIGN AND METHODS This was an open uncontrolled r and omised study in n=112 patients with inadequately controlled type 2 diabetes not previously treated with oral hypoglycaemic agents . Patients beginning treatment with either repaglinide or metformin entered an 8-week titration period ( to optimise dosage : repaglinide , 2 - 4 mg/day ; metformin , 1500 - 2500 mg/day ) followed by a 12-month treatment period . Glycaemic control and cardiovascular risk factors were determined at baseline and at the end of the treatment period . RESULTS Mean ( S.D. ) final drug doses were 3 ( + /-1 ) mg/day in the repaglinide group and 2000 ( + /-500 ) mg/day in the metformin group . Significant improvements in glycaemic control [ glycated haemoglobin , fasting and 2-h postpr and ial plasma glucose ( PPG ) ] were demonstrated in both treatment groups . The decrease in PPG was significantly greater in the repaglinide group ( P<0.05 ) . During the treatment period , fasting plasma insulin ( FPI ) decreased significantly in both groups , more so with metformin ( P<0.05 ) . Two-hour postpr and ial plasma insulin ( PPI ) levels decreased only in the metformin group ( P<0.05 ) . Significant improvements between baseline and final visit were demonstrated in one or both groups in the following cardiovascular risk factors : total cholesterol , low-density lipoprotein cholesterol ( LDL-C ) , triglycerides , plasminogen activator inhibitor , lipoprotein(a ) and homocysteine . No changes were observed in high-density lipoprotein cholesterol ( HDL-C ) , apolipoprotein A-I , apolipoprotein B , fibrinogen , body mass index ( BMI ) or blood pressure . CONCLUSIONS The use of repaglinide or metformin in drug therapy-nai;ve patients with type 2 diabetes over a 12-month period is associated with improvements in both glycaemic control and cardiovascular risk profile . The latter can not necessarily be attributed to the pharmacotherapy per se , but provides reassurance in the context of initiating oral hypoglycaemic drug therapy with these agents One hundred and two women with insulin-resistant polycystic ovary syndrome were r and omized to treatment with a vitamin B preparation , metformin , or both , in conjunction with st and ard infertility treatment . Plasma homocysteine levels were significantly reduced by both B vitamins and metformin , but to a greater degree by B vitamins , and higher pregnancy rates were associated with vitamin B treatment
target: 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
background: 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 .