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Effect of folic acid supplementation on plasma total homocysteine levels and glycemic control in patients with type 2 diabetes: A systematic review and meta-analysis

  • Patcharaporn Sudchada
    Affiliations
    Pharmaceutical Care Research Unit, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
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  • Surasak Saokaew
    Correspondence
    Corresponding author at: Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand. Tel.: +66 54466666x3180-7; fax: ++66 5446 6661.
    Affiliations
    Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand

    Center of Pharmaceutical Outcomes Research (CPOR), Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand

    Pharmacotherapy Outcomes Research Center (PORC), College of Pharmacy, University of Utah, Salt Lake City, UT, USA

    Clinical Epidemiology Program, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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  • Sorattaya Sridetch
    Affiliations
    Pharmaceutical Care Research Unit, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
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  • Siriwan Incampa
    Affiliations
    Pharmaceutical Care Research Unit, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
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  • Sopida Jaiyen
    Affiliations
    Pharmaceutical Care Research Unit, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
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  • Warangkana Khaithong
    Affiliations
    Pharmaceutical Care Research Unit, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
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      Abstract

      Aim

      The evidences illustrating the effects of folic acid supplementation (FAS) in individuals with type 2 diabetes on plasma total homocysteine (tHcy) levels and glycemic control have been contradictory. The aim of the study was to systematically search and quantitatively analyze the effect of FAS on tHcy levels and HbA1c compared with placebo.

      Methods

      We searched PubMed, Scopus, and Embase up to March 2012 without language restriction. Key words “folic acid” and “diabetes mellitus” with slight modifications based on the sources for search strategy were used. References of initially identified articles were examined to identify any other relevant studies. A random-effects model was used for estimation the pooled effect estimates (weighted mean different, WMD).

      Results

      Of 6185 studies identified, 4 studies with 183 patients were included. FAS had statistically significant effect on tHcy levels [WMD, −3.52; 95% confidence interval (CI), −4.44 to −2.60]. However, the effect on HbA1c levels [WMD, −0.37; 95% CI, −1.10 to 0.35] was not significant.

      Conclusions

      Folic acid supplementation in patient with type 2 diabetes mellitus may reduce tHcy levels and have a trend to associate with better glycemic control compared with placebo. Further longitudinal studies on these intervention and outcomes are warranted.

      Keywords

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      References

        • Tunstall-Pedoe H.
        • Woodward M.
        • Tavendale R.
        • A’Brook R.
        • McCluskey M.K.
        Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish Heart Health Study: cohort study.
        BMJ. 1997; 315: 722-729
        • Stengard J.H.
        • Tuomilehto J.
        • Pekkanen J.
        • Kivinen P.
        • Kaarsalo E.
        • Nissinen A.
        • et al.
        Diabetes mellitus, impaired glucose tolerance and mortality among elderly men: the Finnish cohorts of the Seven Countries Study.
        Diabetologia. 1992; 35: 760-765
        • Grundy S.M.
        • Benjamin I.J.
        • Burke G.L.
        • Chait A.
        • Eckel R.H.
        • Howard B.V.
        • et al.
        Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association.
        Circulation. 1999; 100: 1134-1146
        • Chokrungvaranon N.
        • Deer J.
        • Reaven P.D.
        Intensive glycemic control and cardiovascular disease: are there patients who may benefit?.
        Postgrad Med. 2011; 123: 114-123
        • Perry I.J.
        • Refsum H.
        • Morris R.W.
        • Ebrahim S.B.
        • Ueland P.M.
        • Shaper A.G.
        Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men.
        Lancet. 1995; 346: 1395-1398
        • Verhoef P.
        • Hennekens C.H.
        • Malinow M.R.
        • Kok F.J.
        • Willett W.C.
        • Stampfer M.J.
        A prospective study of plasma homocyst(e)ine and risk of ischemic stroke.
        Stroke. 1994; 25: 1924-1930
        • Coull B.M.
        • Malinow M.R.
        • Beamer N.
        • Sexton G.
        • Nordt F.
        • de Garmo P.
        Elevated plasma homocyst(e)ine concentration as a possible independent risk factor for stroke.
        Stroke. 1990; 21: 572-576
        • Malinow M.R.
        • Nieto F.J.
        • Szklo M.
        • Chambless L.E.
        • Bond G.
        Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The Atherosclerosis Risk in Communities Study.
        Circulation. 1993; 87: 1107-1113
        • Selhub J.
        • Jacques P.F.
        • Bostom A.G.
        • D’Agostino R.B.
        • Wilson P.W.
        • Belanger A.J.
        • et al.
        Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis.
        N Engl J Med. 1995; 332: 286-291
        • Arnesen E.
        • Refsum H.
        • Bonaa K.H.
        • Ueland P.M.
        • Forde O.H.
        • Nordrehaug J.E.
        Serum total homocysteine and coronary heart disease.
        Int J Epidemiol. 1995; 24: 704-709
        • Stampfer M.J.
        • Malinow M.R.
        • Willett W.C.
        • Newcomer L.M.
        • Upson B.
        • Ullmann D.
        • et al.
        A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians.
        JAMA. 1992; 268: 877-881
        • Genest Jr., J.J.
        • McNamara J.R.
        • Salem D.N.
        • Wilson P.W.
        • Schaefer E.J.
        • Malinow M.R.
        Plasma homocyst(e)ine levels in men with premature coronary artery disease.
        J Am Coll Cardiol. 1990; 16: 1114-1119
        • Garofolo L.
        • Barros Jr., N.
        • Miranda Jr., F.
        • D’Almeida V.
        • Cardien L.C.
        • Ferreira S.R.
        Association of increased levels of homocysteine and peripheral arterial disease in a Japanese–Brazilian population.
        Eur J Vasc Endovasc Surg. 2007; 34: 23-28
        • Smulders Y.M.
        • Rakic M.
        • Slaats E.H.
        • Treskes M.
        • Sijbrands E.J.
        • Odekerken D.A.
        • et al.
        Fasting and post-methionine homocysteine levels in NIDDM. Determinants and correlations with retinopathy, albuminuria, and cardiovascular disease.
        Diabetes Care. 1999; 22: 125-132
        • Hoogeveen E.K.
        • Kostense P.J.
        • Beks P.J.
        • Mackaay A.J.
        • Jakobs C.
        • Bouter L.M.
        • et al.
        Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study.
        Arterioscler Thromb Vasc Biol. 1998; 18: 133-138
        • Stehouwer C.D.
        • Gall M.A.
        • Hougaard P.
        • Jakobs C.
        • Parving H.H.
        Plasma homocysteine concentration predicts mortality in non-insulin-dependent diabetic patients with and without albuminuria.
        Kidney Int. 1999; 55: 308-314
        • Kark J.D.
        • Selhub J.
        • Bostom A.
        • Adler B.
        • Rosenberg I.H.
        Plasma homocysteine and all-cause mortality in diabetes.
        Lancet. 1999; 353: 1936-1937
        • Hoogeveen E.K.
        • Kostense P.J.
        • Jakobs C.
        • Dekker J.M.
        • Nijpels G.
        • Heine R.J.
        • et al.
        Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn Study.
        Circulation. 2000; 101: 1506-1511
        • Soinio M.
        • Marniemi J.
        • Laakso M.
        • Lehto S.
        • Ronnemaa T.
        Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus.
        Ann Intern Med. 2004; 140: 94-100
        • Ndrepepa G.
        • Kastrati A.
        • Braun S.
        • Koch W.
        • Kolling K.
        • Mehilli J.
        • et al.
        A prospective cohort study of predictive value of homocysteine in patients with type 2 diabetes and coronary artery disease.
        Clin Chim Acta. 2006; 373: 70-76
        • de Luis D.A.
        • Fernandez N.
        • Arranz M.
        • Aller R.
        • Izaola O.
        Total homocysteine and cognitive deterioration in people with type 2 diabetes.
        Diabetes Res Clin Pract. 2002; 55: 185-190
        • Ambrosch A.
        • Dierkes J.
        • Lobmann R.
        • Kuhne W.
        • Konig W.
        • Luley C.
        • et al.
        Relation between homocysteinaemia and diabetic neuropathy in patients with type 2 diabetes mellitus.
        Diabet Med. 2001; 18: 185-192
        • Gonzalez R.
        • Pedro T.
        • Real J.T.
        • Martinez-Hervas S.
        • Abellan M.R.
        • Lorente R.
        • et al.
        Plasma homocysteine levels are associated with ulceration of the foot in patients with type 2 diabetes mellitus.
        Diabetes Metab Res Rev. 2010; 26: 115-120
        • Thambyrajah J.
        • Landray M.J.
        • Jones H.J.
        • McGlynn F.J.
        • Wheeler D.C.
        • Townend J.N.
        A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease.
        J Am Coll Cardiol. 2001; 37: 1858-1863
        • Downs S.H.
        • Black N.
        The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions.
        J Epidemiol Community Health. 1998; 52: 377-384
        • Jadad A.R.
        • Moore R.A.
        • Carroll D.
        • Jenkinson C.
        • Reynolds D.J.
        • Gavaghan D.J.
        • et al.
        Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
        Control Clin Trials. 1996; 17: 1-12
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Higgins J.P.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Gargari B.P.
        • Aghamohammadi V.
        • Aliasgharzadeh A.
        Effect of folic acid supplementation on biochemical indices in overweight and obese men with type 2 diabetes.
        Diabetes Res Clin Pract. 2011; 94: 33-38
        • Aghamohammadi V.
        • Gargari B.P.
        • Aliasgharzadeh A.
        Effect of folic acid supplementation on homocysteine, serum total antioxidant capacity, and malondialdehyde in patients with type 2 diabetes mellitus.
        J Am Coll Nutr. 2011; 30: 210-215
        • Mangoni A.A.
        • Sherwood R.A.
        • Asonganyi B.
        • Swift C.G.
        • Thomas S.
        • Jackson S.H.
        Short-term oral folic acid supplementation enhances endothelial function in patients with type 2 diabetes.
        Am J Hypertens. 2005; 18: 220-226
        • Spoelstra-de M.A.
        • Brouwer C.B.
        • Terheggen F.
        • Bollen J.M.
        • Stehouwer C.D.
        • Smulders Y.M.
        No effect of folic acid on markers of endothelial dysfunction or inflammation in patients with type 2 diabetes mellitus and mild hyperhomocysteinaemia.
        Neth J Med. 2004; 62: 246-253
        • Wald D.S.
        • Law M.
        • Morris J.K.
        Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.
        BMJ. 2002; 325: 1202
        • Stehouwer C.D.A.
        • Schaper N.
        Therapeutic strategies in diabetes.
        Clinical Publishing Services, 2009
        • Ndrepepa G.
        • Kastrati A.
        • Braun S.
        • Koch W.
        • Kolling K.
        • Mehilli J.
        • et al.
        Circulating homocysteine levels in patients with type 2 diabetes mellitus.
        Nutr Metab Cardiovasc Dis. 2008; 18: 66-73
        • Bazzano L.A.
        • Reynolds K.
        • Holder K.N.
        • He J.
        Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials.
        JAMA. 2006; 296: 2720-2726
        • Ebbing M.
        • Bleie O.
        • Ueland P.M.
        • Nordrehaug J.E.
        • Nilsen D.W.
        • Vollset S.E.
        • et al.
        Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial.
        JAMA. 2008; 300: 795-804
        • Lonn E.
        • Yusuf S.
        • Arnold M.J.
        • Sheridan P.
        • Pogue J.
        • Micks M.
        • et al.
        Homocysteine lowering with folic acid and B vitamins in vascular disease.
        N Engl J Med. 2006; 354: 1567-1577
        • Galan P.
        • Kesse-Guyot E.
        • Czernichow S.
        • Briancon S.
        • Blacher J.
        • Hercberg S.
        Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.
        BMJ. 2010; 341: c6273
      1. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial.
        Lancet Neurol. 2010; 9: 855-865
        • Toole J.F.
        • Malinow M.R.
        • Chambless L.E.
        • Spence J.D.
        • Pettigrew L.C.
        • Howard V.J.
        • et al.
        Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.
        JAMA. 2004; 291: 565-575
        • Spence J.D.
        Homocysteine-lowering therapy: a role in stroke prevention?.
        Lancet Neurol. 2007; 6: 830-838
        • Refsum H.
        • Smith A.D.
        Homocysteine, B vitamins, and cardiovascular disease.
        N Engl J Med. 2006; 355: 207-211
        • McNulty H.
        • Pentieva K.
        • Hoey L.
        • Ward M.
        Homocysteine, B-vitamins and CVD.
        Proc Nutr Soc. 2008; 67: 232-237
        • Carlsen S.M.
        • Folling I.
        • Grill V.
        • Bjerve K.S.
        • Schneede J.
        • Refsum H.
        Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease.
        Scand J Clin Lab Invest. 1997; 57: 521-527
        • Wulffele M.G.
        • Kooy A.
        • Lehert P.
        • Bets D.
        • Ogterop J.C.
        • Borger van der Burg B.
        • et al.
        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.
        J Intern Med. 2003; 254: 455-463
      2. Diabetes drug interferes with vitamin B12.
        Harv Heart Lett. 2010; 20: 7
        • Mahajan R.
        • Gupta K.
        Revisiting metformin: annual vitamin b12 supplementation may become mandatory with long-term metformin use.
        J Young Pharm. 2010; 2: 428-429
        • Moreno H.
        • Croce N.
        • Kuffaty J.
        • Chuki E.
        • Berbesi M.
        • Fragachan F.
        Therapeutical effects of folic acid on serum homocysteine in hypertensive patients.
        Am J Hypertens. 2002; 15: 234
        • Ellison J.
        • Clark P.
        • Walker I.D.
        • Greer I.A.
        Effect of supplementation with folic acid throughout pregnancy on plasma homocysteine concentration.
        Thromb Res. 2004; 114: 25-27
        • Cafolla A.
        • Dragoni F.
        • Girelli G.
        • Tosti M.E.
        • Costante A.
        • De Luca A.M.
        • et al.
        Effect of folic acid and vitamin C supplementation on folate status and homocysteine level: a randomised controlled trial in Italian smoker-blood donors.
        Atherosclerosis. 2002; 163: 105-111
        • Vogel T.
        • Dali-Youcef N.
        • Kaltenbach G.
        • Andres E.
        Homocysteine, vitamin B12, folate and cognitive functions: a systematic and critical review of the literature.
        Int J Clin Pract. 2009; 63: 1061-1067
        • Carmel R.
        • Green R.
        • Rosenblatt D.S.
        • Watkins D.
        Update on cobalamin, folate, and homocysteine.
        Hematology Am Soc Hematol Educ Program. 2003; : 62-81
        • Drion I.
        B-vitamin therapy for diabetic nephropathy.
        JAMA. 2010; 304 ([author reply-7]): 636
        • Spence J.D.
        • Bang H.
        • Chambless L.E.
        • Stampfer M.J.
        Vitamin intervention for stroke prevention trial: an efficacy analysis.
        Stroke. 2005; 36: 2404-2409
        • House A.A.
        • Eliasziw M.
        • Cattran D.C.
        • Churchill D.N.
        • Oliver M.J.
        • Fine A.
        • et al.
        Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial.
        JAMA. 2010; 303: 1603-1609
        • Spence J.D.
        • Stampfer M.J.
        Understanding the complexity of homocysteine lowering with vitamins: the potential role of subgroup analyses.
        JAMA. 2011; 306: 2610-2611