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Vitamin E in the prevention of cardiovascular disease: the importance of proper patient selection

Open AccessPublished:March 15, 2013DOI:https://doi.org/10.1194/jlr.R026641
      Vitamin E is a naturally occurring fat-soluble antioxidant which has been proposed as a treatment for both primary and secondary protection against cardiovascular (CV) events. Promising data from observational epidemiological studies associating higher vitamin E dietary intake with lower risk of CV events have not been validated in randomized controlled clinical trials assessing the effect of vitamin E on CV outcomes. While the pendulum of medical opinion has swung to suggest that high dose vitamin E supplements have no place in the treatment and prevention of CV disease, new data is emerging that allows identification of a specific target population for this treatment, namely patients with diabetes mellitus and the haptoglobin genotype 2-2. This review details the scientific basis and clinical evidence related to the effect of vitamin E on CV outcomes, and the importance of proper patient selection in gaining therapeutic benefit from this intervention.
      Vitamin E is a group of eight lipophilic molecules, four of which are tocopherols and four of which are tocotrienols (
      • Wang X.
      • Quinn P.J.
      Vitamin E and its function in membranes.
      ). It is mostly found in nuts and various vegetable oils (
      US Department of Agriculture, Agricultural Research Service
      ). γ-Tocopherol is the most abundant form of vitamin E in Western diet, while α-tocopherol is the most abundant form of vitamin E in plasma, and is most biologically active. In vitro, vitamin E possesses many biological functions, including regulation of cell survival (
      • Mahoney C.W.
      • Azzi A.
      Vitamin E inhibits protein kinase C activity.
      ,
      • Boudreau R.T.
      • Garduno R.
      • Lin T.J.
      Protein phosphatase 2A and protein kinase Calpha are physically associated and are involved in Pseudomonas aeruginosa-induced interleukin 6 production by mast cells.
      ,
      • Zingg J.M.
      Modulation of signal transduction by vitamin E.
      ,
      • Boscoboinik D.
      • Szewczyk A.
      • Hensey C.
      • Azzi A.C.
      Inhibition of cell proliferation by alphatocopherol. Role of protein kinase.
      ,
      • Tasinato A.
      • Boscoboinik D.
      • Bartoli G.M.
      • Maroni P.
      • Azzi A.
      d-alpha-Tocopherol inhibition of vascular smooth muscle cell proliferation occurs at physiological concentrations, correlates with protein kinase C inhibition, and is independent of its antioxidant properties.
      • de Nigris F.
      • Franconi F.
      • Maida I.
      • Palumbo G.
      • Anania V.
      • Napoli C.
      Modulation by alpha- and gamma-tocopherol and oxidized low-density lipoprotein of apoptotic signaling in human coronary smooth muscle cells.
      ), enhancement of endothelial function (
      • Wu D.
      • Liu L.
      • Meydani M.
      • Meydani S.N.
      Effect of vitamin E on prostacyclin (PGI2) and prostaglandin (PG) E2 production by human aorta endothelial cells: mechanism of action.
      ,
      • Heller R.
      • Hecker M.
      • Stahmann N.
      • Thiele J.J.
      • Werner-Felmayer G.
      • Werner E.R.
      Alpha-tocopherol amplifies phosphorylation of endothelial nitric oxide synthase at serine 1177 and its short-chain derivative trolox stabilizes tetrahydrobiopterin.
      ,
      • Heller R.
      • Werner-Felmayer G.
      • Werner E.R.
      Alpha-tocopherol and endothelial nitric oxide synthesis.
      • Desideri G.
      • Marinucci M.C.
      • Tomassoni G.
      • Masci P.G.
      • Santucci A.
      • Ferri C.
      Vitamin E supplementation reduces plasma vascular cell adhesion molecule-1 and von Willebrand factor levels and increases nitric oxide concentrations in hypercholesterolemic patients.
      ), and regulation of inflammatory processes (
      • Yoshikawa T.
      • Yoshida N.
      • Manabe H.
      • Terasawa Y.
      • Takemura T.
      • Kondo M.
      Alpha-tocopherol protects against expression of adhesion molecules on neutrophils and endothelial cells.
      ,
      • Faruqi R.
      • de la Motte C.
      • DiCorleto P.E.
      Alpha-tocopherol inhibits agonist-induced monocytic cell adhesion to cultured human endothelial cells.
      ,
      • Yoshida N.
      • Yoshikawa T.
      • Manabe H.
      • Terasawa Y.
      • Kondo M.
      • Noguchi N.
      • Niki E.
      Vitamin E protects against polymorphonuclear leukocyte-dependent adhesion to endothelial cells.
      ,
      • Noguchi N.
      • Hanyu R.
      • Nonaka A.
      • Okimoto Y.
      • Kodama T.
      Inhibition of THP-1 cell adhesion to endothelial cells by alpha-tocopherol and alpha-tocotrienol is dependent on intracellular concentration of the antioxidants.
      ,
      • Wu D.
      • Koga T.
      • Martin K.R.
      • Meydani M.
      Effect of vitamin E on human aortic endothelial cell production of chemokines and adhesion to monocytes.
      ,
      • Koga T.
      • Kwan P.
      • Zubik L.
      • Ameho C.
      • Smith D.
      • Meydani M.
      Vitamin E supplementation suppresses macrophage accumulation and endothelial cell expression of adhesion molecules in the aorta of hypercholesterolemic rabbits.
      ,
      • Desideri G.
      • Croce G.
      • Marinucci M.C.
      • Masci P.G.
      • Stati M.
      • Valeri L.
      • Santucci A.
      • Ferri C.
      Prolonged, low dose alpha-tocopherol therapy counteracts intercellular cell adhesion molecule-1 activation.
      ,
      • van Dam B.
      • van Hinsbergh V.W.
      • Stehouwer C.D.
      • Versteilen A.
      • Dekker H.
      • Buytenhek R.
      • Princen H.M.
      • Schalkwijk C.G.
      Vitamin E inhibits lipid peroxidation-induced adhesion molecule expression in endothelial cells and decreases soluble cell adhesion molecules in healthy subjects.
      ,
      • Devaraj S.
      • Jialal I.
      Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from activated human monocytes by inhibition of 5-lipoxygenase.
      ,
      • Devaraj S.
      • Jialal I.
      Alpha-tocopherol decreases interleukin-1 beta release from activated human monocytes by inhibition of 5-lipoxygenase.
      ,
      • Devaraj S.
      • Li D.
      • Jialal I.
      The effects of alpha tocopherol supplementation on monocyte function. Decreased lipid oxidation, interleukin 1 beta secretion, and monocyte adhesion to endothelium.
      ,
      • Munteanu A.
      • Zingg J.M.
      • Azzi A.
      Anti-atherosclerotic effects of vitamin E–myth or reality?.
      ,
      • Munteanu A.
      • Taddei M.
      • Tamburini I.
      • Bergamini E.
      • Azzi A.
      • Zingg J.M.
      Antagonistic effects of oxidized low density lipoprotein and alpha-tocopherol on CD36 scavenger receptor expression in monocytes: involvement of protein kinase B and peroxisome proliferator-activated receptor-gamma.
      ,
      • Khanduja K.L.
      • Avti P.K.
      • Kumar S.
      • Pathania V.
      • Pathak C.M.
      Inhibitory effect of vitamin E on proinflammatory cytokines-and endotoxin-induced nitric oxide release in alveolar macrophages.
      • Cachia O.
      • Benna J.E.
      • Pedruzzi E.
      • Descomps B.
      • Gougerot-Pocidalo M.A.
      • Leger C.L.
      Alpha-tocopherol inhibits the respiratory burst in human monocytes. Attenuation of p47(phox) membrane translocation and phosphorylation.
      ). In vivo it is most notable for its antioxidant functions.
      Vitamin E is classified as an antioxidant due to its ability to scavenge lipid radicals and terminate oxidative chain reactions (
      • Wang X.
      • Quinn P.J.
      Vitamin E and its function in membranes.
      ). It can terminate radical chain reactions by interacting with the lipid peroxyl radical, preventing it from generating a new radical and perpetuating the chain reaction by oxidizing other lipids (
      • Wang X.
      • Quinn P.J.
      Vitamin E and its function in membranes.
      ). Following its oxidation, vitamin E can be recycled back to its native unoxidized form by various soluble antioxidants such as vitamin C and ubiquinol. This process prevents the accumulation of vitamin E radicals and their subsequent peroxidation of lipids (
      • Brigelius-Flohé R.
      Vitamin E: the shrew waiting to be tamed.
      ), and is considered by some to be critical for the antioxidant activity of vitamin E (
      • Carr A.C.
      • Zhu B.Z.
      • Frei B.
      Potential antiatherogenic mechanisms of ascorbate (vitamin C) and alpha-tocopherol (vitamin E).
      ). It has been suggested that all of the other biological functions of vitamin E are actually a result of its antioxidant activity (
      • Blum S.
      • Milman U.
      • Shapira C.
      • Levy A.P.
      Pharmacogenomic application of the haptoglobin genotype in the prevention of diabetic cardiovascular disease.
      ).
      Basic research has provided credible mechanisms by which vitamin E might exert cardiovascular (CV) benefit, including inhibition of oxidation of low-density lipoprotein (LDL) cholesterol in plasma (
      • Levy A.P.
      • Blum S.
      Pharmacogenomics in prevention of diabetic cardiovascular disease: utilization of the haptoglobin genotype in determining benefit from vitamin E.
      ).Observational epidemiologic studies suggested that individuals who consumed high amounts of vitamin E through diet or supplements had decreased rates of CV disease (
      • Rimm E.B.
      • Stampfer M.J.
      • Ascherio A.
      • Giovannucci E.
      • Colditz G.A.
      • Willett W.C.
      Vitamin E consumption and the risk of coronary heart disease in men.
      ,
      • Stampfer M.J.
      • Hennekens C.H.
      • Manson J.E.
      • Colditz G.A.
      • Rosner B.
      • Willett W.C.
      Vitamin E consumption and the risk of coronary disease in women.
      ,
      • Hennekens C.H.
      • Buring J.E.
      • Peto R.
      Antioxidant vitamins–benefits not yet proved.
      • Buring J.E.
      • Hennekens C.H.
      Antioxidant vitamins and cardiovascular disease.
      ). These observations laid the foundation for additional, more robust clinical research in this field. Thus, several prospective studies were initiated with the aim of assessing the benefit of vitamin E in primary and secondary prevention of CV morbidity and mortality.

      VITAMIN E IN CARDIOVASCULAR PROTECTION

      Numerous prospective randomized clinical trials assessing the effect of vitamin E supplementation on CV protection have been carried out over the past 15 years. These studies have assessed this intervention in primary and secondary prevention (Table 1).
      TABLE 1Prospective studies assessing vitamin E for cardiovascular protection
      TrialInterventionFollow-up (years)Specific Patient CharacteristicsNumber of PatientsClinical Outcomes
      Studies assessing vitamin E for primary prevention [Results are given in relative measures (95% CI) or absolute numbers (P value)]
      Virtamo et al. (
      • Virtamo J.
      • Rapola J.M.
      • Ripatti S.
      • Heinonen O.P.
      • Taylor P.R.
      • Albanes D.
      • Huttunen J.K.
      Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease.
      )
      α-tocopherol (50 mg/day),  β carotene (20 mg/day), both, or placebo6.1Male, smokers27,271First MI and CV death:
      RR 0.98 (0.87–1.10)
      PPP (
      • de Gaetano G.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project.
      )
      Aspirin (100 mg/day) and  α-tocopherol (300 mg/day) (2 × 2 design)3.6Over 1 CV risk factor4,495CV death, MI, stroke:
      RR 1·07 (0.74–1.56)
      St. Francis (
      • Arad Y.
      • Spadaro L.A.
      • Roth M.
      • Newstein D.
      • Guerci A.D.
      Treatment of asymptomatic adults with elevated coronary calcium scores with atorvastatin, vitamin C, and vitamin E: the St. Francis Heart Study randomized clinical trial.
      )
      Atorvastatin (20 mg/day) plus  vitamin C (1 g/day) plus α-tocopherol (1,000 IU/day) versus placebo4.3CCS ≥ 80th percentile1,005ASCVD event rate:
      −6.9% versus 9.9% (P= 0.08)
      VEAPS (
      • Hodis H.N.
      • Mack W.J.
      • LaBree L.
      • Mahrer P.R.
      • Sevanian A.
      • Liu C.R.
      • Liu C.H.
      • Hwang J.
      • Selzer R.H.
      • Azen S.P.
      Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS).
      )
      DL-α-tocopherol (400 IU/day)  or placebo3LDL > 3.37 mmol/l353CC-IMT change from baseline:
      −0.0023 ± 0.0007 versus  0.0040 ± 0.0007 (P= 0.08)
      ATIC (
      • Nanayakkara P.W.
      • van Guldener C.
      • ter Wee P.M.
      • Scheffer P.G.
      • van Ittersum F.J.
      • Twisk J.W.
      • Teerlink T.
      • van Dorp W.
      • Stehouwer C.D.
      Effect of a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on carotid intima-media thickness, endothelial function, and renal function in patients with mild to moderate chronic kidney disease: results from the Anti-Oxidant Therapy in Chronic Renal Insufficiency (ATIC) study.
      )
      α-tocopherol, pravastatin, and  homocysteine-lowering therapy, consecutively introduced1.5CKD93CC-IMT, ED, renal function,  and albuminuria:
      CC-IMT: 0.68–0.63 mm versus  0.65–0.71 mm (P < 0.001)
      BA-FMD: 4.66–7.56% versus  6.21–4.73% (P < 0.001)
      eGFR: 32–35 ml/min/1.73 m2 versus 35–33 ml/min/1.73 m2 (P= 0.89)
      Urinary albumin excretion:  34% (3–44%) reduction
      WHS (
      • Lee I.M.
      • Cook N.R.
      • Gaziano J.M.
      • Gordon D.
      • Ridker P.M.
      • Manson J.E.
      • Hennekens C.H.
      • Buring J.E.
      Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial.
      ,

      Chae C. U. Albert C. M.Moorthy M. V. Lee I. M.Buring J. E. Vitamin E supplementation and the risk of heart failure in women. Circ. Heart Fail., 5: 176–182.

      )
      α-tocopherol (600 IU),  aspirin, or placebo10.1Women39,876CV death, MI, stroke:
      RR 0.93 (0.82–1.05)
      Cancer:
      RR 1.01 (0.94–1.08)
      Heart failure:
      HR 0.93 (0.71–1.21)
      PHS II (
      • Sesso H.D.
      • Buring J.E.
      • Christen W.G.
      • Kurth T.
      • Belanger C.
      • MacFadyen J.
      • Bubes V.
      • Manson J.E.
      • Glynn R.J.
      • Gaziano J.M.
      Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial.
      )
      α-tocopherol (400 IU every other  day), vitamin C, or placebo8Men14,641CV death, MI, stroke:
      HR 1.01 (0.90–1.13)
      Studies assessing vitamin E for secondary prevention [Results are given in relative measures (95% CI) or absolute numbers (P value)]
      DeMaio et al. (
      • DeMaio S.J.
      • King 3rd, S.B.
      • Lembo N.J.
      • Roubin G.S.
      • Hearn J.A.
      • Bhagavan H.N.
      • Sgoutas D.S.
      Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA).
      )
      DL-α-tocopherol (1,200 IU/day)  or placebo0.33100Restenosis:
      −34.6% versus 50% (P= 0.06)
      CHAOS (
      • Stephens N.G.
      • Parsons A.
      • Schofield P.M.
      • Kelly F.
      • Cheeseman K.
      • Mitchinson M.J.
      Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS).
      )
      DL-α-tocopherol (400 IU/day or  800 IU/d) or placebo1.42,002CV death and nonfatal MI:
      RR 0.53 (0.34–0.83)
      GISSI-Prevenzione (
      Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico
      Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.
      )
      PUFA (1 g/day), DL-α-tocopherol  (300 mg/day), both, or none3.55,658Death, MI, and stroke:
      RR 0.95 (0.86–1.05)
      HOPE (
      • Yusuf S.
      • Dagenais G.
      • Pogue J.
      • Bosch J.
      • Sleight P.
      Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
      )
      α-tocopherol (400 IU/day), ACE  inhibitor, or placebo (2 × 2 design)4.59,541CV death, MI, and stroke:
      RR 1.05 (0.95–1.16)
      WAVE (
      • Waters D.D.
      • Alderman E.L.
      • Hsia J.
      • Howard B.V.
      • Cobb F.R.
      • Rogers W.J.
      • Ouyang P.
      • Thompson P.
      • Tardif J.C.
      • Higginson L.
      • et al.
      Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial.
      )
      Vitamin E (400 IU/day) plus  vitamin C (500 mg BID), HRT, or placebo (2 × 2 design)4Postmenop ausal women423Death, MI, stroke:
      HR 1.5 (0.80–2.9)
      Heart Protection Study (
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      )
      DL-α-tocopherol (600 mg/day),  vitamin C (250 mg/day), and β-carotene (20 mg/day) or placebo520,536CV death, MI, stroke,  revascularization:
      RR 1.00 (0.94–1.06)
      Cancer:
      RR 0.98 (0.89–1.08)
      SPACE (
      • Boaz M.
      • Smetana S.
      • Weinstein T.
      • Matas Z.
      • Gafter U.
      • Iaina A.
      • Knecht A.
      • Weissgarten Y.
      • Brunner D.
      • Fainaru M.
      • et al.
      Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial.
      )
      α-tocopherol (800 IU/day) or  placebo1.4Hemodialysis196MI, ischemic stroke, peripheral  vascular disease, and unstable angina:
      RR 0.46 (0.27–0.78)
      Longitudinal studies assessing CV outcomes according to Hp phenotype in patients with DM [Results are given in relative measures (95% CI) or percentages (P value)]
      Strong Heart Study (
      • Levy A.P.
      • Hochberg I.
      • Jablonski K.
      • Resnick H.E.
      • Lee E.T.
      • Best L.
      • Howard B.V.
      Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: the Strong Heart Study.
      )
      6Native Americans412CV events:
      OR Hp 2-2 versus 1-1: 5.08  (2.37–10.89)
      OR Hp 2-2 versus 2-1: 3.26  (1.67–6.37)
      Burbea et al. (
      • Burbea Z.
      • Nakhoul F.
      • Zoabi R.
      • Hochberg I.
      • Levy N.S.
      • Benchetrit S.
      • Weissgarten J.
      • Tovbin D.
      • Knecht A.
      • Iaina A.
      • et al.
      Haptoglobin phenotype as a predictive factor of mortality in diabetic haemodialysis patients.
      )
      3Hemodialysis3923 years survival rate:
      Hp 2-2 45.1% versus Hp  non-2-2 50% (P < 0.003)
      Costacou et al. (
      • Costacou T.
      • Ferrell R.E.
      • Orchard T.J.
      Haptoglobin genotype: a determinant of cardiovascular complication risk in type 1 diabetes.
      )
      18CV disease free, type 1  diabetics453Angina, ischemic ECG, MI,  angiographic stenosis >50%, or revascularization:
      HR Hp 2-2 versus Hp  1-1: 2.21 (1.05–4.65)
      Roguinet al (
      • Roguin A.
      • Koch W.
      • Kastrati A.
      • Aronson D.
      • Schomig A.
      • Levy A.P.
      Haptoglobin genotype is predictive of major adverse cardiac events in the 1-year period after percutaneous transluminal coronary angioplasty in individuals with diabetes.
      ).
      1Post PTCA935Total MI, total mortality, target  vessel revascularization, MACE (combination of all):
      Hp 2-2, 31.4%; Hp 1-1, 20.9%;  Hp 2-1, 26.4% (P= 0.015)
      Suleiman et al. (
      • Suleiman M.
      • Aronson D.
      • Asleh R.
      • Kapeliovich M.R.
      • Roguin A.
      • Meisel S.R.
      • Shochat M.
      • Sulieman A.
      • Reisner S.A.
      • Markiewicz W.
      • et al.
      Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction.
      )
      30 daysAcute MI50630 days mortality + heart failure:
      OR Hp 1-1 versus Hp 2-2:  0.35 (0.15–0.86)
      Longitudinal studies assessing CV outcomes according to Hp phenotype with and without vitamin E treatment [Results are given in relative measures (95% CI)]
      WHS study data (
      • Lee I.M.
      • Cook N.R.
      • Gaziano J.M.
      • Gordon D.
      • Ridker P.M.
      • Manson J.E.
      • Hennekens C.H.
      • Buring J.E.
      Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial.
      ,
      • Blum S.
      • Vardi M.
      • Levy N.S.
      • Miller-Lotan R.
      • Levy A.P.
      The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes.
      )
      α-tocopherol (600 IU), aspirin,  or placebo10.1Women721CV death, MI, stroke:
      OR in Hp 2-2, 0.87 (0.49, 1.53)
      OR in Hp non-2-2,  1.33 (0.75, 2.37)
      ICARE (
      • Milman U.
      • Blum S.
      • Shapira C.
      • Aronson D.
      • Miller-Lotan R.
      • Anbinder Y.
      • Alshiek J.
      • Bennett L.
      • Kostenko M.
      • Landau M.
      • et al.
      Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial.
      )
      D-α-tocopherol (400 IU/day)  or placebo1.52,967CV death, MI, stroke:
      OR in Hp 2-2, 0.46 (0.25, 0.85)
      HOPE study data (
      • Yusuf S.
      • Dagenais G.
      • Pogue J.
      • Bosch J.
      • Sleight P.
      Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
      ,
      • Levy A.P.
      • Gerstein H.C.
      • Miller-Lotan R.
      • Ratner R.
      • McQueen M.
      • Lonn E.
      • Pogue J.
      The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes.
      )
      Vitamin E (400 IU/day), ACE  inhibitor, or placebo (2 × 2 design)4.5530CV death, MI, stroke:
      OR in Hp 2-2, 0.69 (0.42, 1.13)
      OR in non-Hp 2-2,  1.02 (0.69, 1.50)
      ASCVD, atherosclerotic cardiovascular disease (events includes coronary death, nonfatal MI, coronary revascularization procedures, nonhemorrhagic stroke, and peripheral revascularization procedures); BA-FMD, brachial artery flow-mediated dilatation; CC-IMT, common carotid intima-media thickness; CCS, coronary calcium score; CKD, chronic kidney disease; ED, endothelial dysfunction; ECG, electrocardiogram; MACE, major adverse cardiac events.

      Primary prevention

      In 1998, Virtamo et al. (
      • Virtamo J.
      • Rapola J.M.
      • Ripatti S.
      • Heinonen O.P.
      • Taylor P.R.
      • Albanes D.
      • Huttunen J.K.
      Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease.
      ) published the results of a randomized controlled trial (RCT) in which 27,271 Finnish male smokers aged 50–69 years with no history of myocardial infarction (MI) were randomly assigned to receive vitamin E (50 mg/day), β-carotene (20 mg/day), both agents, or placebo daily for 5–8 years (median, 6.1 years). The end point was the first MI. The incidence of MI decreased 4% among recipients of vitamin E compared with the respective nonrecipients, particularly due to a decrease in fatal events. However, the observed effect did not reach statistical significance. In 2001, de Gaetano et al. (
      • de Gaetano G.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project.
      ) published the results of the Collaborative Group of the Primary Prevention Project (PPP). In this randomized two-by-two factorial design study, the effect of aspirin (100 mg/day) and vitamin E (300 mg/day) in the prevention of cardiovascular events was assessed in 4,495 people with one or more cardiovascular risk factors. After a mean follow-up of 3.6 years the trial was prematurely stopped on ethical grounds when newly available evidence from other trials on the benefit of aspirin in primary prevention had emerged. Vitamin E treatment had not prevented CV events to a significant degree at the time of study closure. However, a subsequent analysis of outcomes in patients with diabetes mellitus (DM) was consistent with the lack of benefit of vitamin E treatment (
      • Sacco M.
      • Pellegrini F.
      • Roncaglioni M.C.
      • Avanzini F.
      • Tognoni G.
      • Nicolucci A.
      Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial.
      ). Similar results were obtained from the St. Francis RCT study published in 2005, in which 1,005 asymptomatic men and women aged 50 to 70 years with coronary calcium scores at or above the 80th percentile for age and gender were randomized to atorvastatin (20 mg/day), vitamin C (1 g/day), and vitamin E (1,000 IU/day) (
      • Arad Y.
      • Spadaro L.A.
      • Roth M.
      • Newstein D.
      • Guerci A.D.
      Treatment of asymptomatic adults with elevated coronary calcium scores with atorvastatin, vitamin C, and vitamin E: the St. Francis Heart Study randomized clinical trial.
      ). All study participants also received aspirin, 81 mg daily. Mean duration of treatment was 4.3 years. None of these interventions had an effect on progression of coronary calcium score, or on clinical outcomes. The authors stipulated that treatment may have reduced cardiovascular events in a subgroup of subjects with very high calcium scores.
      Other studies were designed to assess the effect of vitamin E on the progression of atherosclerosis rather than on definitive clinical outcomes. The results of the Vitamin E Atherosclerosis Prevention Study (VEAPS) were presented in 2002 (
      • Hodis H.N.
      • Mack W.J.
      • LaBree L.
      • Mahrer P.R.
      • Sevanian A.
      • Liu C.R.
      • Liu C.H.
      • Hwang J.
      • Selzer R.H.
      • Azen S.P.
      Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS).
      ). Men and women over 40 years old with LDL cholesterol levels above 3.37 mmol/l (130 mg/dl) and no clinical signs or symptoms of CV disease were randomized to vitamin E (400 IU/day) or placebo and followed for an average of 3 years. The primary trial end point was the rate of change in the common carotid artery far-wall intima-media thickness (IMT) assessed by computer image-processed B-mode ultrasonograms. Compared with placebo, vitamin E supplementation significantly reduced circulating oxidized LDL and reduced LDL oxidative susceptibility. However, vitamin E supplementation did not reduce the progression of IMT. The effect of a treatment strategy consisting of pravastatin, vitamin E, and homocysteine-lowering therapy on carotid IMT, endothelial function, and renal function in patients with mild to moderate chronic kidney disease was evaluated in the Anti-Oxidant Therapy in Chronic Renal Insufficiency (ATIC) study. Vitamin E supplementation was initiated after 6 months of pravastatin treatment, after which homocysteine-lowering therapy was introduced for another 6 months. Patients were randomized to treatment versus placebo groups and were followed for 18 months. This combined stepwise antioxidant approach yielded a significant decrease in IMT, endothelial dysfunction, and albuminuria, but did not affect renal function (
      • Nanayakkara P.W.
      • van Guldener C.
      • ter Wee P.M.
      • Scheffer P.G.
      • van Ittersum F.J.
      • Twisk J.W.
      • Teerlink T.
      • van Dorp W.
      • Stehouwer C.D.
      Effect of a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on carotid intima-media thickness, endothelial function, and renal function in patients with mild to moderate chronic kidney disease: results from the Anti-Oxidant Therapy in Chronic Renal Insufficiency (ATIC) study.
      ).
      In 2005 the results from the Women's Health Study (WHS) were published (
      • Lee I.M.
      • Cook N.R.
      • Gaziano J.M.
      • Gordon D.
      • Ridker P.M.
      • Manson J.E.
      • Hennekens C.H.
      • Buring J.E.
      Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial.
      ). The trial was designed to test whether vitamin E supplementation decreases the risk of CV disease and cancer among healthy women. A group of 39,876 apparently healthy US women aged at least 45 years were randomly assigned to receive vitamin E (600 IU), aspirin, or placebo, using a two-by-two factorial design, and were followed for an average of 10.1 years. The primary outcomes were a composite end point of first major CV event (nonfatal MI, nonfatal stroke, or CV death) and cancer. During follow-up a nonsignificant 7% risk reduction [relative risk (RR), 0.93; 95% confidence interval (CI), 0.82–1.05; P= 0.26] was noted in favor of the vitamin E treatment. The only statistically significant effect was a 24% reduction (RR, 0.76; 95% CI, 0.59–0.98; P= 0.03) in CV death. A secondary analysis of these data showed lack of effect of vitamin E to reduce heart failure events in this population (

      Chae C. U. Albert C. M.Moorthy M. V. Lee I. M.Buring J. E. Vitamin E supplementation and the risk of heart failure in women. Circ. Heart Fail., 5: 176–182.

      ). Overall the authors concluded that vitamin E treatment did not decrease the number of major CV events, did not affect total mortality, and although there was decreased CV mortality in healthy women, the results did not support recommending vitamin E supplementation for CV disease prevention.
      The Physicians Health Study was a randomized double-blind placebo-controlled factorial trial of vitamins E (400 IU every other day) and C (500 mg/day), assessing CV outcomes (MI, nonfatal stroke, and CV death) in 14,641 males over the age of 50 years, of which 94.9% were free from CV disease at enrollment. At a follow-up through 8 years, none of the interventions had any effect on CV outcomes, but vitamin E was associated with an increased risk of hemorrhagic stroke [hazard ratio (HR), 1.74; 95% CI, 1.04–2.91; P= 0.036] (
      • Sesso H.D.
      • Buring J.E.
      • Christen W.G.
      • Kurth T.
      • Belanger C.
      • MacFadyen J.
      • Bubes V.
      • Manson J.E.
      • Glynn R.J.
      • Gaziano J.M.
      Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial.
      ).

      Secondary prevention

      In 1992, DeMaio et al. (
      • DeMaio S.J.
      • King 3rd, S.B.
      • Lembo N.J.
      • Roubin G.S.
      • Hearn J.A.
      • Bhagavan H.N.
      • Sgoutas D.S.
      Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA).
      ) published the results of a RCT aimed at assessing whether vitamin E (1,200 IU/day) can prevent restenosis (defined as stenosis ≥50%) following percutaneous transluminal coronary angioplasty. Follow-up cardiac catheterization showed that patients receiving vitamin E had a 35.5% restenosis versus 47.5% restenosis in patients receiving placebo, but this difference did not reach statistical significance. The first study to assess robust clinical outcomes associated with vitamin E intervention in the setting of secondary prevention was the Cambridge Heart Antioxidant Study (CHAOS) (
      • Stephens N.G.
      • Parsons A.
      • Schofield P.M.
      • Kelly F.
      • Cheeseman K.
      • Mitchinson M.J.
      Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS).
      ). This RCT investigated the effects of vitamin E (400 IU/day or 800 IU/day) on the risk of CV death and nonfatal MI in patients with overt clinical and angiographic coronary atherosclerosis at recruitment. Overall 1,035 patients received the intervention, and 967 received placebo. In a median follow-up of 510 days the risk of the primary trial endpoint of CV death and nonfatal MI was significantly reduced (RR 0.53, P= 0.005), with MI being the contributing factor associated with the observed benefit, while excess CV death rate was noted in the vitamin E treated group. The study was not powered to explain the disparity in treatment effect. Contrary to these findings, the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI)-Prevenzione investigators randomly assigned patients surviving recent MI to n-3 polyunsaturated fatty acids (PUFAs) (1 g daily, n = 2,836), vitamin E (300 mg daily, n = 2,830), both (n = 2,830), or none (control, n = 2,828) for 3.5 years. The primary combined efficacy end point of death, nonfatal MI, and stroke was not affected by vitamin E treatment (
      Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico
      Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.
      ).
      In 2000, the results of the Heart and Outcomes Prevention Evaluation (HOPE) study were published (
      • Yusuf S.
      • Dagenais G.
      • Pogue J.
      • Bosch J.
      • Sleight P.
      Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
      ). In this trial, the investigators enrolled 2,545 women and 6,996 men 55 years of age or older who were at high risk for CV because they had cardiovascular disease or diabetes in addition to one other risk factor. These patients were randomly assigned to treatment groups according to a two-by-two factorial design to receive either vitamin E (400 IU/day) from natural sources or matching placebo, and either an angiotensin-converting enzyme inhibitor (ramipril) or matching placebo, for a mean of 4.5 years. The combined outcome of CV death, nonfatal MI, and stroke, as well as the individual outcomes, did not differ between the groups. The authors concluded that vitamin E had no apparent effect on CV outcomes in this high-risk population. In concurrent publications from the HOPE cohort, lack of vitamin E protection against CV outcomes was noted in patients with DM (
      • Lonn E.
      • Yusuf S.
      • Hoogwerf B.
      • Pogu J.
      • Yi Q.
      • Zinman B.
      • Bosch J.
      • Dagenais G.
      • Mann J.F.
      • Gerstein H.C.
      Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy.
      ) and mild to moderate chronic kidney injury (
      • Mann J.F.
      • Lonn E.M.
      • Yi Q.
      • Gerstein H.C.
      • Hoogwerf B.J.
      • Pogue J.
      • Bosch J.
      • Dagenais G.R.
      • Yusuf S.
      Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: results of the HOPE study.
      ). The HOPE-The Ongoing Outcomes (TOO) study (
      • Lonn E.
      • Bosch J.
      • Yusuf S.
      • Sheridan P.
      • Pogue J.
      • Arnold J.M.
      • Ross C.
      • Arnold A.
      • Sleight P.
      • Probstfield J.
      • et al.
      Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial.
      ) was an extension of the original HOPE study, in which patients were randomly assigned to a daily dose of natural source vitamin E (400 IU) or matching placebo, with the main outcome measures being cancer incidence, cancer deaths, and major CV events (MI, stroke, and CV death). Primary outcomes did not differ, while patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01–1.26; P= 0.03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00–1.47; P= 0.045).
      Additional studies assessed the effect of combination vitamin E and vitamin C on CV outcomes. The Women's Angiographic Vitamin and Estrogen (WAVE) trial, a randomized double-blind trial, was designed to determine whether hormone replacement therapy (HRT) or a combination of vitamin E (400 IU/day) plus vitamin C (500 mg BID) supplements, alone or in combination, influenced the progression of coronary artery disease in 423 postmenopausal women (
      • Waters D.D.
      • Alderman E.L.
      • Hsia J.
      • Howard B.V.
      • Cobb F.R.
      • Rogers W.J.
      • Ouyang P.
      • Thompson P.
      • Tardif J.C.
      • Higginson L.
      • et al.
      Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial.
      ). The HR for death, nonfatal MI, or stroke was 1.5 (95% CI, 0.80–2.9), signifying a trend toward higher risk in vitamin E- and C-treated patients. In the Heart Protection Study, 20,536 adults (aged 40–80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive antioxidant vitamin supplementation (600 mg vitamin E, 250 mg vitamin C, and 20 mg β-carotene daily) versus matching placebo (
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      ). The intervention did not produce any significant reductions in the 5 year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome.
      Contrary to the above, the Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE) study (
      • Boaz M.
      • Smetana S.
      • Weinstein T.
      • Matas Z.
      • Gafter U.
      • Iaina A.
      • Knecht A.
      • Weissgarten Y.
      • Brunner D.
      • Fainaru M.
      • et al.
      Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial.
      ), in which hemodialysis patients with CV disease were randomized to vitamin E (800 IU/day) or placebo, showed a beneficial effect for vitamin E. The RR for a composite of MI, ischemic stroke, peripheral vascular disease, and unstable angina at a median of 519 days was 0.46 (95% CI, 0.27–0.78; P= 0.014). Death was not affected by the intervention.
      In view of the lack of consistent clinical data supporting a beneficial role for vitamin E supplementation in preventing cardiovascular events, the medical community has largely abandoned this avenue of treatment.

      DIABETES, HAPTOGLOBIN GENOTYPE, AND VITAMIN E

      Atherosclerosis is prevalent in diabetics, and over 75% of DM patients die of atherovascular disease (
      • Moreno P.R.
      • Fuster V.
      New aspects in the pathogenesis of diabetic atherothrombosis.
      ). The pathogenesis of atherosclerosis in DM is complex. Endothelial dysfunction is the hallmark of the pathological insult inflicted on blood vessels of DM individuals (
      • Reusch J.E.
      • Wang C.C.
      Cardiovascular disease in diabetes: where does glucose fit in?.
      ,
      • Eckel R.H.
      • Wassef M.
      • Chait A.
      • Sobel B.
      • Barrett E.
      • King G.
      • Lopes-Virella M.
      • Reusch J.
      • Ruderman N.
      • Steiner G.
      • et al.
      Prevention conference VI: diabetes and cardiovascular disease. Writing group II: pathogenesis of atherosclerosis in diabetes.
      ). The role of oxidative stress in mediating the development of atherosclerosis has been formulated in the oxidative hypothesis (
      • Blum S.
      • Vardi M.
      • Brown J.B.
      • Russell A.
      • Milman U.
      • Shapira C.
      • Levy N.S.
      • Miller-Lotan R.
      • Asleh R.
      • Levy A.P.
      Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype.
      ), in which the LDL molecule undergoes oxidative modification. Oxidized LDL is not recognized by the LDL receptor but is readily taken up by the CD36 scavenger receptor pathway in macrophages leading to appreciable cholesterol ester accumulation and foam cell formation (
      • Goyal T.
      • Mitra S.
      • Khaidakov M.
      • Wang X.
      • Singla S.
      • Ding Z.
      • Liu S.
      • Mehta J.L.
      Current concepts of the role of oxidized LDL receptors in atherosclerosis.
      ). Oxidized LDL is pro-inflammatory, causes inhibition of endothelial nitric oxide synthetase, promotes vasoconstriction and monocyte adhesion, and promotes platelet aggregation and thrombosis (
      • Webster M.W.
      Clinical practice and implications of recent diabetes trials.
      ). Both oxidative stress and LDL oxidation are known to be present in patients with DM (
      • Goyal T.
      • Mitra S.
      • Khaidakov M.
      • Wang X.
      • Singla S.
      • Ding Z.
      • Liu S.
      • Mehta J.L.
      Current concepts of the role of oxidized LDL receptors in atherosclerosis.
      ).
      Haptoglobin (Hp) is an abundant plasma glycoprotein synthesized by hepatocytes. Two classes of functional alleles (1 and 2) have been identified, with homozygous (1-1 or 2-2) and heterozygous (2-1) genotypes possible (
      • Bowman B.H.
      • Kurosky A.
      Haptoglobin. The evolutionary product of duplication, unequal crossing over, and point mutation.
      ,
      • Langlois M.R.
      • Delanghe J.R.
      Biological and clinical significance of haptoglobin polymorphism in humans.
      ). The frequency of the 3 Hp genotypes in Western countries is approximately 16% Hp 1-1, 48% Hp 2-1, and 36% Hp 2-2 (
      • Bowman B.H.
      • Kurosky A.
      Haptoglobin. The evolutionary product of duplication, unequal crossing over, and point mutation.
      ,
      • Langlois M.R.
      • Delanghe J.R.
      Biological and clinical significance of haptoglobin polymorphism in humans.
      ) and is the same in individuals with and without DM (
      • Kristiansen M.
      • Graversen J.H.
      • Jacobsen C.
      • Sonne O.
      • Hoffman H.J.
      • Law S.K.A.
      • Moestrup S.K.
      Identification of the haemoglobin scavenger receptor.
      ). The protein products of the Hp 1 Hp 2 alleles differ in their antioxidant function. Hp is essential to the clearance of hemoglobin (Hb), and by forming the Hp-Hb complex Hp prevents oxidative stress on the vasculature exerted by Hb iron. Studies have shown that Hp 2-2-Hb complexes are cleared less efficiently than Hp 2-1-Hb and Hp 1-1-Hb complexes (
      • Bamm V.V.
      • Tsemakhovich V.A.
      • Shaklai M.
      • Shaklai N.
      Haptoglobin phenotypes differ in their ability to inhibit heme transfer from hemoglobin to LDL.
      ,
      • Melamed-Frank M.
      • Lache O.
      • Enav B.I.
      • Szafranek T.
      • Levy N.S.
      • Ricklis R.M.
      • Levy A.P.
      Structure-function analysis of the antioxidant properties of haptoglobin.
      ), particularly in DM individuals (
      • Melamed-Frank M.
      • Lache O.
      • Enav B.I.
      • Szafranek T.
      • Levy N.S.
      • Ricklis R.M.
      • Levy A.P.
      Structure-function analysis of the antioxidant properties of haptoglobin.
      ). Hp-Hb deficient clearance in Hp 2-2 DM individuals results in increased Hp-Hb binding to Apo A1 on high-density lipoprotein (HDL), thereby tethering the pro-oxidative heme moiety to HDL (
      • Bamm V.V.
      • Tsemakhovich V.A.
      • Shaklai M.
      • Shaklai N.
      Haptoglobin phenotypes differ in their ability to inhibit heme transfer from hemoglobin to LDL.
      ). HDL in Hp 2-2 DM individuals is deficient in its ability to stimulate the reverse transfer of cholesterol from macrophages (
      • Bamm V.V.
      • Tsemakhovich V.A.
      • Shaklai M.
      • Shaklai N.
      Haptoglobin phenotypes differ in their ability to inhibit heme transfer from hemoglobin to LDL.
      ). Oxidative modification of the HDL appears to be responsible for these alterations in HDL function in DM individuals with Hp 2-2 (
      • Levy A.P.
      • Hochberg I.
      • Jablonski K.
      • Resnick H.E.
      • Lee E.T.
      • Best L.
      • Howard B.V.
      Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: the Strong Heart Study.
      ).

      Clinical studies assessing the risk of cardiovascular complications in diabetics with Hp 2-2 versus diabetics with Hp non-2-2

      One case-control and five prospective longitudinal studies have assessed the association between Hp genotype and the event rates of stroke, nonfatal MI, CV death, heart failure, and mortality in DM. In the Strong Heart Study (SHS), a population based longitudinal study in Native Americans, 206 incident cases and 206 matched controls were analyzed over an interval of six years (
      • Levy A.P.
      • Hochberg I.
      • Jablonski K.
      • Resnick H.E.
      • Lee E.T.
      • Best L.
      • Howard B.V.
      Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: the Strong Heart Study.
      ). In a multivariate analysis controlling for conventional CV risk factors, the Hp genotype was a highly statistically significant independent predictor of CV outcomes in DM. The odds ratio (OR) in the SHS of having CV disease in DM with the Hp 2-2 genotype was five times greater than in DM individuals with the Hp 1-1 genotype.
      In prospective longitudinal trials, 1,829 patients with DM and the Hp 2-2 genotype and 3,135 patients with DM and the Hp 1-1 or Hp 2-1 genotypes, were followed for periods ranging between 30 days and a mean of 18.8 years. Patients enrolled in the Israel Cardiovascular Vitamin E (ICARE) study (
      • Milman U.
      • Blum S.
      • Shapira C.
      • Aronson D.
      • Miller-Lotan R.
      • Anbinder Y.
      • Alshiek J.
      • Bennett L.
      • Kostenko M.
      • Landau M.
      • et al.
      Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial.
      ), and a subset of patients from the WHS (
      • Blum S.
      • Vardi M.
      • Levy N.S.
      • Miller-Lotan R.
      • Levy A.P.
      The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes.
      ,
      • Levy A.P.
      • Gerstein H.C.
      • Miller-Lotan R.
      • Ratner R.
      • McQueen M.
      • Lonn E.
      • Pogue J.
      The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes.
      ) and HOPE (
      • Roguin A.
      • Koch W.
      • Kastrati A.
      • Aronson D.
      • Schomig A.
      • Levy A.P.
      Haptoglobin genotype is predictive of major adverse cardiac events in the 1-year period after percutaneous transluminal coronary angioplasty in individuals with diabetes.
      ,
      • Burbea Z.
      • Nakhoul F.
      • Zoabi R.
      • Hochberg I.
      • Levy N.S.
      • Benchetrit S.
      • Weissgarten J.
      • Tovbin D.
      • Knecht A.
      • Iaina A.
      • et al.
      Haptoglobin phenotype as a predictive factor of mortality in diabetic haemodialysis patients.
      ) trials, were studied for total mortality, CV mortality, nonfatal MI, and stroke. When comparing DM patients with Hp 2-2 to a group of non-2-2 Hp type patients (Hp 1-1 and 2-1), a harmful effect of Hp 2-2 genotype was observed. For CV mortality, the pooled percentage of patients experiencing an event was 3.4% versus 1.2%, for the Hp 2-2 versus the non-2-2 Hp groups, respectively. For stroke, the percentages were 2.8% versus 1.7%, respectively. Data from a fourth trial were available for nonfatal MI (
      • Suleiman M.
      • Aronson D.
      • Asleh R.
      • Kapeliovich M.R.
      • Roguin A.
      • Meisel S.R.
      • Shochat M.
      • Sulieman A.
      • Reisner S.A.
      • Markiewicz W.
      • et al.
      Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction.
      ), and the combination of these four studies has shown that the percentage of patients experiencing an event in the Hp 2-2 group was 6.29% versus 3.74% in non-2-2 Hp patients. The ORs for CV mortality, stroke, and nonfatal myocardial infarction all suggest a harmful effect for the Hp 2-2 genotype with statistical significance 2.37 (95% CI, 1.32–4.24), 2.08 (95% CI, 1.22–3.55), 1.94 (95% CI, 1.39–2.71), respectively. Combining a total of CV mortality, strokes, and nonfatal MIs also shows a striking difference in events of 9.35% versus 5.76% [OR 2.03 (95% CI, 1.46–2.81)]. Total mortality assessed in three trials (
      • Suleiman M.
      • Aronson D.
      • Asleh R.
      • Kapeliovich M.R.
      • Roguin A.
      • Meisel S.R.
      • Shochat M.
      • Sulieman A.
      • Reisner S.A.
      • Markiewicz W.
      • et al.
      Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction.
      ,
      • Levy A.P.
      • Friedenberg P.
      • Lotan R.
      • Ouyang P.
      • Tripputi M.
      • Higginson L.
      • Cobb F.R.
      • Tardif J.C.
      • Bittner V.
      • Howard B.V.
      The effect of vitamin therapy on the progression of coronary artery atherosclerosis varies by haptoglobin type in postmenopausal women.
      • Asleh R.
      • Guetta J.
      • Kalet-Litman S.
      • Miller-Lotan R.
      • Levy A.P.
      Haptoglobin genotype and diabetes dependent differences in iron mediated oxidative stress in vitro and in vivo.
      ) was higher in the Hp 2-2 group [10.54% versus 6.97%, OR 1.53 (95% CI, 1.17–2.00)]. These effects were maintained after adjusting for the duration of follow-up.

      Controlled clinical studies assessing the effect of vitamin E on rates of CV complications in individuals with diabetes and the Hp 2-2 genotype

      In three of these studies (or their subsets) the effect of vitamin E on patients with the Hp 2-2 genotype versus patients without the Hp 2-2 genotype was evaluated. The ICARE (
      • Milman U.
      • Blum S.
      • Shapira C.
      • Aronson D.
      • Miller-Lotan R.
      • Anbinder Y.
      • Alshiek J.
      • Bennett L.
      • Kostenko M.
      • Landau M.
      • et al.
      Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial.
      ) study was a RCT aimed to evaluate this intervention in DM patients for which the Hp genotype was prospectively collected. Additionally, blood samples from a subset of patients recruited for the WHS (
      • Lee I.M.
      • Cook N.R.
      • Gaziano J.M.
      • Gordon D.
      • Ridker P.M.
      • Manson J.E.
      • Hennekens C.H.
      • Buring J.E.
      Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial.
      ,
      • Blum S.
      • Vardi M.
      • Levy N.S.
      • Miller-Lotan R.
      • Levy A.P.
      The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes.
      ) and HOPE (
      • Yusuf S.
      • Dagenais G.
      • Pogue J.
      • Bosch J.
      • Sleight P.
      Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
      ,
      • Levy A.P.
      • Gerstein H.C.
      • Miller-Lotan R.
      • Ratner R.
      • McQueen M.
      • Lonn E.
      • Pogue J.
      The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes.
      ) studies were analyzed for Hp polymorphism, and the outcomes were reassessed according to the patient's Hp type. In all of these studies, it was found that Hp 2-2 DM conferred a higher risk for CV mortality without intervention (compared with the non-2-2 Hp cohort), and that intervention with vitamin E significantly decreased this risk. Meta-analysis of the HOPE and ICARE data showed that vitamin E significantly reduces a composite of CV death, MI, and stroke in Hp 2-2 diabetes patients (OR 0.58, CI 0.4–0.86), while having no influence in Hp 1-1 or Hp 2-1 diabetes patients (
      • Blum S.
      • Vardi M.
      • Brown J.B.
      • Russell A.
      • Milman U.
      • Shapira C.
      • Levy N.S.
      • Miller-Lotan R.
      • Asleh R.
      • Levy A.P.
      Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype.
      ). In the WHS cohort, vitamin E supplementation was associated with an approximately 15% reduction in composite CV outcomes in Hp 2-2 DM individuals, compared with a 20–25% increase in non-Hp 2-2 DM individuals (
      • Blum S.
      • Vardi M.
      • Levy N.S.
      • Miller-Lotan R.
      • Levy A.P.
      The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes.
      ).

      Lack of benefit of a combination of vitamin C and vitamin E on atherosclerosis in Hp 2-2 diabetic individuals

      A potential inconsistency in the hypothesis that vitamin E supplementation provides cardiovascular protection in Hp 2-2 diabetic individuals, is the failure to demonstrate a protective effect of the combination of vitamin C and vitamin E against the angiographic progression of atherosclerosis in WAVE Hp 2-2 participants. In the initial analysis of WAVE (
      • Waters D.D.
      • Alderman E.L.
      • Hsia J.
      • Howard B.V.
      • Cobb F.R.
      • Rogers W.J.
      • Ouyang P.
      • Thompson P.
      • Tardif J.C.
      • Higginson L.
      • et al.
      Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial.
      ), change of mean lumen diameter (MLD) from baseline to the concluding angiogram was not affected by a combination of vitamin E plus vitamin C supplements. Retrospective analysis of these data after Hp genotypes were obtained on the entire WAVE cohort demonstrated a significant benefit from the combined treatment with vitamin C and vitamin E on MLD progression in Hp 1-1 and a significant worsening in MLD progression in Hp 2-2 individuals, especially in the setting of diabetes (
      • Levy A.P.
      • Friedenberg P.
      • Lotan R.
      • Ouyang P.
      • Tripputi M.
      • Higginson L.
      • Cobb F.R.
      • Tardif J.C.
      • Bittner V.
      • Howard B.V.
      The effect of vitamin therapy on the progression of coronary artery atherosclerosis varies by haptoglobin type in postmenopausal women.
      ). We have proposed that this apparent harmful effect of vitamin C in Hp 2-2 diabetic individuals on angiographic progression of atherosclerosis was due to the ability of vitamin C to promote redox cycling of the increased nontransferrin bound iron (Hp 2-2-Hg complexes) found in Hp 2-2 diabetic individuals (
      • Asleh R.
      • Guetta J.
      • Kalet-Litman S.
      • Miller-Lotan R.
      • Levy A.P.
      Haptoglobin genotype and diabetes dependent differences in iron mediated oxidative stress in vitro and in vivo.
      ). Supporting this hypothesis, divergent effects of α-tocopherol and vitamin C on HDL function have been demonstrated in vitro and in vivo in Hp 2-2 diabetic mice (
      • Asleh R.
      • Levy A.P.
      Divergent effects of alpha-tocopherol and vitamin C on the generation of dysfunctional HDL associated with diabetes and the Hp 2-2 genotype.
      ). It was shown that vitamin C could not block HDL oxidation by glycosylated Hp 2-2-Hb complexes in vitro (glycosylated Hb was prepared by a 3 day incubation with glycolaldehyde), nor could it restore the ability of serum from Hp 2-2 diabetic mice to mediate HDL-mediated cholesterol efflux from macrophages, whereas α-tocopherol could favorably affect both. Importantly, the addition of vitamin C to α-tocopherol in this study was shown to diminish the protective effect of vitamin E on HDL function. These results emphasize that in assessing the effect of antioxidant supplementation on the risk of vascular diabetes complications, all antioxidants are not equivalent and different outcomes may be obtained with different combinations of antioxidants.

      CONCLUSIONS

      Does vitamin E protect against the development of CV disease? The answer appears to be a resounding no when one provides vitamin E indiscriminately to unselected populations. However, vitamin E has been shown to be cardioprotective in certain patient subgroups under high levels of oxidative stress such as those individuals on hemodialysis (SPACE) or in diabetic individuals with the Hp 2-2 genotype (ICARE). A plausible biological rational has been provided. The adoption of a pharmacogenomic approach to the use of vitamin E appears to identify a subgroup of individuals for whom vitamin E provides significant clinical benefit.

      REFERENCES

        • Wang X.
        • Quinn P.J.
        Vitamin E and its function in membranes.
        Prog. Lipid Res. 1999; 38: 309-336
        • US Department of Agriculture, Agricultural Research Service
        USDA National Nutrient Database for Standard Reference, Release 24. Accessed February 11, 2012. 2011 (http://www.ars.usda.gov/ba/bhnrc/ndl)
        • Mahoney C.W.
        • Azzi A.
        Vitamin E inhibits protein kinase C activity.
        Biochem. Biophys. Res. Commun. 1988; 154: 694-697
        • Boudreau R.T.
        • Garduno R.
        • Lin T.J.
        Protein phosphatase 2A and protein kinase Calpha are physically associated and are involved in Pseudomonas aeruginosa-induced interleukin 6 production by mast cells.
        J. Biol. Chem. 2002; 277: 5322-5329
        • Zingg J.M.
        Modulation of signal transduction by vitamin E.
        Mol. Aspects Med. 2007; 28: 481-506
        • Boscoboinik D.
        • Szewczyk A.
        • Hensey C.
        • Azzi A.C.
        Inhibition of cell proliferation by alphatocopherol. Role of protein kinase.
        J. Biol. Chem. 1991; 266: 6188-6194
        • Tasinato A.
        • Boscoboinik D.
        • Bartoli G.M.
        • Maroni P.
        • Azzi A.
        d-alpha-Tocopherol inhibition of vascular smooth muscle cell proliferation occurs at physiological concentrations, correlates with protein kinase C inhibition, and is independent of its antioxidant properties.
        Proc. Natl. Acad. Sci. USA. 1995; 92: 12190-12194
        • de Nigris F.
        • Franconi F.
        • Maida I.
        • Palumbo G.
        • Anania V.
        • Napoli C.
        Modulation by alpha- and gamma-tocopherol and oxidized low-density lipoprotein of apoptotic signaling in human coronary smooth muscle cells.
        Biochem. Pharmacol. 2000; 59: 1477-1487
        • Wu D.
        • Liu L.
        • Meydani M.
        • Meydani S.N.
        Effect of vitamin E on prostacyclin (PGI2) and prostaglandin (PG) E2 production by human aorta endothelial cells: mechanism of action.
        Ann. N. Y. Acad. Sci. 2004; 1031: 425-427
        • Heller R.
        • Hecker M.
        • Stahmann N.
        • Thiele J.J.
        • Werner-Felmayer G.
        • Werner E.R.
        Alpha-tocopherol amplifies phosphorylation of endothelial nitric oxide synthase at serine 1177 and its short-chain derivative trolox stabilizes tetrahydrobiopterin.
        Free Radic. Biol. Med. 2004; 37: 620-631
        • Heller R.
        • Werner-Felmayer G.
        • Werner E.R.
        Alpha-tocopherol and endothelial nitric oxide synthesis.
        Ann. N. Y. Acad. Sci. 2004; 1031: 74-85
        • Desideri G.
        • Marinucci M.C.
        • Tomassoni G.
        • Masci P.G.
        • Santucci A.
        • Ferri C.
        Vitamin E supplementation reduces plasma vascular cell adhesion molecule-1 and von Willebrand factor levels and increases nitric oxide concentrations in hypercholesterolemic patients.
        J. Clin. Endocrinol. Metab. 2002; 87: 2940-2945
        • Yoshikawa T.
        • Yoshida N.
        • Manabe H.
        • Terasawa Y.
        • Takemura T.
        • Kondo M.
        Alpha-tocopherol protects against expression of adhesion molecules on neutrophils and endothelial cells.
        Biofactors. 1998; 7: 15-19
        • Faruqi R.
        • de la Motte C.
        • DiCorleto P.E.
        Alpha-tocopherol inhibits agonist-induced monocytic cell adhesion to cultured human endothelial cells.
        J. Clin. Invest. 1994; 94: 592-600
        • Yoshida N.
        • Yoshikawa T.
        • Manabe H.
        • Terasawa Y.
        • Kondo M.
        • Noguchi N.
        • Niki E.
        Vitamin E protects against polymorphonuclear leukocyte-dependent adhesion to endothelial cells.
        J. Leukoc. Biol. 1999; 65: 757-763
        • Noguchi N.
        • Hanyu R.
        • Nonaka A.
        • Okimoto Y.
        • Kodama T.
        Inhibition of THP-1 cell adhesion to endothelial cells by alpha-tocopherol and alpha-tocotrienol is dependent on intracellular concentration of the antioxidants.
        Free Radic. Biol. Med. 2003; 34: 1614-1620
        • Wu D.
        • Koga T.
        • Martin K.R.
        • Meydani M.
        Effect of vitamin E on human aortic endothelial cell production of chemokines and adhesion to monocytes.
        Atherosclerosis. 1999; 147: 297-307
        • Koga T.
        • Kwan P.
        • Zubik L.
        • Ameho C.
        • Smith D.
        • Meydani M.
        Vitamin E supplementation suppresses macrophage accumulation and endothelial cell expression of adhesion molecules in the aorta of hypercholesterolemic rabbits.
        Atherosclerosis. 2004; 176: 265-272
        • Desideri G.
        • Croce G.
        • Marinucci M.C.
        • Masci P.G.
        • Stati M.
        • Valeri L.
        • Santucci A.
        • Ferri C.
        Prolonged, low dose alpha-tocopherol therapy counteracts intercellular cell adhesion molecule-1 activation.
        Clin. Chim. Acta. 2002; 320: 5-9
        • van Dam B.
        • van Hinsbergh V.W.
        • Stehouwer C.D.
        • Versteilen A.
        • Dekker H.
        • Buytenhek R.
        • Princen H.M.
        • Schalkwijk C.G.
        Vitamin E inhibits lipid peroxidation-induced adhesion molecule expression in endothelial cells and decreases soluble cell adhesion molecules in healthy subjects.
        Cardiovasc. Res. 2003; 57: 563-571
        • Devaraj S.
        • Jialal I.
        Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from activated human monocytes by inhibition of 5-lipoxygenase.
        Free Radic. Biol. Med. 2005; 38: 1212-1220
        • Devaraj S.
        • Jialal I.
        Alpha-tocopherol decreases interleukin-1 beta release from activated human monocytes by inhibition of 5-lipoxygenase.
        Arterioscler. Thromb. Vasc. Biol. 1999; 19: 1125-1133
        • Devaraj S.
        • Li D.
        • Jialal I.
        The effects of alpha tocopherol supplementation on monocyte function. Decreased lipid oxidation, interleukin 1 beta secretion, and monocyte adhesion to endothelium.
        J. Clin. Invest. 1996; 98: 756-763
        • Munteanu A.
        • Zingg J.M.
        • Azzi A.
        Anti-atherosclerotic effects of vitamin E–myth or reality?.
        J. Cell. Mol. Med. 2004; 8: 59-76
        • Munteanu A.
        • Taddei M.
        • Tamburini I.
        • Bergamini E.
        • Azzi A.
        • Zingg J.M.
        Antagonistic effects of oxidized low density lipoprotein and alpha-tocopherol on CD36 scavenger receptor expression in monocytes: involvement of protein kinase B and peroxisome proliferator-activated receptor-gamma.
        J. Biol. Chem. 2006; 281: 6489-6497
        • Khanduja K.L.
        • Avti P.K.
        • Kumar S.
        • Pathania V.
        • Pathak C.M.
        Inhibitory effect of vitamin E on proinflammatory cytokines-and endotoxin-induced nitric oxide release in alveolar macrophages.
        Life Sci. 2005; 76: 2669-2680
        • Cachia O.
        • Benna J.E.
        • Pedruzzi E.
        • Descomps B.
        • Gougerot-Pocidalo M.A.
        • Leger C.L.
        Alpha-tocopherol inhibits the respiratory burst in human monocytes. Attenuation of p47(phox) membrane translocation and phosphorylation.
        J. Biol. Chem. 1998; 273: 32801-32805
        • Brigelius-Flohé R.
        Vitamin E: the shrew waiting to be tamed.
        Free Radic. Biol. Med. 2009; 46: 543-554
        • Carr A.C.
        • Zhu B.Z.
        • Frei B.
        Potential antiatherogenic mechanisms of ascorbate (vitamin C) and alpha-tocopherol (vitamin E).
        Circ. Res. 2000; 87: 349-354
        • Blum S.
        • Milman U.
        • Shapira C.
        • Levy A.P.
        Pharmacogenomic application of the haptoglobin genotype in the prevention of diabetic cardiovascular disease.
        Pharmacogenomics. 2008; 9: 989-991
        • Levy A.P.
        • Blum S.
        Pharmacogenomics in prevention of diabetic cardiovascular disease: utilization of the haptoglobin genotype in determining benefit from vitamin E.
        Expert Rev. Cardiovasc. Ther. 2007; 5: 1105-1111
        • Rimm E.B.
        • Stampfer M.J.
        • Ascherio A.
        • Giovannucci E.
        • Colditz G.A.
        • Willett W.C.
        Vitamin E consumption and the risk of coronary heart disease in men.
        N. Engl. J. Med. 1993; 328: 1450-1456
        • Stampfer M.J.
        • Hennekens C.H.
        • Manson J.E.
        • Colditz G.A.
        • Rosner B.
        • Willett W.C.
        Vitamin E consumption and the risk of coronary disease in women.
        N. Engl. J. Med. 1993; 328: 1444-1449
        • Hennekens C.H.
        • Buring J.E.
        • Peto R.
        Antioxidant vitamins–benefits not yet proved.
        N. Engl. J. Med. 1994; 330: 1080-1081
        • Buring J.E.
        • Hennekens C.H.
        Antioxidant vitamins and cardiovascular disease.
        Nutr. Rev. 1997; 55: S53-S58
        • Virtamo J.
        • Rapola J.M.
        • Ripatti S.
        • Heinonen O.P.
        • Taylor P.R.
        • Albanes D.
        • Huttunen J.K.
        Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease.
        Arch. Intern. Med. 1998; 158: 668-675
        • de Gaetano G.
        • Collaborative Group of the Primary Prevention Project
        Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project.
        Lancet. 2001; 357: 89-95
        • Sacco M.
        • Pellegrini F.
        • Roncaglioni M.C.
        • Avanzini F.
        • Tognoni G.
        • Nicolucci A.
        Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial.
        Diabetes Care. 2003; 26: 3264-3272
        • Arad Y.
        • Spadaro L.A.
        • Roth M.
        • Newstein D.
        • Guerci A.D.
        Treatment of asymptomatic adults with elevated coronary calcium scores with atorvastatin, vitamin C, and vitamin E: the St. Francis Heart Study randomized clinical trial.
        J. Am. Coll. Cardiol. 2005; 46: 166-172
        • Hodis H.N.
        • Mack W.J.
        • LaBree L.
        • Mahrer P.R.
        • Sevanian A.
        • Liu C.R.
        • Liu C.H.
        • Hwang J.
        • Selzer R.H.
        • Azen S.P.
        Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS).
        Circulation. 2002; 106: 1453-1459
        • Nanayakkara P.W.
        • van Guldener C.
        • ter Wee P.M.
        • Scheffer P.G.
        • van Ittersum F.J.
        • Twisk J.W.
        • Teerlink T.
        • van Dorp W.
        • Stehouwer C.D.
        Effect of a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on carotid intima-media thickness, endothelial function, and renal function in patients with mild to moderate chronic kidney disease: results from the Anti-Oxidant Therapy in Chronic Renal Insufficiency (ATIC) study.
        Arch. Intern. Med. 2007; 167: 1262-1270
        • Lee I.M.
        • Cook N.R.
        • Gaziano J.M.
        • Gordon D.
        • Ridker P.M.
        • Manson J.E.
        • Hennekens C.H.
        • Buring J.E.
        Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial.
        JAMA. 2005; 294: 56-65
      1. Chae C. U. Albert C. M.Moorthy M. V. Lee I. M.Buring J. E. Vitamin E supplementation and the risk of heart failure in women. Circ. Heart Fail., 5: 176–182.

        • Sesso H.D.
        • Buring J.E.
        • Christen W.G.
        • Kurth T.
        • Belanger C.
        • MacFadyen J.
        • Bubes V.
        • Manson J.E.
        • Glynn R.J.
        • Gaziano J.M.
        Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial.
        JAMA. 2008; 300: 2123-2133
        • DeMaio S.J.
        • King 3rd, S.B.
        • Lembo N.J.
        • Roubin G.S.
        • Hearn J.A.
        • Bhagavan H.N.
        • Sgoutas D.S.
        Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA).
        J. Am. Coll. Nutr. 1992; 11: 68-73
        • Stephens N.G.
        • Parsons A.
        • Schofield P.M.
        • Kelly F.
        • Cheeseman K.
        • Mitchinson M.J.
        Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS).
        Lancet. 1996; 347: 781-786
        • Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico
        Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.
        Lancet. 1999; 354: 447-455
        • Yusuf S.
        • Dagenais G.
        • Pogue J.
        • Bosch J.
        • Sleight P.
        Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
        N. Engl. J. Med. 2000; 342: 154-160
        • Lonn E.
        • Yusuf S.
        • Hoogwerf B.
        • Pogu J.
        • Yi Q.
        • Zinman B.
        • Bosch J.
        • Dagenais G.
        • Mann J.F.
        • Gerstein H.C.
        Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy.
        Diabetes Care. 2002; 25: 1919-1927
        • Mann J.F.
        • Lonn E.M.
        • Yi Q.
        • Gerstein H.C.
        • Hoogwerf B.J.
        • Pogue J.
        • Bosch J.
        • Dagenais G.R.
        • Yusuf S.
        Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: results of the HOPE study.
        Kidney Int. 2004; 65: 1375-1380
        • Lonn E.
        • Bosch J.
        • Yusuf S.
        • Sheridan P.
        • Pogue J.
        • Arnold J.M.
        • Ross C.
        • Arnold A.
        • Sleight P.
        • Probstfield J.
        • et al.
        Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial.
        JAMA. 2005; 293: 1338-1347
        • Waters D.D.
        • Alderman E.L.
        • Hsia J.
        • Howard B.V.
        • Cobb F.R.
        • Rogers W.J.
        • Ouyang P.
        • Thompson P.
        • Tardif J.C.
        • Higginson L.
        • et al.
        Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial.
        JAMA. 2002; 288: 2432-2440
        • Heart Protection Study Collaborative Group
        MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial.
        Lancet. 2002; 360: 23-33
        • Boaz M.
        • Smetana S.
        • Weinstein T.
        • Matas Z.
        • Gafter U.
        • Iaina A.
        • Knecht A.
        • Weissgarten Y.
        • Brunner D.
        • Fainaru M.
        • et al.
        Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial.
        Lancet. 2000; 356: 1213-1218
        • Moreno P.R.
        • Fuster V.
        New aspects in the pathogenesis of diabetic atherothrombosis.
        J. Am. Coll. Cardiol. 2004; 44: 2293-2300
        • Reusch J.E.
        • Wang C.C.
        Cardiovascular disease in diabetes: where does glucose fit in?.
        J. Clin. Endocrinol. Metab. 2011; 96: 2367-2376
        • Eckel R.H.
        • Wassef M.
        • Chait A.
        • Sobel B.
        • Barrett E.
        • King G.
        • Lopes-Virella M.
        • Reusch J.
        • Ruderman N.
        • Steiner G.
        • et al.
        Prevention conference VI: diabetes and cardiovascular disease. Writing group II: pathogenesis of atherosclerosis in diabetes.
        Circulation. 2002; 105: e138-e143
        • Blum S.
        • Vardi M.
        • Brown J.B.
        • Russell A.
        • Milman U.
        • Shapira C.
        • Levy N.S.
        • Miller-Lotan R.
        • Asleh R.
        • Levy A.P.
        Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype.
        Pharmacogenomics. 2010; 11: 675-684
        • Goyal T.
        • Mitra S.
        • Khaidakov M.
        • Wang X.
        • Singla S.
        • Ding Z.
        • Liu S.
        • Mehta J.L.
        Current concepts of the role of oxidized LDL receptors in atherosclerosis.
        Curr. Atheroscler. Rep. 2012; 14: 150-159
        • Webster M.W.
        Clinical practice and implications of recent diabetes trials.
        Curr. Opin. Cardiol. 2011; 26: 288-293
        • Bowman B.H.
        • Kurosky A.
        Haptoglobin. The evolutionary product of duplication, unequal crossing over, and point mutation.
        Adv. Hum. Genet. 1982; 12: 189-261
        • Langlois M.R.
        • Delanghe J.R.
        Biological and clinical significance of haptoglobin polymorphism in humans.
        Clin. Chem. 1996; 42: 1589-1600
        • Kristiansen M.
        • Graversen J.H.
        • Jacobsen C.
        • Sonne O.
        • Hoffman H.J.
        • Law S.K.A.
        • Moestrup S.K.
        Identification of the haemoglobin scavenger receptor.
        Nature. 2001; 409: 198-201
        • Bamm V.V.
        • Tsemakhovich V.A.
        • Shaklai M.
        • Shaklai N.
        Haptoglobin phenotypes differ in their ability to inhibit heme transfer from hemoglobin to LDL.
        Biochemistry. 2004; 43: 3899-3906
        • Melamed-Frank M.
        • Lache O.
        • Enav B.I.
        • Szafranek T.
        • Levy N.S.
        • Ricklis R.M.
        • Levy A.P.
        Structure-function analysis of the antioxidant properties of haptoglobin.
        Blood. 2001; 98: 3693-3698
        • Levy A.P.
        • Hochberg I.
        • Jablonski K.
        • Resnick H.E.
        • Lee E.T.
        • Best L.
        • Howard B.V.
        Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: the Strong Heart Study.
        J. Am. Coll. Cardiol. 2002; 40: 1984-1990
        • Milman U.
        • Blum S.
        • Shapira C.
        • Aronson D.
        • Miller-Lotan R.
        • Anbinder Y.
        • Alshiek J.
        • Bennett L.
        • Kostenko M.
        • Landau M.
        • et al.
        Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial.
        Arterioscler. Thromb. Vasc. Biol. 2008; 28: 341-347
        • Blum S.
        • Vardi M.
        • Levy N.S.
        • Miller-Lotan R.
        • Levy A.P.
        The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes.
        Atherosclerosis. 2010; 211: 25-27
        • Levy A.P.
        • Gerstein H.C.
        • Miller-Lotan R.
        • Ratner R.
        • McQueen M.
        • Lonn E.
        • Pogue J.
        The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes.
        Diabetes Care. 2004; 27: 2767
        • Roguin A.
        • Koch W.
        • Kastrati A.
        • Aronson D.
        • Schomig A.
        • Levy A.P.
        Haptoglobin genotype is predictive of major adverse cardiac events in the 1-year period after percutaneous transluminal coronary angioplasty in individuals with diabetes.
        Diabetes Care. 2003; 26: 2628-2631
        • Burbea Z.
        • Nakhoul F.
        • Zoabi R.
        • Hochberg I.
        • Levy N.S.
        • Benchetrit S.
        • Weissgarten J.
        • Tovbin D.
        • Knecht A.
        • Iaina A.
        • et al.
        Haptoglobin phenotype as a predictive factor of mortality in diabetic haemodialysis patients.
        Ann. Clin. Biochem. 2004; 41: 469-473
        • Suleiman M.
        • Aronson D.
        • Asleh R.
        • Kapeliovich M.R.
        • Roguin A.
        • Meisel S.R.
        • Shochat M.
        • Sulieman A.
        • Reisner S.A.
        • Markiewicz W.
        • et al.
        Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction.
        Diabetes. 2005; 54: 2802-2806
        • Levy A.P.
        • Friedenberg P.
        • Lotan R.
        • Ouyang P.
        • Tripputi M.
        • Higginson L.
        • Cobb F.R.
        • Tardif J.C.
        • Bittner V.
        • Howard B.V.
        The effect of vitamin therapy on the progression of coronary artery atherosclerosis varies by haptoglobin type in postmenopausal women.
        Diabetes Care. 2004; 27: 925-930
        • Asleh R.
        • Guetta J.
        • Kalet-Litman S.
        • Miller-Lotan R.
        • Levy A.P.
        Haptoglobin genotype and diabetes dependent differences in iron mediated oxidative stress in vitro and in vivo.
        Circ. Res. 2005; 96: 435-441
        • Asleh R.
        • Levy A.P.
        Divergent effects of alpha-tocopherol and vitamin C on the generation of dysfunctional HDL associated with diabetes and the Hp 2-2 genotype.
        Antioxid. Redox Signal. 2010; 12: 209-217
        • Costacou T.
        • Ferrell R.E.
        • Orchard T.J.
        Haptoglobin genotype: a determinant of cardiovascular complication risk in type 1 diabetes.
        Diabetes. 2008; 57: 1702-1706