Vitamins as cofactors

Coenzymes from B vitamins

Most B vitamins are converted into coenzymes, small molecules that particular enzymes require ¹²³⁴.

Vitamin	Coenzyme	Enzymes or reactions	Deficiency
Thiamine (B1)	Thiamine pyrophosphate	Pyruvate, 2-oxoglutarate and branched-chain 2-oxo acid dehydrogenases; transketolase ¹	Beriberi, Wernicke encephalopathy ¹
Riboflavin (B2)	FMN, FAD	Glutathione reductase, MTHFR ²	Ariboflavinosis: cheilosis, glossitis, anaemia ²
Niacin (B3)	NAD+, NADP+	Dehydrogenases ³	Pellagra ³
Pantothenic acid (B5)	Coenzyme A	Acyl-group transfer ⁵	Rare ⁵
Vitamin B6	Pyridoxal 5′-phosphate	Aminotransferases, decarboxylases, glycogen phosphorylase ⁴	Microcytic anaemia, seizures ⁴
Biotin (B7)	Enzyme-bound biotin	Acetyl-CoA, pyruvate, propionyl-CoA and β-methylcrotonyl-CoA carboxylases ⁶	Dermatitis, hair loss, ataxia ⁶
Folate (B9)	Tetrahydrofolate	One-carbon transfers for DNA bases and methionine ⁷	Megaloblastic anaemia ⁸
Vitamin B12	Methylcobalamin, adenosylcobalamin	Methionine synthase, methylmalonyl-CoA mutase ⁹	Megaloblastic anaemia, myeloneuropathy ⁸

In the pyruvate dehydrogenase complex, E1 decarboxylates pyruvate with thiamine pyrophosphate and reductively acetylates a lipoyl group of E2, E2 transfers the acetyl group to coenzyme A, and E3 reoxidises the dihydrolipoyl group with FAD and NAD+ ¹⁰.

Lipoyl group cycle of the pyruvate dehydrogenase complexMitochondrial matrix

S-Acetyldihydrolipoyl-E2Dihydrolipoyl-E2Dihydrolipoamide acetyltransferase (E2; DLAT)Coenzyme A → acetyl-CoA
Dihydrolipoyl-E2Lipoyl-E2Dihydrolipoamide dehydrogenase (E3; DLD)FAD, NAD+ → NADHElectrons pass from the dihydrolipoyl group to FAD and then to NAD+
Lipoyl-E2S-Acetyldihydrolipoyl-E2Pyruvate dehydrogenase (E1; PDHA1, PDHB)Thiamine pyrophosphate, Mg2+, Pyruvate → CO2Decarboxylates pyruvate, then reductively acetylates the lipoyl group

B12 deficiency traps folate as 5-methyltetrahydrofolate, as the one-carbon chapter explains ⁸.

Vitamin C and collagen

Humans must obtain vitamin C from food, and it is needed to make collagen, the main protein of skin, bone and connective tissue ¹¹.

Ascorbate keeps the metal ion of dioxygenases reduced, and the procollagen proline and lysine hydroxylases need it for maximal activity ¹¹. Prolyl 4-hydroxylase, a non-haem iron enzyme, forms 4-hydroxyproline, which greatly raises the thermal stability of the collagen triple helix ¹². In adults, scurvy develops below a plasma ascorbate of 10 µmol/L, with bleeding gums, bruising and poor wound healing; 10 mg daily prevents it ¹¹.

Vitamin K and warfarin

Vitamin K is needed to activate several blood-clotting proteins, and warfarin acts by blocking its recycling ¹³.

γ-Glutamyl carboxylase converts glutamate residues of factors II, VII, IX and X and proteins C, S and Z to γ-carboxyglutamate while oxidising vitamin K hydroquinone to the epoxide ¹³. Vitamin K epoxide reductase reduces the epoxide to the quinone and then to the hydroquinone, and warfarin inhibits both steps ¹⁴.

Vitamin K cycleEndoplasmic reticulum membrane, particularly in liver and bone

Vitamin K hydroquinoneVitamin K epoxideγ-Glutamyl carboxylase (GGCX)Glutamate → γ-carboxyglutamate, CO2, O2Carboxylates factors II, VII, IX and X and proteins C, S and Z
Vitamin K epoxideVitamin K quinoneVitamin K epoxide reductase (VKORC1)WarfarinEach reduction oxidises two active-site cysteines of the enzyme
Vitamin K quinoneVitamin K hydroquinoneVitamin K epoxide reductase (VKORC1)Warfarin

VKORC1 encodes the reductase; its promoter variant c.-1639G>A lowers expression and the warfarin dose required ¹⁵. Vitamin K deficiency prolongs the prothrombin time and causes bleeding ¹³. Without prophylaxis, late vitamin K deficiency bleeding occurred in 4.4 to 7.2 per 100,000 births in western Europe; the estimated relative risk was 81 ¹³.

Supplements in adults without deficiency

In trials of adults without known deficiency, vitamin supplements gave little or no protection against cardiovascular disease, cancer or death ¹⁶.

In an evidence review for the US Preventive Services Task Force, two trials of vitamin C 500 mg daily for 3 to 8 years in 15,031 participants found no benefit ¹⁶. Multivitamins were associated with less cancer (odds ratio 0.93, 95% CI 0.87 to 0.99; 4 trials, 48,859 participants), with absolute differences of −0.2 to −1.2 percentage points in adequately powered trials ¹⁶.

References

Regulator
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Turck D, Bresson JL, Burlingame B, Dean T, Fairweather-Tait S, et al. Dietary reference values for thiamin EFSA Journal, 2016.
doi:10.2903/j.efsa.2016.4653 PubMed 42006014
Funding and finding
Funding
European Food Safety Authority, on request from the European Commission (question EFSA-Q-2011-01225).
Finding
Free thiamin is the precursor of thiamin diphosphate (TDP, thiamin pyrophosphate), the coenzyme of pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and branched-chain alpha-keto acid dehydrogenase and of transketolase in the pentose phosphate pathway; the three dehydrogenases also require cofactors derived from pantothenic acid, riboflavin and niacin. Thiamin deficiency causes several forms of beriberi, dry (sensory and motor peripheral neuropathy) and wet (with congestive heart failure), and Wernicke's encephalopathy and Korsakoff's syndrome.
Regulator
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Turck D, Bresson JL, Burlingame B, Dean T, Fairweather-Tait S, et al. Dietary Reference Values for riboflavin EFSA Journal, 2017.
doi:10.2903/j.efsa.2017.4919 PubMed 32625611
Funding and finding
Funding
European Food Safety Authority, on request from the European Commission (question EFSA-Q-2011-01222).
Finding
Riboflavin is the integral part of the coenzymes FAD and FMN, cofactors of flavoprotein enzymes; flavokinase phosphorylates free riboflavin to FMN, which FAD synthetase converts to FAD. Glutathione reductase uses FAD, methylenetetrahydrofolate reductase (MTHFR) requires FAD, and pyridoxamine phosphate oxidase is FMN-dependent. Signs of riboflavin deficiency (ariboflavinosis) are unspecific: sore throat, hyperaemia and oedema of the pharyngeal and oral mucous membranes, cheilosis, glossitis, seborrhoeic dermatitis, angular stomatitis and normochromic normocytic anaemia.
Regulator
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific Opinion on Dietary Reference Values for niacin EFSA Journal, 2014.
doi:10.2903/j.efsa.2014.3759
Funding and finding
Funding
European Food Safety Authority, on request from the European Commission (question EFSA-Q-2011-01218).
Finding
Niacin (nicotinic acid and nicotinamide) is the precursor of the coenzymes NAD and NADP; many dehydrogenases use NAD or NADP or both, and NAD also takes part in non-redox ADP-ribose transfer reactions. About 60 mg of tryptophan yields 1 mg of niacin. Long-term inadequate intake of tryptophan and niacin can lead to pellagra, with photosensitive dermatitis, tongue and mouth soreness, vomiting, diarrhoea, depression and dementia; untreated pellagra results in death from multiorgan failure.
Regulator
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Dietary Reference Values for vitamin B6 EFSA Journal, 2016.
doi:10.2903/j.efsa.2016.4485 PubMed 40007837
Funding and finding
Funding
European Food Safety Authority, on request from the European Commission (question EFSA-Q-2011-01228).
Finding
All six vitamin B6 derivatives can be converted in the body to pyridoxal 5'-phosphate (PLP) and pyridoxamine 5'-phosphate, cofactors of more than 100 enzymes. PLP serves enzymes of amino acid decarboxylation, transamination and racemisation and is a cofactor of glycogen phosphorylase, delta-aminolevulinate synthase, serine hydroxymethyltransferase, cystathionine beta-synthase and cystathionine gamma-lyase. Vitamin B6 deficiency is rare; its most typical features are hypochromic microcytic anaemia and neurological abnormalities, including convulsive seizures.
Regulator
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific Opinion on Dietary Reference Values for pantothenic acid EFSA Journal, 2014.
doi:10.2903/j.efsa.2014.3581
Funding and finding
Funding
European Food Safety Authority, on request from the European Commission (question EFSA-Q-2011-01219).
Finding
Pantothenic acid is a component of coenzyme A and acyl-carrier proteins and serves in acyl-group activation and transfer. It is ubiquitous in foods and dietary deficiency is rare; deficiency symptoms, including mood changes and sleep, neurological, cardiac and gastrointestinal disturbances, have been described in subjects on a pantothenic acid antagonist and/or a pantothenic acid-deficient diet.
Regulator
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific Opinion on Dietary Reference Values for biotin EFSA Journal, 2014.
doi:10.2903/j.efsa.2014.3580
Funding and finding
Funding
European Food Safety Authority, on request from the European Commission (question EFSA-Q-2011-01205).
Finding
Biotin is a cofactor of acetyl-CoA carboxylase, propionyl-CoA carboxylase, beta-methylcrotonyl-CoA carboxylase and pyruvate carboxylase, to which it is covalently attached in the cell; biotinidase releases biotin from degraded holocarboxylases for reuse. Dietary biotin deficiency is rare and is characterised by fine scaly dermatitis, hair loss, conjunctivitis, ataxia and delayed child development; cases occurred with long-term parenteral nutrition without biotin, in biotinidase deficiency and after large intakes of raw eggs, whose egg-white avidin prevents biotin absorption.
Independent research
Ducker GS, Rabinowitz JD. One-Carbon Metabolism in Health and Disease Cell Metabolism, 2017.
doi:10.1016/j.cmet.2016.08.009 PubMed 27641100
Funding and finding
Funding
G.S.D. is supported by a postdoctoral fellowship from the American Cancer Society (PF-15-190-01-TBE). J.D.R. is supported by NIH grants R01CA163591 and P30DK019525 and Stand Up to Cancer.
Finding
Review. Animals require dietary folate. Tetrahydrofolate (THF) binds one-carbon units at N5 and N10 at three oxidation states: 5-methyl-THF, the most reduced, 5,10-methylene-THF and 10-formyl-THF, the most oxidised; folic acid is reduced to dihydrofolate (DHF) and then THF. SHMT1 (cytosol) and SHMT2 (mitochondria) interconvert serine and glycine with THF and 5,10-methylene-THF, reversibly; in rapidly proliferating cultured cells the main direct source of cytosolic one-carbon units is formate released from mitochondria, reassimilated by the trifunctional MTHFD1. TYMS methylates dUMP to dTMP with 5,10-methylene-THF and is the only folate enzyme that alters THF itself, taking two electrons from it and producing DHF; DHFR regenerates THF with NADPH and is the target of trimethoprim and methotrexate, which trap folate as DHF. Purine synthesis incorporates two 10-formyl-THF units; in proliferating cells each new DNA or RNA base needs on average one 10-formyl-THF, and 5,10-methylene-THF is needed for one in four DNA bases. 5-Fluorouracil is a suicide inhibitor of TYMS; methotrexate most potently blocks DHFR, whereas pemetrexed more potently inhibits TYMS and AICAR transformylase; 5-formyl-THF (folinic acid, leucovorin) is given as rescue. 5-Methyl-THF, made by cytosolic NADPH-dependent MTHFR, is consumed only by cobalamin-dependent methionine synthase; BHMT is limited to liver and kidney. SAM inhibits MTHFR and activates CBS; 5-methyl-THF inhibits GNMT. Transsulfuration is the only route that degrades homocysteine. Folate and cobalamin supplementation lower homocysteine without reducing cardiovascular events in the general population. Dietary folate deficiency in adults manifests as macrocytic anaemia.
Regulator
EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA Panel), Turck D, Bohn T, Castenmiller J, de Henauw S, Hirsch-Ernst KI, et al. Scientific opinion on the tolerable upper intake level for folate EFSA Journal, 2023.
doi:10.2903/j.efsa.2023.8353 PubMed 37965303
Funding and finding
Funding
European Food Safety Authority, on request from the European Commission (question EFSA-Q-2021-00366). Preparatory systematic reviews were conducted by a contractor, Karolinska Institutet in collaboration with the University of Oslo, under an EFSA procurement procedure.
Finding
Folates consist of a pterin moiety linked to p-aminobenzoic acid and one or more glutamates, substituted at N5 or N10 by one-carbon units; natural folates are reduced polyglutamates usually with five to seven glutamates. A jejunal hydrolase (EC 3.4.17.21) converts polyglutamates to monoglutamates, which PCFT (SLC46A1), the most important intestinal transporter, and RFC (SLC19A1) move into enterocytes; 5-methyl-THF is the main circulating form; RFC, the main transporter from blood to tissues, has about 100 times lower affinity for folic acid than for reduced folates. Folylpolyglutamate synthase retains folates as THF polyglutamates; 5-methyl-THF monoglutamate and folic acid are poor substrates, and 5-methyl-THF is lost from cells unless methionine synthase converts it to THF. Folic acid, a fully oxidised monoglutamate, is reduced by DHFR via dihydrofolate to THF. The MTHFR reaction is essentially irreversible under physiological conditions and SAM is its allosteric inhibitor; in cobalamin deficiency 5-methyl-THF is metabolically trapped, SAM falls, MTHFR becomes fully active, and a functional folate deficiency develops with raised plasma 5-methyl-THF and homocysteine, depleted erythrocyte folate and fewer methyl groups for transmethylation. The megaloblastic anaemia of cobalamin deficiency is identical to that of folate deficiency; neurological manifestations (myeloneuropathy from demyelination) can occur with or without anaemia, are almost never seen in folate deficiency, and have an unknown mechanism, with congenital defects of MTHFR and methionine synthase pointing to methionine synthase rather than methylmalonyl-CoA mutase. Folic acid can initiate DNA synthesis in cobalamin deficiency through DHFR but cannot correct the methylation defect. MTHFR 677TT is associated with lower serum folate and higher homocysteine; in a genome-wide study of 2232 Irish adults aged 18 to 28 years MTHFR 677C>T was the only significant modifier of red cell and serum folate. ULs for folic acid retained: 1000 ug/day for adults including pregnant and lactating women, with progression of neurological symptoms in cobalamin-deficient patients as critical effect.
Independent research
Gherasim C, Lofgren M, Banerjee R. Navigating the B12 Road: Assimilation, Delivery, and Disorders of Cobalamin Journal of Biological Chemistry, 2013.
doi:10.1074/jbc.R113.458810 PubMed 23539619
Funding and finding
Funding
This work was supported, in whole or in part, by National Institutes of Health Grant DK45776.
Finding
Review. Mammals have two B12-dependent enzymes: methionine synthase, which uses methylcobalamin, and methylmalonyl-CoA mutase, which uses adenosylcobalamin to convert methylmalonyl-CoA to succinyl-CoA. Methionine synthase works in two half-reactions: methylcobalamin methylates homocysteine to methionine, leaving cob(I)alamin, which removes the methyl group from 5-methyl-THF to give THF and methylcobalamin; occasional oxidation to cob(II)alamin is repaired by reductive methylation needing NADPH, methionine synthase reductase and S-adenosylmethionine. Food cobalamin binds haptocorrin; in the duodenum pancreatic proteases release it, intrinsic factor binds it, and intestinal cells take it up by cubilin/AMN receptor-mediated endocytosis. About 20% of circulating cobalamin is bound to transcobalamin, which delivers it to cells through the transcobalamin receptor. Mutations in the cblG (methionine synthase) and cblE (reductase) loci cause isolated hyperhomocysteinaemia without methylmalonic aciduria.
Independent research
Patel MS, Nemeria NS, Furey W, Jordan F. The Pyruvate Dehydrogenase Complexes: Structure-based Function and Regulation Journal of Biological Chemistry, 2014.
doi:10.1074/jbc.R114.563148 PubMed 24798336
Funding and finding
Funding
Supported, in whole or in part, by National Institutes of Health grants DK 20478 (to M.S.P.), GM050380 (to F.J.) and GM061791 (to W.F.) and by the Veterans Affairs Merit Review (W.F.).
Finding
Review. The pyruvate dehydrogenase complex links glycolysis to the tricarboxylic acid cycle and comprises pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and dihydrolipoamide dehydrogenase (E3), which work sequentially. E1, a thiamin diphosphate-dependent enzyme, decarboxylates pyruvate and reductively acetylates the lipoyl groups covalently attached to E2; E2 transfers the acetyl group to CoA, forming acetyl-CoA; E3 transfers electrons from the dihydrolipoyl groups of E2 to FAD and then to NAD+.
Regulator
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific Opinion on Dietary Reference Values for vitamin C EFSA Journal, 2013.
doi:10.2903/j.efsa.2013.3418
Funding and finding
Funding
European Food Safety Authority, on request from the European Commission (question EFSA-Q-2011-01229).
Finding
Vitamin C is an essential component of the diet, as humans and other primates have lost the ability to synthesise it. It is a cofactor of monooxygenases, dioxygenases and mixed function oxygenases, reducing the active-centre metal ion and maintaining it in a reduced state. Procollagen-proline dioxygenase and procollagen-lysine 5-dioxygenase require vitamin C for maximal activity, and deficiency impairs the synthesis of collagen, the principal protein of skin, bones, teeth and connective tissues. Scurvy occurs in adults at a plasma ascorbate below 10 umol/L and a body pool below 300 mg, with tooth loss, joint pain, poor wound healing, petechiae, bruising and inflamed, bleeding gums; an intake of 10 mg/day prevents it.
Independent research
Shoulders MD, Raines RT. Collagen structure and stability Annual Review of Biochemistry, 2009.
doi:10.1146/annurev.biochem.77.032207.120833 PubMed 19344236
Funding and finding
Funding
Collagen research in the authors' laboratory is supported by NIH grant AR044276; M.D.S. was supported by graduate fellowships from the Department of Homeland Security and the Division of Medicinal Chemistry, American Chemical Society.
Finding
Review. Prolyl 4-hydroxylase, a non-haem iron enzyme, hydroxylates proline residues in the Yaa position of collagen Xaa-Yaa-Gly triplets to (2S,4R)-4-hydroxyproline. Hydroxylation of Yaa-position proline increases dramatically the thermal stability of collagen triple helices, and prolyl 4-hydroxylase activity is required for the viability of Caenorhabditis elegans and the mouse.
Regulator
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Turck D, Bresson JL, Burlingame B, Dean T, Fairweather-Tait S, et al. Dietary reference values for vitamin K EFSA Journal, 2017.
doi:10.2903/j.efsa.2017.4780 PubMed 32625486
Funding and finding
Funding
European Food Safety Authority, on request from the European Commission (question EFSA-Q-2011-01232).
Finding
Vitamin K is the cofactor of gamma-glutamyl carboxylase (GGCX), which converts glutamic acid residues of vitamin K-dependent proteins, including coagulation factors II, VII, IX and X and the anticoagulant proteins C, S and Z, into calcium-binding gamma-carboxyglutamic acid residues; vitamin K hydroquinone is converted to vitamin K epoxide and reduced back by vitamin K epoxide reductase (VKOR), the step of the cycle blocked by warfarin. In adults, deficiency causes a bleeding tendency with a vitamin K-responsive increase in prothrombin time. In infants not given vitamin K prophylaxis, late vitamin K deficiency bleeding occurred in 4.4 to 7.2 per 100,000 births in Western European countries; its relative risk without prophylaxis is estimated at 81.
Independent research
Liu S, Li S, Shen G, Sukumar N, Krezel AM, Li W. Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation Science, 2021.
doi:10.1126/science.abc5667 PubMed 33154105
Funding and finding
Funding
W.L. is supported by NHLBI (R01 HL121718), the W. M. Keck Foundation (Forefront of Science Award), the Children's Discovery Institute (MCII 2020-854), NEI (R21 EY028705) and NIGMS (R01 GM131008). The NECAT beamlines are funded by NIGMS (P30 GM124165), the Eiger detector by NIH-ORIP (HEI S10OD021527), and the Advanced Photon Source by DOE (DE-AC02-06CH11357).
Finding
Eleven crystal structures of human vitamin K epoxide reductase (VKOR) and a VKOR-like paralog with substrates and antagonists. VKOR is an endoplasmic reticulum membrane enzyme; the cycle begins with epoxidation of vitamin K hydroquinone, which drives gamma-carboxylation of coagulation factors, and VKOR reduces the epoxide first to the quinone and then to the hydroquinone, each step coupled to oxidation of two active-site cysteines. Vitamin K antagonists, including warfarin, inhibit VKOR at both the epoxide and the quinone reduction steps.
Textbook or database
Dean L, Kane M. Warfarin Therapy and VKORC1 and CYP Genotype Medical Genetics Summaries, National Center for Biotechnology Information (US), 2026.
PubMed 28520347
Funding and finding
Funding
not stated in the chapter
Finding
Peer-reviewed chapter, first posted 8 March 2012, version 4.0 of 16 June 2026. VKORC1, on chromosome 16p11.2, encodes vitamin K epoxide reductase, which catalyses the rate-limiting step of vitamin K recycling and is the target of warfarin. The promoter variant c.-1639G>A (rs9923231) is associated with lower protein expression, increased warfarin sensitivity and lower dose requirements; the variant allele is the major allele (about 90%) in Asian populations and has a frequency of about 40% in people of European descent and 14% in African Americans. VKORC1 accounts for about 30% of the variation in dose requirement, CYP2C9 usually for less than 10%.
Independent research
O'Connor EA, Evans CV, Ivlev I, Rushkin MC, Thomas RG, Martin A, et al. Vitamin, Mineral, and Multivitamin Supplementation for the Primary Prevention of Cardiovascular Disease and Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force Agency for Healthcare Research and Quality, Evidence Synthesis No. 209, 2022.
PubMed 35767665
Funding and finding
Participants
739,803
Funding
Prepared by the Kaiser Permanente Research Affiliates Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (Contract No. HHSA-290-2015-00007-I, Task Order No. 75Q80118F32006). USPSTF liaisons were consulted on the analytic framework and key questions, and an AHRQ Medical Officer provided project oversight and reviewed the drafts; the USPSTF and AHRQ had no role in study selection, quality assessment or writing.
Finding
Vitamin and mineral supplementation provided little to no benefit in preventing cancer, cardiovascular disease and death, except a possible small benefit of multivitamins for any cancer (OR 0.93, 95% CI 0.87 to 0.99; 4 RCTs, n=48,859; absolute risk difference among adequately powered trials -0.2% to -1.2%); the multivitamin evidence rested on only three adequately powered trials, one with a median of 3.6 years of use and another limited to antioxidants. Two vitamin C trials (n=15,031) of 500 mg/day for 3 to 8 years suggested no benefit for mortality, cardiovascular disease or cancer. The report's suggested citation gives 2022; PubMed lists June 2021.
Industry-funded
Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial JAMA, 2008.
doi:10.1001/jama.2008.600 PubMed 18997197
Funding and finding
Registration
NCT00270647
Participants
14,641
Follow-up
mean 8.0 years
Funding
Supported by NIH grants CA 97193, CA 34944, CA 40360, HL 26490 and HL 34595 and an investigator-initiated grant from BASF Corporation. BASF, Wyeth Pharmaceuticals and DSM Nutritional Products had no role in the study design; conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review or approval of the manuscript.
In-kind support
Study agents and packaging provided by BASF Corporation (vitamin C, vitamin E, beta-carotene), Wyeth Pharmaceuticals (multivitamin) and DSM Nutritional Products.
Finding
Vitamin C 500 mg daily versus placebo, mean follow-up 8.0 years: major cardiovascular events in 619 of 7329 versus 626 of 7312 men (10.8 and 10.9 per 1000 person-years; HR 0.99, 95% CI 0.89 to 1.11); total mortality 857 versus 804 (HR 1.07, 0.97 to 1.18).
Expert consensus
US Preventive Services Task Force, Mangione CM, Barry MJ, Nicholson WK, Cabana M, Chelmow D, et al. Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer: US Preventive Services Task Force Recommendation Statement JAMA, 2022.
doi:10.1001/jama.2022.8970 PubMed 35727271
Funding and finding
Funding
The USPSTF is an independent, voluntary body; the US Congress mandates that the Agency for Healthcare Research and Quality (AHRQ) support its operations. AHRQ staff assisted in developing the research plan, commissioning the evidence review, coordinating expert review and public comment, and writing and preparing the statement; they had no role in approving the final statement or the decision to submit.
Finding
The USPSTF recommends against beta carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer (D recommendation), and concludes that the evidence is insufficient to assess the balance of benefits and harms of multivitamins and of single- or paired-nutrient supplements other than beta carotene and vitamin E (I statements).

Updated 2026-10-21