Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Communication
  • Published:

Changes in cholesterol and triglyceride concentrations in the Vanguard population of the Carotene and Retinol Efficacy Trial (CARET)

European Journal of Clinical Nutrition volume 59, pages 1173–1180 (2005)Cite this article

Abstract

Background:

The Beta-Carotene and Retinol Efficacy Trial (CARET) was terminated 21 months ahead of schedule due to an excess of lung cancers. Deaths from cardiovascular disease also increased (relative risk=1.26 (95% confidence interval (CI) 0.99–1.61)) in the group assigned to a combination of 30 mg beta-carotene and 25 000 IU retinyl palmitate (vitamin A) daily. The basis for increased cardiovascular mortality is unexplained.

Design:

We analyzed data on serum lipids, available for 1474 CARET Vanguard participants who were enrolled in the two CARET pilot studies and transitioned to the Vanguard study. Total cholesterol and triglycerides were measured 2 months prior to, 4 and 12 months following randomization, and annually thereafter for up to 7 y.

Intervention:

In the asbestos-exposed pilot (N=816), participants were assigned to beta-carotene and retinol or to placebo; in the smokers pilot (N=1029), participants were assigned to beta-carotene, retinol, a combination, or placebo.

Results:

Serum cholesterol showed a decline over time in both arms; serum triglycerides had a continuous decline over time in the placebo arm, but an initial increase that persisted in the active arm. Both serum cholesterol concentrations (P<0.0003) and serum triglycerides (P<0.0001) were significantly higher in the participants receiving vitamin A and/or a combination of vitamin A and beta-carotene (n=863) as compared to the placebo group (n=611). Those in this active intervention group had an average cholesterol concentration 5.3 mg/dl (0.137 mmol/l) higher than those in the placebo arm.

Conclusion:

The differences in cholesterol and triglyceride concentrations between the groups following randomization may account in part for the unexpected excess in cardiovascular deaths seen in the active intervention arm of CARET.

Sponsorship:

Supported by grants U01 CA63673, U01 CA63674, U01 CA47989, U01 CA48200, U01 CA48203, U01 CA48196, and U01 CA52596 from the National Cancer Institute, USA.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  • Austin MA, Hokanso JE & Edwards KL (1998): Hypertriglyceridemia as a cardiovascular risk factor. Am. J. Cardiol. 81, 7B–12B.

    Article  CAS  Google Scholar 

  • Bershad S, Rubinstein A, Paterniti JR, Le NA, Poliak SC, Heller B, Ginsberg HN, Fleishmajer R & Brown WV (1985): Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N. Engl. J. Med. 313, 981–985.

    Article  CAS  Google Scholar 

  • Betteridge DJ & Morrell JM (1998): Clinicians' Guide to Lipids and Coronary Heart Disease. London: Chapman and Hall Medical.

    Google Scholar 

  • Bowen D, Cartmel B, Barnett M, Goodman GE & Omenn GS (1999): Predictors of participant retention in two chemoprevention feasibility trials. Ann. Behav. Med. 21, 210–215.

    Article  CAS  Google Scholar 

  • Brown H & Prescott R (1999): Applied Mixed Models in Medicine. Chichester, England: John Wiley and Sons.

    Google Scholar 

  • Cartmel B, Moon TE & Levine N (1999): The effects of long term intake of retinol on selected clinical and laboratory parameters. Am. J. Clin. Nutr. 69, 937–943.

    Article  CAS  Google Scholar 

  • Cooper GR, Myers GL, Smith SJ & Schlant RC (1992): Blood lipid measurements. Variations and practical utility. JAMA 267, 1652–1660.

    Article  CAS  Google Scholar 

  • Ferrara A, Barrett-Connor E & Shan J (1997): Total, LDL, and HDL cholesterol decrease with age in older men and women. The Rancho Bernardo Study 1984–1994. Circulation 96, 37–43.

    Article  CAS  Google Scholar 

  • Frank E, Winkleby MA, Fortmann SP, Rockhill B & Farquhar JW (1992): Improved cholesterol-related knowledge and behavior and plasma cholesterol levels in adults during the 1980s. JAMA 268, 1566–1572.

    Article  CAS  Google Scholar 

  • Goodman GE, Omenn GS, Thornquist MD, Lund B, Metch B & Gylys_Colwell I (1993): The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with cigarette smokers. Cancer Epidemiol. Biomarkers Prev. 2, 389–396.

    CAS  PubMed  Google Scholar 

  • Green A, Williams G, Neale R, Hart V, Leslie D, Parsons P, Marks GC, Gaffney P, Battistutta D, Frost C, Lang C & Russell A (1999): Daily sunscreen application and beta-carotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin; a randomized controlled trial. Lancet 354, 723–729.

    Article  CAS  Google Scholar 

  • Greenberg ER, Baron JA, Karagas MR, Stukel TA, Nierenberg DW, Stevens MM, Mandel JS & Haile RW (1996): Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation. JAMA 275, 699–703.

    Article  CAS  Google Scholar 

  • Grundy SM (1986): Cholesterol and coronary heart disease. A new era. JAMA 256, 2849–2858.

    Article  CAS  Google Scholar 

  • Heart Protection Study Collaborative Group (2002): MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20 536 high-risk individuals: a randomized placebo-controlled trial. Lancet 360, 23–33.

  • Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W & Peto R (1996): Lack of effect of long-term supplementation with beta-carotene on the incidence of malignant neoplasms and cardiovascular disease. New. Engl. J. Med. 334, 1145–1149.

    Article  CAS  Google Scholar 

  • Hughes Jr GS, Ringer TV, Francom SF, Means LK & DeLoof MJ (1994): Lack of effects of beta-carotene on lipids and sex steroid hormones in hyperlipidemics. Am. J. Med. Sci. 308, 16–22.

    Article  Google Scholar 

  • Infante M, Pastorino U, Chiesa G, Bera E, Pisani P, Valente M & Raviasi G (1991): Laboratory evaluation during high-dose vitamin A administration: a randomized study of lung cancer patients after surgical resection. J. Cancer Res. Clin. Oncol. 117, 156–162.

    Article  CAS  Google Scholar 

  • Law MR, Wald NJ & Thompson SG (1994a): By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ 308, 367–373.

    Article  CAS  Google Scholar 

  • Law MR, Wald NJ, Wu T, Hackshaw A & Bailey A (1994b): Systematic underestimation of association between serum cholesterol concentrations and ischaemic heart disease in observation studies: data from the BUPA study. BMJ 308, 363–366.

    Article  CAS  Google Scholar 

  • Lee I, Cook NR, Manson JE, Buring JE & Hennekens CH (1999): Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study. J. Natl. Cancer Inst. 91, 2102–2106.

    Article  CAS  Google Scholar 

  • Manolio TA, Cushman M, Gottdiener JS, Dobs A, Kuller LH & Kronmal RA (2004): Predictors of falling cholesterol levels in older adults: The Cardiovascular Health Study. Ann. Epidemiol. 14, 325–331.

    Article  Google Scholar 

  • Marsden J (1986): Hyperlipidaemia due to isotretinoin and etretinate: possible mechanisms and consequences. Br. J. Dermatol. 114, 401–407.

    Article  CAS  Google Scholar 

  • Murray JC, Gilor RS & Lazarus GS (1983): Serum triglyceride elevation following high-dose vitamin A treatment for pityriasis rubra pilaris. Arch. Dermatol. 119, 675–676.

    Article  CAS  Google Scholar 

  • Newschaffer C, Bush TL & Hale WE (1992): Aging and total cholesterol levels: cohort, period and survivorship effects. Am. J. Epidemiol. 136, 23–34.

    Article  CAS  Google Scholar 

  • Nierenberg DW, Bayrd GT & Stukel TA (1991): Lack of effect of chronic administration of oral beta-carotene on serum cholesterol and triglyceride concentrations. Am. J. Clin. Nutr. 53, 652–654.

    Article  CAS  Google Scholar 

  • Omenn GS, Goodman G, Thornquist M, Rosenstock LS, Barnhart S, Gylys-Colwell I, Metch B & Lund B (1993): The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high risk populations: pilot study with asbestos-exposed workers. Cancer Epidemiol. Biomarkers Prev. 2, 381–387.

    CAS  PubMed  Google Scholar 

  • Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, Barnhart S & Hammar S (1996): Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334, 1150–1155.

    Article  CAS  Google Scholar 

  • Omenn GS, Goodman GE, Thornquist M & Brunzell JD (1994a): Long term vitamin A does not produce clinically significant hypertriglyceridemia: results from CARET, the Beta-Carotene and Retinol Efficacy Trial. Cancer Epidemiol. Biomarkers Prev. 3, 711–713.

    CAS  PubMed  Google Scholar 

  • Omenn GS, Goodman GE, Thornquist M, Grizzle J, Rosenstock L, Barnhart S, Balmes J, Cherniack MG, Cullen MR & Glass A (1994b): The β-Carotene and Retinol Efficacy Trial (CARET) for chemoprevention of lung cancer in high-risk populations: smokers and asbestos-exposed workers. Cancer Res. 54, 2038–2043.

    Google Scholar 

  • Pastorino U, Chiesa G, Infante M, Soresi E, Clerici M, Valente M, Bellon PA & Ravasi G (1991): Safety of high-dose vitamin A. Oncology 48, 131–137.

    Article  CAS  Google Scholar 

  • Rapola JM, Virtamo J, Ripatti S, Huttunen JK, Albanes D, Taylor PR & Heinonene OP (1997): Randomized trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet 349, 1715–1720.

    Article  CAS  Google Scholar 

  • Redlich CA, Chung JS, Cullen MR, Blaner WS, Van Bennekum AM & Berglund L (1999): Effect of long-term beta-carotene and vitamin A on serum cholesterol and triglyceride levels among participants in the Carotene and Retinol Efficacy Trial (CARET). Atherosclerosis 143, 427–434.

    Article  CAS  Google Scholar 

  • Ribaya-Mercado JD, Ordovas JM & Russell RM (1995): Effect of beta-carotene supplementation of the concentrations and distribution of carotenoids, vitamin E, vitamin A and cholesterol in plasma lipoprotein and non-lipoprotein fractions in healthy older women. J. Am. Coll. Nutr. 14, 614–620.

    Article  CAS  Google Scholar 

  • Ringer TV, DeLoof MJ, Winterrowd GE, Francom SF, Gaylor SK, Ryan JA, Sanders ME & Hughes GS (1991): Beta-carotene's effects on serum lipoproteins and immunologic indices in humans. Am. J. Clin. Nutr. 53, 688–694.

    Article  CAS  Google Scholar 

  • Tangrea JA, Adrianza ME, Helxel WE, Taylor PR, Hartman AM, Peck GL & Edwards BK (1993): Clinical and laboratory adverse effects associated with long-term, low-dose isotretinoin: incidence and risk factors. Cancer Epidemiol. Biomarkers Prev. 2, 375–380.

    CAS  PubMed  Google Scholar 

  • The Alpha-Tocopherol, Beta-Carotene Prevention Study Group (1994): The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancer in male smokers. New Engl. J. Med. 330, 1029–1035.

  • Thornquist MD, Omenn GS, Goodman GE, Grizzle JE, Rosenstock L, Barnhart S, Anderson GL, Hammar S, Balmes J, Cherniack M, Cone J, Cullen MR, Glass A, Keogh JP, Meyskens F, Valanis B & Williams JH (1993): Statistical design and monitoring of the Carotene and Retinol Efficacy Trial (CARET). Cont. Clin. Trials 14, 308–324.

    Article  CAS  Google Scholar 

  • Vahlquist C, Michaëlsson G, Vahlquist A & Vessby B (1985): A sequential comparison of etretinate (Tigason®) with special regard to their effects on serum lipoproteins. Br. J. Dermatol. 112, 69–76.

    Article  CAS  Google Scholar 

  • Van Poppel G, Hospers H, Buytenhek R & Princen HM (1994): No effects of beta-carotene supplementation on plasma lipoproteins in healthy smokers. Am. J. Clin. Nutr. 60, 730–734.

    Article  CAS  Google Scholar 

  • Virtamo J, Rapola JM, Ripatti S, Heinonen OP, Taylor PR, Albanes D & Huttunen JK (1998): Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Archives Int. Med. 158, 668–675.

    Article  CAS  Google Scholar 

  • Vivekananthan DP, Penn MS, Sapp SK, Hsu A & Topol EJ (2003): Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomized trials. Lancet 361, 2017–2023.

    Article  CAS  Google Scholar 

  • Wallace RB & Colsher PL (1992): Blood lipid distributions in older persons: prevalence and correlates of hyperlipidemia. Ann. Epidemiol. 2, 15–21.

    Article  CAS  Google Scholar 

  • Weijenberg MP, Feskens EJ & Kromhout D (1996): Age-related changes in total and high-density -lipoprotein cholesterol in elderly Dutch men. Am. J. Public Health. 86, 798–803.

    Article  CAS  Google Scholar 

  • Witztum JL (1994): The oxidation hypothesis of atherosclerosis. Lancet 344, 793–795.

    Article  CAS  Google Scholar 

  • Zech LA, Gross EF, Peck GL & Brewer HB (1983): Changes in plasma cholesterol and triglyceride levels after treatment with oral isotretinoin. A prospective study. Arch. Dermatol. 119, 987–993.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the CARET study participants and CARET study staff.

Author information

Authors and Affiliations

  1. Department of Epidemiology and Public Health and the Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA

    B Cartmel, M R Cullen & C A Redlich

  2. GCRC, Yale University School of Medicine, New Haven, CT, USA

    J Dziura

  3. Department of Internal Medicine, Yale Occupational and Environmental Medicine Program, Yale University School of Medicine, New Haven, CT, USA

    M R Cullen, S Vegso & C A Redlich

  4. University of Michigan, Ann Arbor, MI, USA

    G S Omenn

  5. Fred Hutchinson Cancer Research Center and Swedish Cancer Institute, Seattle, WA, USA

    G E Goodman

Authors
  1. B Cartmel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Dziura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M R Cullen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Vegso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G S Omenn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G E Goodman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C A Redlich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Cartmel.

Additional information

Guarantor: B Cartmel.

Contributors: JD and SV conducted the statistical analysis. All authors participated in the design, interpretation and writing up of the research work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cartmel, B., Dziura, J., Cullen, M. et al. Changes in cholesterol and triglyceride concentrations in the Vanguard population of the Carotene and Retinol Efficacy Trial (CARET). Eur J Clin Nutr 59, 1173–1180 (2005). https://doi.org/10.1038/sj.ejcn.1602229

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ejcn.1602229

Keywords

This article is cited by

Search

Advanced search

Quick links