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

Our plain-English summary of Changes in cholesterol and triglyceride concentrations in the Vanguard population of the Carotene and Retinol Efficacy Trial (CARET), by B. Cartmel, J. Dziura, M.R. Cullen, et al (European Journal of Clinical Nutrition, 2005).

The study

• Authors: B. Cartmel, J. Dziura, M.R. Cullen, S. Vegso, G.S. Omenn, G.E. Goodman, C.A. Redlich
• Journal: European Journal of Clinical Nutrition
• Published: 2005;59(10):1173-80
• Type of article: Randomized trial
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This study examined blood fats (lipids) in the Carotene and Retinol Efficacy Trial (CARET), a lung cancer prevention trial whose active-treatment group had more cardiovascular deaths than its placebo group. The authors analyzed 1474 people from two pilot studies that began in 1985: one of male asbestos-exposed participants and one of male and female smokers. Of these, 863 received vitamin A, alone or with beta-carotene, and 611 received placebo. Smokers given beta-carotene alone were excluded. Cholesterol and triglycerides were measured for up to 7 years. Cholesterol fell in both groups but averaged 5.3 mg/dl higher in the active group. The difference was 7.3 mg/dl in the asbestos-exposed pilot and 2.0 mg/dl in the smokers pilot. Triglycerides were higher in the active group from 4 months on. The authors concluded that these differences may account for some of the excess cardiovascular deaths. They extrapolated very cautiously to the full CARET population, assuming risk rises linearly with each lipid. On that basis they estimated an approximately 6 to 10% difference in cardiovascular mortality, a modest part of the observed difference. They noted that fasting before blood draws was not required and that no data on lipid-lowering drug use were available.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Ancillary analysis of data from a double-blind randomized chemoprevention trial (the CARET pilot and Vanguard participants)
• Who was studied: 1474 CARET pilot/Vanguard participants, with enrollment beginning in 1985. They came from two pilots. The asbestos-exposed pilot had 816 men, of whom 388 active and 365 placebo participants were analyzed. The smokers pilot had 539 men and 490 women, of whom 475 active and 246 placebo participants were analyzed. The 256 smokers assigned to beta-carotene alone were excluded.
• Exposure: The exposure studied was the trial supplements, not asbestos. In the asbestos-exposed pilot, participants received 15 mg beta-carotene plus 25 000 IU retinol per day, or placebo. In the smokers pilot, 239 participants took vitamin A alone for a mean of 24 months. In the Vanguard phase, all active participants received 30 mg beta-carotene plus 25 000 IU retinyl palmitate (vitamin A) per day. Lipids were measured 2 months before randomization, at 4 and 12 months after randomization, and annually thereafter for up to 7 years.
• Main results:
  • In the adjusted analysis, the vitamin A/beta-carotene group had an average cholesterol 5.3 mg/dl (s.e. 1.4) higher than the placebo group (P = 0.0003). The gap did not change further after the 4-month time point.
  • The cholesterol difference between arms was 7.3 mg/dl in the asbestos-exposed pilot and 2.0 mg/dl in the smokers pilot.
  • Triglycerides were higher in the vitamin A/beta-carotene group from 4 months onward. The unadjusted mean difference during the intervention period was 16 mg/dl (P less than 0.0001).
  • Total cholesterol in both groups combined fell by 2.7 mg/dl per year over the trial.
  • Triglycerides in the placebo group fell by 4.9 mg/dl per year.
  • Using unpublished data, the cardiovascular mortality comparison between treatment arms gave RR 1.60 (CI, 0.83 to 3.10) in the asbestos-exposed pilot and RR 0.87 (CI, 0.47 to 1.61) in the smokers pilot.
  • At the New Haven Study Center, more participants on vitamin A/beta-carotene than on placebo started lipid-lowering medication during the trial: 47 (9.6%) vs 23 (4.7%), P less than 0.03.
  • The authors extrapolated very cautiously to the full CARET population, not to the analyzed participants. They estimated that the lipid differences might be associated with an approximately 6 to 10% difference in cardiovascular mortality rates, a modest part of the observed difference. The estimate assumes that cardiovascular mortality risk rises linearly with each lipid.
• The authors' conclusion: The authors concluded that the combined effects of the vitamin A/beta-carotene combination on lipids may account for some of the increase in cardiovascular mortality seen in the active arm of CARET. They called for further study of vitamin A's effects on HDL and LDL.
• Limitations the authors state:
  • There were no data on lipid-lowering drug use for the Vanguard population, so the analysis could not adjust for it. The authors noted that greater drug use in the active group could mask a larger effect.
  • Participants were not required to fast before blood draws. Statistical adjustment for fasting status may not fully correct for this, especially for triglycerides.
  • HDL and LDL cholesterol were not measured.
  • Small numbers and overlapping confidence intervals limit interpretation of the cardiovascular mortality comparison between the asbestos-exposed and smokers pilots.
  • The 6 to 10% mortality estimate assumes a linear increase in cardiovascular mortality risk with each lipid. It also leaves aside the different mix of asbestos-exposed and smoker participants compared with the full CARET population.

Topics

Medical terms in this study, explained in our Lexicon: Lung Cancer, Relative Risk, confidence interval.

Related studies

• Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial — G.S. Omenn, G.E. Goodman, et al. (1996)
• Recruitment for the beta-carotene and retinol efficacy trial (CARET) to prevent lung cancer in smokers and asbestos-exposed workers — G.S. Omenn, G. Goodman, et al. (1992)
• Research cost analyses to aid in decision making in the conduct of a large prevention trial, CARET. Carotene and Retinol Efficacy Trial — M.D. Thornquist, N. Urban, et al. (1993)
• CARET, the beta-carotene and retinol efficacy trial to prevent lung cancer in asbestos-exposed workers and in smokers — G.S. Omenn, G. Goodman, et al. (1991)
• Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease — G.S. Omenn, G.E. Goodman, et al. (1996)
• Lobe of origin and histologic type of lung cancer associated with asbestos exposure in the Carotene and Retinol Efficacy Trial (CARET) — C.A. Brodkin, J. McCullough, et al. (1997)

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