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

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 ¼ 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 ¼ 816), participants were assigned to beta-carotene and retinol or to placebo; in the smokers pilot (N ¼ 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 (Po0.0003) and serum triglycerides (Po0.0001) were significantly higher in the participants receiving vitamin A and/or a combination of vitamin A and beta-carotene (n ¼ 863) as compared to the placebo group (n ¼ 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.

The effect of transdermal estradiol or oral conjugated oestrogen and fenretinide versus placebo on haemostasis and cardiovascular risk biomarkers in a randomised breast cancer chemoprevention trial

“…Interestingly, our data shows no effect of fenretinide on fibrinogen and triglyceride levels differently from other retinoids [45], but is consistent with our previous results [46,47]. The observed association between fenretinide administration and the reduction trend of AT-III is new and requires further investigation to assess its potential clinical impact.…”

“…In order to explain the increased cardiovascular mortality observed in the Carotene and Retinol Efficacy Trial (CARET), Cartmel et al suggested a possible contribution of hypercholesterolemia and hypertriglyceridemia in the treatment arm compared to placebo [45]. On the contrary, fenretinide has a neutral effect on tests of liver function, lipid profile and blood cell counts as compared to other retinoids [46].…”

Frequent Hemodialysis Network (FHN) randomized trials: Study design

“…At the end of the Vanguard phase, the Data Safety and Monitoring Board will inform the National Institutes of Health about the advisability of continuing one or both trials. Employed successfully in other trials, 36,37 this phased approach combining pilot and efficacy components into a single study allows subjects enrolled in the feasibility phase to be included in the final analysis of primary and secondary outcomes.…”

Vitamin A and Beta-Carotene Concentrations in Adults with HIV/AIDS on Highly Active Antiretroviral Therapy

“…Despite the lack of a consistent explanation for this result, serum beta-carotene is transported in lipoproteins, mainly in LDL-c. Beta-carotene concentrations less than 0.25 mmol/L have been associated with an increased risk of coronary atherosclerotic disease progression in HIV-infected patients (30); the most likely mechanism seems to be reduced oxidation of LDL-c.…”