Association Between Beta-Carotene Supplementation and Mortality: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Systematic review and meta-analysis of randomized controlled trials in 216,734 adults from diverse settings, including general populations and patients with cancer, HIV/AIDS, cardiovascular disease, smokers, and institutionalized elderly. The pooled evidence came from 31 trials with a median follow-up of 4.6 years.

Oral beta-carotene supplementation was tested across 31 randomized trials, with doses ranging from 3 mg/d to 75 mg/d, including schedules such as 20 mg/d, 50 mg/d, 55 mg every other day, and 50 mg on alternate days. Some trials used beta-carotene alone and others combined it with additional antioxidants or vitamins/minerals; comparators were placebo or no intervention, with follow-up typically lasting years.

Beta-carotene supplementation did not reduce overall mortality or most cause-specific mortality outcomes. Total mortality was unchanged overall (RR 1.02, 95% CI 0.98-1.05), as were cancer mortality (RR 0.98, 95% CI 0.90-1.07), cardiovascular mortality (RR 1.04, 95% CI 0.98-1.11), and cerebrovascular mortality (RR 0.94, 95% CI 0.82-1.06). Lung cancer mortality was significantly increased (RR 1.14, 95% CI 1.02-1.27), while HIV-related mortality was reduced in a limited subset of studies (RR 0.55, 95% CI 0.33-0.92). Overall, the findings do not support a mortality benefit from beta-carotene and raise concern for harm in lung cancer risk.

Substantial clinical heterogeneity existed across trials in population, baseline risk, dose, co-supplementation, and follow-up duration. Many outcomes were based on subgroup or cause-specific analyses rather than trials designed primarily for mortality, and some results came from limited subsets of studies. The review also pooled diverse settings and eras, which may limit direct applicability to any single population.