VITAL Trial's Design Limits Flawed Broad Dismissal of Vitamin D Benefits

Original analysis by James Lyons-Weiler, Brownstone Institute, December 30, 2025.

The 2019 VITAL trial, published in the New England Journal of Medicine, tested 2,000 IU daily vitamin D3 in over 25,000 mostly sufficient older adults (mean baseline 30.8 ng/mL 25(OH)D; only 12.7% deficient <20 ng/mL) for 5.3 years. It found no reduction in invasive cancer incidence or major cardiovascular events, leading to widespread claims that vitamin D supplementation is ineffective.

However, key design elements limited its scope: placebo participants could take up to 800 IU externally (diluting contrast), broad endpoints ignored mechanisms and latency, and the population was largely vitamin D-replete. The trial effectively compared moderate-to-high versus moderate intake in sufficient individuals over a short period relative to cancer development.

A notable signal emerged in cancer mortality: suggestive reductions (HR ~0.83 overall, strengthening post-latency adjustment), with fewer advanced cancers, especially in normal-BMI subgroups. This aligns with vitamin D's roles in immune modulation, differentiation, and anti-angiogenesis, potentially slowing progression rather than preventing initiation.

VITAL's null primary results are valid within constraints but do not disprove benefits in deficient populations or for mortality/progression.

Recent evidence supports nuance: A 2024 umbrella review found strong evidence for vitamin D3 reducing total cancer mortality (OR 0.90). A 2025 individual-patient-data meta-analysis of RCTs estimated 12% lower cancer mortality with daily supplementation. Observational data consistently link higher 25(OH)D to reduced colorectal cancer risk.

Smaller trials in lower-baseline groups (e.g., Lappe et al.) show incidence reductions with vitamin D plus calcium. Daily (not bolus) dosing appears key for mortality benefits.

Future trials need deficient enrollment, strict controls, longer follow-up, and progression-focused endpoints. Correcting deficiency remains advisable for at-risk groups pending clearer data.

Sources:
- Manson JE et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. NEJM 2019;380:33-44.
- Chandler PD et al. Effect of Vitamin D3 Supplements on Development of Advanced Cancer. JAMA Netw Open 2020;3:e2025850.
- Petrelli F et al. Vitamin D3 and cancer risk in healthy subjects: Umbrella review. Clin Nutr ESPEN 2024;63:776-786.
- Kuznia S et al. Efficacy of vitamin D3 supplementation on cancer mortality: IPD meta-analysis. Ageing Res Rev 2025 (German Cancer Research Center report).
- Wimalawansa SJ. Vitamin D’s Impact on Cancer Incidence and Mortality: Systematic Review. Nutrients 2025;17:2333.
- Bjelakovic G et al. Vitamin D supplementation for prevention of mortality. Cochrane Database Syst Rev 2014;1:CD007470.
- McCullough ML et al. Circulating Vitamin D and Colorectal Cancer Risk. J Natl Cancer Inst 2019;111:158-169.
- Lappe JM et al. Vitamin D and calcium supplementation reduces cancer risk. Am J Clin Nutr 2007;85:1586-1591; JAMA 2017;317:1234-1243.

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