Article Identification

• Title: “Vitamin D Supplementation and Prevention of Cancer and Cardiovascular Disease”
• Citation: Manson JE, Cook NR, Lee IM, et al. N Engl J Med. 2019;380(1):33-44.
• DOI/PMID: 10.1056/NEJMoa1809944

Quick Reference Summary

• In this large, randomized, placebo-controlled trial (N=25,871), daily vitamin D3 supplementation at 2000 IU/day did not reduce the incidence of invasive cancer (HR 0.96; 95% CI 0.88 to 1.06; P=0.47) or major cardiovascular events (HR 0.97; 95% CI 0.85 to 1.12; P=0.69).
• Absolute event rates were similar in the vitamin D and placebo groups for both total invasive cancers (793 vs. 824) and major cardiovascular events (396 vs. 409), indicating no statistically significant risk reductions.

Core Clinical Question

Among generally healthy men aged ≥50 years and women aged ≥55 years, does daily supplementation with 2000 IU of vitamin D3, compared with placebo, reduce the incidence of invasive cancer or major cardiovascular events (myocardial infarction, stroke, or cardiovascular death)?

Background

• Disease or Condition Overview:
  • Nutritional deficiency of vitamin D has long been linked with bone health problems; more recent observational data suggested potential roles in cancer and cardiovascular disease (CVD) prevention.
  • Despite widespread use of vitamin D supplements, definitive large-scale evidence of benefit for cancer or CVD prevention had been limited prior to this trial.
• Prior Data on the Topic:
  • Observational studies: Lower 25-hydroxyvitamin D levels have been associated with higher risk of cancer and cardiovascular events, but confounding factors (e.g., outdoor activity) made causality uncertain.
  • Smaller trials and meta-analyses: Many tested lower doses or short durations; some suggested a decrease in cancer mortality but little effect on cancer incidence or major CVD outcomes.
• Current Standard of Care:
  • Vitamin D is widely used for bone health and prevention of fractures; recommended dietary allowances are 600-800 IU/day.
  • There is insufficient consensus regarding high-dose supplementation (≥2000 IU/day) for preventing cancer or CVD.
• Knowledge Gaps Addressed by This Study:
  • Whether higher-dose vitamin D supplementation (2000 IU/day) reduces risk of total invasive cancer or major cardiovascular events in the general population.
  • The role of vitamin D across diverse racial groups (including >5000 Black participants).
• Study Rationale: To conduct a large-scale, long-term, randomized, placebo-controlled trial with rigorous adjudication of cancer and CVD outcomes in a generally healthy population.

Methods Summary

• Study Design: Nationwide, randomized, double-blind, placebo-controlled trial with a 2×2 factorial design (vitamin D3 [2000 IU/day] and marine omega-3 fatty acids [1 g/day]).
• Setting and Time Period: Conducted in the United States from 2011 through 2017 (median follow-up 5.3 years).
• Population Characteristics: Men ≥50 years and women ≥55 years, no history of cancer (except nonmelanoma skin cancer) or CVD at baseline.
• Inclusion/Exclusion Criteria:
  • Included: Willingness to limit extra vitamin D supplementation to ≤800 IU/day, completion of a 3-month placebo run-in.
  • Excluded: History of renal failure, hypercalcemia, dialysis, cirrhosis, or other serious conditions that would preclude safe participation.
• Intervention Details: Vitamin D3 (cholecalciferol) 2000 IU daily.
• Control/Comparison: Matching placebo capsule.
• Primary and Secondary Outcomes:
  • Primary: Invasive cancer of any type; major cardiovascular events (myocardial infarction, stroke, CVD mortality).
  • Secondary: Specific cancers (breast, prostate, colorectal) and cancer mortality; expanded composite CVD events (major events + revascularization).
• Statistical Analysis Approach: Intention-to-treat, Cox proportional hazards models.
• Sample Size Calculations: Powered (>85%) to detect hazard ratios of ≥0.85 for risk reduction of cancer and ≥0.80 for major CVD events.
• Ethics and Funding: Approved by Partners HealthCare–Brigham and Women’s Hospital IRB. Funded by the National Institutes of Health; vitamin D donated by Pharmavite.

Detailed Results

• Participant Flow and Demographics:
  • 25,871 randomized: 51% women; mean age 67.1 years; 20% Black participants.
  • Baseline mean serum 25-hydroxyvitamin D ~30.8 ng/mL (77 nmol/L).
• Primary Outcome Results:
  • Invasive cancer (any):
    • Vitamin D group: 793 events
    • Placebo group: 824 events
    • Hazard ratio (HR) 0.96 (95% CI, 0.88 to 1.06; P=0.47)
  • Major cardiovascular events:
    • Vitamin D group: 396 events
    • Placebo group: 409 events
    • HR 0.97 (95% CI, 0.85 to 1.12; P=0.69)
• Absolute Event Numbers and Effect Sizes:
  • Cancer incidence rates: ~3.1% overall; no significant absolute risk difference.
  • Major CVD events: ~1.5% overall; no significant absolute risk difference.
• Secondary Outcome Results:
  • Cancer mortality (341 total deaths): HR 0.83 (95% CI, 0.67 to 1.02)
  • Site-specific cancers: breast (HR 1.02), prostate (HR 0.88), colorectal (HR 1.09)—none were statistically different from placebo.
  • All-cause mortality: HR 0.99 (95% CI, 0.87 to 1.12); no significant difference.
• Subgroup Analyses: Suggestive (but not definitive) lower cancer incidence among participants with lower BMI; no strong signal of benefit in other subgroups.
• Adverse Events/Safety Data: No increase in hypercalcemia, kidney stones, or GI symptoms.

Results Table

(*) Not statistically significant, though possibly suggestive

Authors' Conclusions

• Primary Conclusions:
  • Daily supplementation of 2000 IU vitamin D did not significantly reduce the incidence of invasive cancer or major cardiovascular events over a median follow-up of 5.3 years.
• Authors’ Interpretation of Results:
  • These findings do not support initiating high-dose vitamin D supplementation solely for cancer or CVD prevention.
  • Data hint at possible differences in cancer outcomes by body mass index, but these require further study.
• Clinical Implications Stated by Authors:
  • Although no overall benefit was seen for primary outcomes, vitamin D remains important for bone health; further long-term or targeted studies may be needed.
• Future Research Recommendations:
  • Further trials in populations with significant vitamin D deficiency or longer follow-up to explore mortality outcomes and subpopulations (e.g., by BMI).

Literature Review

• Previous Studies and Meta-Analyses:
  • The Role of Vitamin D in Cardiovascular Diseases (Nutrients. 2023;15(16)): Recent large observational data remain inconclusive regarding vitamin D and cardiovascular outcomes. Some suggest inverse associations with CVD, but confounders often exist.
  • The Vitamin D Assessment (ViDA) study – Design and main findings (J Steroid Biochem Mol Biol. 2020;198:105562): Monthly high-dose vitamin D (100,000 IU) did not significantly reduce cardiovascular disease or total cancer incidence (median 3.3 years). This aligns with VITAL’s null results on major CVD events and cancer incidence.
  • Update on the Vitamin D and OmegA-3 trial (VITAL) (J Steroid Biochem Mol Biol. 2016;155(Pt B):252–6): Provided the trial’s rationale: wide interest in vitamin D for CVD and cancer prevention but few definitive large trials; VITAL was designed to fill this gap.
  • Total Vitamin D Intake and Risks of Early-Onset Colorectal Cancer and Precursors (PMID: 34245763): Suggests possible associations of vitamin D with lower early-onset CRC in younger adults, but specific data in this population remain emerging.
• Contrasting Methodological Quality:
  • VITAL used a large, diverse sample with rigorous adjudication and daily dosing. Some earlier trials (e.g., ViDA) tested bolus monthly doses and had shorter follow-up; differences in dosing and population may contribute to slight discrepancies in cancer or cardiovascular endpoints.
• Comparisons with Guidelines:
  • Current guidelines (e.g., US Preventive Services Task Force statements) do not recommend routine high-dose vitamin D beyond bone health indications, reflecting insufficient evidence for CVD or cancer prevention. This trial’s findings continue to reinforce that position.
• This Trial’s Contribution:
  • VITAL was among the first large-scale, long-term trials testing a moderate/high daily vitamin D dose in a racially diverse population. Confirms, as of 2025, that routine high-dose supplementation for primary prevention of cancer or CVD is not supported by strong evidence, aligning with prior meta-analyses and the ViDA study.

Critical Analysis

A. Strengths

• Large sample size (25,871) and diverse demographics (including >5000 Black participants).
• Rigorous randomization and placebo-controlled design.
• Daily dosing regimen, reducing confounding from bolus administration.
• High adherence rate (over 80%) and robust outcome adjudication.

B. Limitations

• Median follow-up of 5.3 years may be insufficient to detect long-latency oncology outcomes.
• Tested a single 2000 IU/day dose; dose-response or severely deficient groups remain less explored.
• Post hoc subgroup findings (e.g., BMI differences in cancer risk) could be spurious and require replication.
• Some participants began outside vitamin D supplementation over time despite instructions (though rates were relatively low).

Clinical Application

• How Findings Change Current Practice:
  • These results support a conclusion that routine use of 2000 IU/day vitamin D solely to prevent cancer or cardiovascular disease in adults without known deficiency is not warranted.
  • Particular subsets of patients (e.g., those with marked vitamin D deficiency, low BMI) might still benefit, but data remain inconclusive.
• Specific Populations or Scenarios Most Applicable:
  • Patients at normal risk of CVD or cancer who already meet standard recommendations for vitamin D for bone health.
  • This study does not address those with severe deficiency or malabsorption syndromes.
• Implementation and Integration:
  • Clinicians should continue to emphasize vitamin D for bone health while recognizing that robust evidence does not support recommending high-dose vitamin D for primary cancer or CVD prevention at a population level.

How To Use This Info In Practice

Clinicians can safely counsel patients that, based on long-term trial evidence through 2025, routine high-dose vitamin D supplementation does not prevent invasive cancer or major cardiovascular events and should be individualized, primarily guided by bone health needs, baseline deficiency, or specific high-risk scenarios.