VITAL (Vitamin D arm)

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Published
Manson JE, et al. "Vitamin D supplements and prevention of cancer and cardiovascular disease". The New England Journal of Medicine. 2019. 380(1):33-44.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

Among men aged ≥50 and women aged ≥55, does vitamin D supplementation safely reduce the risk of cancer or cardiovascular disease compared to placebo?

Bottom Line

Among men aged ≥50 and women aged ≥55, vitamin D supplementation did not reduce the risk of invasive cancer or cardiovascular disease compared to placebo.

Major Points

In the United States, vitamin D supplementation increased in the 2000s, including high-dose supplementation.[1] Observational studies had noted an association between lower vitamin D and greater risks of cancer and CVD,[2][3][4][5] but high-quality clinical trial evidence was lacking to confirm a potential benefit from vitamin D supplementation in the general population.

Published in 2019, the VITamin D and OmegA-3 TriaL (VITAL) randomized 25,871 men and women aged ≥50 and 55 years old, respectively, to vitamin D3 at 2000 units daily or placebo. (This was a 2x2 factorial design trial and also randomized individuals to fish oil or placebo). With 5 years of follow-up, there was no difference in major CVD events (HR 0.97; 95% CI 0.85 to 1.12) or invasive cancer (HR 0.96; 95% CI 0.88 to 1.06). In a secondary analysis that excluded the first 2 years of follow-up, there was fewer cancer deaths with vitamin D than placebo (HR 0.75; 95% CI 0.59 to 0.96), but this was 1 of 15 prespecified endpoints assessed and the authors did not adjust for multiple comparisons. The likelihood of inappropriately rejecting a null hypothesis increases with the number of simultaneous outcomes assessed, and adjusting for multiple comparisons is a common methodology to account for this.[6]

The later-published D-Health trial (2022)[7] randomized 21,315 participants to vitamin D or placebo. At 5 years of follow-up there was no difference in cancer deaths, but notably the point estimate for cancer mortality was in the opposite direction (though null; HR 1.15; 95% CI 0.96 to 1.39) than what was seen in VITAL (though also null; HR 0.83; 95% CI 0.67 to 1.02). There was no benefit of vitamin D on CVD mortality (HR 0.96; 95% CI 0.72 to 1.28) in D-Health. Taken together, VITAL and D-Health do not support routine use of vitamin D supplementation for CVD and cancer prevention.

Guidelines

USPSTF Vitamins and Minerals to Prevent CVD and Cancer (2022, adapted)[8]

  • This guideline lacks specific recommendations about vitamin D in relation to cancer and CVD, but the authors note that there is a need to complete studies with a significant duration to determine the association between vitamin D supplementation and CVD and cancer events.

Design

  • Double-blind, RCT, 2x2 factorial design of vitamin D and omega-3 fatty acids; the present review only considers the vitamin D arm
  • N=25,871
    • Vitamin D (n=12,927)
    • Placebo (n=12,944)
  • Enrollment: 2011-2014
  • Median follow-up: 5.3 years
  • Analysis: Intention-to-treat
  • Primary Outcomes:
    • Invasive cancer of any type
    • Major CVD event

Population

From the overall group.

  • Demographics: Female sex 51%, NH White 71%, Black race 20%, non-Black Hispanic 4%, Asian or Pacific Islander 2%, Native American or Alaskan native 1%, other/unknown 2%
  • BMI: 28 kg/m2
  • Medical problems: Hypertension on treatment 50%, smoking 7%, diabetes 14%
  • On lipid-lowering medication: 38%

Inclusion Criteria

  • Man aged ≥60 years or woman aged ≥65 years with at least a high school education
  • No prior cancer, aside from nonmelanoma skin cancer
  • No prior MI, stroke, or revascularization procedure (ie CABG or PCI)
  • Vitamin D supplement intake ≤800 IU/day or willing to decrease or stop vitamin D during the trial

Exclusion Criteria

  • Calcium supplement intake ≤ 1200 mg/day
  • No fish oil or willing to stop during the trial
  • Not on anticoagulation
  • No history of kidney stones, kidney failure, or ESRD use, hypercalcemia, parathyroid disease, cirrhosis, saroicoidosis, granulomatosis
  • No allergy to fish or fish oil

Interventions

  • This was a 2x2 factorial design, each participant was randomized to both arms:
  • All were randomized to:
    • Vitamin D3 at 2000 IU per day
    • Placebo
  • All were also randomized to:
    • Marine n-3 fatty acids at 1g per day
    • Placebo

Outcomes

Presented as vitamin D vs. placebo. The authors did not adjust for multiple comparisons.

Primary Outcomes

Any invasive cancer
793 vs. 824 with event (HR 0.96; 95% CI 0.88 to 1.06)
Major CVD event
MI, stroke, or CVD mortality
396 vs. 409 with event (HR 0.97; 95% CI 0.85 to 1.12)

Secondary Outcomes

Invasive cancer type
Breast: 124 vs. 122 with event (HR 1.02; 95% CI 0.79 to 1.31)
Prostate: 192 vs. 219 with event (HR 0.88; 95% CI 0.72 to 1.07)
Colorectal: 51 vs. 47 with event (HR 1.09; 95% CI 0.73 to 1.62)
Cancer mortality
154 vs. 187 with event (HR 0.83; 95% CI 0.67 to 1.02)
Major CVD event, expanded definition
Major CVD events or revascularization (PCI or CABG)
536 vs. 558 events with event (HR 0.96; 95% CI 0.86 to 1.08)
MI: 169 vs. 176 with event (HR 0.96; 95% CI 0.78 to 1.19)
Stroke: 141 vs. 149 with event (HR 0.95; 95% CI 0.76 to 1.20)
CVD mortality: 152 vs. 138 with event (HR 1.11; 95% CI 0.88 to 1.40)
All-cause mortality
485 vs. 493 with event (HR 0.99; 95% CI 0.87 to 1.12)
Excluding first 2 years of follow-up
Any invasive cancer: 490 vs. 522 events (HR 0.94; 95% CI 0.83 to 1.06)
Cancer mortality: 112 vs. 149 events (HR 0.75; 95% CI 0.59-0.96)
Major CVD event: 274 vs. 296 (HR 0.93; 95% CI 0.79 to 1.09)
All-cause mortality: 368 vs. 384 (HR 0.96; 95% CI 0.84 to 1.11)

Additional Analyses

Additional CVD events
PCI': 182 vs. 188 with event (HR 0.97; 95% CI 0.79 to 1.19)
CABG': 73 vs. 98 with event (HR 0.75; 95% CI 0.55 to 1.01)
MI mortality': 24 vs. 15 with event (HR 1.60; 95% CI 0.84 to 3.06)
Stroke mortality': 19 vs. 23 with event (HR 0.84; 95% CI 0.46 to 1.54)

Subgroup Analysis

There was no difference in major CVD events by any prespecified subgroups. As is shown in Table 3 on page 40, there might be a differential benefit of vitamin D among those with lower BMI.

Adverse Events

  • There were no significant differences between the two groups in terms of incidence of hypercalcemia, kidney stones, or GI symptoms.

Criticisms

  • Follow-up might have been inadequate to detect cancer and CVD benefits at 5.3 years.
  • Some individuals were on vitamin D prior to the beginning of the trial.
  • Only one dose of vitamin D.
  • Vitamin D insufficiency was not included as an eligibility criteria.
  • Did not adjust for multiple comparisons.

Funding

Multiple institutions within the NIH.

Further Reading

  1. ↑ Rooney MR et al. Trends in Use of High-Dose Vitamin D Supplements Exceeding 1000 or 4000 International Units Daily, 1999-2014. JAMA 2017. 317:2448-2450.
  2. ↑ Judd SE & Tangpricha V Vitamin D deficiency and risk for cardiovascular disease. Am J Med Sci 2009. 338:40-4.
  3. ↑ Wang TJ et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008. 117:503-11.
  4. ↑ Gupta D et al. Prevalence of serum vitamin D deficiency and insufficiency in cancer: Review of the epidemiological literature. Exp Ther Med 2011. 2:181-193.
  5. ↑ Garland CF et al. The role of vitamin D in cancer prevention. Am J Public Health 2006. 96:252-61.
  6. ↑ Chen SY et al. A general introduction to adjustment for multiple comparisons. J Thorac Dis 2017. 9:1725-1729.
  7. ↑ Neale RE et al. The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality. Lancet Diabetes Endocrinol 2022. 10:120-128.
  8. ↑ Mangione CM et al. Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2022. 327:2326-2333.
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