VITAL

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Authors of Journal Review

Aleksey Gitelson, Rachel Seidel, Sierra Strouse, Catherine Tuman

Clinical Question

In men age 50 or older and women age 55 or older, does vitamin D supplementation safely reduce the risk of cancer or cardiovascular disease compared to placebo?

Bottom Line

In men age 50 or older and women age 55 or older, 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 has increased exponentially. Studies have shown lower rates of cancer and cardiovascular deaths with increased sun exposure which therefore increased endogenous Vitamin D synthesis. VITAL, the Vitamin D and Omega-3 Trial, performed a large-scale trial to assess the correlation between Vitamin D supplements and prevention of cancer and cardiovascular disease.

The study used a randomized, double-blind, placebo-controlled trial methodology, with a two-by-two factorial design, of Vitamin D3 at a dose of 2000 IU per day and marine n-3 fatty acids at a dose of 1 gram per day. Of 25,871 participants, cancer was diagnosed in 1617 participants with a median follow-up of 5.3 years (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). No significant difference existed between the placebo group and the vitamin D supplement group on breast, prostate, or colorectal cancer prevention. A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). No significant difference existed between the placebo group and the vitamin D supplement group in regards to incidence of major cardiovascular events. There was no excess risk of hypercalcemia or other adverse effects.

Post-hoc analysis showed a possible benefit regarding the rate of total death from cancer after exclusion of early follow-up data. The confidence interval for this data did not cross 1. Subgroup analyses noted the possibility of differential effects on cancer incidence according to BMI. Due to the size and long duration greater than five years, the VITAL trial had sufficient power to determine the effects of Vitamin D on cancer and cardiovascular disease prevention. Other strengths included the racial, ethical, and geographical diversity, daily vitamin D dosing, high rates of follow-up and adherence, target vitamin D levels, baseline and follow-up blood samples from many participants, and rigorously adjudicated endpoints. Previous trials of Vitamin D with or without calcium have also proven no significant effects on the incidence of cancer, although some have shown benefit regarding the rate of death from cancer. In a meta analysis composed of four trials from 2014, there was no significant difference in the incidence of cancer (95% CI 0.94 to 1.06) but there was a significant difference rate of death from cancer (95% CI 0.75 to 0.98), which also matched the results of another meta analysis. A limitation of the trial included testing only one dose of vitamin D.

Guidelines

Treatment with either vitamin D2 or vitamin D3 was recommended for deficient patients. At the present time, there is not sufficient evidence to recommend screening individuals who are not at risk for deficiency or to prescribe vitamin D to attain the non calcemic benefit for cardiovascular protection.

  • Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Krstic G, Wetterslev J, Gluud C. Vitamin D supplementation for prevention of cancer in adults. Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No.: CD007469. DOI: 10.1002/14651858.CD007469.pub2.
  • Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30 full-text, correction can be found in J Clin Endocrinol Metab 2011 Dec;96(12):3908

Design

A nationwide, randomized, double-blind, placebo-controlled trial, with a two-by-two factorial design, of Vitamin D3 at a dose of 2000 IU per day and marine n-3 fatty acids at a dose of 1 gram per day

  • N = 25,871
  • Vitamin D group (N = 12,927) 6,463 were assigned to active vitamin D and active n-3 fatty acid 6,464 were assigned to active vitamin D and placebo n-3 fatty acids
  • Placebo group (N= 12,944) 6,470 were assigned to placebo vitamin D and active n-3 fatty acid 6,475 were assigned to placebo vitamin D and placebo n-3 fatty acid

Setting: Nationwide Enrollment:

  • Randomization to receive vitamin D, n-3 fatty acids, both active agents, or both placebos took place from November 2011 through March 2014. The trial intervention ended as planned on December 31, 2017

Mean Follow-up:

  • Participants received follow-up questionnaires at 6 months and 1 year after randomization and annually therefore to collect information on adherence to trial regimens, outside use of * Vitamin D supplements, development of major illnesses, updates on risk factors, and potential side effects of the trial agents.

Analysis: Intention-to-treat principle Primary Outcome: Invasive cancer of any type and major cardiovascular events (composite MI, Stroke, Death)

Population

25,871 participants Recruited through the US

  • Males 50 yo+
  • Females 55 yo+
  • 5,106 black participants

Groups were balanced according to sex & goal of at least 5000 black participants

Randomization:

  • Computer generated within sex, race, & 5-yr groups in blocks of eight

Inclusion Criteria

Inclusion Criteria - at trial entry:

  • No history of cancer (except nonmelanoma skin cancer)
  • No history of cardiovascular disease
  • Required to agree to limit the use of Vit D from all supplement sources (including MV) to 800 IU per day
  • Required to complete a 3-month placebo run-in phase

Exclusion Criteria

Safety exclusions:

  • Renal failure or dialysis
  • Cirrhosis
  • History of hypercalcemia
  • Or other serious condition that would preclude participation

Interventions

  • Vitamin D3 2000 IU per day
  • Marine n-3 fatty acids at a dose of 1g per day

Outcomes

Cancer:

  • Primary: Similar event rates were observed in the primary end point of invasive cancer between the two groups (HR 0.96; 95% CI 0.88 - 1.06; P=0.47). No significant difference in incidence of breast, prostate, or colorectal cancer.
  • Secondary: There was no difference in death from cancer compared to the placebo (HR 0.83, 95% CI 0.67-1.02).

Cardiovascular Disease and All-Cause Mortality:

  • Primary: There was no significant difference in major CV events between the two groups (HR 0.97; 95% CI 0.85 - 1.12; P = 0.69).
  • Secondary: No significant differences between the two groups in cumulative incidence of secondary CV end points.

No meaningful change in rates of major CV events or death from any cause after data from the first 2 years of follow-up were excluded.


Subgroup Analysis

  • There was a possibility of differential on cancer incidence according to BMI, with normal-weight participants in the experimental group having lower incidence of cancer than those in the placebo group.
  • Although trials are ongoing, no prospective trials are assessing this subgroup.
  • After post-hoc analysis excluding events in the first two years, the rate of death from cancer was significantly lower with vitamin D than with placebo (HR 0.75; 95% CI 0.59 - 0.96

Adverse Events

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

Criticisms

  • The median duration of follow-up was 5.3 years.
  • The trial tested only one dose of vitamin D.
  • Trials are ongoing to add information regarding other doses, although some are using bolus dosing.
  • A 2-year post-intervention follow-up is ongoing to capture latency effects and increase statistical power to assess end points


Funding

National Institutes of Health and Brigham and Women's Hospital provided funding for the VITAL trial.

Further Reading

Manson JE, Cook NR, Lee IM, et al. Vitamin D supplements and prevention of cardiovascular disease and cancer. N Engl J Med 2019;380(1):33-44.