Need a VITALity Boost? Rethink Vitamin D and Fish Oil Supplements

Author(s)
Anthony M. Todd, PharmD
Sean E. Smithgall, PharmD, BCACP
Nicole A. Slater, PharmD, BCACP

Reviewed By
Kristin Rieser, PharmD, BCACP
Sarah L. Anderson, PharmD, BCPS, BCACP

Citation
Manson JE, Cook NR, Lee IM, et al. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. 2019; 380(1): 23-32. and Manson JE, Cook NR, Lee IM, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019; 380(1): 33-44.

The Problem

 

Vitamin D and fish oil (aka omega-3 fatty acids) were the most widely used vitamin and nutritional supplement in 2011-2012.¹  Both have been commonly touted for their potential benefits in reducing cancer and cardiovascular disease.^2-6 While vitamin D and omega-3 fatty acid supplements are wildly popular, the evidence supporting their health benefits is inconclusive and inconsistent. The VITAL study sought to determine whether vitamin D and/or marine omega-3 fatty acids can prevent cardiovascular disease (CVD) and cancer when used by the general population.^7,8

 

What’s Known

 

Epidemiological studies have shown that 25-hydroxyvitamin D levels > 30 ng/mL are associated with the lowest risk of cancer and > 20 ng/mL for CVD.^9,10 While the recommended dietary allowance of vitamin D to maintain bone health is only 600 international units (IU) for most adults and 800 IU for older adults >70 years old, the Endocrine Society recommends a dose of 1500 to 2000 IU per day to raise the blood level of 25-hydroxyvitamin D consistently above 30 ng/mL.¹¹ The primary function of biologically active vitamin D (1,25-dihydroxyvitamin D) is to raise serum calcium levels by increasing intestinal absorption of dietary calcium, stimulating osteoclastic activity to mobilize calcium from bone, and increasing calcium reabsorption in the kidney.¹¹ But 1,25-dihydroxyvitamin D may have numerous pleiotropic effects due to the presence of vitamin D receptors in many tissues and cells throughout the body.¹¹

 

While some studies have shown promising results for reducing the risk of cancer and CVD using omega-3 fatty acids, others have not.^4-6,12-14 The American Heart Association (AHA) recommends that patients with documented coronary heart disease consume at least  1 g per day of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA), preferably by consuming oily fish.¹⁵ Most of the evidence supporting the benefits of omega-3 fatty acids has been attributable to EPA, which, in addition to lowering triglycerides, may also have anti-inflammatory, antioxidative, plaque-stabilizing, and membrane-stabilizing properties. The recent REDUCE-IT trial demonstrated that 4 g per day of pure EPA when added to statin therapy lowered the risk of CV events in high-risk patients; although, the benefit was observed only in those with a pre-existing CVD and in those not currently taking ezetimibe.⁶   (For more info see the iForumRx Commentary: Cardiovascular Risk with Elevated Triglycerides – Does Icosapent Ethyl REDUCE-IT?)

 

What’s New

 

The VITAL study was a randomized, double-blind, placebo-controlled trial with a two-by-two factorial design conducted in 25,871patients in the United States from November 2011 to December 31, 2017. The median follow-up was 5.3 years.

 

Men aged ≥50 years and women aged ≥55 years were eligible for the study if they had no history of cancer (except nonmelanoma skin cancer) or CVD. Participants agreed to limit the use of vitamin D from all outside supplemental sources to 800 IU per day and to stop use of omega-3 fatty acids if they were using them prior to randomization. Participants were required to complete a 3-month placebo run-in.  Exclusion criteria included renal failure or dialysis, cirrhosis, a history of hypercalcemia, use of anticoagulants, history of kidney stones, hypo/hyperparathyroidism, sarcoidosis or other granulomatous diseases.

 

Patients were first randomized to active or placebo vitamin D (2,000 IU once daily) and then randomized to either active or placebo omega-3 fatty acids (1 g per day as a capsule containing 460 mg of EPA and 380 mg DHA).  There were total of four possible treatment groups with some patients receiving both vitamin D and fish oil … and others taking only placebos.

The primary efficacy outcomes were major CVD [composite of myocardial infarction (MI), stroke, and death from cardiovascular causes] and invasive cancer of any type. Secondary cardiovascular (CV) outcomes were major CV events plus coronary revascularization and the individual components of the primary CV outcome. Secondary cancer outcomes were incident colorectal, breast, and prostate cancers, and death from cancer.

 

Baseline characteristics were well-matched between groups (Table 1).

 

Table 1. Baseline characteristics of the VITAL study participants.
Characteristic	Total (N=25,871)
Age, mean (yr)	67.1
Female sex (%)	50.6
Non-Hispanic white race (%)	71.3
Black race (%)	20.2
Nonblack Hispanic race (%)	4.0
Asian or Pacific Islander race (%)	1.5
Native American race (%)	0.9
Other/unknown race (%)	2.1
Body-mass index (kg/m2)	28.1
Current smoking (%)	7.2
HTN treated with medication (%)	49.8
Current use of cholesterol-lowering medication (%)	37.5
Diabetes (%)	13.7

At 2 years, only 3.8% in the vitamin D group and 5.6% in the placebo group reported outside study use of vitamin D (>800 IU per day); at 5 years, the rates were 6.4% and 10.8%, respectively. The outside study use of omega-3 fatty acid supplements remained below 3.5% in both the omega-3 fatty acid and placebo groups throughout follow-up.

 

Unfortunately, neither vitamin D nor omega-3 fatty acids significantly reduced the risk of CVD or cancer when compared to placebo (Table 2).

 

Table 2. Incidence of the Primary Endpoints Based on Assignment
Based on Vitamin D Assignment
Endpoint	Vitamin D Group* (N=12,927)	Placebo Group** (N=12,944)	HR (95% CI)
Major Cardiovascular Event (N)	396	409	0.97 (0.85 to 1.12)
Invasive Cancer of Any Type (N)	793	824	0.96 (0.88 to 1.06)
Based on Omega-3 Fatty Acid Assignment
Endpoint	Omega-3 Group^ (N=12,933)	Placebo Group^^ (N=12,938)	HR (95% CI)
Major Cardiovascular Event (N)	386	419	0.92 (0.80 to 1.06)
Invasive Cancer of Any Type (N)	820	797	1.03 (0.93 to 1.13)

* Includes both active (N=6463) and placebo (N=6464) omega-3 fatty acids

** Includes both active (N=6470) and placebo (N=6474) omega-3 fatty acids

^ Includes both active (N=6463) and placebo (N=6470) vitamin D

^^ Includes both active (N=6464) and placebo (N=6474) vitamin D

 

None of the secondary CV end points were statistically different between the vitamin D and placebo groups. Death from cancer after the first 2 years of follow-up – a secondary cancer end point which was not prespecified in the analysis plan – was significantly lower in the vitamin D group  (117 and 149 participants; HR, 0.75; 95% CI, 0.59 to 0.96).

 

The only secondary CV endpoint which was significantly lower in the omega-3 fatty acid group was total MI, which occurred in 145 vs. 200 placebo participants (HR, 0.72; 95% CI, 0.59 to 0.90). Several non-prespecified CV endpoints were also lower in the omega-3 fatty acid group including percutaneous coronary intervention, total coronary heart disease, and death from MI. None of the secondary cancer end points were statistically different.

 

In subgroup analyses, the rate of invasive cancer was significantly reduced with vitamin D compared to placebo in patients with a body mass index <25 kg/m² (HR, 0.76; 95% CI, 0.63 to 0.90). The rate of major CV events was significantly reduced with omega-3 fatty acids compared to placebo in participants who consumed <1.5 servings of fish per week (HR, 0.81; 95% CI, 0.67 to 0.98). Interestingly, the results suggest that the largest cancer and CV benefits were seen in African-Americans. There were no interactions between the two active treatments in the two-by-two factorial design.

 

Our Critical Appraisal

 

The VITAL study is the first large trial testing the effects of vitamin D and omega-3 fatty acids for the primary prevention of cancer and CVD in the general population. The study has several strengths, including a very robust trial design, large sample size with racial and geographic diversity, long duration of follow-up, and high rates of adherence to the trial regimens. Those assigned to the active vitamin D group achieved target 25-hydroxyvitamin D concentrations > 30 ng/mL. Additionally, the dose of omega-3 fatty acids used is recommended by the AHA for cardioprotection for the secondary prevention of CHD events and is twice the recommended dose for cardioprotection in healthy populations without established CHD.

 

The VITAL study is not without limitations. Questionnaires assessing adherence and potential side effects of the trial regimen are prone to bias and underreporting. Also, the use of outside vitamin D and omega-3 fatty acid supplements, while relatively small but potentially underreported, could have confounded the results, diluting the effects of the trial regimens. Furthermore, it is plausible that DHA could diminish the efficacy of the omega-3 fatty acids since pure EPA has not been shown to raise LDL levels.¹⁶ Finally, the median follow-up of 5.3 years may not be long enough to see a difference in rates of CV events or cancer in a relatively healthy primary prevention population.  An ongoing follow-up study of the VITAL study participants may provide some additional data regarding latent effects that may require more time to emerge.  We’ll see.

 

The Bottom Line

 

The use of vitamin D and omega-3 fatty acid supplements do not provide a VITALity boost. They provided negligible benefits for the primary prevention of cancer and major CV events. Unless patients have a comorbid condition warranting the use of these supplements, we recommend against the routine use of vitamin D and omega-3 fatty acid supplements.

 

The Key Points

• Previous studies have demonstrated an inconsistent benefit from vitamin D and omega-3 fatty acid supplements.
• The VITAL study showed that supplementation with vitamin D at a dose of 2000 IU per day and omega-3 fatty acids at a dose of 1 g per day failed to reduce the risk of cancer and major CV events for primary prevention in the general population.
• An ongoing 2-year post-intervention follow-up of the VITAL study participants may capture latent effects and increase statistical power to further assess outcomes.

NOTE:  This program will be available for recertification credit through the American Pharmacists Association (APhA) Ambulatory Care Review and Recertification Program.  To learn more, visit https://www.pharmacist.com/ambulatory-care-review-and-recertification-activities.