Intro: A lot of our readers may not be familiar with the VITAL study on Omega 3 and Vitamin D supplementation, but I’m sure many of you, have seen news articles which have sprung forth out of the data generated in the study. Starting in 2009,  the study followed over 25,000 subjects for over five years to evaluate the benefits (if any) of long term supplementation with either Vitamin D or Omega 3 fatty acids on heart disease and cancer. Since that time, there have been a number of additional studies which have revisited the VITAL dataset. As a result, there is more to learn than might immediately be evident in the initial papers.

Initially the data indicated little benefit in the primary endpoints measured (more on that in a second) and ever since, any number of articles in the scientific and popular press have been quick to report the results so as to shed the most negative light possible on the use of these popular nutritional supplements. Consider these quotes and headlines, all implying the lack of benefits from VIT D/ Omega3 supplementation supposedly proven in the VITAL dataset.

 

Vitamin D, Omega-3 Fatty Acids Don't Lower Rates of Cancer or CVD (AM J. Nursing Feb 2019)                      

Vitamin D does not reduce cancer or cardiovascular events in healthy adults, trial finds. (BMJ Nov 2018)  

No Benefits to Vitamin D and Omega-3s in Reducing Major CV Events, Cancer. (Am Hosp. Assoc. 2018)

 “taking fish oil supplements seems to have little to no benefits to heart health.” (Mayo Clinic Newsletter)

“Research indicates that omega-3 supplements don’t reduce the risk of heart disease.” (NIH Newsletter)

 

I know many of you have seen similar headlines. Your patients have seen them too. The above examples range from merely misleading to absolutely false. As a result, many casual readers may have the false impression there is little benefit to supplementation, but that is not what the VITAL data shows. My reading of a number of other studies which looked at the VITAL dataset made me want to share a bit more detail of what the VITAL data does (and doesn’t) tell us. For this issue, I’m taking a different tack by first briefly summarizing two of the initial studies by lead author JoAnn Manson MD. I’ll follow that up with subsequent findings from several later papers which have issued out of the original VITAL data. Hopefully we can flesh out a more accurate picture of what we know surrounding Vitamin D and Omega 3 supplementation and give you a better understanding of why so much of the reporting on this study is misleading. As a result, this article is less “brief” than our usual summaries.

Mark R. Payne DC

 

The Studies:

Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease (1)

Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer (2)

 

 Keypoints:

• ·         The VITAL trial was a nationwide, randomized, placebo-controlled trial of marine Omega 3 fatty acids (1 g/d) and vitamin D3 (2000 IU/d) in the primary prevention of CVD and cancer.

• ·         The main point of the study was to observe for any benefits in “primary prevention of cancer and CVD among the 25,871 participants.

• ·         The initial study compared the incidence rates for TWO strictly defined primary endpoints: 1) the rate of “total invasive cancer” and 2) “major cardiovascular events” (defined as a composite of three different cardiovascular events; myocardial infarction, stroke, and CVD mortality).  

 

Author’s Conclusions:

• ·         Supplementation with 2000 IU per day vitamin D3 did NOT result in a lower incidence of “total invasive cancer” or the composite index of “major cardiovascular events” than placebo. (1,2)

• ·         Daily supplements of 1G of Omega 3 FAs did NOT significantly reduce the incidence of “total invasive cancer” or the composite index of “major cardiovascular events” compared to placebo. (1,2)

 

And so, case closed. End of story. Based on the above findings (both of which were unequivocally expressed in the author’s conclusions) a lot of press has been generated to the effect that supplementation with these vital nutrients is without benefit. But fortunately the story doesn’t end there. The VITAL data has since generated a number of papers which delve deeper into the data and show us there’s more to be learned. Here is a quick summary of some key points from subsequent papers and references for the interested reader.

 

Bear in mind, all of the key points of subsequent studies listed below are on the same VITAL dataset obtained in the original studies. These are not just other studies that happen to have come to different conclusions. They are a deeper look into the same VITAL data.

 

 Key Points: 

“In this randomized clinical trial, supplementation with vitamin D reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort, with the strongest risk reduction seen in individuals with normal weight.” (6)

   “Supplemental n-3 FAs did not significantly reduce the primary cardiovascular endpoint of major CVD events (composite of myocardial infarction [MI], stroke, and CVD mortality; hazard ratio [HR]=0.92 [95% confidence interval 0.80–1.06]) but was associated with significant reductions in total MI (HR=0.72 [0.59–0.90]), percutaneous coronary intervention (HR=0.78 [0.63–0.95]), and fatal MI (HR=0.50 [0.26–0.97]) but not stroke or other cardiovascular endpoints.” (3) 

“In the Vitamin D and Omega-3 Trial (VITAL), 840 mg/d of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) resulted in a 28% reduced risk for heart attacks, 50% reduced risk for fatal heart attacks, and 17% reduced risk for total coronary heart disease events.” (5) 

“These findings suggest that vitamin D3 may reduce the risk of developing advanced cancer among adults without a diagnosis of cancer at baseline” (6)

 

“Mean 1-year 25(OH)D increased by 11.9 ng/mL in the active group and decreased by 0.7 ng/mL in placebo. The largest increases were noted among individuals with low baseline and African Americans.” (7

 

“Vitamin D did not significantly reduce the primary endpoint of total invasive cancer incidence (hazard ratio [HR] = 0.96 [95% confidence interval 0.88-1.06]) but showed a promising signal for reduction in total cancer mortality (HR = 0.83 [0.67-1.02]), especially in analyses that accounted for latency by excluding the first year (HR = 0.79 [0.63-0.99]) or first 2 years (HR = 0.75 [0.59-0.96]) of follow-up.” (4)

 

“Updated meta-analyses that include VITAL and other recent vitamin D trials indicate a significant reduction in cancer mortality but not in cancer incidence or CVD endpoints” (4)

 

 “Updated meta-analyses that include VITAL and other recent trials document coronary risk reduction from supplemental marine n-3 FAs but no clear CVD risk reduction from supplemental vitamin D.”   (3)

 

Reviewer's Comments: 

Much of the negative press around the VITAL studies seems to have risen out of the strictly defined endpoints of the original studies like the “major cardiovascular events” composite and just possibly, a bias toward negative reporting on nutritional supplementation. What we actually find is that while the primary endpoints may not have been affected by supplementation, once you drill down into the data of the subgroups you start to see the benefits.

Vitamin D3 doesn’t appear to do much for heart disease but it does seem to benefit cancer outcomes…IF you look out two years or longer. Short term benefits for cancer??? Not so much.

Omega 3 supplementation didn’t do anything for cancer or the original cardiovascular composite endpoint ( Myocardial infarction, stroke, or death from cardiovascular causes) but appears to benefit certain secondary endpoints by significantly reducing the total number of myocardial infarctions and fatalities due to Myocardial infarctions. Not dying from a heart attack would seem like a pretty good benefit to me. But what do I know.

 Finally, it seems to me that the dosages were still pretty small in this study. Daily doses of 2000 IU of Vit. D3 and 1G of Omega 3 FAs could hardly be considered “mega” doses. Perhaps we will see future studies to tell us whether there is any linearity in benefits with larger dosages.

  I’ve limited this review to key points concerning heart health and cancer. But there’s a lot more to the VITAL “family” of studies; lung health, risk of falls, macular degeneration, kidney function, bone structure/architecture, fractures.  Maybe we’ll get to some of these in future articles. IMHO, those of you who are recommending reasonable supplementation with Omega 3 and Vitamin D3 are practicing in keeping with the literature. The potential upsides appear to be good and the downsides are virtually nil. Keep up the good work.

 

Reviewer: Mark R. Payne DC

 

References:   

1) JoAnn E Manson, Nancy R Cook, I-Min Lee, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease N Engl J Med. 2019 Jan 3;380(1):33-44.  doi: 10.1056/NEJMoa1809944. Epub 2018 Nov 10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425757

 2) JoAnn E. Manson, M.D., Dr.P.H., Nancy R. Cook, Sc.D., I-Min Lee, M.B., B.S., Sc.D., et al. Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. January 3, 2019; 380:23-32 DOI: 10.1056/NEJMoa1811403 https://www.nejm.org/doi/full/10.1056/nejmoa1811403

3) JoAnn E. Manson, MD, DrPH, Shari S. Bassuk, ScD, Nancy R. Cook, ScD, I-Min Lee, MBBS, ScD, Samia Mora, MD, MHS, Christine M. Albert, MD, MPH, Julie E. Buring, ScD, and VITAL Research Group.  Vitamin D, Marine n-3 Fatty Acids, and Primary Prevention of Cardiovascular Disease: Current Evidence. Circ Res. 2020 Jan3 126(1) 112-128 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001886/

4) JoAnn E Manson 1, Shari S Bassuk 2, Julie E Buring 3, VITAL Research Group.  Principal results of the VITamin D and OmegA-3 TriaL (VITAL) and updated meta-analyses of relevant vitamin D trials. J. Steroid Biochem Mol Biol. 2020 Apr. https://pubmed.ncbi.nlm.nih.gov/31733345/

 5) Penny M. Kris-Etherton, PhD, RDN, Chesney K. Richter, PhD,et al  Recent Clinical Trials Shed New Light on the Cardiovascular Benefits of Omega-3 Fatty Acids Methodist Debakey Cardiovasc J. 2019 Jul-Sep; 15(3): 171–178. doi: 10.14797/mdcj-15-3-171 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822654/

 6) Paulette D. Chandler, MD, MPH,1 Wendy Y. Chen, MD, MPH,2,3 Oluremi N. Ajala, MD, MPH, et al. Effect of Vitamin D3 Supplements on Development of Advanced Cancer A Secondary Analysis of the VITAL Randomized Clinical Trial JAMA Netw Open. 2020 Nov; 3(11): e2025850. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675103/\

 7) Heike Luttmann-Gibson1, Samia Mora, Carlos A Camargo, et al. Serum 25-hydroxyvitamin D in the VITamin D and OmegA-3 TriaL (VITAL): Clinical and demographic characteristics associated with baseline and change with randomized vitamin D treatment. 2019 Dec;87:105854.  doi: 10.1016/j.cct.2019.105854. Epub 2019 Oct 24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875603/