Life Extension Magazine®

Issue: Nov 2019

Rebuttal to Recent Trials on Vitamin D and Fish Oil

Modest potencies of fish oil and vitamin D did not achieve primary prevention endpoints, according to a recent clinical trial. However, secondary subgroup analysis uncovered critically important benefits.

By Suzanne Schiff

Higher intake and/or blood levels of vitamin D and omega-3 fatty acids are linked to reduced rates of cancer, cardiovascular events, and other health problems.

A clinical trial published in the New England Journal of Medicine garnered widespread media attention late last year. That’s because the study purportedly failed to demonstrate the efficacy of vitamin D and/or fish oil.1,2

Life Extension® analyzed the design and results of this trial.

The first glaring flaw was the potencies of both nutrients studied were insufficient, and far below what many experts recommend.

And yet, even at these inadequate doses, both supplements (vitamin D and fish oil) demonstrated important benefits that were largely overlooked by many media sources.

In one arm of the study, there was a 25% reduction in cancer deaths in the vitamin D group when the first two years of follow-up were excluded. This fact is important because cancer can take years to manifest into a clinically relevant disease.

What this means is that longer-term use (more than two years) of vitamin D, even in a modest dose, can reduce the risk of dying from cancer. What’s startling is these favorable data (i.e. 25% cancer mortality reduction) come from the same study the media used to question the value of vitamin D.

Much of the media twisted this study’s findings to state that vitamin D provides no benefit against cancer. The reality is that findings from this study indicate that short-term supplementation with vitamin D did not confer cancer-protection effects.

In this same study, fish oil supplementation led to a 28% reduction in risk for heart attack and a 50% reduction in fatal heart attacks.1,2 Yet the media chose to report on the primary endpoints in order to discredit these beneficial results.

Contrary to the attacks on fish oil supplements, the media reported positively on an expensive fish oil drug comprised of the EPA fraction of fish oil.

The fish-oil-drug study demonstrated robust cardiovascular protection in people with higher blood triglyceride levels. The study found that those receiving the omega-3 drug had a 20% reduced rate of death from cardiovascular causes, a 31% reduced rate of heart attack, and a 28% reduced rate of stroke.3

If you are confused about contradictory reporting about the same or similar studies, we clarify the nuances in this article, and in the opening editorial on page 7 of this month’s issue.

The public deserves to understand the practical realities as they relate to low-cost opportunities to enjoy healthy aging.

The VITAL Trial: What Went Wrong?

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The name of the clinical trial that the media used to bash vitamin D and fish oil was VITAL.

A key problem with the VITAL trial is inadequate dosing.

By choosing a dose dramatically lower than the optimal amounts, researchers doomed the study to failure from the start. In the end, the study findings didn’t show the supplements were ineffective, only that the supplements are ineffective (by some measures) when used at inadequate doses.

The VITAL trial used 2,000 IU of vitamin D and 840 mg of EPA/DHA from fish oil daily.1,2

The Vitamin D Council (and Life Extension®) has long recommended daily doses of 5,000 IU to 8,000 IU of vitamin D, especially since deficiency in the vitamin is strikingly common in the United States.

More than 75% of adolescents and adults have inadequate levels of vitamin D.4-6 In the elderly and other high-risk groups, the percent of deficient individuals and the magnitude of the deficiency can be higher.

Studies of omega-3 fatty acids have shown a strong cardiovascular protective effect in individuals with the highest percentage of omega-3s in their blood.7,8

Life Extension has determined that doses of 2,400 mg of EPA/DHA from fish oil daily are often required to maintain optimal levels. That’s almost three times the modest dose (840 mg) used in the VITAL trial.

The blood levels of vitamin D and omega-3 fatty acids in the VITAL trial further demonstrate how inadequate the dosing was.

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What You Need to Know

Vitamin D and Omega 3 Rebuttal

  1. Adequate blood levels of vitamin D and omega-3 fatty acids are required to maximize the health benefits associated with these nutrients.

  2. A recent trial that used low doses of vitamin D and omega-3 fatty acids failed to show a benefit for the primary cancer and cardiovascular outcomes they assessed, though benefits were seen for several other outcomes.

  3. Life Extension believes the study was critically flawed due to inadequate dosing for both vitamin D and fish oil supplementation, which was insufficient to raise blood levels of both nutrients to optimal levels.

  4. Based on guidelines set forth by the Vitamin D Council, and numerous studies of the protective effects of high omega-3 levels, Life Extension recommends maintaining blood levels between 50 ng/mL and 80 ng/mL for vitamin D and an omega-3 index of 8% to 12%.

  5. We recommend doses of 5,000 IU to 8,000 IU of vitamin D and 4,000 mg of fish oil daily to maintain these optimal levels. Regular blood testing, available through Life Extension, is important to guide adjustments to these doses to achieve the maximum benefits.

Insufficient Blood Levels

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During the VITAL trial, average blood levels of vitamin D rose from approximately 30 ng/mL to 41 ng/mL. The omega-3 index (which measures EPA/DHA in blood) went from 2.7% to slightly over 4%.1,2

The optimal ranges typically recommended by Life Extension are between 50 ng/mL to 80 ng/mL for vitamin D (25-hydroxyvitamin D) and 8% to 12% for the omega-3 index.

Research is increasingly demonstrating that these higher levels are associated with the greatest protection from various forms of disease.

For example, a meta-analysis of clinical trials published last year found that in women over the age of 54, those with vitamin D levels higher than 58 ng/mL had a remarkable 82% lower incidence of breast cancer than women with low levels of vitamin D.9

Research has also shown a steep relationship between blood levels of omega-3 fatty acids and healthy outcomes.

One study published in the journal Preventive Medicine found that the greatest protection from death by cardiovascular causes was in individuals with an omega-3 index (blood test) greater than or equal to 8%.7 That’s well above the levels found in most subjects in the VITAL trial (whose omega-3 index score was slightly over 4%).7,8

Life Extension recommends periodic blood testing for vitamin D and the omega-3 index. This can help determine individualized dosing requirements to achieve optimal levels.

Overlooked Benefits in the VITAL Trial

Media attention on the VITAL trial focused on the lack of benefit for the primary outcomes it evaluated: i.e. whether vitamin D or omega-3s reduced the risk for developing cancer and cardiovascular disease.

But even at the low doses used, there were benefits observed on secondary outcomes.

The VITAL trial followed subjects for an average of 5.3 years. There was a 25% reduction in cancer deaths in those receiving vitamin D when the first two years of follow-up were excluded.2

In other words, some people who died from cancer in the first two years of the study were likely already on the path to cancer or had preexisting cancer when the study began.

In these individuals, any dose of vitamin D would have been unlikely to make a difference. But in the longer term, the rates of cancer deaths dropped in the vitamin D group, suggesting a protective effect against new cancers down the road.

Fish oil supplementation also had impressive benefits, including a 28% reduction in risk for heart attack (myocardial infarction) and a 50% reduction in fatal heart attacks. Subjects in the fish oil group also had a 22% reduction in the need for angioplasty procedures for coronary artery disease.1

When looking at overall cardiovascular events, fish oil had the greatest positive impact in individuals who reported lower fish consumption in their diet (less than 3-4 ounces of fish per week). In these people, fish oil supplementation resulted in a 19% reduction in all major cardiovascular events, including a 40% reduction in heart attacks.1

These are extremely significant benefits that were widely overlooked in reports about the trial.

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The Importance of a Healthy Omega Balance

One major consideration that is missing from studies evaluating the effects of omega-3 fatty-acid supplementation is the further complicating issue of omega-6 fatty acids. Omega-6s are polyunsaturated fatty acids, like omega-3s. However, despite the similarity in name, they have different effects.

While omega-3s are critical building blocks in the brain, have cardioprotective effects, reduce abnormal clot formation, and reduce inflammation in the body, excessive intake of omega-6s can be harmful to health.25-27

The problem lies in the fact that our bodies evolved on a diet with an omega-6 to omega-3 ratio closer to an ideal of 4 to 1. Unfortunately, the typical modern diet is now closer to a ratio of 20 to 1.25 These excess omega-6s are a hidden menace in our food supply, amplifying our risk for chronic disease.

Modern diets are often loaded with omega-6s from soy and corn oils, including those in salad dressings, and in many processed and packaged foods, chicken and chicken dishes, baked goods and desserts, potato and corn chips, pizza, French fries, and more.28

While omega-3 supplements are important, an optimal omega-6 to omega-3 balance requires drastically reducing the intake of omega-6 fatty acids from an average American diet at the same time.

Life Extension believes that people should strive for a <4:1, i.e. less than 4 grams of omega-6s for each gram of omega-3. Refer to the article on page 42 of this issue for more details about achieving healthier omega-6 to omega-3 balance.

So, when evaluating clinical trials of omega-3s, an overlooked, confounding factor to consider is to what degree the study subjects over-ingested omega-6 fats, which counteract many of the expected benefits of omega-3s.

Robust Results in the REDUCE-IT™ Trial

The negative primary findings of the VITAL trial run contrary to the results of many other studies of vitamin D and omega-3 fatty acids. Each year, dozens of new studies are published attesting to the importance of vitamin D and omega-3s for various aspects of health.10-24

One of the most notable recent trials was the REDUCE-IT™ study, the results of which were published this year in the New England Journal of Medicine.3 This large trial randomized subjects at high risk for cardiovascular events to receive 4,000 mg/day of this EPA-only omega-3 drug or a placebo.

This study demonstrated definitive benefits. Overall, the rate of death due to cardiovascular causes was reduced by 20%. Heart attacks were reduced by 31% and strokes by 28%.

The researchers found further benefits when evaluating other indicators of the severity of cardiovascular disease. The need for urgent or emergency heart revascularization procedures (such as angioplasty, stenting or bypass surgery) was reduced by 35%. The need for hospitalizations for chest pain (unstable angina) was 32% lower in the omega-3 supplement group.

The REDUCE-IT™ trial demonstrated that for high-risk patients, this high-dose EPA fish oil supplement can have a profound impact on cardiovascular health.

A notable difference between the VITAL and REDUCE-IT™ studies was the potency of fish oil omega-3s. VITAL used only 840 mg of EPA/DHA, whereas REDUCE-IT™ used a drug that contained 4,000 mg of EPA only. That’s almost five times the omega-3s in REDUCE-IT™ compared to the VITAL trial. Yet both studies showed favorable benefits.

Our concern with an EPA-only drug is that users may deprive themselves of the DHA fraction of fish oil that is needed for critical cellular functions. The high cost of the fish oil drug ($250 a month) makes it cost prohibitive for most consumers.

Summary

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Results of the VITAL study of vitamin D and omega-3 fatty acids received negative media attention. But this study was flawed due to woefully inadequate dosing.

Yet even these low potencies showed health benefits in different subgroups that were almost completely ignored in the media.

The REDUCE-IT™ trial showed robust primary benefits. It used high doses of an expensive (patented) fish oil drug that provided only EPA, but none of the DHA fraction of fish oil.

Most aging individuals require doses of 5,000 IU to 8,000 IU of vitamin D and 2,400 mg of EPA/DHA from fish oil daily to attain optimal levels.

Blood tests (25-hydroxyvitamin D and the omega-3 index) can enable one to achieve optimal vitamin D and omega-3 status.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

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  2. Manson JE, Cook NR, Lee IM, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019 Jan 3;380(1):33-44.
  3. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22.
  4. Ginde AA, Liu MC, Camargo CA, Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009 Mar 23;169(6):626-32.
  5. Cashman KD, Dowling KG, Skrabakova Z, et al. Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr. 2016 Apr;103(4):1033-44.
  6. Snijder MB, van Dam RM, Visser M, et al. Adiposity in relation to vitamin D status and parathyroid hormone levels: a population-based study in older men and women. J Clin Endocrinol Metab. 2005 Jul;90(7):4119-23.
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  8. von Schacky C, Harris WS. Cardiovascular risk and the omega-3 index. J Cardiovasc Med (Hagerstown). 2007 Sep;8 Suppl 1:S46-9.
  9. McDonnell SL, Baggerly CA, French CB, et al. Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations >/=60 vs <20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort. PLoS One. 2018;13(6):e0199265.
  10. Patil MB, Ragav ED. A Clinical, Biochemical Profile of Type-2 Diabetes in Women with Special Reference to Vitamin-D Status in Obese and Non-Obese. J Assoc Physicians India. 2018 Dec;66(12):21-4.
  11. Hwang J, Zmuda JM, Kuipers AL, et al. Serum Vitamin D and Age-Related Muscle Loss in Afro-Caribbean Men: The Importance of Age and Diabetic Status. J Frailty Aging. 2019;8(3):131-7.
  12. Skrajnowska D, Bobrowska-Korczak B. Potential Molecular Mechanisms of the Anti-cancer Activity of Vitamin D. Anticancer Res. 2019 Jul;39(7):3353-63.
  13. Yodoshi T, Orkin S, Arce-Clachar AC, et al. Vitamin D deficiency: prevalence and association with liver disease severity in pediatric nonalcoholic fatty liver disease. Eur J Clin Nutr. 2019 Aug 23.
  14. Wu Y, Hu Z, Cai M, et al. Decreased 25-Hydroxyvitamin D Levels in Patients With Vestibular Neuritis. Front Neurol. 2019;10:863.
  15. Sordillo JE, Rifas-Shiman SL, Switkowski K, et al. Prenatal Oxidative Balance and Risk of Asthma and Allergic Disease in Adolescence. J Allergy Clin Immunol. 2019 Aug 19.
  16. Sakamoto A, Saotome M, Iguchi K, et al. Marine-Derived Omega-3 Polyunsaturated Fatty Acids and Heart Failure: Current Understanding for Basic to Clinical Relevance. Int J Mol Sci. 2019 Aug 18;20(16).
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  18. Gao H, Geng T, Huang T, et al. Fish oil supplementation and insulin sensitivity: a systematic review and meta-analysis. Lipids Health Dis. 2017 Jul 3;16(1):131.
  19. Moertl D, Hammer A, Steiner S, et al. Dose-dependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: a double-blind, placebo-controlled, 3-arm study. Am Heart J. 2011 May;161(5):915 e1-9.
  20. Xyda SE, Vuckovic I, Petterson XM, et al. Distinct influence of omega-3 fatty acids on the plasma metabolome of healthy older adults. J Gerontol A Biol Sci Med Sci. 2019 Jun 4.
  21. Martins BP, Bandarra NM, Figueiredo-Braga M. The role of marine omega-3 in human neurodevelopment, including Autism Spectrum Disorders and Attention-Deficit/Hyperactivity Disorder—a review. Crit Rev Food Sci Nutr. 2019 Mar 18:1-16.
  22. Jovic M, Loncarevic-Vasiljkovic N, Ivkovic S, et al. Short-term fish oil supplementation applied in presymptomatic stage of Alzheimer’s disease enhances microglial/macrophage barrier and prevents neuritic dystrophy in parietal cortex of 5xFAD mouse model. PLoS One. 2019;14(5):e0216726.
  23. Yang Y, Kim Y, Je Y. Fish consumption and risk of depression: Epidemiological evidence from prospective studies. Asia Pac Psychiatry. 2018 Dec;10(4):e12335.
  24. Niroomand M, Fotouhi A, Irannejad N, et al. Does high-dose vitamin D supplementation impact insulin resistance and risk of development of diabetes in patients with pre-diabetes? A double-blind randomized clinical trial. Diabetes Res Clin Pract. 2019 Feb;148:1-9.
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  28. Available at: https://epi.grants.cancer.gov/diet/foodsources/fatty_acids/table3.html. Accessed August 23, 2019.

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