Life Extension Magazine®

Issue: Nov 2019

Impact of Fish Oil and Vitamin D on Human Health

Superficial media reports questioned the value of vitamin D and fish oil. Closer examination revealed reductions in cancer deaths and fatal heart attacks.

By William Faloon

William Faloon
William Faloon

Late last year, the media reported top-line results from two large clinical trials.

One used relatively low doses of fish oil and vitamin D, and the other used high doses of an EPA-only, omega-3 drug.1-3

The first study, called VITAL, showed that relatively low doses of fish oil (1,000 mg daily) and vitamin D (2,000 IU daily) did not reduce risk of invasive cancer or of a predetermined combination of cardiovascular endpoints.1,2

This is not surprising, because these doses are below those that Life Extension® considers necessary to create optimum benefit.

Interestingly, however, even these relatively low doses of fish oil and vitamin D did show evidence of benefit in several subgroups in the VITAL study:1,2

  • 25% reduction in cancer deaths in the vitamin D group when the first two years of follow-up were excluded,

  • 28% reduction in heart attack risk, and 50% reduction in fatal heart attack risk, in the fish oil group, and

  • 22% reduction in angioplasty procedures (opening a narrowed coronary blood vessel, often with a stent) in the fish oil group.

These favorable aspects of the VITAL study were ignored by most media outlets.

Instead, they focused only on the primary endpoints, which overlooked the statistically significant reduction in heart attack risk, and also overlooked reduced cancer death rates (after the first two years of the study were excluded).1,2

The daily dose of vitamin D used in the VITAL study was 2,000 IU. This dose raised the mean blood level of 25-hydroxyvitamin D from a baseline of about 30 ng/mL to 41 ng/mL.2

Our experience indicates that 25-hydroxyvitamin D blood levels usually need to reach 50 ng/mL and higher to achieve meaningful benefits.

The daily dose of EPA/DHA from fish oil in the VITAL study was 840 mg.1 This is about one-third of the optimal amount of supplemental EPA/DHA most people need to derive health benefits.

So, while this study (VITAL) did not meet the primary endpoints over the five-year study period, even these relatively low doses of fish oil and vitamin D demonstrated interesting findings in some subgroup analyses of cardiovascular and oncological outcomes.

The second study, called REDUCE-IT™, tested a high-dose fish oil drug comprised only of EPA. Compared to the placebo, there was an average 25% reduced incidence of cardiovascular disorders across a broad spectrum.3

The media reported favorably on this study, but did not fully distinguish between EPA/DHA fish oil supplements and this expensive EPA-only fish oil drug.

I’m going to discuss some intriguing details about these two studies that go beyond the sensationalized headlines.

I try not to fault the news media for the misleading headlines they generate.

In today’s soundbite-frenzied world, typical readers only want succinct summaries. Most want to be spared the details and read only a “curbside chat” about findings that can mean the difference between life and death.

In the period around November 2018, results from two, large, randomized controlled trials generated news reports about the impact of fish oil and vitamin D on cardiovascular health and cancer risk.1-3

The first study, called VITAL,1,2 showed that relatively low-dose fish oil and vitamin D, did not reduce the primary cardiovascular endpoint, which in this study included several different disease outcomes combined into one (i.e. heart attack, stroke, and death from cardiovascular disease).

This finding caused the majority of media to report only on the primary endpoints of the VITAL trial and proclaim that fish oil and vitamin D do not prevent heart attacks or cancer.

This same study, however, showed evidence of benefit in several subgroup analyses that were compelling enough for other news sources, primarily scientific and medical professional sources, to speculate that some subgroups may achieve beneficial results, especially in regard to heart attack risk but also some aspects of cancer risk.1,2

Why the difference? Some reporters focused only on the primary endpoint and either ignored or discounted the rest of the study that showed benefits in various subgroups.

While primary endpoint data may have more methodological design relevance, there are reasons why the subgroup analyses pertain more to what informed supplement users do today.

For example, a statistically significant beneficial impact was observed in the heart attack subgroup, but no benefit was observed in stroke or cardiovascular death (other than death due to heart attack). So, the composite cardiovascular endpoint did not achieve statistical significance.

Vitamin D and Cancer Risk

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Cancer is usually a slowly developing process that can take many years to manifest as a clinically relevant and/or symptomatic disease.

The VITAL study showed that supplementation with 2,000 IU a day of vitamin D over the course of the five-year trial, brought about no reduction in risk of invasive cancer.2

When the first two years of the study were excluded, there was a 25% reduction in cancer death rates in the subgroup analysis.2

Because cancer takes time to clinically manifest, excluding the first two years of data in clinical trials yields a more realistic assessment of the actual effect of the intervention.

Although this modest dose of vitamin D did not reduce cancer risk overall, African Americans who received vitamin D experienced a suggestive 23% reduction in cancer risk.2 This is an impressive finding, since African Americans—as all people of color—are prone to having inadequate vitamin D blood levels.4

Reduced Cancer Deaths

In the VITAL clinical trial, one of the primary endpoints was invasive cancer of any type.2

The study randomized 25,871 subjects who were 67 years old on average. Subjects in the vitamin D group did not experience a statistically significant reduction in the frequency of the primary cancer endpoints.

The VITAL trial design had some weaknesses as it relates to cancer prevention, as follows:

Baseline blood levels of 25-hydroxyvitamin D were about 30 ng/mL.2 This level is higher than the typical American’s, who takes too little vitamin D or does not supplement at all.

This indicates that the study group was already benefiting from vitamin D and less likely to show further improvement after mean 25-hydroxyvitamin D blood levels increased to mean 41 ng/mL during the study period.

According to a number of experts, the optimal blood level of 25-hydroxyvitamin D is 50 ng/mL and higher. There is published data suggesting that any level of 25-hydroxyvitamin D over 30 ng/mL reduces disease risks.5-8 This means that individuals in the VITAL study group may have already been benefitting from vitamin D before they entered the study, since their baseline was around 30 ng/mL.

The daily vitamin D3 dose of 2,000 IU used in the VITAL study was likely too low. This is substantiated by research funded by Life Extension® 10 years ago showing that 85% of serious supplement users had blood levels of 25-hydroxyvitamin D below 50 ng/mL.9 This is why many people nowadays supplement with an additional 5,000 IU of (low-cost) vitamin D3.

A primary endpoint of this study was invasive cancer of any type. There was a suggestive 17% reduction in cancer deaths, which became a 25% reduction in analyses that excluded the first two years of follow-up.2

Since cancer is normally a slowly developing disease, the benefits of nutritional interventions like vitamin D typically become clear only after several years. Those with pre-existing malignancies—meaning they already had them before the study started—would not be expected to benefit during the study’s first two years.

The amount of supplemental vitamin D needed varies considerably among individuals, based on absorption and body mass.10 Heavier people need higher vitamin D doses than thin individuals. When vitamin D is taken with a fatty meal, absorption increases by 32%.11

In the VITAL study, each person received the same low vitamin D dose (2,000 IU/day) and there is no indication they were told to take it with a fatty meal. These two factors would result in widely differing blood levels of 25-hydroxyvitamin D among study subjects.

Heart Attack and Fish Oil

While the primary, composite, cardiovascular endpoint of heart attack, stroke, and cardiovascular death showed no over-all benefit, additional analysis revealed robust reductions in heart attack incidence and fatal heart attacks in the fish-oil-only group.

Specifically, the omega-3 fatty acid intervention lowered the risk of heart attack by 28% and the risk of fatal heart attack by 50% but had no benefit on stroke or cardiovascular deaths not related to heart disease.1

Additionally, omega-3 fatty acids reduced the rate of angioplasty procedures by 22%.1

Angioplasty technology has advanced significantly in recent years, enabling doctors to insert a catheter directly into severely occluded coronary arteries and insert stents (when warranted) that spare patients the miseries and risks of open heart surgery (coronary artery bypass).

In participants whose consumption of fish was low (defined as less than 3-4 ounces per week), omega-3 fatty acid supplementation led to a 19% reduction in major cardiovascular events, including a 40% reduction in heart attack, as well as a trend toward a reduction in death from any cause.1 This emphasizes the importance and value of omega-3 fish oil supplementation in individuals consuming low amounts of fish.

In our experience, the dose (840 mg/day) of EPA/DHA is too low to confer a meaningful reduction in over-all cardiovascular risk for most individuals. This was demonstrated by the VITAL study itself, based on a blood test called the omega-3 index.

Insufficient Omega-3 Blood Levels

The omega-3 index test measures the percent of omega-3 in the blood. The optimal range is generally between 8% to 12%.

In the VITAL study, the subjects’ omega-3 index baseline measurements were 2.7% and increased to 4% after one year.1 This 4% number is half the minimum amount of omega-3 blood level needed to confer meaningful reductions in cardiovascular risk for most people.

Yet even this modest elevation of omega-3 blood levels (from 2.7% to 4%) resulted in benefits for reducing heart attack risk, fatal heart attack, and the need for angioplasty.1 To put the low-dose used in the VITAL study into further context, the American Heart Association recommends 2,000 mg to 4,000 mg of EPA/DHA a day to lower triglycerides.12

The American Heart Association suggests this higher dose of EPA/DHA providing that the fish oil capsules are taken under a physician’s care, which is typical of mainstream organizations. The American Heart Association’s recommendation is based on a large body of evidence showing triglyceride-lowering effects of marine-derived omega-3s.13-16

The REDUCE-IT™ Fish Oil Study

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In contrast with the relatively low dose of fish oil used in the VITAL study, the REDUCE-IT™ trial used a therapeutic dose (4,000 mg/day) of a drug that consisted only of the EPA fraction of fish oil. The name of this fish oil drug is Vascepa®.3

A total of 8,179 subjects participated in REDUCE-IT™.

There was a 25% reduction in the primary cardiovascular endpoint, a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.3

REDUCE-IT™ also observed several other important benefits of four grams of EPA daily:3

  • Cardiovascular death reduced by 20%

  • Fatal or nonfatal heart attacks reduced by 31%

  • Fatal or nonfatal stroke reduced by 28%

  • Urgent or emergent coronary revascularization reduced by 35%

  • Hospitalization for unstable angina reduced by 32%

The estimated out-of-pocket cost, assuming no insurance coverage, is about $250 a month for this EPA-only fish oil drug.

Concern About EPA-Only Fish Oil Drugs

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Vascepa®, an EPA-only drug is marketed to doctors as fish oil that lowers triglycerides without raising LDL cholesterol levels.17

To the physician, this may sound appealing compared to a competitive fish oil drug called Lovaza®, which contains EPA and DHA.

We are troubled that patients taking the EPA-only fish oil drug (Vascepa®) are unlikely to take other fish oil supplements. This ignores the important impact the DHA component of the omega-3 family has on other critical life-sustaining processes, especially brain health.

Impact of Contradictory Headlines

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Considerable evidence demonstrates disease-risk-reducing effects with proper potencies of vitamin D and fish oil.18-21

Favorable news headlines of VITAL and REDUCE-IT™ studies in November 2018 may have motivated some people to initiate supplementation with these nutrients.

Yet the majority of media reporting was biased against vitamin D and fish oil, in some cases stating that the VITAL study proved them to be worthless.

The same news media sources touted findings from the REDUCE-IT™ trial as proving fish oil’s efficacy in heart attack prevention.

The media’s knee-jerk reactions to create sensational headlines, as opposed to meticulously reviewing the actual studies, created contradictory opinions that will cause an undetermined number of Americans to have less-than-optimal blood levels of omega-3s and vitamin D.

This misinterpretation translates into needless suffering and premature death.

A further analysis of the VITAL and REDUCE-IT™ studies appears on page 70 of this month’s issue.

Real-World Disease Prevention

There is an old adage that says if you are going to do something, then do it right.

When it comes to fish oil and vitamin D supplements, taking the proper dose with a fatty meal enables people to achieve optimal blood levels and emulate benefits shown in many published studies.

The media create superficial and, in some cases, misleading headlines about important health issues.

Unlike mainstream news outlets, Life Extension® meticulously analyzes clinical trial findings and interprets them in the context of the totality of published scientific evidence. The box on the next page reveals some of the contradictory headlines that were published around the time period of September 2018 to January 2019.

As it relates to reducing one’s risk of cardiovascular diseases and cancer, a lot more than modest doses of fish oil and/or vitamin D are required, which is what most readers of Life Extension® Magazine practice every day.

For longer life,

For Longer Life

William Faloon, Co-Founder
Life Extension® Buyers Club

Divergent Media Headlines About VITAL and REDUCE-IT™ Study Results


VITAL Study Headlines

Here are headlines from major media sources describing findings from the VITAL study that evaluated lower-dose fish oil and vitamin D on cardiovascular and cancer risk. Note how some of them contradict each other:

  • Fish-oil Drugs Protect Heart Health, Two Studies Say. Washington Post, November 10, 2018

  • New Study: Fish Oil and Vitamin D Pills No Guard Against Cancer or Serious Heart Trouble. USA Today, November 10, 2018

  • Vitamin D and Fish Oils Are Ineffective for Preventing Cancer and Heart Disease. The New York Times, November 10, 2018

  • Big Studies Give Mixed News on Fish Oil, Vitamin D. Medical Xpress, November 10, 2018

  • Fish Oil and Vitamin D Supplements May Not Help Prevent Heart Attacks and Cancer, Study Says. Time, November 10, 2018

  • Vitamin D and Fish Oil Supplements Mostly Disappoint in Long-Awaited Research Results. NPR, November 10, 2018

  • Vitamin D, Omega-3 Supplements Do Not Prevent Cancer or Heart Disease, Study Says. CNN, November 10, 2018

  • Fish Oil Cuts Heart Attack Risk, Vitamin D Lowers Odds of Cancer Death. Reuters, November 12, 2018

  • Eating More Fish or Taking Omega-3 Fish Oil Supplements Can Cut Heart Attack Risk, Studies Find. CBS News, November 12, 2018

  • Fish, Fish Oil May Lower Your Heart Attack Risk. HealthDay, November 12, 2018

  • Should You Keep Taking Those Fish Oil and Vitamin D Pills? NPR, November 15, 2018

  • When Do Fish Oils Yield Good Results? The VITAL Study. Pharmacy Times, November 16, 2018

  • Should You Give Up on Vitamin D and Omega-3s? Not So Fast. The Globe and Mail, November 16, 2018

  • Fish Oil, Vitamin D Fall Short of Expectations. The Business Journals, November 19, 2018

  • Fish Oil: Hunting for Evidence to Tip the Scales. Wall Street Journal, January 2, 2019

  • The Slippery Slope of Fish Oil Supplements. Philly Voice, January 16, 2019

  • Vitamin D Supplements Aren’t Living Up to Their Hype. Science News, January 27, 2019

REDUCE-IT™ Study Headlines

Here are headlines from major media sources describing findings from the REDUCE-IT™ study that evaluated higher-dose, EPA-only fish oil on cardiovascular risks. These headlines were published around the same time as the VITAL study results:

  • Fish Oil Drug May Prevent Heart Attack and Strokes in High-Risk Patients. New York Times, September 25, 2018

  • Health Watch: Super Fish Oil May Cut Risk of Heart Disease and Stroke. CBS N.Y., September 25, 2018

  • REDUCE-IT: 25% Reduction in MACE with High-Dose EPA. Medscape, September 25, 2018

  • Commentary: A Heartwarming Breakthrough for Patients At Risk Of Heart Disease. Chicago Tribune, October 1, 2018

  • Drug with Fish Oil Cuts Risk Of Heart Attack, Stroke, Study Finds. NBC News, November 10, 2018

  • Big Fish Oil Study Unveiled in Chicago Shows Promise in Heart Disease Prevention. Chicago Sun-Times, November 10, 2018

  • Vascepa® (icosapent ethyl) 26% Reduction in Key Secondary Composite Endpoint of Cardiovascular Death, Heart Attacks and Stroke Demonstrated in REDUCE-IT™ Supports 25% Overall Reduction in Five-Point Major Adverse Cardiovascular Event Primary Composite Endpoint. AP News, November 10, 2018

  • Detailed Results Show Amarin Fish Oil Drug Offered A Major Cardiovascular Benefit—But Come with A Blemish. STAT News, November 10, 2018

  • REDUCE-IT: ‘A New Era’ in CVD Prevention with High-Dose EPA. Medscape, November 10, 2018

  • Icosapent Ethyl Reduces Cardiovascular Death Risk 20% in REDUCE-IT Trial. MD Magazine, November 11, 2018

  • Vascepa and Statins Significantly Reduce Cardiovascular Events. Diagnostic and Interventional Cardiology, November 13, 2018

  • Fish Oil Drug Vascepa Looks Heart Healthy—but Is It Really? Daily Beast, November 20, 2018

References

  1. 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 Jan 3;380(1):23-32.
  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. Harris SS. Vitamin D and African Americans. J Nutr. 2006 Apr;136(4):1126-9.
  5. Holick MF. The role of vitamin D for bone health and fracture prevention. Curr Osteoporos Rep. 2006 Sep;4(3):96-102.
  6. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842-56.
  7. Dawson-Hughes B, Heaney RP, Holick MF, et al. Estimates of optimal vitamin D status. Osteoporos Int. 2005 Jul;16(7):713-6.
  8. Aloia JF, Patel M, Dimaano R, et al. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr. 2008 Jun;87(6):1952-8.
  9. Available at: https://www.lifeextension.com/magazine/2010/1/startling-findings-about-vitamin-d-levels-in-life-extension-members/page-01. Accessed August 26, 2019.
  10. 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.
  11. Dawson-Hughes B, Harris SS, Lichtenstein AH, et al. Dietary fat increases vitamin D-3 absorption. J Acad Nutr Diet. 2015 Feb;115(2):225-30.
  12. Kris-Etherton PM, Harris WS, Appel LJ, et al. Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease. Circulation. 2002 November 19, 2002;106(21):2747-57.
  13. Covington MB. Omega-3 fatty acids. Am Fam Physician. 2004 Jul 1;70(1):133-40.
  14. Calder PC. The role of marine omega-3 (n-3) fatty acids in inflammatory processes, atherosclerosis and plaque stability. Molecular Nutrition & Food Research. 2012;56(7):1073-80.
  15. Davidson MH. Mechanisms for the hypotriglyceridemic effect of marine omega-3 fatty acids. Am J Cardiol. 2006 Aug 21;98(4a):27i-33i.
  16. Goodfellow J, Bellamy MF, Ramsey MW, et al. Dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. J Am Coll Cardiol. 2000 Feb;35(2):265-70.
  17. Available at: https://www.vascepa.com/. Accessed August 26, 2019.
  18. Meyer BJ, Groot RHM. Effects of Omega-3 Long Chain Polyunsaturated Fatty Acid Supplementation on Cardiovascular Mortality: The Importance of the Dose of DHA. Nutrients. 2017 Nov 30;9(12).
  19. Svensson M, Schmidt EB, Jorgensen KA, et al. N-3 fatty acids as secondary prevention against cardiovascular events in patients who undergo chronic hemodialysis: a randomized, placebo-controlled intervention trial. Clin J Am Soc Nephrol. 2006 Jul;1(4):780-6.
  20. Harris WS, Del Gobbo L, Tintle NL. The Omega-3 Index and relative risk for coronary heart disease mortality: Estimation from 10 cohort studies. Atherosclerosis. 2017 Jul;262:51-4.
  21. Harris WS, Luo J, Pottala JV, et al. Red blood cell polyunsaturated fatty acids and mortality in the Women’s Health Initiative Memory Study. J Clin Lipidol. 2017 Jan - Feb;11(1):250-9 e5.

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