Tag Archives: omega 3

Krill Oil: How its latest “success” proves it to be an epic failure…again

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Those familiar with our work know that we have spent quite a bit of time evaluating the therapeutic outcomes of marine-derived omega-3 fatty acids. Our recent review of the topic has been downloaded and widely circulated amongst healthcare providers and the general public, worldwide. In that review, we covered the types of fish used, how fish oil is made, sustainability issues, bioavailability differences, quality control concerns and much more; including the research comparing omega-3 fatty acid from fish oil and krill oil. You can get the article as a PDF file here.

Just a month after publishing our paper online, a few more studies comparing fish oil and krill oil were published that initially appeared to suggest that omega-3 fatty acids from krill oil may indeed have a slightly better bioavailability than those from fish oil and/or had triglyceride lowering effects similar to fish oil; but after only a month of scrutiny, these studies are exposed as epic failures of how marketing-driven research leads to bad science and confusing outcomes.

First- as a brief review for those who haven’t read our whitepaper. Our position was that the EPA and DHA in krill oil should function in much the same way as EPA and DHA from fish oil- assuming equal amounts of the fatty acid become bioavailable after consumption. The typical claims made by the marketers of krill oil is that, because krill oil omega-3s are delivered as phospholipids (PL, rather than triglycerides), they will have (or have been shown to have) higher bioavailability than fish oil omega-3s. Our whitepaper clearly shows that the studies used by marketers to “prove” such assertions are either not clinically or statistically significant; or are not appropriately designed to make such comparisons. However, the biggest issue is not their failure to prove better bioavailability, or the fact that krill oil appears to be nearly ¼ free fatty acids upon analysis (not all PL as claimed); but the fact that commercially available krill oil products are extremely low in EPA and DHA, while still costing much more than fish oil products (containing much more EPA and DHA). In fact, in the only trial comparing equivalent doses, researchers needed to use 14 krill oil capsules to get the same amount of EPA and DHA as 4 capsules of fish oil.

This is where the first of the new studies fits in. Published in December of 2013 in the open access Lipids in Health and Disease, this paper has such a hopeful title: Enhanced increase of omega-3 index in healthy individuals with response to 4-week n-3 fatty acid supplementation from krill versus fish oil [Free Download]. The cross-over designed trial appears to compare an equal amount of EPA and DHA from krill oil and fish oil (and a corn oil placebo); and indeed reports a higher increase in the omega-3 index (the percent of EPA and DHA within RBC phospholipids) during the time subjects were taking krill (compared to fish oil); although both fish and krill oil were better than placebo. They report that the various oils were provided in six- 500 mg capsules (3 with breakfast, 3 with dinner); describing the fish oil as a “TG 18/12” oil. Going one step further; they analyze and report the fatty acid composition of each of the three oil products; and this is where things get fishy.

They claim the fish oil to which they compared the krill oil was a TG 18/12, which is the usual designation for un-concentrated fish body oil providing 180 mg of EPA and 120 mg of DHA per 1000 mg of oil. However, their fatty acid composition lists a very unusual fatty acid profile for this fish oil: including 32% linoleic acid- an omega-6 fatty acid. Normally, fish oil contains about 2-3% omega-6 fatty acids; so what is going on with this oil? Well, we were not the only ones to wonder about this. In early January of 2014, a commentary of the above trial was also published in the same journal, asking about the strange fatty acid profile of this fish oil, along with a few other points of contention. You can find that Commentary Here.

Incredibly, the authors of the original paper explained it this way in their rebuttal [Found Here]: Our primary objective was to compare effects of consumption of same amount of n-3 fatty acids from krill or fish oil. When designing a double blinded placebo controlled randomised cross over trial, it was felt that the amounts of treatment products as well as the bioactives of interest be maintained consistent across different interventions. However, the n-3 PUFA content of the krill oil fell below that of fish oil. In order to match the concentrations of n-3 PUFA and volumes between krill and fish oil, the fish oil was diluted with the placebo, corn oil at a ratio of 1.3:1.0.[Emphasis added] Yes, you read that correctly. They used the lowest dose of fish oil they could find (one shown to have lower bioavailability than the concentrated TG forms) and still needed to dilute it with corn oil so they could reduce its omega-3 content for a head-to-head comparison to krill oil. The authors also admit: We agree that we could have included the information about dilution of fish oil in the original manuscript itself. While we will avoid the obvious question about motive usually entertained when a manufacturer of krill is involved in such a study; this begs the question of the type of expertise used in the peer-reviewing process that missed the obvious questions about the fatty acid profile of the fish oil.

This report, with the commentary and rebuttal, only solidifies our view that krill oil simply cannot deliver a cost-effective payload of EPA and DHA to be considered as a therapeutic alternative to fish oil. Krill oil products do not even have the amount of EPA and DHA found in the lowest concentrations of fish oil, while their cost is sometimes double or triple the same. From a therapeutic standpoint, concentrated TG forms can deliver 4-8 times more EPA and DHA per capsule, at an affordable price.

This brings us to the second paper, published in the February 2014 edition of Nutrition Research. Again, the title of this article (written by scientist employed by the manufacturer of the krill product used) was deceptively hopeful: Krill oil supplementation lowers serum triglycerides without increasing low-density lipoprotein cholesterol in adults with borderline high or high triglyceride levels. Unfortunately, the data proved to be anything but a straight-forward TG-lowering effect from krill oil- although their analysis is so flawed that it almost defies explanation.

The study was designed much like TG-lowering studies of fish oil. Three-hundred patients with high triglycerides were recruited and given placebo or 3 to 4 grams of krill oil providing 0, 100, 200, 400 or 800 mg of EPA/DHA over 12 weeks. Blood lipids and omega-3 index were measured at baseline, six weeks and 12-weeks after consuming the krill products. The data speaks for itself; after 12-weeks of krill oil consumption the change in TG levels in these individuals with a mean TG at baseline=231 was as follows: Placebo (+3.9%), 100 mg (-10%), 200 mg (-3.8%), 400 mg (-6.7%), 800 mg (+0.9%)- none of these reached statistical significance. The authors claim that the lack of efficacy and dose-response was due to the overwhelming intra-individual TG measurements and high standard deviation- making it impossible to measure fasting TG as an outcome. How then, with these numbers (even showing an increase in TG using 800 mg of EPA and DHA) were they able to declare a TG-lowering effect in the title?

The reviewers of the paper allowed these authors to circumvent the “limitations” of the study and use “an explorative data analysis approach to increase the statistical power of the study.” In essence what they did was to pool together all the doses, including the 6-week data points which happened to be better for nearly all the doses, and analyzed the data as if a theoretical average EPA/DHA content of 385 mg was given to all the subjects. The authors then boldly declare that “Relative to subjects in the placebo group, those administered krill oil had a statistically significant calculated reduction in serum TG levels of 10.2%.” Even if we accepted this flawed explorative data analysis, this data showed only a 6.3% reduction from baseline TG levels- a level that even if achieved in this study, represents a small clinical difference. In contrast, fish oil studies routinely see drops in TG (from baseline) of >25%, show clear dose-response and are maintained or even continue to improve between 6 and 12 weeks.

The fact that such a flawed study that failed to reach any statistical-significant reductions in TG based on the primary objective (12-weeks) and initial statistical plan was permitted to use statistical manipulation to imply a positive outcome is incomprehensible. Clinicians and patients would read the title and abstract of this paper thinking that krill oil was able to reduce TG levels in these subjects- when in fact, at the end of 12 weeks the data shows that it did not. This paper should be retracted, rewritten to describe it as a failure to meet its TG-lowering objective and republished.

While I am certain the marketing departments of krill manufacturers and distributors are eager to share with you their “latest success stories”- now you have the rest of story- revealing krill oil’s epic failure as a therapeutic contender in the omega-3 world.

[Dr. Guilliams discussed this and many more issues related to fish oil (from the whitepaper) in a discussion with Dr. Hoffman’s on his Intelligent Medicine podcast. Download and Listen Here.]

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New Technical Report on choosing the best Omega-3 product for therapeutic use

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Dr. Guilliams’ latest Technical Report reviews the evidence supporting fish oil as the standard marine-derived omega-3 fatty acid, and discusses the various product types, their bioavailability, ethyl esters vs. triglycerides, pertinent quality control issues and gives take home recommendations. Since the wide range of therapeutic uses and forms, as well as sources and delivery forms of marine-derived omega-3 fatty acids is a source of confusion for patients and clinicians alike, this Point Institute paper reviews the evidence and explains the data supporting the use of fish oil, which has become the known standard in the world of marine derived Omega 3 products. The paper discusses the various types of marine derived Omega 3 products and the considerations which should be made when selecting one. Other topics include common concerns, such as allergies to fish oil, and the difference between Krill vs. Fish oil sources. The paper also discusses the research on the bioavailability of various structures and forms such as ethyl esters vs. triglyceride, as well as the differential uses of DHA and EPA, what defines pharmaceutical grade products, quality control issues, and ends with take-home recommendations for product selection.

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Fish Oil and Prostate Cancer Risk- Is There a Link?

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Several widely publicized clinical trials in the past weeks and months purport that the use of omega-3 fatty acids, especially those from supplemental fish oil, has no therapeutic value or are even potentially harmful to consume. This short communication [pdf of this article] is written to help put these reports within the context of the studies’ own limitations and also the broader fish oil research that has gone virtually unreported during the same time. 

Let’s begin with the most recent study purporting to link fish oil with prostate cancer risk. The report was published online in the J. of the National Cancer Institute (Online Abstract) and soon afterward, headlines such as “Men who take fish oil omega-3 supplements at 71% higher risk of prostate cancer: study”[1] began floating around the internet, print and national television. One would assume by such headlines that this study was specifically designed to look at prostate cancer risk in men consuming fish oil supplements- it was not. In fact, this study didn’t even look at fish oil (or even dietary fish) consumption in these subjects!

Instead, this report was a secondary analysis of data collected from the previously concluded SELECT (Selenium and Vitamin E Cancer Prevention Trial) trial, which recruited men over 50 with no history of prostate cancer who were then randomized to receive vitamin E, selenium, a combination of vitamin E plus selenium, or placebo and followed for prostate cancer incidence (NCI’s SELECT Website). The data from this report is considered a case-cohort design, attempting to find an association between plasma phospholipid fatty acid levels in case subjects (those diagnosed with prostate cancer during the length of the trial) and compare those with study cohorts (similar subjects within the trial not diagnosed with prostate cancer during the length of the trial). It is important to note that the original vitamin E/selenium study was not designed to detect the association between plasma phospholipids and cancer risk and patients were not asked about their fish or fish oil supplement use at either the start or the length of the trial.

Nevertheless, they report that higher levels of 3 specific omega-3 fatty acids (EPA,DHA,DPA- combined) as a percent of plasma phospholipid fatty acids- were associated with a higher incidence of prostate cancer during the SELECT trial.  While the authors are much more cautious in their direct indictment of omega-3 supplementation within their publication (since they have no data related to supplementation), one of the authors said in a press release “We’ve shown once again that use of nutritional supplements may be harmful” Here are a few reasons these conclusions and statements are unwarranted and misrepresent the data.

  • The fatty acid levels reported here represent only a single blood draw taken at the start (baseline) of each participant’s entry into the study, often years before a prostate cancer diagnosis was assigned to the subject. Since plasma phospholipid fatty acid content fluctuates with dietary intake on a day to day basis, a single time point may only reflect dietary habits within the previous week prior to the blood draw and may have no correlation to long-term omega-3 intake or blood levels.
  • While the omega-3 fatty acid differences between groups were statistically different, they were not clinically significant. That is, the omega-3 levels reported would be considered “average” in all subject groups and the largest difference in the levels reported between groups could have been achieved with very low omega-3 consumption in a few weeks’ time.(see endnote #2)[2]
  • The authors admit that because of the high cost of phospholipid testing, that only case subjects diagnosed through 2007 (and their cohorts) were originally to be tested. But since “new finding” of associations between fatty acids and prostate cancer came to light- more subjects with high-grade cancer were analyzed in the 8th and 9th year of the trial. This highly unusual change in data set would have been disallowed in most other peer-review settings. The original data set was not published.
  • In almost all cases of associative data, a number of variables are used to adjust the data. Typically these adjustments include most variables that might influence risk. While these data were adjusted for education, diabetes, family history of prostate cancer and the SELECT intervention assignment; these data were not adjusted for the most striking variables that affect risk in this population- age, race, BMI and PSA levels- information which may have nullified these statistical associations. How these reviewers ignored this most obvious adjustment and permitted the data to be reported without these adjustments is baffling.

Omega-3 associated with lower prostate cancer, breast cancer, CHD and total mortality.

Beyond the specific conclusion of this study is the broader epidemiological and scientific question of plausibility. The authors readily admit that there is no plausible scientific explanation for how long-chain fatty acids like EPA and DHA could actually cause prostate cancer. There is also the inconvenient fact that several people groups which consume high levels of omega-3 fatty acids and have plasma phospholipids much higher than the participants in this study have extremely low incidence of prostate cancer (i.e. Japan). More importantly, studies that specifically look at fish and fish oil consumption show a dramatic decrease in prostate cancer risk in older men, seeing a slightly higher risk associated only with salted and smoked fish intake. [3] Other large meta-analysis have shown that even when overall prostate cancer incidence may be unaffected by omega-3 intake, prostate cancer mortality is dramatically lower in individuals with higher intake of marine omega-3 fatty acids.[4]

In fact, in a highly under-reported study published this year in the Annals of Internal Medicine, plasma phospholipid omega-3 fatty acids (much like the SELECT data above) were associated with lower total mortality- especially related to CHD deaths.[5] However, in this study the plasma phospholipid fatty acid difference between the highest and lowest groups were highly clinically relevant (200-300% difference), as compared to the clinically irrelevant differences in the SELECT trial data (6% difference-see endnote #2).

Lost in all this has been another significant report published in the British Medical Journal which associates the intake of fish and marine omega-3 fatty acids with a reduced risk for breast cancer.[6] This meta-analysis of 21 independent prospective cohort studies showed an overall 14% reduction in the relative risk for breast cancer related to marine omega-3 fatty acids. This risk reduction was associated with both the consumption of fish and fish oil, as well as tissue biomarker analysis (i.e. plasma phospholipids). They even suggested a “dose-response” relationship which suggested that the risk of breast cancer was reduced by 5% for each 100mg/day of marine omega-3 consumed.

Summary:

When the data from the subcohort of the SELECT trial is analyzed and placed alongside the growing epidemiological, interventional and mechanistic data (see below) – the purported relationship between consuming omega-3 fatty acids (in the diet or through dietary supplements) with an increased risk of prostate cancer cannot be supported. Furthermore, since this study did nothing to ascertain the consumption of fish or omega-3-containing supplements in these subjects, it makes the sensationalized media reports about this study even more disturbing. In addition, the fact that the association data was not adjusted for the most obvious factors (such as PSA levels, race, BMI and age) leaves us unsure that there is any association at all; and leaves many others to suppose that strong bias may be at play here. We find it quite telling that one of the key authors of the trial is quoted in the DailyMail as saying ‘There is not really a single example of where taking a supplement lowers chronic disease risk.’ [7] On the contrary, we believe the current overall scientific evidence suggests that consumption of omega-3 fatty acids from fish oil supplements is not only safe at a wide-range of doses, but has proven efficacy in reducing risk for a wide-range of chronic conditions.                                                                                                                     

Recent animal or basic research on omega-3 fatty acids and prostate cancer


[1] http://www.nydailynews.com/life-style/health/evidence-prostate-cancer-omega-3-link-article-1.1395853

[2] For instance, the greatest difference between DHA levels in these subjects was reported as 0.18% (2.91% in the no cancer group and 3.09% in the high-grade cancer group, difference P=0.009). For comparison, other studies have shown that fish oil intake equivalent to a single serving of fish per week can raise DHA levels 0.63%, and do so in about 12 days. (AJCN 2012; 96:748). As Duffy MacKay, VP of Science & Regulatory Affairs at the Council for Responsible Nutrition said about the most recent study, these difference in omega-3 levels “literally could have occurred if somebody ate a fish sandwich on their way to get their blood drawn” 

[3] Consumption of Fish Products across the Lifespan and Prostate Cancer Risk PLoS One. 2013; 8(4): e59799).

[4] Fish consumption and prostate cancer risk: a review and meta-analysis. Am J Clin Nutr. 2010 Nov;92(5):1223-33

[5] Plasma phospholipid long-chain ω-3 fatty acids and total and cause-specific mortality in older adults: a cohort study. Ann Intern Med. 2013 Apr 2;158(7):515-25.

[6] Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. BMJ. 2013 Jun 27;346:f3706