Cardiovascular Protections from Omega 3 supplements now Doubtful

[MateoBeach]

I have been taking a combined Omega3 supplement (EPA and DHA fish oil)to improve my cardiovascular risk profile along with a statin, baby ASA and careful BP management. I am a carnivore/omnivore but only eat fish twice per week usually. (Please don’t beat me up over my diet PBWF folks!) I am not diabetic, pre-diabetic, have excellent lipid and inflammatory markers currently. So probably not enough at risk for any marginal benefit from the Omega-3 supplementation. The benefits of Omega 3 supplements now appears very doubtful. Here is an analysis by Peter Attia which summarizes the situation regarding the REDUCE-IT and STRENGTH Trials. Paul

“REDUCE-IT was a randomized, double-blind, placebo-controlled trial designed to investigate whether supplementation with icosapent ethyl – an ester derivative of the omega-3 fatty acid eicosapentaenoic acid (EPA) – would reduce incidence of major adverse cardiovascular events (MACE) in statin-treated participants with established cardiovascular disease (CVD) or diabetes. A total of 8179 patients were randomized to receive either 4 g daily of icosapent ethyl or a mineral oil placebo and were followed for a median of 4.9 years. The results revealed a lower incidence of MACE, including cardiovascular death, in the icosapent ethyl group vs. the placebo group (17.2% vs. 22.0% of participants, respectively, P < 0.001), corresponding to a hazard ratio of 0.75 and an absolute risk reduction of 5%. The apparent health benefits of icosapent ethyl indicated by this trial subsequently prompted the U.S. Food and Drug Administration to approve commercial use of this drug for reduction of cardiovascular risk.

What did the new analysis show?Ridker et al.’s analysis examined biomarkers of lipid metabolism and inflammation among icosapent ethyl- and placebo-treated REDUCE-IT participants at baseline, 1 year into the study, and 2 years into the study. No significant differences between treatment groups were observed in any biomarkers at baseline, but examination of subsequent time points revealed a remarkable trend. The icosapent ethyl group exhibited virtually no changes from baseline in any of the biomarkers investigated, but the placebo group demonstrated worsening of many of these markers.In the mineral oil-treated placebo group, inflammatory markers interleukin 6 (IL-6) and interleukin 1β (IL-1β) increased 26% and 48%, respectively (from 3.27 to 3.97 pg/mL for IL-6, from 0.06 to 0.09 pg/mL for IL-1β). Homocysteine, a known marker of CVD risk, increased from 1.69 to 1.84 mg/L (9.5%), while Lp(a) rose 8%, from 11.4 to 13.6 mg/dL and lipoprotein-associated phospholipase A2 rose 26%, from 134 to 167 nmol/min/mL. Mineral oil also produced smaller but noteworthy increases in LDL-C (6%) and oxidized low-density lipoprotein (5%). All of these changes were highly statistically significant (P < .001), indicating the mineral oil is likely not a neutral placebo and instead results in net negative effects. (It’s not entirely clear how clinically significant these findings were, mind you, but it’s noteworthy that every biomarker moved in exactly the wrong direction.) These findings raise the possibility that the apparent “benefits” of icosapent ethyl in REDUCE-IT may be an artifact caused by comparison with a harmful placebo. In other words, if the mineral oil caused harm, did the drug, by doing nothing, merely seem beneficial by comparison?

An Open DebateUnfortunately, we can’t know the answer to this question based on the information from the original study or the follow-up analysis. Further, it remains a possibility that these biomarkers would have demonstrated a gradual worsening over the follow-up period even if the placebo had been innocuous, and that icosapent ethyl thus had a positive effect of slowing or preventing that progress. However, data from the STRENGTH trial – which compared treatment with 4 g of combined EPA and DHA (the omega-3 docosahexaenoic acid) vs. corn oil placebo – showed no worsening of biomarkers among the placebo group at 1-year follow-up, suggesting that the trends observed with mineral oil in REDUCE-IT do indeed reflect a net harmful effect. (Notably, no significant differences in MACE incidence were observed between EPA/DHA and control groups in this trial.)Still, biomarker data don’t necessarily predict net clinical outcomes, so the only reliable way of knowing whether or not the icosapent ethyl is effective in reducing incidence of MACE or cardiovascular death would be to perform a new randomized trial with a more truly neutral placebo. Commentaries published in response to Ridker et al.’s analysis echo calls for such a study, though the prospects for funding are dubious. And yet, after years of serious investigation, no one – including the manufacturers of icosapent ethyl – has a plausible mechanism of action of how EPA would reduce residual risk of MACE. Combined with the results from Ridker et al.’s analysis, that certainly suggests that it may be time for the FDA to reevaluate its recommendations regarding the use of icosapent ethyl as a treatment for CVD – as we all must do whenever new and relevant information arises.”

jamanetwork.com/journals/ja...

peterattiamd.com/a-new-anal...

[cujoe]

MB, I'll have to dig through my files to do your post justice, but Patrick did a recent post that as I remember it (sans my daily dose of algae-sourced DHT . . .), re-embraced Omega3s for cognitive and heart health - with no adverse contribution to PCa development/progression.

This is a topic that has been back and forth since my PCa diagnosis circa 2010. Wendy Demark (later Demark-Wahnefried) did several studies that looked at the effects of low fat + flax supplementation on PCa, first in combination and then later (with controls for low-fat OR flax supplementation) that seemed to support Omega3 metabolized from flax (my assessment, not hers, specifically). In a long ago, exchange with Patrick, he indicated that she had reversed her assessment for that research. I was never able to verify that myself.

Also, in 2013, the Fred Hutchinson meta-study on fish oil and PCa blew the doors off previous suggestions that fish oil supplementation was beneficial for PCa. In fact, the press release from that study said the following:

SEATTLE – July 10, 2013 – A second large, prospective study by scientists at Fred Hutchinson Cancer Research Center has confirmed the link between high blood concentrations of omega-3 fatty acids and an increased risk of prostate cancer.

Published in the online edition of the Journal of the National Cancer Institute, the latest findings indicate that high concentrations of EPA, DPA and DHA – the three anti-inflammatory and metabolically related fatty acids derived from fatty fish and fish-oil supplements – are associated with a 71 percent increased risk of high-grade prostate cancer. The study also found a 44 percent increase in the risk of low-grade prostate cancer and an overall 43 percent increase in risk for all prostate cancers.

The increase in risk for high-grade prostate cancer is important because those tumors are more likely to be fatal.

(emphasis is mine)

* * *

At the time I was mega-dosing with 3 grams of Fish Oil tabs per day, as per recommendations of benefit for PCa progression from elsewhere!?! Ooooops! I stopped the fish oil immediately and assumed I had been guilty of the proverbial "pouring gasoline on my then-smoldering PCa fire". I have later seen that the Hutch Study was seriously flawed and, if so, Patrick's post in support of Omega3s/Fish Oil might seem justified.

And while I've never seen a head to head study on algae-derived DHT & EPA vs from fish oil, I considered (thinking of Wendy Demark's work with flax) that the source of the Omega3s might be a factor; i.e., plant-based vs animal-sourced vs synthetic.

I think it might have been in a podcast between Rich Roll and Dr. Mark Hyman where the situation was framed as a trade off between the risk to brain health/cognitive function (low DHA/EPA) vs prostate cancer risk (high DHA/EPA).

Several years ago, I decided to split the difference and shoot for some cognitive benefit while also shooting for low PCa progression risk. I do that by using a liquid algae-based EPA/DHA supplement and a child's dosage that is 1/2 that recommended for an adult.

Other than the fact I can't remember what day it is, where I am, or what my name is, it seems to be working just fine. When I have time to dig a bit, I'll link to some of the research referenced above.

A good topic and one that never seems, like most related to diet and lifestyle, to ever get fully resolved. Hope all is well is Cabo. Maybe see you this fall in NE? Either way, Stay S & W, Ciao - K9 terror

[Sunlight12 in reply to cujoe]

"that the source of the Omega3s might be a factor; i.e., plant-based vs animal-sourced vs synthetic. "

Following on that idea, I also wonder if some variances in results might be due to production methods - is the product kept cool during processing, are light and oxygen blocked to prevent degradation of the oil, etc.

-Sun

[cujoe in reply to Sunlight12]

Sunlight - This study from 2015 indicates you may be right in your concerns about quality degradation due to oxidation.

Fishing for answers: is oxidation of fish oil supplements a problem?, J Nutr Sci. 2015; 4: e36. Published online 2015 Nov 23.

ncbi.nlm.nih.gov/pmc/articl...

[Sunlight12 in reply to cujoe]

Oh wow - this is awesome! Many thanks, cujoe!!

-Sun

[cujoe in reply to Sunlight12]

btw, i keep my liquid dha/epa supplement in the fridge. When severe oxidation of fish oil supplements occurs, you can tell by the somewhat rancid odor. As I long ago learned from a seasoned fisherman, fresh fish has NO fishy smell. When buying fresh fish from the market, he insisted in being allowed to smell it first. Even a slight fishy smell indicated that it was not really "fresh".

As the saying goes, "Eat Well to Stay Well."

[Sunlight12 in reply to cujoe]

Thanks for passing on that good info from the fisherman!! Gosh, I love the incredible amount of knowledge there is on this forum! Off to smell my fish oil (*mentally noting that that is not a phrase commonly heard in daily conversation*lol), which - like you - I keep in the fridge 😊

-Sun

[Cooolone]

Another excellent thought provoking post! I hope one day I can get to a place where some of you guys are, it amazes me how you are able to track and keep up with these studies, trials and data! Can't say THANK you loud enough!

It's all about the metabolic side of things for us who walk this path of course. How we examine everything that may interact or contribute to our condition.

When I was diagnosed originally back in 17' there were so many things out of whack (blood) it wasn't funny! And I felt great, thought I was healthy and eating habits were ok. Lol is all I'll say! It's been an interesting journey since then, with much education along the way. But lipids, glucose and cardiovascular consideration are and should be on every advanced patients radar screen!

Recently, for the first time on my scans was a passing note of some calcification of arteries... After only a few years dealing with ADT... So radar is ON! Lol

For the record I take Statins, take the prescription based Omega-3 and a few more drugs for the PCa. Add to it the supplements I take and so many of us do. We try to "nudge" a millennia of biochemistry to our will... Hehehe! I find it interesting, and will continue to as well. I'm not sure the Omega-3 was better than the Fenofibrate for lowering my lipids, but I do remember somewhere the incidence of Omega-3 being beneficial for PCa. I will have to dig through my collection of links and such to see if my brain is working correctly. But I remember that is why I was ok with switching.

All the best and thank you for posting!

[cujoe in reply to Cooolone]

Cool. I also first got a heads-up about possible cardio issues (re: arterial calcification) with my CT/bone scan series @ BCR#1 in 2017. Nal, Patrick, and others had posted about the need for adequate Mg+D3+K2+ boron (in addition to Ca) for bone health; i.e., to direct Ca to bones and NOT to kidneys, arteries, joints, etc. I believe that is why most studies on Ca+D3 supplementation have not shown benefits to bone health - and while not part of any study i'm aware of, I would guess that since the Ca is NOT contributing to bone health means it might well be causing problems elsewhere.

I was able to make the connection from the 2017 scans to an earlier surprise visit to the ER due to kidney stones in 2014. My lipids were also not ideal, so I added the lovastatin = RYR product Cholestene several years back. That got me to a near ideal profile and I have continued to use it. (A generic statin would actually be less expensive than the Cholestene, but I'm sticking with what is currently working - plus I expect I would now have to stop and let my lipids get wacky again to get a statin script?)

The lipid and arterial Ca issues, while related, are best solved by making sure Ca is headed to the bones and lipid profile is under control. (Supplement as needed.) As a final note, I agree with Patrick that Ca consumption should not exceed around 1,000 mg daily, as excess Ca (and according to this B&W study, phosphorus, as well) is a known contributor to PCa development/progression. (I am mostly WFPB and have not supplemented with Ca in 20 years or more as I know I get an adequate amount in my diet. I do regularly supplement with D3, K2, and boron and shoot for a D3 level between 50 & 80.

Calcium and phosphorus intake and prostate cancer risk: a 24-y follow-up study, Am J Clin Nutr. 2015 Jan; 101(1): 173–183. Published online 2014 Nov 19.

ncbi.nlm.nih.gov/pmc/articl...

Good that, like me, your scan has gotten your attention. As we all know, long-term ADT can do a real number on bone health. I've never been on long-term ADT, but am still going to do a DEXA scan soon to make sure I'm not headed for trouble in that area. It is a scan that all PCa patients should have done BEFORE going on ADT - to establish a benchmark for bone density issues as treatment progresses (and age takes it's natural toll on bone health/density.) This will be my first and I am 10 years out from RALP+IMRT and 6 years since my first round of ADT. If I can't get doc to approve it, I'll pay for it out-of-pocket, as most places you can get a DEXA at a quality fitness center for $100-$150. I'm also doing a regular routine of walk-in labs (LEF has a program with LabCorp that is reasonably affordable) to monitor hormones. That is another area where having more info would contribute to better treatment design, but that we aren't getting outside of clinical trials. Be your own advocate and do what you need to always know where you stand - that's the attitude I've adopted since BCR#2 back in mid-2020.

Best of luck to you unraveling the many mysteries of cardio+bone health. And, as always, Try to Stay Safe & Well. Ciao - K9

[MateoBeach in reply to cujoe]

Thank you for this info, Cap’n K-9. When you schedule a DEXA scan, be sure they provided body composition analysis including total body fat index and visceral fat, and appendicular muscle mass index as well as the bone T and Z scores for BMD. All of that information is there on the scan, but some centers don’t have the software modules to analyze and report full body composition reports.

[cujoe in reply to MateoBeach]

Thanx for the specifics, doc. Attia says most DEXA scanners (scammers?) do a lousy job with the data, so your list is what I will use to find the best one I can. Attia's explanation of T and Z scores was instructive for me, as I never took statistics.

I'm in for my Gyno RT set-up this Thursday and am going to see if I can get the Cancer Center to also schedule a DEXA? I rather be at the beach in Cabo that day . . . but fine spring weather has returned and I even got a short visit from Jdm3 and crew over the weekend. We discussed the possibility of some meet and greet as a group or one-on-one in NE this fall. Are you still thinking of fall color travel? Inquiring minds and all that . . .

Enjoy the beach - see U in Sept? Ciao - K9

[MateoBeach in reply to cujoe]

Yes, Cujoe. Traveling to Vermont for Fall color cycling and touring October 2-11. Flying into Burlington also Middlebury, Stowe and Woodstock, two nights each. And am open for considering another trip for a meetup. Cabo is wonderful of course while Oregon is still encased in Winter. We return to Bend May 19 to let the Summer adventures begin. Starting with a motorcycle and RV camping tour to British Columbia (Kootenay Rockies). Ciao. S &W.

[cujoe in reply to MateoBeach]

You timing should be good for the color and your arrival is the weekend after my NH event. Usually fall color is just getting started there for that. Your selections of stops covers the best VT has to offer. Closest thing to English countryside the US has to offer. I'll do some thinking on what I might do to extend my travel time 'till you arrive. Jdm3 and I discussed general notions about your trip east - and maybe our mutual friend from OZ will show and be around then, as well. If I travel by car, I have unlimited flexibility - by air, not so much so.

BTW, I got a call from MO's nurse this morning saying DEXA would be added to my July appt. As the RT dosages add up, at some point I will not need to turn on the lights at night. Gyno setup on Thurs. Bring on another PSMA!

From May on seems you and Willie will both be On the Road Again . . . goin' places that I've never been . . .

youtube.com/watch?v=dBN86y3...(Not working as expected?)

Safe travels, esp on that exotic 2-wheeler. Ciao - K9

[Cooolone in reply to MateoBeach]

I didn't see any of that information in the results of my last scan... I will definitely keep all that in mind as well, thank you!

[pjoshea13]

Hi Paul,

I took a reputable high-dose marine omega-3 supplement for many years. While it didn't kill me & may have helped me attain old age, the PCa literature on supplementation became increasingly confusing. And yet that seemed not to be the case for food sources. So I decided to get my omega-3 from marine food sources.

The fish counter at the best supermarket is, alas, not a good source for fatty fish.

I will grab mackerel when I (rarely) see it. It has 5.5g per 100g.

Years ago, when the dirt on salmon farms stated to appear, I gave up on fresh salmon, except from certain sources. What was the point of eating fish fed meat by-products & a dye to put color into the flesh - with little or no omega-3? (I trust Norwegian & Scottish sources.)

Recently, I was in a supermarket that offered two options: salmon from Chile at $10/lb & salmon from the Faroe Islands at $20/lb. I loaded up on the latter & had several memorable breakfasts of the delectable fatty flesh. I expect that I got 4g per 100g.

But, the most reliable source is canned Alaskan salmon. The fish farms can fake fresh Alaskan salmon. Years ago, they used to provide fatty salmon with a delicate color to top restaurants - absolutely delicious. Then, after the bad press on farmed salmon, when the demand for wild salmon grew, they reduced the fat content and upped the color for that market. The middle-men made the money; the fish monger couldn't tell the difference. Only a DNA test will tell [1].

The distinctive cans (stackable to reduce shipping costs to Alaska) pretty much guarantee that the contents will be wild-caught salmon. Sockeye has 2.7g/100g. Pink salmon has less.

Kippers (a breakfast treat for me, but not everyone) has 3.3g per 100g. I have tried Canadian kippers but prefer those from Scotland. (See the Scottish Gourmet [2])

Sardines: 3g per 100g. According to King Oscar, a can = 2,400 mg., a perfect dose imo.

It's easy if you like food sources. My wife will touch none of it. After 55 years of marriage, we have irreconcilable dietary differences.

In terms of 3oz servings - omega-3 (mgs):

- the best Atlantic farmed salmon: 1,820 (cold-smoked should be high too)

- canned sockeye: 1,080

- canned pink salmon: 920

- canned sardines: 830

- farmed trout: 750

- mussels: 665

- Pacific oysters: 585 (east coast: 333). Fried Pacific oysters for breakfast is a treat. They come schucked.

-Patrick

[1] usa.oceana.org/reports/ocea...

[2] scottishgourmetusa.com/?gcl...

[MateoBeach in reply to pjoshea13]

Thank you Patrick. Great information on food sources. I also like Norwegian smoked salmon (lox).

[marnieg46 in reply to pjoshea13]

Yes Patrick I'll add my thanks to those from Paul.

Having put a fair bit of time and planning into moving towards Mediterranean diet choices and putting more effort into making sure we have fresh fish twice a week I read the article about Omega 3 supplementation with some trepidation and wondered if I should reconsider our present intake via food choices...but obviously not.

Your list pretty well identifies most of what we eat. Close to where we live is an excellent fresh fish market that is rich in a wide range of good quality fresh seafood that you're never lost for variety. Our pantry is always stocked with all of the canned foods you mention and the boy is particularly fond of tuna...Sirena brand in olive oil...pole and line caught. He would eat at least one a day just by itself...I need salad with mine. Fresh muscles steamed with just a touch of balsamic vinegar and a tiny bit of pepper....are a favourite too. But now about those...Pacific oysters...you haven't lived until you've tried Sydney rock oysters...absolute perfection. And Crystal Bay prawns...another treat. When it comes to fish we both like Barramundi and so that ticks the fatty fish box. So if I compare our choices with your list I think we're doing OK in the omega 3 area. At least I hope so.

[PCaWarrior]

DO-HEALTH

frontiersin.org/articles/10...

[MateoBeach in reply to PCaWarrior]

Testing too many interventions in too small a population over too short a period, unless one is just looking for motivational inspiration to reduce cancer risk. My risk is already 100%. Darn it.