Transcript

MIC CAVAZZINI: There’s a letter to the Editor in the Lancet of April 1956 that starts like this;
“Sir,-Scant attention seems to be paid by the medical profession and by food administrators to a very important change in the dietaries of the more civilised countries that has been occurring over recent decades with increasing intensity. I refer to a chronic relative deficiency of the polyethenoid essential fatty acids (E.F.A.).” (These days we’d call them polyunsaturated).

It is true that the matter was raised in your columns a year ago, but then no less a person than a professor of nutrition stated that such deficiency rarely if ever occurs in man ; Professor Yudkin, however, has the disadvantage of not having worked upon E.F.A.

Our own experimental work, humble in scope, combined with a careful assessment of the literature, has led us to exactly the opposite conclusion. The causes of death that have increased most in recent years are lung cancer, coronary thrombosis, and leukaemia ; I believe that in all three groups deficiency of E.F.A. may be important. Your readers with stereotyped minds should stop reading at this point.”

The author of this letter was Oxford physician Hugh Macdonald Sinclair who was the first to put forward a comprehensive theory as to how a nutritional imbalance of “bad fats” and “good fats” contributed to "diseases of civilization." The controversy that he described has, in a way, continued to this day as outlined in a viewpoint piece in December’s Internal Medicine Journal titled, “Omega-3 fatty acids and cardiovascular prevention: is the jury still out?”

In today’s episode of [IMJ On-Air] we’ll hear from lead author Prof Christian Hamilton-Craig. The journal, and this podcast, are both produced for the Royal Australasian College of Physicians, to which I am but humble servant, Mic Cavazzini.

Now Hugh Sinclair’s hypothesis was largely ignored for fifteen years. But in 1971 Danish researchers published the results from a cross-sectional study of Inuit people living on the west coast of Greenland, who as you can imagine, ate a fish-based diet rich in polyunsaturated fatty acids. To quote from the abstract, “The most remarkable finding was a much lower level of pre-β-lipoprotein and consequently of plasma-triglycerides in Greenlandic Eskimos than in Danish controls. These findings may explain the very low incidence of ischæmic heart-disease and the complete absence of diabetes mellitus in Greenlandic Eskimos.”

Basically, the polyunsaturated fatty acids known as omega-3s, were turning up in tissue after being consumed in fish. And that association between a fishy diet and lowered cardiovascular risk has been replicated in multiple population studies over the years. So much so that since 2002, the American Heart Association has recommended that all patients with documented coronary heart disease consume 1000 mg of \ omega 3 fatty acids per day, preferably coming from oily fish of which a serving size of 100g should do the trick. For patients without documented CHD, a serving of fish at least twice a week is recommended, or also other foods rich in linolenic acid such as flaxseed, canola, soybean and walnuts.

The 2008 guidelines from the National Heart Foundation of Australia are pretty much identical. But here’s the rub. Despite the compelling epidemiological evidence and preclinical evidence, the findings from intervention trials have not always been consistent. From several large RCTs over the past 25 years there have been just as many negative or neutral associations as there have been positive ones. Today’s guest has tried to makes sense of in his recent IMJ review. But before we hear from him let me hand you over to the journal’s sub-editor for general cardiology, and the deputy editor in Chief, Dr Paul Bridgman. He practices at both Christchurch Hospital in Aotearoa New Zealand and teaches at the University of Otago.

PAUL BRIDGMAN:           Kia ora katoa, everyone. I'm Paul Bridgman. I'm here as an editor of the Internal Medicine Journal. And also as someone who feels he should eat more fish and is trying to eat more fish, and is doing that on the basis not have a deep understanding of the academic literature, but because the popular press makes me think it might be a good idea. I'm delighted today to have Christian Hamilton -Craig with us. Christian knows more about this than I do. He's recently published in the Internal Medicine Journal, The Journal of the Royal Australasian College of Physicians. Christian you with us from Noosa, I gather? Welcome.

CHRISTIAN HAMILTON-CRAIG:   Thank you, Paul. I'm Christian Hamilton Craig. I'm a cardiologist at the University of Queensland. I'm speaking to you from Gubbie Gubbie country on the Sunshine Coast, where I work as a clinical cardiologist in Noosa. Thank you very much for the opportunity to speak, and particularly to my co-authors, Karam, David and Steve Nicholls, who know a lot more about this topic even than I do. And we enjoyed writing this article, which came together out of out of actually a lipid meeting where we were sitting around and musing about the controversies around Omega-3 fish oils, and we thought, “Well, why don't we write a proper review article to inform both ourselves and others?”

PAUL BRIDGMAN:           Thank you very much to you and the team, Christian. So I guess fresh fish and Omega-3 are slightly different things. Can you start by telling us what is omeg-3?

CHRISTIAN HAMILTON-CRAIG:   Yes, so Omega-3 oils are a group of fatty acids, which predominantly comprised that the plant derived ALA, which is alpha-linoleic acid from plants, and then the two other important ones, which EPA and DHA predominantly derived from seafood. And the important point being that they are called so called essential in that they rely on intake with very little production within your body. And these two, Omega-3 fatty acids, EPA, which has 20 carbons, or DHA, which has 22 carbons are very closely related, are predominantly found in fish and sea foods in some smaller amounts in some legumes and nuts, but not a lot.

PAUL BRIDGMAN:           And there's a wide range of putative biological effects, do you have a feeling for it you think might be the most important?

CHRISTIAN HAMILTON-CRAIG:   Yeah, I think, in high doses, triglyceride lowering is important. And so our patients that have significant hypertriglyceridemia should be treated with high dose fish oils. But that's a slightly different group from what we've concentrated on in this paper, which is use of fish oils, or omega-3 oils for prevention of cardiovascular disease, both primary and secondary prevention. And that's a tricky group, because there's been controversial or discordant findings in the literature.

But we think that –or the literature proposes that high dose fish oils lower triglycerides, well, they do. But they're also anti-thrombotic, somewhat anti-inflammatory. They do appear to have some membrane stabilization properties which reduce arrhythmias in the posting five patients, and therefore is thought to improve cardiovascular outcomes, we think, but the jury's still out.

PAUL BRIDGMAN:           I think you're correct that it's in the primary and secondary prevention of coronary events, that is probably the area of widest interest here. Unlike dietary modification, we do have randomized controlled data with the Omeg-3. Do you want to talk us through, first of all,. the pros are the positive studies.

CHRISTIAN HAMILTON-CRAIG:   In brief, I mean, this area first came about with some early research on observing Greenland Inuit who had a very high marine intake of EPA-DHA, which was then trialed in an Italian trial, the GISSI-P trial in post infarct patients published in 1999, about 11,000 patients using a moderate dose of EPA-DHA, so about 800 milligrams a day. In that particular trial, they showed a decrease in cardiovascular events, particularly in a arhythmic sudden cardiac death post-infarct. So we still think that's probably a useful group, and there was a quasi randomized post coronary bypass study that also had reduced outcomes. So that's a positive trial.

This was followed by two other positive trials, which are different. There's a Japanese intervention trial which used EPA alone—and I think later we'll discuss EPA versus combined EPA-DHA—but the Japanese trial didn't have a placebo group. So there was a reduction in events, but it's not a placebo controlled trial. More recently, and I think more famously, there's the REDUCE-IT trial, which is a big trial published by the large trials group in America. And this used a so called purified icosapent ethyl EPA, which has just been approved by the TGA in Australia for clinical use. And it was high risk patients with either coronary heart disease or at high risk, and are given a big dose 4000 milligrams a day. And dosing is probably an important part of this story. So in that trial, there was a significant difference in the two groups, but we might I come to why that is later, because there may be issues with the comparator placebo in that trial, which may have changed outcomes.

So, those three, the Gissi-P, the Japanese trial and the REDUCE-IT it showed reductions in events. Whereas Steve Nichols, co-author, and just recent past President of the cardiac society was the lead author of the STRENGTH trial, which is a large trial using a similar dose about four grams. But they had used a combined EPA-DHA, so, both types of oils. And in that trial, there was no difference. So it wasn't a negative trial. It was a neutral trial. And the combination of these evidence has left us scratching our heads a bit as to what the truth might be.

PAUL BRIDGMAN:           Yes Steve's group certainly went for a good dose and strength. What do you think the significance is that they included DHA as well as EPA in their active arm there?

CHRISTIAN HAMILTON-CRAIG:   This is a personal understanding, and forgive me if I the biochemistry is complex. But my understanding is that the EPA is also metabolized into DHA after ingested when it's actually metabolized by the body. And the majority of the act, action of officials at the membrane level is probably DHA-mediated. So I'm not convinced that EPA alone is the answer. But I just don't think we have enough data to separate the two. So my personal practice is I use EPA,DHA combined, because it's—that's what you get in your average fish oil capsule is a combination of the two oils. I'm not clear that the so-called purified EPA alone makes a huge difference for the cost. And the cost is not clear—they’ve just entered the market in Australia. And we don't have a clear price point. So, I don't know.

PAUL BRIDGMAN:           So I guess STRENGTH was a neutral trial. I gather the confidence intervals may overlap with REDUCE-IT. How do you put the two of them together?

CHRISTIAN HAMILTON-CRAIG:   Yeah, I think that's true. So there is a quite a nice metaanalysis looking at both STRENGTH and REDUCT-IT combined. And they do a forest plot, which is one of those plots which have the confidence intervals and they do, indeed, overlap. And if you look at the totality of evidence in a metaanalysis group of about 135,000 patients recently published, it suggests—but I guess not confirms—that supplementation with Omega-3s does reduce the risk of major cardiovascular events by about 5 percent, and the risk of cardiovascular death by 6 percent. So reasonable improvements—this is relative reductio—so I guess the absolute risk reduction is modest. So there's some controversy around which fish oils to use in which groups but I think there's little controversy about dietary fish. And just to explain to the audience about 100 grams of salmon—so a pink salmon, Atlantic or Pacific salmon—will give you about 1000 milligrams of EPA-DHA combined. And most pieces of salmon if you go to a fish shop is probably around the 200 gram mark roughly. So it’s a reasonable dose, in fish. But not in white fish. So the type of fish you eat does matter.

PAUL BRIDGMAN:           Perhaps we'd just come back to the placebo comparator in REDUCE-IT. I think many of the audience will know those concerns. So that was a mineral oil placebo rather than corn oil. Do you know Christian if anyone's tried to unpack that map through what the adverse effects on the surrogate endpoints might be and looked at if it had been a corn oil comparator?

CHRISTIAN HAMILTON-CRAIG:   It's an unusual scientific situation where for some reason the trial shows a mineral oil rather than a more neutral corn oil that was used in the other trials. And in this trial, there's a very elegant sub-study published fairly recently by Paul Ridker (see also Nicholls 2020) showing that in the placebo group or REDUCE-IT, LDL cholesterol went up, lipoprotein-A, a went up, CRP went up by large amount 38 percent, interleukins et cetera, went up. And so, the so-called placebo group actually had a worse biochemical profile, possibly due to the placebo itself than the treated group. And the problem that creates is that the difference between the two groups may be attributable in part to a so-called toxic effect of the placebo. No one's actually unpicked, how much of an effect that had. In the response by the authors they said it has so-called “small or difficult to measure” effect, but it really casts doubt on the reliability of that trial in terms of the efficacy of the fish oil as opposed to the toxicity of the comparator. And all of the other placebo-controlled arms such as JUPITER, CANTOS and STRENGTH, used a corn oil, which is neutral. So I think that leaves the science of it in equipoise.

PAUL BRIDGMAN:           So is it fair Christian to ask you how often do you eat fish currently?

CHRISTIAN HAMILTON-CRAIG:   It is fair, I live in Queensland and, in fact, the access to good quality oily fish isn't as good in Queensland as other states, I think most of it gets exported. So I'll try and eat fish twice a week if I can. And I do take some omega-3 supplements; I take one capsule of triple strength fish oil, and triple strength oil has about 1500 milligrams of EPA-DHA. But in a primary prevention patients such as myself without having had a previous event the benefit of EPA-DHA supplementation may be very small. So one of the things you know we can do is actually measure the EPA-DHA effect in the body.

MIC CAVAZZINI:                And maybe just to clarify before you do when, when sorry, when you're talking about your supplementation Christian or even these trials, or we're talking daily capsules of 1000 milligrams.

CHRISTIAN HAMILTON-CRAIG:   Yeah, if it's a if it's a patient who is in the high risk groups, and that is established coronary artery disease, secondary prevention, left ventricular dysfunction or prior bypass surgery, then I use about two capsules a day. So a reasonable dose of a triple strength soil. Triple strength fish oils are slightly larger capsules, but obviously, much more potent than the single strength. And the single strength capsules that you get cheap from the pharmacy, you'd probably have to have five or six a day, which people don't do. So I just recommend ordering a triple strength online or from your local pharmacy. And having to a day.

MIC CAVAZZINI:                As you say, it's hard to imagine anyone having five capsules a day. And it's hard to imagine anyone but the Inuit eating that much oily fish per day.

CHRISTIAN HAMILTON-CRAIG:   Yeah, that's right.

MIC CAVAZZINI:                So it can't be the only source. Or as you say, in private primary prevention, maybe it's not that essential, inverted commas.

CHRISTIAN HAMILTON-CRAIG:   Yeah, I think the evidence doesn't really support prevention with primary prevention using fish oils. I think in our paper, we sort of try and distil down what are the three groups that have the greatest benefit from fish oil supplementation, and they are patients that secondary prevention; patients who with ejection fraction below 50 percent, particularly after a myocardial infarction; and interestingly, those patients that have low omega-3 levels. Ad so you can measure the Omega three index in the red cells—it’s like an HbA1c—it measures the amount of EPA,DHA in the red cell membrane. And that costs about $100, by the major pathology providers, there's no Medicare rebate for that. And in selected patients, I will do that in those who are either high risk and I want to know that the therapy is effective. Or those who are not taking fish oil supplements and who I think have an inadequate intake, in which case measuring their level will confirm whether they will likely benefit from supplementation or not.

PAUL BRIDGMAN:           And for the clinician question, what's your point there for thinking that supplementation may be of benefit.

CHRISTIAN HAMILTON-CRAIG:   If they're below 4 percent then they definitely are at high risk. And your target is to supplement to a dose above 8 percent. My personal index was 7.9 percent, which I think is sufficient, and that's with intermittent fish and a little bit of fish oil capsule. So just to give you a rough idea.

PAUL BRIDGMAN:           So I just have to ask a bit more about fish intake. Say you're a Queenslander, you can't afford seven twice a week or you don't want to eat salmon more than once a week, what other fish should our Queenslanders be looking at, Christian?

CHRISTIAN HAMILTON-CRAIG:   Look, oily fish are defined as—is predominantly salmon and pink fish such as trout. The Australian Heart Foundation document from 2008 actually goes into the different types of fish that you can have. But, you know, a fish oil capsule is probably cheaper than fish. Fish is pretty expensive up here. And just to remind the audience, fish oils are actually not derived from fish. They're derived from the algae that the fish ingest. And then the algae is metabolized into the omega-3 oil. So it really is a plant product, if you look at the very beginnings of it, and you can get pure plant based and you're free oils that don't have fish in the production. And in then derived from algae for those vegan patients or patients with dietaries (requirements).

PAUL BRIDGMAN:           Christian, we've talked about fish oil. How about krill oil?

CHRISTIAN HAMILTON-CRAIG:   Well, David Colquhoun has lectured us on this in the past and says that—he calls krill oil, “con oil”, somewhat facetiously, but it's a very expensive way of getting the same product. So there's really no difference in the type of fish oil that you have. What the person needs to look at is the back of the bottle. How much EPA-DHA, are you getting in a dose, and you need at least 1000 or maybe 2000 milligrams of the active ingredient. And som I don't think that krill oil is necessarily the way to go, it's just a more expensive way of taking the same product.

PAUL BRIDGMAN:           Okay. What else should we be asking your question? Mic, so you have a feeling where we should go?

MIC CAVAZZINI:                I had a question. I only skimmed over the article I didn't have a lot of time to pick through it. But the line in the intro that there is a rationale; the reported anti-inflammatory or anti -hrombotic properties, lower circulating triglycerides and something about how omega-3s keep vessels impermeable to plaque forming lipoproteins. Is all of that evidence hard and fast—it’s  been observed in clinical studies and then dug into in preclinical work.

CHRISTIAN HAMILTON-CRAIG:   I think the preclinical work and the biochemical background is sound. The difference between EPA and EPA-DHA is slightly unclear. I think it's an area which does attract interest from both public health providers and the general public themselves. So they're interested, people want to know, should they be eating fish or fish oils, and therefore there is an imperative to improve the evidence base and tighten up the science. And really, what we would need to do is have an appropriately powered large scale trial in patients with an adequate dose of fish oil, in whom that effect is accurately measured, so that we're measuring their omega-3 index, and then with a comparator that's genuinely neutral placebo. That would be the next step. And that will probably have to be a fairly large-scale funded trial. And currently, I'm not aware of any plans to do such a trial.

MIC CAVAZZINI:                And the guidelines at the moment, typically just point to secondary prevention people with a documented history of coronary heart disease?

CHRISTIAN HAMILTON-CRAIG: Predominantly, yes, because they're the groups in which omega-3 supplementation has been shown to have benefit in multiple trials and meta analyses.

MIC CAVAZZINI:                So you wouldn't change anything about what's been said in those?

CHRISTIAN HAMILTON-CRAIG:   I don't think so. I think the only the only change I really learned out of this, is that a bit like anywhere else in medicine, if you can measure something and measure its effect, you probably should. And so I offer that to patients—I don't push for it. But I think if you really want to know, if you're giving someone a treatment, and that treatment is effective, and it's a measurable effect, then you should probably measure it in that individual. Because just to deepen that; fish oil consumption, fish oil absorption and fish oil dosing are all factors. And so people can be consuming a reasonable amount of fish but not absorbing it, for example. And hence, their omega-3 levels really are the key to unlocking this whole area. I, think.

PAUL BRIDGMAN:           There's certainly a lot of work to be done there.

CHRISTIAN HAMILTON-CRAIG:   There is.

PAUL BRIDGMAN:           Thank you, Christian, I think very helpful to unpack the science for us there. I will continue to eat fish because I enjoy it, and I am now much more informed of the scientific evidence and the uncertainties, really, that we all face, that we all have about this.

CHRISTIAN HAMILTON-CRAIG:   Excellent. Thank you very much for the opportunity and I hope people do continue to eat fish. I think the other closing comment I would say is that there's certainly no harm and definitely some benefit. So the benefit outweighs the risk.

MIC CAVAZZINI: Many thanks to Christian Hamilton-Craig for joining this episode of IMJ On-Air, and to Paul Bridgman for volunteering yet more of his time on top of his editorial work for the Internal Medicine Journal. Neither guest has any conflicts of interest to declare.  

At our webpage racp.edu.au/podcast., you’ll find a transcript of this episode with links to all the references mentioned, including of course, the article “Omega-3 fatty acids and cardiovascular prevention: is the jury still out?”. All members of the RACP have free access to the IMJ, the Journal of Paediatrics and Child Health and the Occupational Health Journal, the three academic publications of the Royal Australasian College of Physicians.

And you also have access to a library of hundreds of video lectures designed around the trainee curricula. These can be found at elearning.racp.edu.au along with other online courses helping trainees to prepare for divisional exams. For Fellows, there are courses walking you through activities that meet the MBA’s requirements of Strengthened CPD via auditing of one’s practice outcomes, and collecting feedback. 

This podcast was produced on the lands of the Gadigal people of the Yura nation. I pay respect to their elders past and present. I’m Mic Cavazzini, thanks for listening.