Thursday, December 2, 2010

Diet-Heart Controlled Trials: a New Literature Review

Many controlled studies have measured the cardiovascular effects of replacing animal ("saturated") fats with seed oils (predominantly the omega-6 polyunsaturated fat linoleic acid) in humans. A number of these studies recorded heart attacks and total mortality during the following 1-8 years. Several investigators have done meta-analyses (literature reviews) to try to tease out overall conclusions from these studies.

I'm pleased to point out a new meta-analysis of these controlled trials by Dr. Christopher Ramsden and colleagues (1). This paper finally cleans up the mess that previous meta-analyses have made of the diet-heart literature. One recent paper in particular by Dr. Dariush Mozaffarian and colleagues concluded that overall, the controlled trials show that replacing animal fat with linoleic acid (LA)-rich seed oils reduces heart attack risk (2). I disagreed strongly with their conclusion because I felt their methods were faulty (3).

Dr. Ramsden and colleagues pointed out several fundamental flaws in the review paper by Dr. Mozaffarian and colleagues, as well as in the prevailing interpretation of these studies in the scientific literature in general. These overlap with the concerns that I voiced in my post (4):
  1. Omission of unfavorable studies, including the Rose corn oil trial and the Sydney diet-heart trial.
  2. Inclusion of weak trials with major confounding variables, such as the Finnish mental hospital trial.
  3. Failure to distinguish between omega-6 and omega-3 fatty acids.
  4. Failure to acknowledge that seed oils often replaced large quantities of industrial trans fats in addition to animal fat in these trials.
Dr. Ramsden and colleagues accounted for all of these factors in their analysis, which has never been done before. They chose inclusion criteria* that made sense, and stuck with them. In addition, they did an impressive amount of historical work, digging up old unpublished data from these trials to determine the exact composition of the control and experimental diets. The paper is published in the British Journal of Nutrition, an excellent journal, and overall is written in a scientific and professional manner.

What did they find?
  • Interventions that replaced animal and trans fat with seed oils that were rich in LA but low in omega-3 caused a non-significant trend toward increased heart attacks (13% increase) and overall mortality.
  • Interventions that replaced animal and trans fat with a combination of LA and omega-3 fats significantly reduced heart attacks (by 22%). The numbers for total mortality followed a similar trend.
In other words, LA-rich seed oils do not prevent heart attacks (and may actually promote them), but correcting an omega-3 deficiency and reducing industrial trans fat intake may be protective. This is similar to what I've been saying for a while now, based on my own interpretation of the same studies and others. However, Dr. Ramsden and colleagues have taken the idea to a new level by their thorough and sophisticated detective work and analysis. For example, I didn't realize that in virtually all of these controlled trials, the intervention group reduced its trans fat intake substantially in addition to reducing animal fat. From the paper:
...experimental diets replaced common ‘hard’ margarines, industrial shortenings and other sources of [trans fat] in all seven of the [controlled trials] included in the meta-analysis by Mozaffarian et al. The mean estimated [trans fat] content of the seven control diets was 3·0 [% of calories] (range 1·5–9·6 [%]).
...the displacement of [trans fat], rather than the substitution of mixed n-3/n-6 [polyunsaturated fat] for [saturated fat], may account for some or all of the 22% reduction in non-fatal [heart attacks and heart attack] death in our meta-analysis. By contrast, the increased [heart attack] risks from n-6 specific [polyunsaturated fat] diets in our meta-analysis may be underestimated as n-6 [polyunsaturated fat] also replaced substantial quantities of [trans fat] (Table 3). The consistent trends towards increased [heart attack] risk of n-6 specific [polyunsaturated fat] diets may have become significant if the n-6 [polyunsaturated fat] replaced only [saturated fat], instead of a combination of [saturated fat] and [trans fat].
In other words, it looks like trans fat is probably the issue, not animal fat, but these trials replaced both simultaneously so we can't know for sure. I will note here that trans fat does not generally promote atherosclerosis (thickening and hardening of arteries) in animal models, so if it does truly increase heart attack risk as many studies suggest, it's probably through a mechanism that is independent of atherosclerosis.

The article also contains an excellent discussion of the Finnish mental hospital trial (5, 6) and why it was excluded from the meta-analysis, in which Dr. Ramsden and colleagues point out major design flaws, some of which I was not aware of. For example, trans fat intake was on average 13 times higher in the control groups than in the experimental groups. In addition, one of the control groups received more than twice as much of the antipsychotic drug thioridazine, which is known to be highly toxic to the heart, as any other group. Ouch. I'm glad to see this study finally discussed in an open and honest manner. I discussed my own problems with the Finnish trial in an earlier post (7).

I was also glad to see an open discussion of the Oslo Diet-heart study (8), in which diet changes led to a reduction in heart attack risk over five years. Dr. Mozaffarian and colleagues included it in their analysis as if it were a controlled trial in which animal fat was replaced by seed oils only. In reality, the investigators changed many variables at once, which I had also pointed out in my critique of Dr. Mozaffarian's meta-analysis (9). Here's what Dr. Ramsden and colleagues had to say about it:
First, experimental dieters were instructed to substitute fish, shellfish and ‘whale beef’ for meats and eggs, and were actually supplied with ‘considerable quantities of Norwegian sardines canned in cod liver oil, which proved to be popular as a bread spread’(32)... Second, the experimental group consumed massive amounts of soybean oil, which provided large quantities of both LA (15·6 en %) and ALA (2·7 en %). ALA consumption was about 4·5 times average US intake(42), or about twelve typical flax oil pills (1 g pill ¼ 560 mg ALA) per d. In addition, the fish and cod liver oil consumption provided Oslo (598N latitude) dieters with 610 IU (15·25 mg) of daily vitamin D3, recently linked to lower blood pressure, plaque stabilisation, and reduced [heart attack risk] (64). Furthermore, experimental dieters were encouraged to eat more nuts, fruits, and vegetables; to limit animal fats; and to restrict their intake of refined grains and sugar.
trans fat intake was also reduced substantially by excluding margarine in the experimental group. Other review papers have used this trial as a justification to replace animal fat with seed oils. Hmm... The only reason they get away with this is because the trial was published in 1966 and almost no one today has actually read it.

One criticism I have of Dr. Ramsden's paper is that they used the Oslo trial in their analysis, despite the major limitation described above. However, they were extremely open about it and discussed the problem in detail. Furthermore, the overall result would have been essentially the same even if they had excluded the Oslo trial from the analysis.

Overall, the paper is an excellent addition to the literature, and I hope it will bring a new level of sophistication to the dialogue on dietary prevention of cardiovascular disease. In the meantime, brace yourselves for an avalanche of criticism from the seed oil brigade.

* Guidelines that determine which studies to include in the analysis. For example, you want to exclude any study that wasn't randomized, because it will not be interpretable from a statistical standpoint. You also want to exclude trials where major variables differ between groups besides the specific variable you're trying to test. The Finnish mental hospital trial fails by both criteria.


Chris Masterjohn said...

Sanity has arrived to the science community!

Anonymous said...
This comment has been removed by the author.
Vladimir Heiskanen (Valtsu) said...

Haha, quite nice quotes! One of the "greatest" and most respected Finnish health authorities, Matti Uusitupa, still refers very often to that old mental hospital study. According to him, it's one of the most important studies proving the health dangers of animal fats. He was the headmaster(!!!) of University of Kuopio (2001-2009) and now he's the chairman of the respected heart association of Finland (Suomen Sydänliitto ry).

Anonymous said...

Thank you tips, it really helped me, because now I was in need of such information.

Dr. B G said...


This a bad*ss summary and thank you as always for your wonderful assessments of the new and old body of literature!

Have you also seen this from Harvard, Dr. Mozaffarian? Seems like the tides may actually be shifting ever SO SLIGHTLY. *haa!*

Lipids. 2010 Oct;45(10):893-905. Epub 2010 Mar 31.

Saturated fat and cardiometabolic risk factors, coronary heart disease, stroke, and diabetes: a fresh look at the evidence.
Micha R, Mozaffarian D.

Recall, he authored also the BEST prospective trial that showed higher saturated fat intake reversed coronary plaque:

David said...

And here is one of Mozzfarian's conclusions from the abstract in Lipids referred to by Dr. B.G.:

"Based on consistent evidence from human studies, replacing SFA with polyunsaturated fat modestly lowers coronary heart disease risk, with ~10% risk reduction for a 5% energy substitution; whereas replacing SFA with carbohydrate has no benefit and replacing SFA with monounsaturated fat has uncertain effects."

Patty said...

Thanks for always summarizing in a manner that us non-scientists types can comprehend. The only part that confuses me is the line between significant and non-significant:

" a non-significant trend toward increased heart attacks (13% increase)" and "significantly reduced heart attacks (by 22%)"

Where is the line, and is this subjective or a predefined line in the meta-analysis world? Thanks!

David Pier said...

So, what is your current thinking on canola (not for deep-frying, of course), provided that it is carefully processed to prevent the formation of trans fats and to maximize tocopherol concentration?
From the little research I have been able to find so far, animal and human tissue membrane composition is actually quite constant regarding saturated, monounsaturated, and polyunsaturated composition. What is variable is the mix of pufas, determined by diet and adipose stores.
I ask not as someone who actually wants to use canola himself, but as someone who is trying to counsel friends and family on gradual change that doesn't disrupt their current habits and budgets very much. Good quality canola (oxymoron?) seems like a cheap and easy way to improve the w-3/w-6 balance.

John said...

Maybe popular thought will change ever so slowly: I believe I saw a reference to the Krauss saturated fat meta-analysis in Men's Health!

trix said...

Saw this Unilever funded study, seems pretty biased in favor of n-6 PUFA oils/spreads here, unless I am misinterpreting it:
More of the same anti-animal fats?
Unilever makes veg oils and spreads.

. said...

Many modern myths (created by the ideology of Nutritionism) are falling apart these days. It would be good if modern studies focused more on food instead of nutrients. Titles like "Meta-analysis of RCT of real food vs processed food: Ancestral/traditional diets are superior for humans, as we allways knew after all" would be much better.

Heart Group’s Omega-6 Advice Takes a Huge Hit -,0,w

Tucker Goodrich said...

Congratulations, Stephen. Nice to see your theories and view of the science getting some main-stream confirmation.

Unknown said...

Hi Stephan,

You might want to check whether this quote from the paper is accurate: "may account for some or all of the 22% reduction in non-fatal [heart attack] death in our meta-analysis"

Nnon-fatal death is a new one on me. Or maybe it's a koan?

Great paper, anyway!

TedHutchinson said...

Evelyn Tribole Meta-analysis Reveals “Heart Healthy Omega-6 Fat”Increases Risk of Heart Disease has also posted on this topic.

Jack said...


Good questions on canola oil. I used to fry things in canola oil. Never again. For frying (which I don’t really do anymore), I suppose ghee or organic palm shortening would be good, but I’m not well versed on that.

As far as canola being 'carefully processed', I understand what you mean. I recently bought a jar of organic mayonnaise that had fantastic ingredients, save for one that made me hesitate… "cold pressed canola oil". That's a far cry better than normal canola, which is heated for processing, but since canola is about 30-35% poly on average, it still has enough to be in the camp of too much unnecessary omega-6 in my opinion, even in cold form. EV olive oil only has about 10-15% poly on average.

Canola oil may be a tick or two 'better' than corn oil, or soybean oil since it's much higher in MUFA, but it's also better to eat a spoonful of nasty hydrogenated margarine in place of a spoonful of chlorine bleach. It doesn't make the margarine any healthier.

Tell your friends and loved ones the truth. Tell them about cooking with coconut oil, red palm oil, and grass fed ghee. Stephan did a post a while back on lard that was very informative as well. Butter and extra virgin olive oil are good too, but I really keep to low temps with those. The best oils to cook with are those that are very high in saturated fats and very low in any other type of component that does not stand up well to high heat, which I’ll bet you already know based on how you posed your question.

Jack K :)

Anonymous said...
This comment has been removed by the author.
David Pier said...

Any oil, whether vegetable or mineral, along with a little surfactant, will suffocate insects. I imagine they used canola because it is cheap and (sort of) edible. I'm sure olive oil has been used in all sorts of suspicious concoctions though history, but that alone doesn't indicate anything.

Allan Folz said...

" The only part that confuses me is the line between significant and non-significant... Where is the line, and is this subjective or a predefined line in the meta-analysis world? "

No offense but first do you understand what statistical significance is?
It is the chance that a study's results are true, and NOT due to randomness, AKA luck of the draw.

Consider I think I have a "magic" quarter that will tell me the sex of the child in my pregnant wife. Heads it's a boy, tails it's a girl. My wife has had three children and it was right every time. What's the statistical significance that my quarter is magic? I also used it on all my wife's friends. In 10 pregnancies it was right 9 times! What is the statistical significance that it is magic. I took it to the hospital for a week and in 100 mothers it was right an incredible 82 times. What is the statistical significance that it was magic? In every case the statistical significance is higher, but that doesn't change the fact there's no such thing as magic quarters. It was *always* the luck of the draw, the quarter is *always* a random correlation.

As for the "line", it is subjective, though has been generally agreed upon in academia. Less than 5% is unlikely to be published. Less than 10% is ignored. Any research paper will report what the significance of their results is. The usual minimum is 5%, bigger studies may shoot for 2%, 1%, or even .1%.

The weakness of meta-studies is that the randomness is additive (well not strictly additive, but it increases as the number of studies I'm looking at increase). If I have 20 studies, each with a 5% chance of being wrong, the chance I have at least one wrong study in the group is greater than 5%.

HTH. There are good primers on statistical significance if you want to do a search.

Vladimir Heiskanen (Valtsu) said...

Just wondering... Dairy fat also contains TFA. How large part of control groups' trans fatty acids could be natural TFA's from butter? Even though intervention group got up to 13x more TFA's, what are the absolute amounts in grams? Are the amounts clinically significant?

Might-o'chondri-AL said...
This comment has been removed by the author.
Michael Barker said...

Thanks Stephan, I am making a major effort to change the diets of Ketosis Prone type 2 diabetics.
I know that saturated fats work far better as a substitute for carbs but I need good well thought out proof to make my case. This helps.

SamAbroad said...

@Valtsu, the TFA's in dairy are good for you, that's the conjugated linoleic acid that supplement hawkers are touting as the ulimate weight-loss/anti-cancer supplement du jour.

It's the man-made TFA's that are created via the hydrogenation are fat are the ones to avoid.

Helen said...
This comment has been removed by the author.
Helen said...

@ Might-o'chondri-Al -

I read about that, too:

"In the research, Clarke and her colleagues show that polyunsaturated fatty acids can be strengthened by replacing their most vulnerable hydrogen atoms, which are easily stripped away, with much more stable deuterium, an isotope of hydrogen with one extra neutron. The result is the creation of a fatty acid that serves the same function as its predecessor, but without the same susceptibility to oxidation."

Hooray! We're saved! Surely, nothing could go wrong with *this* improved food product.

Vladimir Heiskanen (Valtsu) said...

SamAbroad: Yea that's a thing I know, luckily. I'm just wondering if the absolute amounts of those toxic plant oil trans fatty acids are really significant (not statistically but clinically) between those groups. The 13-fold difference could be like 0.1g vs 1.3g and in that case even the "13-fold" intake (of 1.3 grams a day) would probably(?) be not so significant to the participants' health.

Stephan Guyenet said...

Hi Valtsu,

TFA intakes ranged from 0.0% to 2.0% of calories depending on the period and location.

Anonymous said...

Doesn't this study indicate that a healthy balance of n-6 vs. n-3 is healthier than a diet of pure SFA? Or did I misread this?

Neonomide said...

I read it that safa may be about as benign as adequate omega 3 and low-enough omega 6 intake - when trans fats are absent.

I must say that I have been rather perplexed by overall about studies on omega 6 heart health. I think it still may be that crap &%¤#&%¤ processing is a factor and different omega 6 oils have different effects. Instead of nutritionism, we perhaps should be more aware of the quality of our oils and fats, in a way is it industrial based or not.

I must get this paper, though it seems that my institutional access does not have it...

Vladimir Heiskanen (Valtsu) said...

Thanks Stephan. Do you know if that 2.0% intake could be high enough to raise CHD risk significantly? (Maybe also assuming that a part of that 2.0% is from their butter intake?)

Kuntsa said...

According to Fineli, butter fat (and milk fat in general) has 2.4 % of trans fats. If you get 40 % of your energy from butter, you get 1 % of calories from butter's transfats.

mini said...

Interesting to see that this info in an article in the weekend Sunday Times. About time the mainstream media pick this up.

john said...

Hi Stephan,

Been perusing your blog for over a year now and appreciate all the hard work (particularly coming from another busy neuroscientist).

You've used the term "seed oil" a lot lately and I'm not entirely clear on what that entails. I know in the past you've discussed how vegetable oils are bad (partially hydrogenated in particular) but I'm not sure what's what anymore. Could you make a handy list of healthy/unhealthy oils? The impression I get is vegetable oils like canola oil, peanut oil and soybean oil are bad while coconut and olive oil are good. Not sure what to think of something like flax seed oil (not that anyone cooks in this).

Thanks for the help!


Anonymous said...

I'm so glad to see research into this topic. I can't help but think that previous research into thi has been biased due to commercial interests.

Bea said...

Hey Dr. Guyanet,

I'm from Seattle as well. I'm actually a Biochemistry major at the University of Washington. Just curious if you do your research here at the U.

Nice to see there are others out here in this city that thinks paleo is kick ass.

Thanks for all you contribute in this blog. I've learned quite a bit.

Long time follower,

Bea said...
This comment has been removed by the author.
Allan Folz said...


A nice summary of all the major vegetable oils is here.

john said...

^Thanks a lot that's very useful. Site looks pretty solid too. Sounds like butter is making a 'comeback'.

majkinetor said...

Stephen wrote:
"I will note here that trans fat does not generally promote atherosclerosis (thickening and hardening of arteries) in animal models, so if it does truly increase heart attack risk as many studies suggest, it's probably through a mechanism that is independent of atherosclerosis."

The trans fatty acids inhibit the w-3 EPA/DHA pathway.
See the <a href="> picture of the pathway </a> from M.Enigs book "Know your fats". This also leads to deficit of these crucial fatty acids for CVD prevention.