Tuesday, November 5, 2013

A Few Thoughts on Catalyst's 'Heart of the Matter'

Catalyst recently did a two part series called 'Heart of the Matter'.  Part 1 discussed the controversy around vilifying saturated fat for cardiovascular disease.  Part 2 discussed the pros and cons of statins and the influence of pharmaceutical companies.

As expected some people raised objections to the show, and some even argued for part 2 to not be aired.  Although the critics rarely argued with evidence, instead claiming it was unbalanced, biased and full of emotive language and hyperbole.  They are correct, but many of the critics don’t have much of a high ground to stand on
On the whole I think it was productive and there were several really important messages that the average person needed to hear. 

Heart of the Matter Part 1 - Dietary Villains

Cholesterol Levels and CVD 

After an intro, Dr Ernest Curtis and Dr Stephen Sinatra talk about how in their practices they saw that people with CVD can have low cholesterol and high cholesterol and a not significant number of people either have high cholesterol and no CVD or low cholesterol and CVD.  This is anecdotal, but studies support this.

This study found that in people hospitalised for coronary artery disease:

  • Almost half had an LDL below 100 mg/dl
  • 17.6% had an LDL below 70 mg/dl
  • 45.4% had an HDL ≥ 40 mg/dl
  • Almost 10% had an HDL ≥ 60 mg/dl [1

This data alone can’t discredit the lipid hypothesis or determine CVD risk from your various blood lipids.  To do so you would need to compare it to blood lipid levels in the population.  This data is probably also confounded by statin use in people who are at risk, although even still, this data suggests that blood lipids probably aren’t the major factor and that we should probably look elsewhere. 

Shortly afterwards we get the ‘cholesterol is made by the body and is essential to life’, implying that it’s automatically good.  SOCS3 is also made by the body and is also essential to life, but that doesn’t stop it from causing leptin resistance. 

Ancel Keyes 

Next is a discussion on Ancel Keyes and accusations that he cherry-picked the data, etc.  But the correlation Ancel Keyes made was still there with all the other countries.  The problem is that if standard diet epidemiology is bad because of confounders and self-fulfilling prophecies, then diet epidemiology that compares diet and disease between countries is a disaster because it is subject to far more confounding variables.  Read Denise Minger’s post: ‘The Truth About Ancel Keys: We’ve All Got It Wrong’ 

Diet Trials 

Then there’s a discussion on low fat trials and CVD, SFA vs. PUFA and CVD and SFA increasing cholesterol (see The Diet Heart Hypothesis).  In this part we have some real pearls of wisdom from the conventional side 

“Many analyses have, in fact, actually shown that, you know, we can say with convincing evidence that intake of saturated fats leads to an increase in blood cholesterol” 

Yes, but where’s the pathology or the CVD endpoints.  The real question is ‘does SFA cause disease?’  You can’t say that because ‘A causes B and B causes C, therefore A causes C’.  CETP inhibitors and other failed approaches would like to have a word with you. 

“If saturated fat is completely benign, if it's actually beneficial, where's the evidence in support of that? Where's the evidence of an alternative cause? We are particularly keen to get some dietary advice, because otherwise what do we offer people?” 

This false dichotomy is often used: ‘if something isn’t harmful, then it’s beneficial/protective’.  Claims for both harm and benefit/protection require evidence.  Stuff can be neutral/have no effect, which should be the null hypothesis. 

If there is inconclusive evidence for specific diet advice, then don’t give it.  Probably 80+% of the value of diet advice is simply ‘don’t eat as much junk food’.  You can always offer people the advice to lose weight, exercise, stop smoking, etc, which is generally low risk and beneficial for other aspects of life and health as well. 


Afterwards you have Yudkin vs. Keyes, Framingham, George McGovern, the Lyon Diet Heart Study and finally some pretty average alternative mechanisms for atherosclerosis. 

The first proposed mechanism is where high blood pressure damages the blood vessels (a response to injury type hypothesis).  The problem is that the response to injury hypothesis isn’t well supported [2] and while hypertension is a good risk factor for CVD [3] it’s not good enough to be suggestive of a dominant causal mechanism for those without extremely high blood pressure. 

The other proposed mechanism is sugar >> insulin >> blood vessel inflammation.  Except, insulin seems to be anti-inflammatory [4], and have both positive and negative effects on blood vessel health [5]*.  Just because in insulin resistance causes problems and there is hyperinsulinemia in IR, doesn’t mean elevated insulin signalling causes the problem, as it could just as easily be from a reduction in insulin signalling. 

In line with inflammation, we hear about the problems of too much omega 6 and the benefits of increasing omega 3, which is essentially what happened in the Lyon Diet Heart Study (see table 3). 

We also have some more pearls of wisdom from the conventional side: 

“It's very hard to find any positives about butter in term of its impact on cardiovascular disease.” 

The same false dichotomy as before: if something isn’t good then it’s implied that it’s bad. 

“We certainly probably gave some advice which was a good way to avert one pathway, but people then tracked down another pathway, and that's what's led to the revision of dietary guidelines.” 

As an aside, this compartmentalisation (one nutrient, one disease and one drug, one disease) is in my opinion one of the most annoying things about modern medicine.  Some compartmentalisation is helpful, but I think we would improve our understanding if we looked at the whole system and how it interacts.  Stuff that adversely affects one system tends to adversely affect others and vice versa (see Some Thoughts on Chronic Disease) 

But anyway, the guidelines are still low fat with a view that dietary fat increases the risk for obesity simply because fat is an energy dense macronutrient per gram. 

“Fat is an energy-dense macronutrient, so consuming too much fat may lead to excess energy (kilojoule) intake and weight gain; 672” [6] 

The 672 study discusses many things including a section on ad libitum low carb diets being greater than or equal to calorie restricted low fat diets. 

“A meta-analysis of randomized controlled trials of low carbohydrate diets ( ! 60 g carbohydrate per day) without energy restriction versus low fat diets ( ! 30% of total calories from fat) with energy restriction revealed greater weight loss at 6 months for the low carbohydrate diets, although there was no significant difference at 1 year [Nordmann et al., 2006]. It should be noted that the excess weight loss in the low carbohydrate diets has been attributed to a greater caloric reduction” [7] 

“Finally, a recent 2-year randomized trial of low carbohydrate, Mediterranean, or low fat diets showed greater weight loss with the low carbohydrate and Mediterranean diets [Shai et al., 2008].” [7] 

Anyway, the section from the dietary guidelines may have come from this 

“At least one randomized trial comparing the effects of fat intake on weight regain has demonstrated lower weight regain in those randomized to the low fat diet, due to a lower total energy intake” [7] 

I’ll leave you to think about the problems with inferring ‘dietary fat >> increased risk of obesity’ from this statement 

* When looking at the literature related to insulin and blood vessels there’s a lot on the renin-angiotensin aldosterone system (RAAS) causing insulin resistance and CVD.  Will the RAAS be the new cholesterol and will salt be the new PUFA? 

My Thoughts on Atherosclerosis 

The trouble is that the exact sequence of events in atherosclerosis is unknown.  Although it seems to me that several factors may be involved: 

1) The LDL particle may need to penetrate the endothelium which then reduces antioxidant exposure in the bloodstream, increases oxidant exposure from vascular smooth muscle cells and causes the endothelial cells to initiate an inflammatory response (the response to retention hypothesis).  This is determined largely by LDL particle number (concentration gradient), but I suspect that there may need to be an increase in endothelial permeability from endothelial dysfunction.  LDL particle number can increase from insulin resistance and low thyroid function.  Endothelial dysfunction can be a result of mitochondrial dysfunction and inflammation 

2) The LDL particle must be modified to have its cholesterol be taken up by macrophages to form foam cells and ultimately atherosclerotic plaque (the oxidative modification hypothesis).  Since the bloodstream contains many antioxidants either: there needs to be a problem with the antioxidants in the bloodstream (endothelial dysfunction), the LDL particle needs to penetrate the endothelium (response the retention) or there are specific oxidants – like hypochlorous acid and peroxynitrite – that bypass the antioxidants in the bloodstream or otherwise are probably what’s modifying the LDL in the endothelium (see Atherosclerosis) 

3) There may need to be a hyperinflammatory immune response or poor HDL function, so that cholesterol is preferentially kept in macrophages instead of being transported back to the liver by HDL.  The hyperinflammatory immune response can be a result of low vitamin A, D and zinc, dysbiosis, chronic stress and inflammation, but can be locally caused by endothelial dysfunction.  Impaired HDL function can be due to products of myeloperoxidase modifying HDL.  Also having a high total cholesterol to HDL-C ratio suggests poor HDL function 

Heart of the Matter Part 2 - Cholesterol Drug War 

This episode discusses some things that shouldn’t be too surprising, such as: 

  • Statins are widely prescribed and highly profitable drugs
  • There are incentives for doctors to prescribe statins and “doctors who receive money from drug companies have more favourable attitudes and prescribing habits towards that drug.” 
  • RCTs funded by drug companies show greater benefits and fewer side effects
  • Statins are portrayed as having a greater benefit for a wider range of people than they actually do and as having fewer side effects as they actually do 

We also hear about how statins also inhibit coenzyme Q10 synthesis.  Which begs the question of why the ‘best practice’ guidelines don’t tell doctors to also prescribe coenzyme Q10 when they prescribe statins? 

We also get this gem: 

“The marketing concentrates on the fact that you can lower your cholesterol as if that was the end in itself, which it is not. Cholesterol's just a lab number. Who cares about lowering cholesterol unless it actually translates into a benefit to patients?” - Professor Rita Redberg 

Which is why it’s called ‘the lipid hypothesis’, rather than ‘the lipid fact’.  You can say that based on epidemiological data if something lowers cholesterol it will probably reduce the incidence of CVD in a population.  But you need to test that hypothesis for every single thing you come across (and this doesn’t just apply to the lipid hypothesis). 

Cost vs. Benefit 

An important part of the episode is how they discussed the costs of taking statins (side effects) and benefits of taking statins (reductions in all-cause mortality).  That statins are really only effective for men in secondary prevention, that statins aren’t that effective as the risk reduction doesn’t come anywhere near figures like 50-80%, and that the side effects of statins have been downplayed. 

The number needed to treat (NNT) is an important figure.  When looking at these links remember that the NNT is based on a 5 year period which makes the numbers seem a little low.   Also remember that the side effects are probably higher and aren’t limited to diabetes and muscle damage, they can be as simple as minor quality of life issues. 


I think when discussing a treatment plan (whether it’s drugs, surgery, etc) doctors should say ‘here are the benefits, here are the costs, you can decide whether you want to take the treatment’. 

On a somewhat related note: 

Assoc Prof David Sullivan
“In alerting patients to some undesirable possibilities, and, in fact, maybe even through the power of suggestion, lead them to believe that they're experiencing those particular issues, which they would then blame on the drug when in fact it might be arising from other factors.” 

I think David Sullivan is right.  There is such a thing as the nocebo effect.  But what about cases where the side effects from statins like memory loss and muscle pain being blamed on ‘aging’ or where the side effects are put up with because the patient is so afraid of cholesterol and believes they are getting a greater benefit than they really are?  It’s difficult to know in what direction this balances out, but I suspect there is more underreporting going on than nocebo induced symptoms. 

‘High’ Cholesterol 

The changing definition of high cholesterol is something I take issue to.  High cholesterol should be defined based on risk or based on population averages or percentiles.  Being defined on risk makes the most sense and if you were to take that approach then you would look at studies that investigated the relationship between cholesterol and  all-cause mortality.  A meta-analysis did this and found the lowest all-cause mortality tends to occur at around 4.2 to 6.3 mmol/l.  There are pretty minor increases in mortality as you go higher than 6.3 (only for men though) or lower than 4.2.  So if you want to define high cholesterol, it should be at the lowest: ‘greater than 6.3 mmol/l’, but you should probably also define low cholesterol as well, to err on the side of caution. 

Total cholesterol
Pooled except MRFIT, men
Pooled women

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