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.
Atherosclerosis
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.
See:
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
|
<160
|
160-199
|
200-239
|
≥240
|
Pooled except MRFIT, men
|
1.17
|
1.00
|
1.02
|
1.14
|
MRFIT men
|
1.17
|
1.00
|
1.05
|
1.22
|
Pooled women
|
1.10
|
1.00
|
0.94
|
0.97
|
[8]
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