The American Heart Association
(AHA) recently released a presidential advisory on dietary fats and
cardiovascular disease (CVD) [1]. As you would expect from the AHA, they claim
that “…randomized controlled trials that
lowered intake of dietary saturated fat and replaced it with polyunsaturated
vegetable oil reduced CVD by ≈30%, similar to the reduction achieved by statin
treatment” and conclude that “lowering
intake of saturated fat and replacing it with unsaturated fats, especially
polyunsaturated fats, will lower the incidence of CVD”.
I recently published a
meta-analysis on the randomised controlled trials (RCTs) that replaced
saturated fat (SFA) with polyunsaturated fat (PUFA) to see if this intervention
reduces the risk of coronary heart disease (CHD) (blog)
[2]. I concluded that “available evidence from adequately controlled randomised controlled
trials suggest replacing SFA with mostly n-6 PUFA is unlikely to reduce CHD
events, CHD mortality or total mortality”.
So not surprisingly I disagree with the AHA’s presidential advisory and
will explain why below.
Speaking of which, as my
meta-analysis was published about a month ago some people asked if I thought
the presidential advisory was a response to that. I doubt it.
The authors would have to have been made aware of my meta-analysis
(without there being significant media coverage), organise themselves, then
write this paper and get it past review in less than month. They also didn’t cite it my meta-analysis,
but one could argue that could be because of other reasons. I think it’s more likely that this is a
response to the updated meta-analysis by Ramsden et al in April 2016 after
recovering data from the Minnesota Coronary Survey [3].
In this post I’m going to
focus on the presidential advisory, mostly the RCT evidence, and not the media
coverage. From what I’ve seen, the media
coverage badly misrepresents the evidence.
They claim SFA is bad and draw special attention to coconut oil,
claiming that coconut oil is worse than butter because it has more SFA. This is a position you can only take if you
ignore that SFA also increases HDL-C (as a result SFA doesn’t significantly
affect the total-C:HDL-C ratio) and HDL-C is associated with a lower risk of
CHD/CVD, ignore meta-analyses of observational studies, and ignore the almost
total absence of RCTs for anything related to SFA and CHD/CVD other than
replacing SFA with PUFA [1]. The conventional position is not that SFA is
bad, but that replacing SFA with PUFA will reduce the risk of CHD/CVD. Replacing SFA with MUFA is not a particularly
defensible position unless you only look at blood lipids and ignore
meta-analyses of observational studies.
The AHA’s Selection Criteria
The claim that RCTs where SFA
was replaced with PUFA reduced the risk of CVD by ~30% doesn’t come from an
earlier meta-analysis, but is from a meta-analysis the AHA did in the
presidential advisory. The AHA looked at
previous systematic reviews and meta-analyses for RCTs (Mozaffarian et al 2010,
Hooper et al 2015, and Chowdhury et al 2015) and applied the following
inclusion criteria to select their core trials:
- Compared high SFA with high PUFA
- Didn’t include trans fats (TFA) as a major component
- Controlled the dietary intake of the intervention and control groups
- Had at least 2 years of sustained intake of the assigned diets
- Proved adherence by objective biomarkers such as serum cholesterol or blood or tissue levels of polyunsaturated fatty acids
- Collected and validated information on cardiovascular or coronary disease events
These criteria are very
reasonable. (1) and (6) are actually
essential. In my meta-analysis I tried
to account for (2) and (3) with my ‘adequately controlled’ and ‘inadequately
controlled’ categories, and I reported changes in serum cholesterol for every
trial (5). The rationale for (4) makes
some sense and the AHA say “trials of
serum cholesterol–lowering agents show that a reduction in coronary heart
disease (CHD) incidence occurs with a lag of 1 to 2 years”. However, the primary reason given is that “the 2-year minimum duration is that changes
in polyunsaturated fatty acids very slowly equilibrate with tissue fatty acid
levels; it takes ≈2 years to achieve 60% to 70% of the full effect”. This isn’t necessary for adherence and isn’t
relevant for the proposed mechanism. The
proposed mechanism for PUFA reducing the risk of CHD is by lowering LDL-C,
which short term feeding studies and the National Diet Heart Study found
maximally occurs within days or a couple of weeks [4]
After applying their criteria,
they included the following trials as part of their core trials:
- Los Angeles Veterans Administration Trial (LAVAT)
- Oslo Diet Heart Study (ODHS)
- Finnish Mental Hospital Study (FMHS)
- Medical Research Council Trial (MRCT)
The Core Trials
When briefly summarising each
trial, the AHA mentions key facts like the number of participants, the basics of
the interventions and the number of events and deaths in each group. However, the AHA doesn’t address the major
issues in most of those trials which are discussed in my recent meta-analysis
and I’ll also mention below:
Los Angeles Veterans Administration Trial
I see there being two key
issues in LAVAT. Firstly, that the researchers
mostly omitted conventional margarines and hydrogenated shortenings (major sources
of TFA) from the high PUFA diet [5]. Secondly, the α-tocopherol (vitamin E) intake
in the high SFA group was 9.4-fold lower than the experimental group
(22.6 mg vs. 2.4 mg) [6] and was
deficient, being only 16.0% of the current RDA (15 mg) [7]. These issues were not reported in the
monograph [8], which
the AHA cites, but in the other papers that I cited here, which can be easily
found by looking at the Cochrane meta-analyses (the AHA cites the one by Hooper
et al 2015).
There’s the argument that
smoking is a confounder in LAVAT. The
high PUFA and high SFA groups had similar number of low or non-smokers, but
despite randomisation and a large number of participants, the experimental group
had more moderate smokers and fewer heavy smokers [9]. My guess at a reasonably appropriate way to
account for this is to take the incidence of endpoints in person years
stratified by smoking status, weight them according to the total number of
participants in each smoking stratification and sum that all together (see
table below). This results in the effect
of higher moderate smokers and lower heavy smokers probably cancelling each
other out to a large extent. Interestingly,
there was an interaction between smoking and the high SFA, vitamin E deficient
control diet such that much of the increased risk of CHD/CVD in the high SFA
group was in the moderate and heavy smokers (supporting an oxidative stress
model of CHD)
Total incidence
in person years
|
Average weighted
incidence in person years
|
|||||
SFA
|
PUFA
|
RR
|
SFA
|
PUFA
|
RR
|
|
SD,MI
|
2.37
|
1.87
|
0.79
|
2.40
|
1.88
|
0.78
|
SD,MI,CI
|
3.18
|
2.16
|
0.68
|
3.21
|
2.18
|
0.68
|
Hard EP
|
3.51
|
2.38
|
0.68
|
3.51
|
2.38
|
0.68
|
CVD M
|
2.55
|
1.73
|
0.68
|
2.55
|
1.74
|
0.68
|
Oslo Diet Heart Study
The high PUFA group received a
multifactorial dietary intervention that included advice to increase fish,
shellfish and whole plant food consumption, advice to moderate sugar
consumption and restrict shortening (a major source of TFA, and hydrogenated
marine oils were a major source of fat in Norway at the time of trial), and the
high PUFA group received sardines canned in cod liver oil [10].
This isn’t mentioned in the
main publications of the trial [11] [12]
([11] is the one
cited by the AHA), but is mentioned in the monograph [10], in an
online version of the relevant chapter from the monograph [13],
by Ramsden et al in the 2010 and 2016 versions of their meta-analysis [14]
[15],
and by Hoenselaar is his review [16]
(and no doubt others have done the same in peer-reviewed journals).
ODHS should not have been included
with the core trials for failing to meet the TFA (2) and controlled diet (3)
criteria. The AHA excluded DART and
STARS because SFA was replaced with PUFA and carbohydrate, but included ODHS
despite all the other dietary variables that are likely more meaningful than
replacing SFA with carbohydrate, which the AHA doesn’t even think affects the
risk of CHD/CVD.
Finnish Mental Hospital Study
The AHA includes FMHS as part
of their core trials and refers to the core and non-core trials as ‘randomised
controlled trials’. However, FMHS isn’t
a randomised trial. Some have suggested
that it’s a cluster randomised trial (in this case that the hospitals, rather
than the patients, were randomly allocated to go on the high SFA or high PUFA
diet first). However, there is no
mention of this in any of the publications from the trial. Even if the researchers did flip a coin to
randomly allocate the hospitals, a cluster randomisation with 2 clusters is
probably quite inadequate. Hooper et al
2012 [17] and 2015 [18]
in their meta-analyses required at least 6 clusters and excluded FMHS for that
reason.
A couple of issues in FMHS
demonstrates that how 2 clusters can be inappropriate. The control group in FMHS received more of a
cardiotoxic antipsychotic drug called thioridazine in hospital N (0.82 vs.
1.79) and slightly less in hospital K (0.43 vs. 0.14), which averaged to an
overall greater use in the control group (0.63 vs. 0.97) [14]
[19]. Also, the participants in the control group
remained in the hospitals longer than those in the experimental group, which
led to an overestimation of the effect size also points to inadequate
randomisation. Fortunately the AHA
correctly used the RR from incidence by age-adjusted person years to account
for this.
In addition, due to the more
detailed dietary information provided in FMHS [19],
Ramsden et al [14]
was able to estimate TFA intake in both of the groups and found TFA intake to
be lower in the experimental group in both hospital K (0.0 vs. 2.0% of total
energy intake) and hospital N (0.2 vs. 0.6% of total energy intake).
Medical Research Council Trial
I don’t see there being any
major issues in MRCT and is the only one of the four core trials that I
categorised as adequately controlled in my meta-analysis. Some minor issues include: that the methods
used to reduce SFA intake in the high PUFA group included forbidding “butter, other margarines, cooking-fat,
other oils, fat meat, whole milk, cheese, egg yolk, and most biscuits and
cakes”. This was very would be
expected to reduce TFA intake in the high PUFA group to some degree and these
methods were very common in the diet heart trials. And also that the participants were
instructed to consume at least half of the soybean oil unheated and most of the
participants achieve this by drinking the oil produced [20]. This doesn’t represent the way in which oils
are usually used, which is for cooking, and cooking causes heat damage to oils.
The Non-Core Trials
The AHA considered the
following to be non-core trials:
- St Thomas Atherosclerosis Regression Study (STARS)
- Diet And Reinfarction Trial (DART)
- Houtsmuller et al (HDAT)
- Rose Corn Oil Trial (RCOT)
- Minnesota Coronary Survey (MCS)
- Sydney Diet Heart Study (SDHS)
Trial
|
Reason for exclusion
|
My comment
|
STARS
|
Replaced SFA with PUFA and carbohydrate
|
Carbohydrate was 10% lower (234.2 vs 267.1 g/d). Doesn’t address what are likely to be far
more meaningful dietary changes besides SFA, PUFA and carbohydrate (similar
to ODHS, see my paper)
|
DART
|
Replaced SFA with PUFA and carbohydrate
|
Carbohydrate only increased from 44% to 46% of total
energy intake
|
HDAT
|
Researchers were not blinded
|
This wasn’t one of their criteria, but it was a very
badly reported study with lots of issues and unknowns
|
RCOT
|
Small number of participants (N =54) and short duration
|
Small number of participants wasn’t one of their
criteria and wasn’t mentioned when discussing STARS. Debatable whether it should have been
included with the AHA criteria as it did have mostly 2 year follow up
|
MCS
|
Average duration 384 days, withdrawals, intermittent
treatment
|
Could have used data from participants who remained in
the study for ≥ 1
year as they had an average of 2.9 years on the diet
|
SDHS
|
Replaced SFA with PUFA and TFA
|
See below
|
Sometimes the exclusion of
these trials was justified, sometimes it was not. On balance the non-core trials are
unfavourable for the diet heart hypothesis.
RCOT, MCS and SDHS are unfavourable, DART was pretty neutral, and while
STARS and HDAT were favourable, they are both quite small. So the exclusion of the non-core trials
helped the AHA get an impressive RR when conducting a meta-analysis on their
core trials, which is part of what makes me wonder whether the criteria were
designed to get such a favourable result.
Also, in relation to MCS, the
AHA also said “another concern is the use
of lightly hydrogenated corn oil margarine in the polyunsaturated fat diet.
This type of margarine contains trans linoleic acid, the type of trans fatty
acid most strongly associated with CHD”.
However, this ignores several points made by Ramsden et al about TFA
intake in MCS (see below):
“Because the trans fatty acid contents of MCE study diets are not
available, one could speculate that the lack of benefit in the intervention
group was because of increased consumption of trans fat. Indeed, in addition to
liquid corn oil the intervention diet also contained a serum cholesterol
lowering soft corn oil polyunsaturated margarine, which likely contained some
trans fat. The MCE principal investigator (Ivan Frantz) and co-principal
investigator (Ancel Keys), however, were well aware of the cholesterol raising
effects of trans fat prior to initiating the MCE. Moreover, Frantz and Keys
previously devised the diets used in the institutional arm of the National Diet
Heart Feasibility Study (NDHS), which achieved the greatest reductions in serum
cholesterol of all NDHS study sites. Hence, it is highly likely that this
experienced MCE team selected products containing as little trans fat as
possible to maximize the achieved degree of cholesterol lowering. Perhaps more
importantly, it is clear from the MCE grant proposal that common margarines and
shortenings (major sources of trans fat) were important components of the
baseline hospital diets and the control diet (but not the intervention diet).
Thus, confounding by dietary trans fat is an exceedingly unlikely explanation
for the lack of benefit of the intervention diet.” [3]
It seems that the AHA uses TFA
and multifactorial dietary interventions as justification to exclude trials
when it’s convenient and ignores these issues when it’s not.
Should the Sydney Diet Heart Study be dismissed so easily?
Some have suggested that the
high PUFA group in SDHS had a higher intake of TFA due to the use of Miracle
Margarine, which has been suggested to have been
rich in TFA at the time of the trial [21]. However, Ramsden et al [22] [23] has provided
some arguments suggesting that TFA is likely to be a major factor in SDHS. The AHA ignores this debate and uncertainty
and confidently states that the study was comparing a high SFA diet with a high
PUFA and TFA diet because the high PUFA group was given a margarine high in
TFA.
“The Sydney Diet Heart Study showed that using a margarine rich in
trans unsaturated fat to replace saturated fat increased CHD events, confirming
similar adverse results in epidemiological studies.”
I’m going to play the AHA’s
game and assume for this section that the high PUFA group in SDHS did in fact
have a higher intake of TFA, but *spoiler alert*, they’re not going to like to
outcome
To get a rough indication of
the TFA intake in the high PUFA in SDHS let make a few assumptions and rough
calculations. (1) Assume that the
Miracle Margarine used in SDHS was composed of 25-40% TFA, which based on study
looking at the TFA content of safflower margarines of that time that was cited
by Gutierrez* in her rapid response [21], and (2) assume
that the high PUFA group replaced roughly half their original fat intake (which
I think is a reasonable estimate given the change in SFA intake) with similar
amount of miracle margarine and safflower oil.
Therefore Miracle Margarine provided about 9.18% of total energy intake and
TFA intake from Miracle Margarine would be 2.29-3.67%. Ramsden et al estimated that TFA intake in
the high SFA group was 1.6% [14]. The high PUFA group were advised to restrict common
margarines and shortenings (which are major sources of TFA), but let’s assume
they were 50-75% compliant. Therefore, a
generous estimate of TFA intake would be 1.60% in the high SFA group and
2.69-4.47% in the high PUFA group.
High SFA group
|
High PUFA group
|
|||
Baseline
|
Follow up
|
Baseline
|
Follow up
|
|
Total fat (%)
|
39.4
|
38.1
|
39.9
|
38.3
|
SFA (%)
|
15.9
|
13.5
|
16.4
|
9.8
|
MUFA (%)
|
14.9
|
13.8
|
14.9
|
11.5
|
PUFA (%)
|
6.6
|
8.9
|
6.6
|
15.1
|
The RR in SDHS was 1.57 for
CHD mortality and 1.49 for total mortality.
The AHA cites two analyses of observational studies which found using a
substation analysis that replacing 2% of energy from SFA with the same energy
from TFA increased the risk of CVD mortality by 5% [24]
and 16% [25],
and total mortality by 16% [25]. Even assuming a TFA intake of 4.47% in the
high PUFA group, using the 5% increased risk of CVD mortality with 2% SFA >
TFA substitution results in an amended RR of 1.50 for CVD mortality. So I’ll continue to be generous and use the
16% increased risk to calculate an altered RR in the table below. The RR is still comfortably > 1.00 whether
you assume a TFA intake in the high PUFA group of 2.69% or 4.47%.
TFA intake in
high PUFA group
|
Altered RR for CVD
mortality
|
Altered RR for total
mortality
|
Assume 2.69%
|
1.43
|
1.36
|
Assume 4.47%
|
1.21
|
1.15
|
In summary, in the bottom row
in the table above I’ve granted that Miracle Margarine is 40% TFA (upper-end),
assumed it contributed about 9.18% of total energy intake, granted that the high
PUFA group were only 50% compliant in restricting common margarines and
shortenings, and finally used the most favourable of the AHA’s cited data for
SFA > TFA substitution. After doing
all this to alter the RR to account for potential differences in TFA intake, SDHS
is still an unfavourable study for the diet heart hypothesis!!! This should be a serious wakeup call to the
AHA and other diet heart advocates.
* In her rapid response, Gutierrez
says “the PUFA-supplemented
(intervention) group may have been provided with atherogenic trans fat, and the
investigators cannot prove otherwise” [21]. However, this argument cuts both ways – ‘the
high PUFA group may have had a lower or similar intake of TFA and critics
cannot prove otherwise’ – and is similar to the stupid argument of ‘you can’t
prove that God doesn’t exist’
Total Mortality
The AHA only conducted one
meta-analysis that pooled the primary end-points from each of their core trials,
which includes:
- LAVAT: CVD mortality
- ODHS: the number of participants with total CHD events (doesn’t count multiple events in the same person more than once, and includes ‘soft’ events like angina)
- MRCT: the number of participants with total CHD events
- FMHS: CHD mortality
The figures here are all
correct, even appropriately using the age-adjusted person years in FMHS, which
is actually surprising given the previous meta-analyses
A major issue here is that the
AHA doesn’t conduct a meta-analysis for total mortality. This is important because whole point of
trying to reduce your risk of CHD or CVD is to reduce your overall risk of
morbidity and mortality. One can argue
that the AHA is justified to focus on CHD/CVD since that is the purpose of the
association, but what good does it do to reduce your risk of CHD/CVD if doing
so increases your risk of non-CHD/CVD morbidity and mortality, such that you
would be no better off?
This is particularly relevant
for the AHA’s selection of trials. While
the high PUFA group in LAVAT and FMHS had a lower risk of CHD and CVD mortality
(RR = 0.80 and 0.59), they had a near identical risk of total mortality (RR =
0.98 and 1.01), because non-CHD/CVD mortality was higher [8] [26]. As those trials were both many times larger
than ODHS and MRCT, and therefore have a much larger
weighting, the pooled RR of the AHA’s core trials for total mortality is 0.98 (CI = 0.90-1.07, P = 0.65).
So will replacing SFA with
PUFA reduce your risk of dying? Even
with the AHA’s selection of trials and even while ignoring the major issues in
LAVAT, ODHS and FMHS, the answer is still no.
That is a very well written post. I like the fact that you went into such depth to explain even the smallest of things. Really appreciate your efforts and I know everyone else does too.
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