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Tuesday 23 June 2015

Lee Hooper et al., 2015 - the latest Cochrane meta-analysis of saturated fat reduction RCTs

A new Cochrane meta-analysis of saturated fat reduction trials by Lee Hooper et al. has barely made a splash in the blogosphere, and my mention of it on Twitter barely merited a retweet.
This is a pity, because this is a question that is not really resolved.
A matter of particular interest to me about RCT meta-analysis is whether it agrees with prospective cohort meta-analysis. Another feature of Hooper's work that's instructive, which I intend to discuss, is her ongoing disagreement with Dariush Mozzafarian's analysis of fatty acid substitution.

Reduction in saturated fat intake for cardiovascular disease, The Cochrane Library, June 10 2015. Hooper L, Martin N, Abdelhamid A, Smith GD. DOI: 10.1002/14651858.CD011737

We include 15 randomised controlled trials (RCTs) (17 comparisons, ˜59,000 participants), which used a variety of interventions from providing all food to advice on how to reduce saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of cardiovascular events by 17% (risk ratio (RR) 0.83; 95% confidence interval (CI) 0.72 to 0.96, 13 comparisons, 53,300 participants of whom 8% had a cardiovascular event, I² 65%, GRADE moderate quality of evidence), but effects on all-cause mortality (RR 0.97; 95% CI 0.90 to 1.05; 12 trials, 55,858 participants) and cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 12 trials, 53,421 participants) were less clear (both GRADE moderate quality of evidence). There was some evidence that reducing saturated fats reduced the risk of myocardial infarction (fatal and non-fatal, RR 0.90; 95% CI 0.80 to 1.01; 11 trials, 53,167 participants), but evidence for non-fatal myocardial infarction (RR 0.95; 95% CI 0.80 to 1.13; 9 trials, 52,834 participants) was unclear and there were no clear effects on stroke (any stroke, RR 1.00; 95% CI 0.89 to 1.12; 8 trials, 50,952 participants). These relationships did not alter with sensitivity analysis. Subgrouping suggested that the reduction in cardiovascular events was seen in studies that primarily replaced saturated fat calories with polyunsaturated fat, and no effects were seen in studies replacing saturated fat with carbohydrate or protein, but effects in studies replacing with monounsaturated fats were unclear (as we located only one small trial). Subgrouping and meta-regression suggested that the degree of reduction in cardiovascular events was related to the degree of reduction of serum total cholesterol, and there were suggestions of greater protection with greater saturated fat reduction or greater increase in polyunsaturated and monounsaturated fats. There was no evidence of harmful effects of reducing saturated fat intakes on cancer mortality, cancer diagnoses or blood pressure, while there was some evidence of improvements in weight and BMI.

In other words, no benefit from reducing SFA per se (some non-significant trends towards small benefits) on mortality and hard endpoints such as heart attacks. Non-significant trends and even null associations have been written up here as if they are meaningful. The Cochrane Collaboration surely wouldn't allow this in a review of drug trials, so why is it okay here?
Beneficial association between reduced SFA and cardiovascular events (17% RR), which is dependent on what SFA is replaced with, i.e. only PUFA. Because there is no reduction in individual classes of serious events, it's possible that the symptomatic relief of angina is the main benefit being shown here, but those figures aren't presented. In any case, this is almost certainly an effect of higher PUFA intakes and not SFA reduction.

An interesting point here is that this is the opposite of the prospective cohort data. Jakobsen et al. and Farvid et al. state that replacing SFA with PUFA (5%E) is associated with a 13% lower rate of CHD mortality, yet has (in Farvid et al.) non-significant effects on cardiovascular events in the randomised model. Non-randomised results from Farvid et al.:

“When the highest category was compared with the lowest category, dietary LA was associated with a 15% lower risk of CHD events (pooled RR, 0.85; 95% confidence intervals, 0.78-0.92; I(2)=35.5%) and a 21% lower risk of CHD deaths (pooled RR, 0.79; 95% confidence intervals, 0.71-0.89; I(2)=0.0%). A 5% of energy increment in LA intake replacing energy from saturated fat intake was associated with a 9% lower risk of CHD events (RR, 0.91; 95% confidence intervals, 0.87-0.96) and a 13% lower risk of CHD deaths (RR, 0.87; 95% confidence intervals, 0.82-0.94).”

Results from Jakobsen et al.

“For a 5% lower energy intake from SFAs and a concomitant higher energy intake from PUFAs, there was a significant inverse association between PUFAs and risk of coronary events (hazard ratio: 0.87; 95% CI: 0.77, 0.97); the hazard ratio for coronary deaths was 0.74 (95% CI: 0.61, 0.89).”

Subgroup analysis reveals that this effect on cardiovascular events in Hooper et al. 2015 is specific to PUFA and, though it is related to LDL, it depends on PUFA, not CHO, being the LDL-lowering replacement for SFA.

We found no important effects of reducing SFA compared to usual or control diets on mortality when we subgrouped studies by SFA replacement (with PUFA, MUFA, CHO, or protein), mean duration, baseline SFA intake, or difference in SFA between intervention and control arms, decade of publication, or degree of reduction of serum total cholesterol. "
"There was a reduction in LDL in participants with reduced SFA compared to usual diet (MD -0.19 mmol/L, 95% CI -0.33 to -0.05, I² 37%, 5 RCTs, 3291 participants, P 0.006). There was no clear differential effect on LDL depending on the replacement for SFA (PUFA, MUFA, CHO or a mixture). "

- " the subgroup of studies which achieved a reduction in serum total cholesterol of at least 0.2 mmol/L reduced cardiovascular events by 26%, while studies that did not achieve this cholesterol reduction showed no clear effect."


"When we subgrouped according to replacement for SFA, the PUFA replacement group suggested a 27% reduction in cardiovascular events, while there were no clear effects of other replacement groups."

So - lowering LDL has no association with benefit except when PUFA is increased, and no association with mortality even so.

This is not evidence of harms from SFA. 

This is consistent with an effect of the PUFA foods (possibly confounded by anti-atherogenic effects of their significant alpha-tocopherol, gamma-tocopherol, and Co-enzyme q10 content, and the anticoagulant effects of the hydrogenated vitamin K analogues formed during oil processing) being distinct from the effects of SFA lowering.

A substitution of PUFA for SFA in the context of a diet high in refined carbohydrate, which was the norm for most trials in Hooper at al., would produce a less atherogenic lipoprotein protein - less ApoCIII, for example (See anything by Ron Krauss). You would get the same effect by reducing carbohydrate without cutting SFA (ditto), which is why substitution of PUFA for CHO, even the small increments measured in prospective cohort meta-analysis, shows more benefit than substitution of PUFA for SFA . But substituting PUFA for CHO wasn't the (intentional) plan of any of the studies in Hooper et al. though it may well have happened incidentally as a result of calorie lowering or better food choices due to the educational aspect of these trials. (N.B. trials included were potentially biased by the intervention arms having education and support not available to controls, and by the SFA-lowering advice meaning less cakes, biscuits, more fish, veges, but the Finnish Mental Hospital trial where controls were handicapped by cardiotoxic drugs was excluded - EDITED - Excellent discussion of this paper by Steve Hamley here).

"The number of cardiovascular deaths was relatively small (1096), so while we can be quite confident in reporting a reduction in cardiovascular events (4377 events) with SFA reduction, and a lack of effect on total mortality (3276 deaths) within the studies' time scales, the effect on cardiovascular mortality is less clear. The risk ratio of 0.95 (95% CI 0.80 to 1.12) may translate into a small protective effect, but this is unclear. The lack of effect on individual cardiovascular events is harder to explain; there were 1714 MIs, 1125 strokes and 1348 non-fatal MIs, 2472 cancer deaths, 3342 diabetes diagnoses and 5476 cancer diagnoses. Lack of clear effects on any of these outcomes is surprising, given the effects on total cardiovascular events, but may be due to the relatively short timescale of the included studies, compared to a usual lifespan during which risks of chronic illnesses develop over decades."

By the same token, harmful effects of higher PUFA intakes may also take years to develop.

Where is the table for all-cause non-CHD mortality? Trend for cancer diagnoses = 0.94 (NS), trend for cancer deaths = 1.00 - no sub-group analysis. 

"One surprising element of this review is the lack of ongoing trials. In all previous reviews we have been aware of ongoing trials, the results of which were likely to inform the review, but for this review we have not noted any new trials on the horizon and so perhaps the current evidence set is as definitive as we will achieve during the 'statin era'."

I predict that towards the end of the "statin era" we will begin to see RCTs of LCHF and Paleo diets in the primary and secondary prevention of CVD/CHD. And I predict that, given the very low bar set by SFA restricted diets - which seem here to be not much better for you than the rubbish people normally eat before they end up in hospital, which was after all the composition of the control diets - LCHF and Paleo diets will do pretty well in this regard.

Hooper disputes Mozzafarian's exaggerated analysis still.  "A recent review by Mozaffarian 2010, which again included very similar studies to the last version of this review, with the Finnish Mental Hospital study and Women's Health Initiative data added, stated that their findings provided evidence that consuming PUFAs in place of saturated fat would reduce coronary heart disease. However, their evidence for this was limited and circumstantial, as they found that modifying fat reduced the risk of myocardial infarction or coronary heart disease death (combined) by 19% (similar to our result). As the mean increase in PUFAs in these studies was 9.9% of energy, they infer an effect of increasing PUFAs by 5% of energy of 10% reduction in risk of myocardial infarction or coronary heart disease death. "

According to Hooper's 2010 editorial she thinks this back-dated evidence, from times when PUFA baselines were lower than today, justifies current PUFA intakes - it does not necessarily warrant an increase on the scale suggested by Mozaffarian.

"Mozaffarian and colleagues go further in presenting
their results as a 10% risk reduction for each additional
5% of PUFA consumption, although they present no evidence
of a dose-response relationship (not presenting
subgrouping or meta-regression by PUFA intake) and do
not explain how much of the PUFA consist of ω-3 fats
in each trial.
This review addresses an important question and
re-opening the debate on the effectiveness of replacing saturated
by polyunsaturated fats on coronary heart disease
is very welcome. However, dietary patterns have changed
over the 20–50 years since these studies ware carried out.
It would be useful to examine the full data set, including
more recent trials before concluding, as the abstract does,
that “a shift toward greater population PUFA consumption
in place of SFA would significantly reduce rates of CHD.”
Such a shift has already occurred since these trials were

carried out, and further shifts may be unhelpful."

Hooper L. Meta-analysis of RCTs finds that increasing consumption of polyunsaturated fat as a replacement for saturated fat reduces the risk of coronary heart disease. Evid Based Med2010;15:108–109doi:10.1136/ebm1093.

C-enzyme Q10 and tocopherols as confounders in PUFA oils

Coenzyme Q10 consumption promotes ABCG1-mediated macrophage cholesterol efflux: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers

This shows that consumption of Co-Q10 improves HDL functionality, e.g. is anti-atherogenic. There is likely a separate effect on oxLDL as well.
Dose was 100mg 2x daily.

Vegetable oils are among the richest dietary sources of CoQ10.
the amount is much lower than in the experiment above, but enough to boost intake for most people. Absorption of coenzyme Q10 decreases with increasing supplemental dose.

Do oils raise serum co-Q10 levels?
Serum Co-Q10, alpha-tocopherol, and gamma-tocopherol are associated in women

"CoQ10 was significantly and positively correlated to α- and γ-tocopherol, and BMI was positively associated with CRP and γ-tocopherol in both groups."
Gamma tocopherol is generally considered to be a reliable marker of soy and corn oil consumption; soy and corn oils supply all 3 nutrients. It is most likely that the increase in Co-Q10 has the same origin as the increase in tocopherols. And maybe the same origin as the increased BMI, i.e. those of these oils that are highest in gamma-tocopherol - soy and corn.

Thursday 4 June 2015

Statins and cancer stories - the stupidest thing you'll read this week.

If this isn't the stupidest thing I've read since that "high-protein diets kill mice fed lots of casein, ergo humans shouldn't eat paleo diet (which a priori eliminates casein)" story last week.

Statins 'could halve the risk of dying from cancer'

Apparently, people taking statins have much lower rates of cancer mortality. Cue more research and RCTs aimed at proving a new use for this class of drugs and sell even more prescriptions.

However, there are reasons why this claim (or carefully couched suggestion) amounts to quackery of the "false hope" sort. False hope for gullible GPs especially.

The studies did not show statins would prevent cancer. But they suggest taking them daily could save thousands of lives, by slowing the spread of diseases.
Doctors said it was not clear why they had such an effect, but the drugs reduce cholesterol, which is known to help the spread of disease.

Please do not bang your head quite so hard on your desk, no doctor recommends that (yet).

There are some basic things these "experts", and I use the inverted commas wisely, don't seem to know, or at least don't admit to knowing in a press release.

I summed up two of them in a letter to the Herald yesterday (unpublished so far).

Dear Sir/Ma'am,

According to a study reported in yesterday's Herald, people who take statin drugs are less likely to die from cancer. However, this effect has not been seen in 27 randomised, controlled trials. Statins are prescribed to people with high cholesterol. People with low cholesterol have an increased risk of cancer, and a greatly decreased likelihood of being prescribed statins. This might help to explain what is being presented as a possible protective effect of statins against cancer.

Yours sincerely,

George Henderson

References: (who includes references in letters to the Editor? I do. Maybe that's why they don't get published)

Serum cholesterol and cancer risk: an epidemiologic perspective.

Lack of Effect of Lowering LDL Cholesterol on Cancer: Meta-Analysis of Individual Data from 175,000 People in 27 Randomised Trials of Statin Therapy

I wanted to save space to increase the odds of publication, so left out two other confounders;

1) People who take statins are goodie-goods. If the doctor tells them to take pills, they take them. If the doctor tells them to stop smoking, they stop. And so on. In fact doctors are less likely to prescribe statins to smokers.

2) Lots of people stop taking statins because of their side effects. Side effects - the inability to tolerate statins - could signify underlying diseases of ageing or nutritional deficiencies that also increase cancer risk or mortality.

If statins reduced cancer mortality an effect would be seen in RCTs. Statins cannot reduce cancer mortality by lowering LDL cholesterol, which is a protective risk factor for many common cancers, and for non-coronary mortality in ageing populations.

I'm not ruling out a cytotoxic effect of statins in certain cancers or a potentiating effect with specific cancer meds, but that's not what's being touted here, and were there a general effect of this sort with regard to more common cancers it would have shown in the RCTs.

Monday 1 June 2015

Japanese epidemiology puts another hole in the lipid hypothesis

Everyone is reading this masterful analysis (PDF) of the lipid hypothesis from Japan, a country where it doesn't even seem true, which hasn't stopped the Japanese authorities from recommending cholesterol limits. The whole thing is worth reading, and sections of it are particularly congruent with the reverse lipid hypothesis of hepatology - that saturated fat protects the liver.

That this reversal comes from Japan is particularly interesting, because Japan is the poster boy of the lipid hypothesis - low intake of saturated fat (2.2%E in the Seven Countries Study), low CHD mortality, and has long been used to support the pious hope that if our SFA intakes were only low enough we'd see a comparable reduction in CHD. The reason there's no correlation between SFA and CHD in meta-analysis is, so they say, because we all eat too much SFA, except for the Japanese (oh, and the people of the former USSR and its satellites, who have fantastically high CHD mortality, but let's ignore that). The limbo argument - you can't get under the CHD bar if you're not low enough - is one of those last-ditch defenses of lipid hypothesis epidemiology.
Another is the undisputable truth that in many countries, the ones we know best, CHD mortality did fall at around the same time that SFA intakes declined. Steven Hamley makes the valid point that this SFA was in practice mostly replaced with refined carbohydrate, which no epidemiologist would predict to have lowered CHD based on any data we have. I'll link to this post of Steven's here and recommend regular reading of his blog for anyone interested in this topic.

Here's the mortality trend graph for the USA, typical of NZ, Australia, Canada, Finland and other big dairy and meat countries. SFA goes down a little, CHO goes up, CHD goes down a lot and keeps falling after 1972. Okay.

Here's the same data for Japan.

Ignore the glitch in the coding; it's obvious that CHD mortality fell from about 1970 or 1971. What happened to Japanese fat intake? Saturated fat intake doubled between 1965 and 1975, kept climbing thereafter. Serum cholesterol levels have been going up too.
What we see here is exactly the same CHD mortality pattern in two countries with directly opposing saturated fat and serum cholesterol trends. Two countries which were placed by Keys et al. at opposite extremes, kept apart by their difference in SFA intakes and serum cholesterol.

There are two or three possible explanations. One is that there is an optimal SFA intake, higher than 1965 Japan, lower than 1965 USA, pretty much where both countries are today. This has a certain biological plausibility (though it does require belief in Paleo just-so-stories), but it doesn't match other epidemiology (replacing dietary SFA with CHO elevates serum SFA, reduces LDL particle size, increases CHD events, and doesn't alter CHD mortality. Which higher or lower SFA doesn't correlate with anyway within any population band, be it Japan or Finland).

The second explanation is an improvement in treatment. This is usually countered with the objection that statins weren't available till the 1980's. So - warfarin, nitrates, beta-blockers - were those all being prescribed for no reason? Sure they didn't lower cholesterol, but if that isn't the dominant factor in CHD it's plausible that they had a significant effect as doctors got better at using them.

The third explanation is that this was an epidemic with an unknown or unappreciated cause, and it passed like historical epidemics do. For example, a pathogen wiped out by vaccination or other changes. Smoking, which does fit the trends and which does get some credit. Smog and industrial and agricultural pollution; the mortality trends closely match the beginnings of environmental and workplace regulation of pollutant exposure in both the USA and Japan. Silent Spring was published in 1962 and the period 67-72 represents a tipping point during which restrictions on household smoke, industrial emissions, agricultural residues, workplace exposures, and vehicular emissions began, and after which they became increasingly strict. Another consideration is that 1972 or thereabouts marked the end of national conscription in many western countries. After that date there was a growing expectation that people wouldn't and couldn't be expected to do things any longer if they didn't want to. Turn on, tune in, drop out. The decline of the stress-driven West began, though how this played out in Japan I have no idea. Micronutrition also improved, with the availability of out-of-season foods, new cultivars and imports. Increased PUFA intakes should be seen as part of this trend - the PUFA aspect of the lipid hypothesis was really a proposal for nutrient megadosing to achieve a pharmacological effect not seen, according to Keys et al., with normal intakes of PUFA.

What are we left with today as primary causes of CHD? A significant residue of chemical atherogenesis from pollution and smoking; the effects of malnutrition and the oxidative stress of deficiency, made worse by high-energy diets and the adulterants and contaminants of food processing technology; and above all the effects of metabolic diseases - MetSyn, hyperinsulinaemia, type 2 diabetes, and so on.
The disease patterns of the present are not just those of the past repeated with more or less intensity.