The Lipid Hypothesis – Closing in on the Truth

Today was a big day at the annual conference of the American Heart Association in Chicago. The results of the long and eagerly awaited IMPROVE-IT trial were presented.

You may think IMPROVE-IT is just another ordinary study of the efficacy of a particular cholesterol lowering drug. But it’s more than that because it tests the important and heavily debated lipid hypothesis.

The Lipid Hypothesis - Closing in on the Truth

The lipid hypothesis implies that cholesterol, particularly LDL-cholesterol plays a key role in causing atherosclerosis and coronary heart disease. It means that when it comes to heart disease, measures that elevate blood levels of LDL-cholesterol are usually bad and measures that lower it are good.

Initially, the lipid hypothesis was mainly supported by observational data showing a linear relationship between blood cholesterol and mortality from coronary heart disease (1).

The association between cholesterol and overall mortality appears more complicated. Studies have shown a correlation between cholesterol levels and overall death rate in young and middle-aged people but not among the elderly (2,3). However, the mortality curve appears J-shaped which means that those with the lowest cholesterol levels have increased mortality.

It has also been suggested that the relationship between cholesterol and cardiovascular risk may not be the same for men and women. A Norwegian study (4) found an inverse relationship between cholesterol levels and mortality among women, for whom, according to the authors, moderately raised cholesterol may prove to be not only harmless but even beneficial.

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Intervention Trials

The main limitation of observational studies is that the variable being tested is not randomly distributed. In other words, there may be underlying reasons for high and low cholesterol. In theory, these reasons could affect outcome, and therefore cholesterol might be nothing more than a surrogate.

In controlled intervention trials, a hypothesis is tested using specific methods designed to examine the efficacy of an intervention. Drug trials where half of the patients are treated with a certain drug and half are treated with placebo are a typical example of controlled intervention trials.

In fact, the validity of the lipid hypothesis has been tested in controlled interventional trials.

Lifestyle and Cholesterol

The largest controlled intervention trial on diet and heart disease to date, the Women’s Health Initiative (4) randomly assigned more than 48 thousand women, 50 – 79 years old, to a low-fat intervention or a comparison group. LDL-C was significantly lowered in the intervention group compared to the comparison group. Nonetheless, after six years of follow-up, there were no differences between the groups in the incidence of coronary heart disease and stroke.

The MRFIT trial (5) evaluated 12,866 high-risk middle-aged men who were randomly assigned either to a special intervention program consisting of stepped-care treatment for high blood pressure, counseling for cigarette smoking, and dietary advice for lowering blood cholesterol levels or to their usual sources of health care in the community. LDL-C was significantly lowered in the special intervention group compared to the “usual care” group. However, during a follow-up of seven years, there was no significant difference in total death rates between the groups and no differences in the number of deaths from heart disease.

The results of these two large trials strongly indicate that lifestyle measures aimed at lowering LDL-C do not improve survival or reduce mortality from coronary heart disease.

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12165790_mStatins and Cholesterol

Most experts agree that the use of statins has revolutionized the treatment of coronary heart disease. Double-blind placebo-controlled trials have shown that statins reduce mortality and lower the risk of future cardiovascular events.

Statins effectively lower blood cholesterol, particularly LDL cholesterol.

If the lipid hypothesis is correct, most of the efficacy of statins is due to their cholesterol-lowering effects.

But statins might also work through other mechanisms.

The Jupiter trial (6) suggested that treatment with statins may have beneficial effects on people with relatively low levels of LDL cholesterol. The individuals who participated in this trial all had elevated levels of hs-CRP which is a marker of inflammation.

These results may suggest that cholesterol is only a byproduct and that the efficacy of statins may be explained by other mechanisms, such as reducing inflammation.

Statins are potent inhibitors of cholesterol biosynthesis. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering.

In fact, recent studies (7) indicate that some of the cholesterol-independent or “pleiotropic” effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting blood clotting mechanisms.

Ezetimibe

Ezetimibe is a drug that lowers cholesterol by a mechanism that is very different from that of statins. Ezetimibe blocks the absorption of cholesterol from the small intestine. This leads to an increased availability of LDL-receptors on the surface of cells leading to increased uptake of cholesterol by liver cells and therefore lowering of blood cholesterol levels.

When added to statin therapy ezetimibe generally lowers cholesterol by an additional 20-25% over the statin alone.

In the US ezetimibe is marketed by Merck as Zetia (ezetimibe alone) and Vytorin (ezetimibe in combination with a statin called simvastatin).

The IMPROVE-IT Trial

The IMPROVE-IT study tested the hypothesis that further lowering of LDL cholesterol by adding ezetimibe to statin therapy in patients with coronary artery disease will improve outcome.

IMPROVE-IT began enrolling patients with acute coronary syndrome in 2005. It was designed to evaluate the effects of concomitant simvastatin and ezetimibe therapy compared to simvastatin therapy alone on the composite endpoint of cardiovascular death, nonfatal myocardial infarction, rehospitalization for unstable angina, coronary revascularization, or stroke.

A total of 18,144 high-risk patients were randomized within ten days of an acute coronary event to either ezetimibe or placebo on top of a statin. The patients had LDL cholesterol levels between 50-125 mg/dL (1.3-3.2 mmol/L), or between 50-100 mg/dL 1.3-2.6 mmol/L) if already on a cholesterol lowering drug. The average LDL cholesterol at baseline was 95 mg/dL (2.5 mmol/L).

The average age of the patients was 64, and about a fourth were women. Patients were followed for an average of six years. There were 5,250 primary endpoint events (cardiovascular death, myocardial infarction, hospital admission for unstable angina, coronary revascularization more than a month after randomization, or stroke).

Primary endpoint events occurred in 34.7% of the control group versus 32.7% of the treatment group. This represents a 6.4% relative risk reduction and a 2% absolute risk reduction. This means that 50 patients would need to be treated for seven years to prevent one event. Interestingly 49 out of 50 patients treated saw no benefit.

There was no difference between the groups in overall death rate or death rate from cardiovascular disease, but there were significant reductions in the rate of myocardial infarction (13%, p =0.002), stroke (14%, p=0.052), and ischemic stroke (21%, p=0.008). The effect was similar across subgroups, except for diabetics, who had a larger benefit than those without diabetes.

As expected, LDL cholesterol was significantly lowered in the treatment arm; median levels were 69.9 mg/dL (1.8 mmol/L) in the control group versus 53.2 mg/dL (1.4 mmol/L) in the treatment group. No safety issues were found, and there were no differences between the groups in cancer, muscle or gall-bladder related events.

Thus, although the effect was modest, the results of the IMPROVE-IT trial suggest that lowering cholesterol more than can be achieved with statins may improve clinical outcome.

Interestingly, however, in this high-risk group, the lowering of LDL cholesterol did not significantly affect mortality. Furthermore, 98 percent of the patients didn’t benefit from treatment.

Anyhow, there is no denying that the lipid hypothesis is still alive and well.

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bhrdoc
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bhrdoc

Nice summary Axel. I am bothered by the fact that 42% of subjects dropped out of the trial. I wonder if the results would have been larger (or smaller) were that not the case.

Axel F Sigurdsson
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Axel F Sigurdsson

I agree Barbara. It’s a large percentage. I think a secondary analysis, addressing the results of only the patients who stayed on the study drug, is scheduled for presentation at the AHA meeting tomorrow.

Mie
Guest
Mie

It is surprisingly large, indeed. However, it seems there was no significant difference between the control and the treatment arm in this sense?

Axel, anything on the per protocol analysis?

Gina
Guest
Gina

Wondering if I should take the Lipitor my doc wants me to take. Female, age 49. 5’5 128lbs., nonsmoker, nondrinker, exercise (cardio and strength) 5-6 days a week. LDL-P 2,283. LDL-C 126, hDL 56. No other risk factors other than genetics. Will be able to send all numbers when I return home to view. My dad takes a statin.

Laura Schultz Jaymes
Guest

Gina, I hope you were not “talked into” taking a statin. There is NO reason for you to alter your LDL and HDL through drug use. Your cholesterol markers are bad due to your diet; Too many carbs and not enough fat. Grains are especially problematic. Grains turn to sugar, and your numbers show you are eating too many. Statins are no the answer and SHAME ON YOUR DOC for suggesting them. The side effects of statins are awful, not to mention they have been known to cause heart disease. Please go to FB and check out a few pages… Read more »

RichardOrnishForLife
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RichardOrnishForLife

Axel, thanks for the article, I like particularly the last line 🙂 But, I am cannot help being puzzled. What do you mean when you write that LDL was significantly lowered in the WHI study? Have either you or I missed something? The study authors write the following: “Because there are no apparent changes that would have mitigated a potentially favorable effect on CVD, the lack of an appreciable CVD effect maybe attributable to the limited decrease (only 2.7 mg/dL [0.07 mmol/L]) in LDL-C level, as well as the modest differences in other potentially favorable dietary components. Based on a… Read more »

Axel F Sigurdsson
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Axel F Sigurdsson

Yes, In the WHI trial LDL was significantly lowered in the treatment arm, just take a look at the abstract: Low-density lipoprotein cholesterol levels, diastolic blood pressure, and factor VIIc levels were significantly reduced by 3.55 mg/dL, 0.31 mm Hg, and 4.29%, respectively;

You may argue that the effect on LDL cholesterol was small. That’s fine and I agree.

But you asked what I meant. I only meant it was statistically significant. And it was.

RichardOrnishForLife
Guest
RichardOrnishForLife

Ok Doc, thanks for the explanation. It just that the LDL hypothesis is not about statistically lower LDL as such, it’s about lowering LDL meaningfully. This is at least how I understand it. I have 3 more points: 1) Almost every health parameter show more or less J or U-shaped-curve: BMI, blood-pressure, alcohol intake, possible even glucose levels. I think this is an important issue to point out. Old people with cancer and other chronic disease often looses radically weight at the last years. While predisposing to death they have low blood-pressure and very low BMI. However, we should be… Read more »

Mark Rossow
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Mark Rossow

I readily grant that I may be missing something here, but if

1. There was no difference between the groups in overall death rate, or death rate from cardiovascular disease,

2. There were significant reductions in the rate of myocardial infarction, stroke, and ischemic stroke in the treatment group, and

3.No safety issues were found and there were no differences between the groups in cancer,

then what cause of death increased in the treatment group, so that that group died at the same rate as the control group?

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Mark
I assume the reductions in MI and stroke were reductions in non-fatal events.
You’re right, overall mortality and cardiovascular mortality were similar in both groups.
We therefore have to assume that mortality from non-cardiovascular causes was similar as well.

Erik Arnesen
Guest

The difference in LDL-c in MRFIT was also very small between the groups, and the mortality rate was so low that it was greatly underpowered. Besides, some of the participants were already on cholesterol-lowering diets, unlike e.g. the Oslo study.

Anyway, I don’t think the findins on Ezetimibe will change much in practise, it is already routinely used. But it supports the lipid hypothesis, and the results from PSCK9-inhibitor studies may bolster it further.

Axel F Sigurdsson
Admin
Axel F Sigurdsson

I wonder if the small effect on LDL cholesterol seen in the WHI and MRFIT reflects what can be achieved by lifestyle intervention in terms of lowering LDL cholesterol. In other words; targeting LDL cholesterol through diet will not affect LDL cholesterol enough to be clinically meaningful (unless everybody goes “Ornish”). Obviously dietary choices will never get our LDL cholesterol levels as low as statins and PCSK9-inhibitors can. So, when it comes to lowering of LDL cholesterol, lifestyle measures don’t stand a chance. So, the survival of the lipid hypothesis will continue to be the lifeblood of the pharmaceutical industry… Read more »

Eliot
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Eliot

Are there any studies underway on PCSK-9 alone? I have only seen those in combination with statins. Seems like that would put the controversy to rest once and for all.

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Elliot
All the ongoing trials on people with known cardiovascular disease are with PCSK9-inhibitors added to statin therapy. It’s not considered ethical to not give statins in this population.
There are probably some ongoing studies on PCSK9 inhibitors alone in other populations. For example it has been suggested that PCSK9 inhibitors may be useful in those who are statin intolerant.

RichardOrnishForLife
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RichardOrnishForLife

Doc, “In other words; targeting LDL cholesterol through diet will not affect LDL cholesterol enough to be clinically meaningful (unless everybody goes “Ornish”)”. This seems plausible. However, it’s about the cumulative burden. Modest changes in diet will yield modest changes in lipid profile. The intake of SFA at the highest quartile of consumption in rural Japan of the 1970s was 3 grams less per day compared to the lowest quartile of consumption in Nurse’s health study. The mean age at the randomization in statin trials is 63 and the mean duration few years. I think the same goes for diet… Read more »

Gudmundur Johannsson
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Gudmundur Johannsson

I do not agree with your comment: “targeting LDL cholesterol through diet will not affect LDL cholesterol enough to be clinically meaningful (unless everybody goes “Ornish”).” On the contrary, LCHF can have a remarkable impact on LDL in patients with metabolic syndrome. Total chol. 7.12 3.89 HDL 1.08 1.25 TG 2.76 1.15 LDL 4.8 2.1 A familiy physician in Iceland with a history of CVD and metabolic syndrome published an article in one of the newspapers where he described his experience with LCHF. The table above shows his labresults before and after. The column on the left is from the… Read more »

Axel F Sigurdsson
Admin
Axel F Sigurdsson

You’re right Gudmundur. Thanks. I realize I didn’t make myself clear enough. Of course I too have seen people influence their LDL cholesterol levels through diet. I was merely referring to the clinical trials where it has turned out be difficult to get a meaningful lowering of LDL cholesterol through lifestyle or dietary measures, at least if you compare it to the effect of statins On the other hand we should keep in mind that risk can be influenced without lowering LDL-cholesterol. Remember the LYON-Heart study were men with coronary artery disease who were randomized to a Mediterranean diet fared… Read more »

Erik Arnesen
Guest

Regarding the Lyon study – according to the 1999 paper, high cholesterol and blood pressure were indeed significant predictors of events. “… each increase of 1 mmol/L of total cholesterol increased the risk of recurrence by 20% to 30%”.

So, “neither the Mediterranean dietary pattern nor any major bias has altered the usual and expected relationships between the major risk factors of CHD and recurrence.”

George Henderson
Guest
George Henderson

The low LDL levels in these patients at baseline seem to suggest that coronary cases already have lower LDL than the healthy population of the same age.

Erik Arnesen
Guest

Perhaps reverse causation – their LDL levels was low because of the disease. Anyway, LDL cholesterol is a modest *biomarker* of risk, but that doesn’t mean it’s not a necessary cause of atherosclerosis. «The causes of vascular disease are weak risk factors for vascular disease»: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244267/

Mie
Guest
Mie

Err, you do realize that the article you linked puts the focus on LDL & other classical risk factors, stating that age as a risk factor needs to be considered differently than now, from the point of view of cumulative risk due to life-long high LDL levels?

“On the contrary, we will try to demonstrate that the reason that the causes of vascular disease are weak risk factors for clinical events is primarily a function of how we treat age as a determinant of vascular disease”

And “modest”, please.

Mie
Guest
Mie

Arghh, goddamn I suck at reading! I failed to notice the word “not” in this

“but that doesn’t mean it’s not a necessary cause of atherosclerosis”

part of your message. Scratch my message above, will you. Please. 🙂

George Henderson
Guest
George Henderson

I think the word “cause” and the notion of causality is fooling us here.
If you drive drunk and crash your car, you are more likely to die going 100k than going 90k.
But the primary cause of your death is surely the decision to drive drunk, and the immediate cause is losing control (probably because you’re drunk).
This sort of confusion is why epidemiologists use the criteria defined by Bradford Hill back in the 60s.
Applying these criteria to diet isn’t done often enough, but this is an example.
https://www.dcscience.net/mente-aim-2009.pdf

Axel F Sigurdsson
Admin
Axel F Sigurdsson

George
IMPROVE-IT selected patients with LDL cholesterol below 125 mg/dl (3.2 mmol/L) or below 100 (2.6 mmol/L), i.e. patients with higher LDL cholesterol levels were excluded.
These were the two main inclusion criteria:
1. Clinically stable subjects may be eligible to enroll within 10 days following hospital admission with high-risk acute coronary syndrome (either STEMI or Non-STEMI or unstable angina)
2. Subjects not taking a statin must have an LDL-C of 125 mg/dl or less. Subjects taking a statin must have an LDL-C of 100 mg/dl or less.

George Henderson
Guest
George Henderson

Thanks!

If CHD hits people with already low LDL, then either it’s specific to a type of LDL (pattern B, small dense or whatever) and/or LDL is not causal, but is taken hostage by the disease process at any concentration, with slight reductions in its involvement as levels drop.

Do we know anything about changes in other risk factors? TG/HDL ratio? ApoA/B?

“Ezetimibe also significantly improved levels of plasma total cholesterol, apolipoprotein B, high-density lipoprotein(2)-cholesterol and lipoprotein(a), and elicited a trend toward lower triglyceride levels.”

https://www.ncbi.nlm.nih.gov/pubmed/12713767

If that’s so, the jury is still out on LDL level per se.

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Thanks George
You’re probably right; the jury’s still out on LDL cholesterol per se.
Triglycerides were lowered and HDL cholesterol was raised by ezetimibe in IMPROVE-IT. So, we can’t exclude the possibility that this could partly explain the effect of the drug. There’s no proof that it’s only due to lowering of LDL cholesterol.

michael goroncy
Guest
michael goroncy

Yo! Axel
I am not good at maths….you wrote “. The patients had LDL cholesterol levels between 50-125 mg/dL (1.3-3.2 mmol/L), or between 50-100 mg/dL 1.3-3.2 mmol/L) “…This is ‘black magic’ or incorrect.
50-100 mg/dL should read 1.3-2.56 mmol/L.

An RCT separating ‘Primary care’ and ‘Secondary care’ would be useful.
The anti-inflammatory and Nitric oxide effects of Statins has been known for many years.

BTW: Why do the Americans keep using the ‘imperial system’ which frustrates the shit out of most people having to convert. Perhaps their general population are not capable.
There are only 2 other Countries that use this method….Liberia and Myanmar(Burma).

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Michael.
I’ll correct this error.
Thanks for reading so thoroughly.

mo Ab
Guest
mo Ab

michael, why do we call them Freedom Fries rather the French Fries/pomme frittes?

Jim Ford
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Jim Ford

You wrote: “but there were significant reductions in the rate of myocardial infarction (13%, p =0.002), stroke (14%, p=0.052), and ischemic stroke (21%, p=0.008)”

Are those relative or absolute reductions?

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Jim.
These numbers were presented as relative risk reductions.

Andrés
Guest
Andrés

There are some errata about the “significant reductions”. From CardioSource: Other endpoints including MI (13.1% vs. 14.8%, p = 0.002), stroke (4.2% vs. 4.8%, p = 0.05), ischemic stroke (3.4% vs. 4.1%, p = 0.008), and CV death/MI/stroke (20.4% vs. 22.2%, p = 0.003) were all significantly lower in the ezetimibe/simvastatin arm; They also say (just to add the numbers): no differences were noted for all-cause mortality (15.4% vs. 15.3%, p = 0.78), CV mortality (6.9% vs. 6.8%, p = 0.99) and need for coronary revascularization (21.8% vs. 23.4%, p = 0.11). And as stated by bhrdoc: Premature discontinuation was… Read more »

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Thanks Andrés
Appreciate the details. However I wonder; where’s the errata?

The relative risk reduction presented was 13% for MI, 14% for stroke and 21% for ischemic stroke. You’ll find it on Medscape/Heartwire and also in Larry Husten’s summary.

I know you’ll not get exactly the same results (but close) if you calculate from the numbers you provided from CardioSource which is probably because they’re lacking decimals.

Andrés
Guest
Andrés

Oops! The erratum was on my mental syllogisms. I was thinking that to give rise to a meager overall 6.4% reduction in the primary endpoint those relative risk improvements should be lower. My fault. Curious how everyone of them is higher than computed from the absolute risk numbers though. Even more. In the MI case if we take the numbers of absolute risk with one more digit favoring a higher relative risk reduction so 13.05% (instead of 13.1%) versus 14.85% (instead of 14.8%) it gives rise to a relative risk reduction of (14.85-13.05)/14.85=12.12% still lower than 13%. It doesn’t put… Read more »

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Andrés.
I agree, difficult to get exactly the same numbers for relative risk reduction when you calculate from the numbers provided. But I guess that’s a minor issue and has some hidden explanations, maybe as I suggested partly because of the decimals.
I tend to agree with you also on the general result, modest at best. And the lack of effect on mortality is quite disappointing in such a large study.

Mie
Guest
Mie

Axel,

“I tend to agree with you also on the general result, modest at best. And the lack of effect on mortality is quite disappointing in such a large study.”

Well, since the statin-only arm had very low LDL, too, it’s kinda to be expected that the differences wouldn’t be that dramatic.

RichardProOrnish
Guest
RichardProOrnish

George, that was a bizarre conclusion. The people who have low LDL in Western socities and have not yet gone through cardiadic event are the ones that are terminally ill or have been put on statins due to preventative measures. The latter group have often received statins due to chest pains. Cholesterol levels are quickly reduced, but the existing atheroma plaque is not. Moreover, as these Swedish researchers observered, LDL levels decline temporarily after MI. This trial was about people who were assigned to the trial immeadiately after their first cardiadic event. https://www.lakartidningen.se/Functions/OldArticleView.aspx?articleId=14031 Erik, right on. Whether LDL predicts risk… Read more »

George Henderson
Guest
George Henderson

HDL predicts risk and can be modulated to improve prognosis by Mediterranean diet, with better results than lowering LDL by drugs. Probably other diets too – LCHF is pretty good for moving this marker too, but hasn’t been trialed for CHD like Med has. Drugs that move HDL are hopeless (this includes high intakes of alcohol), but drugs, for obvious reasons, have never proved anything about diet. If low LDL is reverse causation by these patients being aware of ill health and trying to improve prognosis before the event, were their other risk factors also better than those of the… Read more »

Rafał Bigda (fifek)
Guest

Very interesying article, dr Sigurdsson! But what about obesity survival paradox, where hypercholesterolemia, obesity and high blood pressure are inverserly corellated to outcome in patients with chronic heart failure?
https://www.sciencedirect.com/science/article/pii/S073510970400172X

Dr Dave Morris
Guest
Dr Dave Morris

So lest check in with who did this research in the first place becasue one thing there is categorical evidence for is overwhelming disotrtion and bias from drug companies making it fundamentally untrustworthy unelsss we can fine tooth comb the original data – the drop out rate alone makes this suspiscious to say the least. But then even if we are being charitable what do we ultimately find – no evidence of reduction in mortality – so what’s the point? Your death certificat date stays the same. So maybe you will have reduced MI’s but you also will have increased… Read more »

davebrown9
Guest
davebrown9

“The lipid hypothesis implies that cholesterol, particularly LDL-cholesterol plays a key role in causing atherosclerosis and coronary heart disease. It means that when it comes to heart disease, measures that elevate blood levels of LDL-cholesterol are usually bad and measures that lower it are good.” The use of statins to lower cholesterol may not seem to cause harm beyond the usual side effects. However, the still oft-repeated warning to replace saturated fats with polyunsaturated oils causes considerable harm. Excerpts from page 18 of “Health Preserver : Defining the Versatility of Vitamin E” by Wilfred Shute, MD, 1977: “I … believe… Read more »

RichardOrnishForLife
Guest
RichardOrnishForLife

Davebrown9, I am an “Ornish-head” and follow the Ornish diet to keep my LDL within physiologic range, <1,8mmol (69,6mg/dl). I prefer tahini on my rye bread. However, Ido consume regularly but sparingly canola-oil based margarine. Given the 100 years worth progressive research into diet-heart, I think that skipping the animal fats is a no brainer. Age-adjusted CHD mortality fell around 80% in both Finland and New Zealand starting from the 1970s. This was explained by the change in mean cholesterol levels over few decades (the change occurred prior the wide-scale adoption of statins). The most important dietary change that took… Read more »

George Henderson
Guest
George Henderson

Butter was 4.8% of fat calories in the USA in 1954, according to Ancel Keys – unlikely to be a big contributor to CHD there.
In New Zealand almost all butter (a lot) was eaten on white bread or in biscuits and cakes (4oz butter, 4oz sugar, 4oz flour and an egg).
This is a bit different from cooking spinach in butter or putting sauce bearnaise on a steak. It’s even different from bulletproof coffee.

davebrown9
Guest
davebrown9

@Richard While CHD mortality has dropped substantially in many developed countries, morbidity remains extremely high compared to the pre-omega-6 industrial seed oil era. I suspect that the Ornish low-fat approach restricts the absolute amount of omega-6 to where it furnishes substantial protection from CHD. As for me, I have been consuming between 2 and three pounds of butter a week for several decades; this in addition to full-fat dairy products of all sorts including two gallons of raw, whole milk per week. I’m considerably healthier than I was 7 years ago when I was still consuming peanut butter sandwiches for… Read more »

Someone
Guest
Someone

Thanks for the artcile, and keeping us up to date 🙂

Did I understood this correctly:

“this leads to an increased availability of LDL-receptors on the surface of cells leading to increased uptake of cholesterol by liver cells and therefore lowering of blood cholesterol levels”

So in practise does this then also mean that number of LDL particles in the blood stream is reduced by ezetimibe ?

All in all, effects are still quite limited as long as there isn’t any reduction death rates.

Is there any known remarkable side effects known for ezetimibe ?

Axel F Sigurdsson
Admin
Axel F Sigurdsson

You’re welcome Someone
Ezetimibe seemed to be well tolerated in this particular study.
You’re right. In theory ezetimibe should lower LDL particle number as should statins. However, ezitimibe is a very weak LDL-lowering agent compared to statins.

Stephen H. Li
Guest
Stephen H. Li

Thanks for all your work Doc Axel.

Which has the stronger anti-inflammatory effects, statins or ezetimibe?

Could too much dose intake of ezetimibe, possibly lead to increased internal bleeding?

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Stephen
Haven’t heard or read that internal bleedings are a problem with ezetimibe.
Statins have an anti-inflammatory effect. To my knowledge ezetimibe has no such effect.

RichardOrnish4life
Guest
RichardOrnish4life

Doc, will ezetemibe be back in your arsenal of drugs after the positive trial that demonstrated a benefit even when compared to a group with already very low cholesterol levels? Dave, what do you mean with morbity? A significant decline in serum cholesterol, and mortality from cardiovascular disease and all-causes in former communist nations of Eastern Europe took place beginning in the early 1990’s when the communist subsidies on meat and animal fats were abolished after the breakup of the Soviet Union. Likewise, the significant decline in serum cholesterol, and mortality from cardiovascular disease and all-causes in the pre and… Read more »

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Richard.
Ezetimibe has always been in my arsenal of drugs. We use it primarily in patients with severe hypercholesterolemia who don’t reach targets by statins alone.

davebrown9
Guest
davebrown9

Richard, Morbidity refers to the incidence of disease. Mortality refers to the death rate from disease. Mortality in Finland declined dramatically but both CHD morbidity and mortality remain unacceptably high as is true in all developed countries. To me it’s clear that the novel dietary factor that contributes most to morbidity and mortality is still being ignored. Interestingly, the edible oils industry has taken steps to reduce the omega-6 linoleic acid content of the food supply so as to make frying oils last longer. Excerpt: “High oleic oil is any oil that is high in monounsaturated fats. Olive and canola… Read more »

George Henderson
Guest
George Henderson

The latest Finnish study (KIHD) shows no correlation between saturated fat and CHD mortality or events even in a population where some people are eating a LOT of it (mostly dairy).
But there is a protective effect of PUFA (canola and fish) whether it replaces SFA or carbohydrate in the diet. Up to about 5%E, not much difference above that. Easy to get 5% PUFA on a LCHF diet.
https://www.ncbi.nlm.nih.gov/pubmed/25256234

Mie
Guest
Mie

George,

it’s probably not surprising that SFA isn’t problematic when considered in isolation, that is, without any regard on what it’s replacing? The whole point is – and has been – that PUFA is the better option.

George Henderson
Guest
George Henderson

True Mie,
PUFA is the better option for CHD mortality (at least in epidemiology, not so much in RCTs), but makes no difference to overall mortality (meaning that if it prevents CHD deaths, it is also causing non-CHD deaths).
However, PUFA is also the better option to carbohydrates; in fact, replacing 5%E from carbohydrate with 5%E from linoleic acid is slightly better than replacing SFA.
https://www.epccs.eu/d/386/high-dietary-linoleic-acid-intake-associated-with-lower-risk-of-coronary-heart-disease-events

Generally anyone switching to a LCHF diet is going to get more PUFA and less carbohydrate. If the goal is to treat CHD, it currently looks as if a Mediterranean type LCHF diet is best.

Mie
Guest
Mie

“PUFA is the better option for CHD mortality (at least in epidemiology, not so much in RCTs), but makes no difference to overall mortality (meaning that if it prevents CHD deaths, it is also causing non-CHD deaths).” First of all, there’s trial evidence of better CHD health too, not necessarily mortality-specific as e.g. the effects of exhange on e.g. lipid levels aren’t necessarily that high, trial populations heterogenous etc. Second of all, if tot. mortality doesn’t change, it doesn’t (necessarily) mean that PUFA causes non-CHD. This needs to be shown specifically, it cannot be deduced from trials powered mainly in… Read more »

George Henderson
Guest
George Henderson

True, that would need to be tested separately. The current finding is that the whole policy of switching SFA for PUFA has this effect, not the individual components.
The outlier study, Mann et al. 1997, suggests that it is in fact the restriction of animal fat, cholesterol, and SFA that is strongly (and specifically) associated with increased non-CHD mortality, rather than the PUFA.
This is about mortality not events, the effect is strong and significant, and death has been found to be diagnosed with more certainty than other endpoints,

RichardOrnishForLife
Guest
RichardOrnishForLife

George, there are several issues why it is hard to show an effect on SFA to CHD within a homogenous population where everyone eats a high fat diet. One of them is inter-individual variation (not to be consumed with intra-individual variation which refers to regression dilution bias). Interindividual varition; individual differences in the response to the dose The differences in fat intake are usually minor in homogeneous cultures. However, the cholesterol levels in every population follows a normal distribution: a same diet will lead to wide variety of cholesterol levels between individuals, even though everything else is kept constant. If… Read more »

George Henderson
Guest
George Henderson

To believe in an effect of SFA, considered monotonically and not as a component of an unhealthy food (e.g. a donut), even when powerful data sets don’t show it, is the opposite of causality. The presumption of causality in epidemiology is based – among other things – on the STRENGTH of the association – in part because error will exist (and not just in the one direction that you’d like it to exist). There is also the question of dose-response. If people eating twice as much SFA in a homogenous population (this was the difference between upper and lower quartiles… Read more »

RichardOrnishForLife
Guest
RichardOrnishForLife

George, there’s not a single serious lipid researchers who keeps touting about lipoprotein sub-types. The sub-fraction talk comes from the low-carb echo-chamber aided by those wishing to selling expensive lab services to ill-informed. Unfortunately, I cannot reply in you properly, have a work to do: “All of this was exciting because, as cardiac geneticist Sekar Kathiresan says, “If there’s one thing in medicine that’s certain, it’s that LDL causes heart attack”. https://www.cureffi.org/2014/11/19/primer-on-pcsk9-genetics/ The 7CS study revealed that if you 100 people ingesting the same diet, the median cholesterol will be higher in the population that consume more SFA (inter-individual variation… Read more »

George Henderson
Guest
George Henderson

So here we have a decision to make. We can dismiss research into lipoprotein subclasses as having no bearing on one’s risk of heart disease because they are costly to test (even though LDL/HDL and TG/HDL are fairly good cheap proxies) and because they would imply a benefit for LCHF (which we will still see on a standard obsolescent lipid panel anyway). Or, we can throw away everything but the LDL and total cholesterol readings on the vintage lipid panel and while we’re at it ignore the protective associations for high LDL in older people who don’t have CAD or… Read more »

RichardOrnishForLife
Guest
RichardOrnishForLife

Yes, the longest-living people seem to all come within cultures with the highest sugar intake. These countries also have the most dense network of McDonalds outlets. Do you think there’s something else going on, such as high infant mortality in less developed nations? Not to speak of state-of-the art medicine. Life saving drugs such as Ezetimibe are widely available in developed nations. I’ve never really understood the infatuation with mortality within the low-carb echo-chamber. Doesn’t the quality of life mean anything? Speaking of mortality and diet you should check the blue zones. As a rule people in these cultures eat… Read more »

George Henderson
Guest
George Henderson

The prospective benefits of high LDL in people without pre-existing disease kick in when they are in their mid-50s in some studies. Does fast food prolong life? Well, if it’s low in saturated fat and high in sugar and PUFA, then cholesterol would be lower, wouldn’t it? I don’t discount the possibility that lowering LDL by eating a plant-based diet protects against CHD, if your gut will tolerate that sort of food and you can derive nutrition from it. The problem is twofold. One, this is probably not a diet that helps prevent any other disease. Two, most people with… Read more »

Mie
Guest
Mie

George,

all LDL subtypes are atherogenic in large quantities. And they are affected by different fats, too, BTW.

And I don’t think anyone is suggesting throwing away everything in risk prediction but LDL and/or tot. cholesterol, especially as there are quite a few people (met. syndrome/DM2 patients) who often have discordance in the sense that despite lower LDL count – compared to people without the aforementioned conditions – they still have higher risk of CVD.

George Henderson
Guest
George Henderson

Right, I am of course responding to RichardOFL’s reductio ad absurdum rather than making a position statement. It is rather well known that the Ornish diet lowers HDL. If RichardORL thinks that LDL is the only marker we should bother about – well, he would wouldn’t he? No doubt there is an echo chamber somewhere for that. The HDL effect seems to be depended on the functionality of HDL in reverse transport https://www.nejm.org/doi/full/10.1056/NEJMoa1409065 “HDL has numerous antiatherosclerotic actions that are not readily reflected by HDL cholesterol levels. A key function of HDL is to promote reverse cholesterol transport from the… Read more »

Mie
Guest
Mie

George,

from what I’ve gathered, HDL functionality isn’t necessarily independent of HDL-C in all cases. That is, the lower the HDL levels, the less functional HDL seems to be. In some cases, at least.

In addition, certain conditions, e.g. DM2, impair HDL functionality.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332215/

And certain dietary choices,

https://www.ncbi.nlm.nih.gov/pubmed/16904539

https://www.ncbi.nlm.nih.gov/pubmed/12489064

https://www.fabresearch.org/viewItem.php?id=9189

RichardOrnishForLife
Guest
RichardOrnishForLife

Guys,

ex low-carber Doc, Spencer Nadolsky is doing a month full n=1 vegan trial and with fancy (and expensive) lipid tests. Should be interesting. Perhaps Axel-Doc could try out a similar dietary routine as well.
https://www.facebook.com/DrSpencerNadolsky/posts/882519015114850

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