The straight dope on cholesterol – Part IX - Attia

 Peter once again provides an excellent summary and then proceeds into Part 9 of his cholesterol tome.
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The straight dope on cholesterol – Part IX

Previously, across 8 parts of this series we’ve laid the groundwork to ask perhaps the most important question of all:

What should you eat to have the greatest chance of delaying the arrival of cardiovascular disease?

Before we get there, since this series has been longer and more detailed than any of us may have wanted, it is probably worth reviewing the summary points from the previous posts in this series (or you can just skip this and jump to the meat of this post).

What we’ve learned so far

1. Cholesterol is “just” another fancy organic molecule in our body but with an interesting distinction: we eat it, we make it, we store it, and we excrete it – all in different amounts.
2. The pool of cholesterol in our body is essential for life. No cholesterol = no life.
3. Cholesterol exists in 2 forms – unesterified or “free” (UC) and esterified (CE) – and the form determines if we can absorb it or not, or store it or not (among other things).
4. Much of the cholesterol we eat is in the form of CE. It is not absorbed and is excreted by our gut (i.e., leaves our body in stool). The reason this occurs is that CE not only has to be de-esterified, but it competes for absorption with the vastly larger amounts of UC supplied by the biliary route.
5. Re-absorption of the cholesterol we synthesize in our body (i.e., endogenous produced cholesterol) is the dominant source of the cholesterol in our body. That is, most of the cholesterol in our body was made by our body.
6. The process of regulating cholesterol is very complex and multifaceted with multiple layers of control. I’ve only touched on the absorption side, but the synthesis side is also complex and highly regulated. You will discover that synthesis and absorption are very interrelated.
7. Eating cholesterol has very little impact on the cholesterol levels in your body. This is a fact, not my opinion. Anyone who tells you different is, at best, ignorant of this topic. At worst, they are a deliberate charlatan. Years ago the Canadian Guidelines removed the limitation of dietary cholesterol. The rest of the world, especially the United States, needs to catch up. To see an important reference on this topic, please look here.
8. Cholesterol and triglycerides are not soluble in plasma (i.e., they can’t dissolve in water) and are therefore said to be hydrophobic.
9. To be carried anywhere in our body, say from your liver to your coronary artery, they need to be carried by a special protein-wrapped transport vessel called a lipoprotein.
10. As these “ships” called lipoproteins leave the liver they undergo a process of maturation where they shed much of their triglyceride “cargo” in the form of free fatty acid, and doing so makes them smaller and richer in cholesterol.
11. Special proteins, apoproteins, play an important role in moving lipoproteins around the body and facilitating their interactions with other cells. The most important of these are the apoB class, residing on VLDL, IDL, and LDL particles, and the apoA-I class, residing for the most part on the HDL particles.
12. Cholesterol transport in plasma occurs in both directions, from the liver and small intestine towards the periphery and back to the liver and small intestine (the “gut”).
13. The major function of the apoB-containing particles is to traffic energy (triglycerides) to muscles and phospholipids to all cells. Their cholesterol is trafficked back to the liver. The apoA-I containing particles traffic cholesterol to steroidogenic tissues, adipocytes (a storage organ for cholesterol ester) and ultimately back to the liver, gut, or steroidogenic tissue.
14. All lipoproteins are part of the human lipid transportation system and work harmoniously together to efficiently traffic lipids. As you are probably starting to appreciate, the trafficking pattern is highly complex and the lipoproteins constantly exchange their core and surface lipids.
15. The measurement of cholesterol has undergone a dramatic evolution over the past 70 years with technology at the heart of the advance.
16. Currently, most people in the United States (and the world for that matter) undergo a “standard” lipid panel, which only directly measures TC, TG, and HDL-C. LDL-C is measured or most often estimated.
17. More advanced cholesterol measuring tests do exist to directly measure LDL-C (though none are standardized), along with the cholesterol content of other lipoproteins (e.g., VLDL, IDL) or lipoprotein subparticles.
18. The most frequently used and guideline-recommended test that can count the number of LDL particles is either apolipoprotein B or LDL-P NMR, which is part of the NMR LipoProfile. NMR can also measure the size of LDL and other lipoprotein particles, which is valuable for predicting insulin resistance in drug naïve patients, before changes are noted in glucose or insulin levels.
19. The progression from a completely normal artery to a “clogged” or atherosclerotic one follows a very clear path: an apoB containing particle gets past the endothelial layer into the subendothelial space, the particle and its cholesterol content is retained, immune cells arrive, an inflammatory response ensues “fixing” the apoB containing particles in place AND making more space for more of them.
20. While inflammation plays a key role in this process, it’s the penetration of the endothelium and retention within the endothelium that drive the process.
21. The most common apoB containing lipoprotein in this process is certainly the LDL particle. However, Lp(a) and apoB containing lipoproteins play a role also, especially in the insulin resistant person.
22. If you want to stop atherosclerosis, you must lower the LDL particle number. Period.
23. At first glance it would seem that patients with smaller LDL particles are at greater risk for atherosclerosis than patients with large LDL particles, all things equal.
24. “A particle is a particle is a particle.” If you don’t know the number, you don’t know the risk.
25. With respect to laboratory medicine, two markers that have a high correlation with a given outcome are concordant – they equally predict the same outcome. However, when the two tests do not correlate with each other they are said to be discordant.
26. LDL-P (or apoB) is the best predictor of adverse cardiac events, which has been documented repeatedly in every major cardiovascular risk study.
27. LDL-C is only a good predictor of adverse cardiac events when it is concordant with LDL-P; otherwise it is a poor predictor of risk.
28. There is no way of determining which individual patient may have discordant LDL-C and LDL-P without measuring both markers.
29. Discordance between LDL-C and LDL-P is even greater in populations with metabolic syndrome, including patients with diabetes. Given the ubiquity of these conditions in the U.S. population, and the special risk such patients carry for cardiovascular disease, it is difficult to justify use of LDL-C, HDL-C, and TG alone for risk stratification in all but the most select patients.
30. To address this question, however, one must look at changes in cardiovascular events or direct markers of atherosclerosis (e.g., IMT) while holding LDL-P constant and then again holding LDL size constant. Only when you do this can you see that the relationship between size and event vanishes. The only thing that matters is the number of LDL particles – large, small, or mixed.
31. HDL-C and HDL-P are not measuring the same thing, just as LDL-C and LDL-P are not.
32. Secondary to the total HDL-P, all things equal it seems smaller HDL particles are more protective than large ones.
33. As HDL-C levels rise, most often it is driven by a disproportionate rise in HDL size, not HDL-P.
34. In the trials which were designed to prove that a drug that raised HDL-C would provide a reduction in cardiovascular events, no benefit occurred: estrogen studies (HERS, WHI), fibrate studies (FIELD, ACCORD), niacin studies, and CETP inhibition studies (dalcetrapib and torcetrapib). But, this says nothing of what happens when you raise HDL-P.
35. Don’t believe the hype: HDL is important, and more HDL particles are better than few. But, raising HDL-C with a drug isn’t going to fix the problem. Making this even more complex is that HDL functionality is likely as important, or even more important, than HDL-P, but no such tests exist to “measure” this.

Did you say “delay?”

That’s right. The question posed above did not ask how one could “prevent” or eliminate the risk cardiovascular disease, it asked how one could “delay” it. There is a difference. To appreciate this distinction, it’s worth reading this recent publication by Allan Sniderman and colleagues. Allan sent me a copy of this paper ahead of publication a few months ago in response to a question I had posed to him over lunch one day. I asked,

“Allan, who has a greater 5-year risk for cardiovascular disease, a 25 year-old with a LDL-P/apoB in the 99^th percentile or a 75-year-old with a LDL-P/apoB in the 5^th percentile?”

The paper Allan wrote is noteworthy for at least 2 reasons:

1. It’s an excellent reminder that age is a paramount risk factor for cardiovascular disease.
2. It provides a much better (causal) model for atherosclerosis than the typical age-driven models, and explains why age is an important risk factor.

What do I mean by this? Most risk calculators (e.g., Framingham) take their inputs (e.g., age, gender, LDL-C, HDL-C, smoking, diabetes, blood pressure) and calculate a 10-year risk score. If you’ve ever played with these models you’ll quickly see that age drives risk more than any other input. But why? Is there something inherently “risky” about being older?

Sniderman and many others would argue (and I agree) that the reason age is a strong predictor of risk has to do with exposure to apoB particles — LDL, Lp(a), and apoB-carrying remnants. Maybe it’s because I’m a math geek, but such models just seem intuitive to me because I think of most things in life in terms of calculus, especially integrals, the “area under a curve.”

[I once tried to explain to a girlfriend who thought I wasn’t spending enough time with her that my interest in her should be thought of in terms of the area under the curve, rather than any single point in time. That is, think in terms of the integral function, not the point-in-time function. Needless to say, she broke up with me on the spot (in the middle of a parking lot!), despite me drawing a very cool picture illustrating the difference, which I’ve re-created, below.]

The reason age is such a big driver of risk is that the longer your artery walls are exposed to the insult of apoB particles, the more likely they are to be damaged, for all the reasons we covered in Part IV of this series. [This paper also reviews the clinical situation of PCSK9 mutations which builds a very compelling case for the causal model of apoB particles in the development of atherosclerosis].

What does eating have to do with cardiovascular risk?

So now that everyone is on the edge of their seat in anticipation of this punch-line, let me provide two important caveats.

First, there are no long-term studies – either in primary or secondary prevention – examining the exact question we all want to know the answer to with respect to the role of dietary intervention on cardiovascular disease. There are short-term studies, some of which I will highlight, which look at proxies for cardiovascular disease, but all of the long-term studies (looking at secondary prevention), are either drug studies or multiple intervention studies (e.g., cholesterol-lowering drug(s) + blood pressure reducing drug(s) + dietary intervention + exercise + …).

In other words, the “dream” study has not been done and won’t be done for a long time. The “dream” study would follow 2 randomized groups for many years and only make one change between the groups. Group 1 would consume a standard American diet and group 2 would consume a very-low carbohydrate diet. Furthermore, compliance within each group would be excellent (many ways to ensure this, but none of them are inexpensive – part of why this has not been done) and the study would be powered to detect “hard outcomes” (e.g., death), instead of just “soft outcomes” (e.g., changes in apoB, LDL-C, LDL-P, TG).

Second, everything we have learned to date on the risk relationship between cardiovascular disease and risk markers is predicated on the assumption that a risk maker of level X in a person on diet A is the same as it would be for a person on diet B.

Since virtually all of the thousands of subjects who have made up the dozens of studies that form the basis for our understanding on this topic were consuming some variant of the “standard American diet” (i.e., high-carb), it is quite possible that what we know about risk stratification is that this population is not entirely fit for extrapolation to a population on a radically different diet (e.g., a very-low carbohydrate diet or a ketogenic diet). Many of you have asked about this, and my comments have always been the same. It is entirely plausible that an elevated level of LDL-P or apoB in someone consuming a high-carb diet portends a greater risk than someone on a ketogenic or low-carb diet. There are many reasons why this might be the case, and there are many folks who have made compelling arguments for this hypothesis.

But we can’t forget the words of Thomas Henry Huxley, who said, “The great tragedy of science is the slaying of a beautiful hypothesis by an ugly fact.” Science is full of beautiful hypothesis slayed by ugly facts. Only time will tell if this hypothesis ends up in that same graveyard, or changes the way we think about lipoproteins and atherosclerosis.

The role of sugar in cardiovascular disease

Let’s start with what we know, then fill in the connections, with the goal of creating an eating strategy for those most interested in delaying the onset of cardiovascular disease.

There are several short-term studies that have carefully examined the impact of sugar, specifically, on cardiovascular risk markers. Let’s examine one of them closely. In 2011 Peter Havel and colleagues published a study titled Consumption of fructose and HFCS increases postprandial triglycerides, LDL-C, and apoB in young men and women. If you don’t have access to this journal, you can read the study here in pre-publication form. This was a randomized trial with 3 parallel arms (no cross-over). The 3 groups consumed an isocaloric diet (to individual baseline characteristics) consisting of 55% carbohydrate, 15% protein, and 30% fat. The difference between the 3 groups was in the form of their carbohydrates.

Group 1: received 25% of their total energy in the form of glucose
Group 2: received 25% of their total energy in the form of fructose
Group 3: received 25% of their total energy in the form of high fructose corn syrup (55% fructose, 45% glucose)

The intervention was relatively short, consisting of both an inpatient and outpatient period, and is described in the methodology section.

Keep in mind, 25% of total energy in the form of sugar is not as extreme as you might think. For a person consuming 2,400 kcal/day this amounts to about 120 pounds/year of sugar, which is slightly below the average consumption of annual sugar in the United States. In that sense, the subjects in Group 3 can be viewed as the “control” for the U.S. population, and Group 1 can be viewed as an intervention group for what happens when you do nothing more in your diet than remove sugar, which was the first dietary intervention I made in 2009.

Despite the short duration of this study and the relatively small number of subjects (16 per group), the differences brought on by the interventions were significant. The figure below shows the changes in serum triglycerides via 3 different ways of measuring them. Figure A shows the difference in 24-hour total levels (i.e., the area under the curve for serial measurements – hey, there’s our integral function again!). Figure B shows late evening (post-prandial) differences. Figure C shows the overall change in fasting triglyceride level from baseline (where sugar intake was limited for 2 weeks and carbohydrate consumption consisted only of complex carbohydrates).

The differences were striking. The group that had all fructose and HFCS removed from their diet, despite still ingesting 55% of their total intake in the form of non-sugar carbohydrates, experienced a decline in total TG (Figure A, which represents the daily integral of plasma TG levels, or AUC). However, that same group experienced the greatest increase in fasting TG levels (Figure C). Post-prandial TG levels were elevated in all groups, but significantly higher in the fructose and HFCS groups (Figure B). The question this begs, of course, is which of these measurements is most predictive of risk?

Historically, fasting levels of TG are used as the basis of risk profiling (Figure C), and according to this metric glucose consumption appears even worse than fructose or HFCS. However, recent evidence suggests that post-prandial levels of TG (Figure B) are a more accurate way to assess atherosclerotic risk, as seen here, here, and here. One question I have is why did the AUC calculations in Figure A show a reduction in plasma TG level for the glucose group?

The figure below summarizes the differences in LDL-C, non-HDL-C, apoB, and apoB/apoA-I.

Again, the results were unmistakable with respect to the impact of fructose and HFCS on lipoproteins, and by extension, the relative lack of harm brought on by glucose in isolation. [Of course, removal of glucose and fructose/HFCS would have been a very interesting control group.]
One of the simultaneous strengths and weaknesses of this study was the heterogeneity of its subjects, who ranged in BMI from 18 to 35, in age from18 to 40, and in gender. While this provided at least one interesting example of age-related differences in carbohydrate metabolism (older subjects had a greater increase in triglycerides in response to glucose than younger subjects), it may have actually diluted the results. There were also significant differences between genders in the glucose group.
What was most interesting about this study was the clear difference between the 3 groups that was not solely a function of fructose load. In other words, the best outcome from a disease risk standpoint was in the glucose group, while the worst outcome was not in the all-fructose group, but in the 50/50 (technically 55/45) mixed group. This is a very powerful indication that while glucose and fructose alone can be deleterious in excess, their combination seems synergistically bad.

The role of saturated fat in cardiovascular disease

In the next week or two I’ll be posting an hour-long comprehensive lecture I gave at UCSD a few weeks ago on this exact topic. Rather than repeat any of it here, I’ll highlight one study that I did not include in that lecture. The study, Effect of a high saturated fat and no-starch diet on serum lipid subfractions in patients with documented atherosclerotic cardiovascular disease, published in 2003, treated 23 obese patients (average BMI 39) with known cardiovascular disease (status post coronary artery bypass surgery and/or stent placement) with a high-fat ketogenic diet. Because the study was free-living and relied on self-reporting, not all subjects had documented levels of elevated serum B-OHB. However, the subjects were instructed to avoid starch and consume 50% of their caloric intake via saturated fat, primarily in the form of red meat and cheese. There were no restrictions on fruits and vegetables, which may have accounted for the observation that not all subjects were ketotic during the 6-week intervention. In total, only 5 of the 23 patients achieved documented ketosis.
All of the subjects were on statins and entered the study at a goal LDL-C level target of 100 mg/dL, which may have been the only way the authors could get the IRB to approve such a study.
The table below shows the changes in lipoprotein fractions following the intervention (there was no control group):

This study was conducted during the height of the “outcry” over the Atkins diet. While most doctors reluctantly agreed that Dr. Atkins’ diet could reduce body fat, most believed it was still very dangerous. In the words of Dean Ornish, “Sure you can lose weight on a low-carb diet, but you can also lose weight on heroin and no one would recommend that!”

Fair point. In fact, the authors of this study acknowledged that they “strongly expected” this dietary intervention to increase risk for cardiovascular disease, which is why they only included subjects on statins with low LDL-C. However, as you can see from the table above, the authors were startled by the results. The subjects experienced a significant reduction in plasma triglycerides and VLDL triglycerides, without an increase in LDL-C or LDL-P. In fact, LDL size and HDL size increased and VLDL size decreased – all signs of improved insulin resistance. Furthermore, fasting glucose and insulin levels also decreased significantly. The mean HOMA-IR was reduced from 5.6 to 3.6 (normal is 1.0) and TG/HDL-C from 3.3 to 2.0 (normal is considered below 3, but “ideal” is probably below 1.0) in just 6 weeks. Taken together, these changes, combined with the dramatic change in VLDL size, suggest insulin resistance was dramatically improved while consuming a diet of 50% saturated fat!

As all of these patients were taking statins, we’re really robbed of seeing the impact of this diet on LDL-P, which did not change. Also, CRP levels rose (though not clinically or statistically significantly).

Putting it all together

It is very difficult to make the case that when carbohydrates in general, and sugars in particular, are removed or greatly reduced in the diet, insulin resistance is not improved, even in the presence of high amounts of saturated fats. When insulin resistance improves (i.e., as we become more insulin sensitive), we are less likely to have the signs and symptoms of metabolic syndrome. As we meet fewer criteria of metabolic syndrome, our risk of not only heart disease, but also stroke, cancer, diabetes, and Alzheimer’s disease goes down.

Furthermore, as this study on the Framingham cohort showed us, the more criteria you have along the spectrum of metabolic syndrome, the more difficult it becomes to predict your risk, due to a widening gap in discordant risk markers, as shown in this figure.

As I noted at the outset, the “dream” trial has not yet been done, though we (NuSI) plan to change that. Until then each of us has to make a decision several times every day about what we will and won’t put in our mouths. Much of this blog is dedicated to underscoring the impact of carbohydrate reduction on insulin resistance and metabolic syndrome.

The results of the trials to date, combined with a nuanced understanding of the lipoprotein physiology and their role on the atherosclerotic disease process, bring us to the following conclusions:

1. The consumption of sugar (sucrose, high fructose corn syrup) increases plasma levels of triglycerides, VLDL and apoB, and reduces plasma levels of HDL-C and apoA-I.
2. The removal of sugar reverses each of these.
3. The consumption of fructose alone, though likely in dose-dependent fashion, has a similar, though perhaps less harmful, impact as that of fructose and glucose combined (i.e., sugar).
4. The addition of fat, in the absence of sugar and starch, does not raise serum triglycerides or other biomarkers of cardiovascular disease.
5. The higher the level of serum triglycerides, the greater the likelihood of discordance between LDL-C and LDL-P (and apoB).
6. The greater the number (from 0 to 5) of inclusion criteria for metabolic syndrome, the greater the likelihood of discordance between LDL-C and LDL-P (and apoB).

I would like to address one additional topic in this series before wrapping it up – the role of pharmacologic intervention in the treatment and prevention of atherosclerotic disease, so please hold off on questions pertaining to this topic for now.

Related Posts

• The straight dope on cholesterol – Part VI
• The straight dope on cholesterol – Part V
• The straight dope on cholesterol – Part IV
• The straight dope on cholesterol – Part VIII
• The straight dope on cholesterol – Part III

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Read the complete article here.

Dr William Davis was interviewed on the Dr Oz show

Cardiologist, Track Your Plaque founder and Wheat Belly author Dr William Davis was interviewed on the Dr Oz show tagged 'Are You Addicted to Wheat' on Monday Dec 3 2012. The complete show can be seen in three parts here.

http://www.doctoroz.com/episode/are-you-addicted-wheat

Cholesterol & heart disease – there is a relationship - Zoë Harcombe

Cholesterol & heart disease – there is a relationship, but it’s not what you think

Written by Zoë on November 23, 2010
  

I do a fortnightly newsletter called “Diet & Health Today” in our on line support club. The club is there to help people to lose weight by eating food – real food! Apparently that makes us radical and controversial. The main article in Diet & Health Today is called “The Big Issues” and we have tackled things from “how we have misapplied thermodynamics to weight loss” to “what role does exercise play in losing weight”.

This is a copy of possibly one of the most serious Diet & Health Today articles that I may do. It is dedicated to Anne (Annem in the club) who asked me a great question about cholesterol. It made me do what I had been meaning to do ever since I read Dr Malcolm Kendrick’s The Great Cholesterol Con…

Dr MK ran some analysis on World Health Organisation (WHO) data. The WHO has extensive data from almost 200 countries on more health measures than you could imagine – definitely worth a look one rainy, wintry afternoon. This is where Dr MK presented the world with two different Seven Country Studies – (for those of you who aren’t familiar with the history, it was the Ancel Keys’ Seven Countries Study that started all the fat heart hypothesis stuff). Dr MK took the seven countries with the lowest saturated fat intake and then the seven countries with the highest saturated fat intake. You may need to read this twice – but he found: “Every single one of the seven countries with the lowest saturated fat consumption has significantly higher rates of heart disease than every single one of the countries with the highest saturated fat consumption.”

The next chapter in The Great Cholesterol Con goes on to look at cholesterol and heart disease (and overall death rates) and quotes many great studies where it is shown that lower cholesterol is associated with higher mortality. However, it did leave me thinking – having run the data on saturated fat and heart disease, let’s just run all the data on the cholesterol and heart disease and get to the bottom of this hypothesis from all parts of the allegations.

It actually didn’t take that long – less than a couple of hours one Saturday afternoon. You go to the WHO statistics area of their web site and then pick data for cholesterol from risk factors (how judgemental to start with!) and then look under: Global burden of disease (mortality); All causes; Non communicable diseases and then G Cardiovascular disease (shortened to CVD). CVD deaths include ischemic heart disease and cerebrovascular disease – that means fatal heart attacks and fatal strokes to us. You find the most recent year where you can get both sets of data to compare like with like. This turns out to be 2002. You download their very user friendly spreadsheet data (CSV) – cut and paste it into an excel file and then try to remember how the heck to do scatter diagrams in excel!
Before telling you the results, we need to go back for a quick reminder on what we know about cholesterol and then hopefully this can serve as a factsheet for all the cholesterol questions we continually get.
 
The role of cholesterol
It is virtually impossible to explain how vital cholesterol is to the human body. If you had no cholesterol in your body you would be dead. Every single cell of your body is covered by a membrane (think of a membrane as the ‘skin’ or protective barrier around each cell). This membrane is made largely of cholesterol, fat and protein. Membranes are porous structures, not solid walls, letting nutrients and hormones in while keeping waste and toxins out. If cholesterol were removed from cell membranes they would literally explode from their internal water pressure. Human beings quite simply die without cholesterol.

Cholesterol is vital for hormone production – the sex hormones and therefore the entire human reproductive system are totally dependent on cholesterol. Hence, not only would humans die without cholesterol, the human race would die out.

Cholesterol is vital for digestion. The human body uses cholesterol to synthesise bile acids. Without cholesterol-rich, bile salts, the human body could not absorb essential fatty acids or the fat soluble vitamins (A, D, E and K) and serious, even life threatening, deficiencies could develop. (It is interesting, therefore, that nature puts cholesterol in virtually every food that contains fat – providing a digestion mechanism in tandem).

Cholesterol is vital for the brain, central nervous system and memory functions (hence how the side effects of statins include memory loss, mental confusion and people generally just not feeling themselves). Even though the brain is only 2% of the body’s weight, it contains approximately 25% of the body’s cholesterol. The vital connections between nerve endings in the brain, which help to conduct the electrical impulses that make movement, sensation, thinking, learning, and remembering possible, are largely made up of cholesterol.

Cholesterol is critical for bones and for all the roles performed by vitamin D. Vitamin D is best known for its role in calcium and phosphorus metabolism, and thus bone health, but we are continually learning more about potential additional health benefits of vitamin D from mental health to immune health. Vitamin D can be ingested (and is, interestingly again, found in foods high in cholesterol) and it can be made from skin cholesterol. Modern ‘health’ advice to avoid the sun, take cholesterol-lowering drugs, eat a low cholesterol diet (whatever the heck that is supposed to be) – combined with there not even being a recommended dietary allowance for vitamin D – is undoubtedly contributing to avoidable modern illness.

One of the key reasons that we need to spend approximately one third of our lives sleeping is to give the body time to produce cholesterol, repair cells and perform other essential maintenance.
This gives you the headlines of the vital functions that cholesterol performs, but hang on to that bottom line – it is utterly vital and we die instantly without it.

You may be familiar with the term essential fatty acids or essential amino acids (proteins break down into amino acids). The term ‘essential’ used like this in nutrition means that it is essential that we consume it in our diet because the body can’t make it. The body makes cholesterol. That says to me that cholesterol is even more vital than essential fatty acids or essential amino acids – even though these too are life critical – and therefore the design of the human body is such that it was not left to chance that we needed to get cholesterol from food. Of the 500 or so roles that the liver has – one is to produce cholesterol. It is too vital to be left to chance.
 
What went wrong?
So, how did something so life vital become more vilified than a mass murderer? I think it comes down to three things (and I don’t take credit for this view – it is there to be worked out by anyone who traces back the history and Kendrick, Uffe Ravnskov and all the thincs.org guys have led the way):
1) Rabbits;
2) Ancel Keys;
3) Money!

1) In 1913, a Russian chap called Nikolai Anitschkow decided to feed rabbits purified cholesterol and he managed to get their blood cholesterol levels in excess of 1,000 mg/dl (nearly 26 mmol/L! Most UK people have levels of 5-7 mmol/L). He then noticed the formation of “vascular lesions closely resembling those of human atherosclerosis” forming in the arteries of the rabbits. The obvious flaw in the experiment should have been that rabbits are strict herbivores. They do not eat animal products, which is the only source of cholesterol. Hence rabbits are in no way designed to digest cholesterol or animal fat and no one should be surprised if cholesterol or animal fat ended up stuck in any part of the poor rabbit. The only surprise is that no one thought to ask Anitschkow why he was feeding cholesterol and animal fat to herbivores. Interestingly, far less well known is that a parallel test was done on rats and dogs (omnivores) and feeding cholesterol to these species failed to produce lesions.

2) Ancel Keys. Remember the Minnesota experiment that I so often refer to? A brilliant and unbiased piece of research, which has given the world one of the best insights into low calorie dieting ever done – it was pure genius. This study made Ancel Keys the man of the moment and I guess he wanted to follow it with something equally impactful. There is an anecdote in The Great Cholesterol Con and on p113 of The Obesity Epidemic where Henry Blackburn, one of Keys’ closest colleagues, tries to explain what may have fuelled Keys drive to find a connection between diet and heart disease.
What is little known is that Keys originally tried to establish a link between cholesterol in food and cholesterol in the blood (our cholesterol levels when we have a blood test) because he thought (probably because of poor Bugs Bunny) that cholesterol in the blood causes heart disease.

Keys did multiples of studies, changing the diets of his human ‘guinea pigs’, and he presented his conclusions in The Journal of Nutrition, November 1955: “It is concluded that in adult men the serum cholesterol level is essentially independent of the cholesterol intake over the whole range of natural human diets. It is probable that infants, children and women are similar.” i.e. I only tested adult men and there is no relationship between cholesterol eaten and cholesterol in the blood and it is probable that there will similarly be no relationship for women or children.

In 1997 Keys put this even more assertively: “There’s no connection whatsoever between cholesterol in food and cholesterol in blood. And we’ve known that all along. Cholesterol in the diet doesn’t matter at all unless you happen to be a chicken or a rabbit.”

Did you know – even the UK Food Standards Agency (FSA) and UK National Health Service (NHS) admit this?

- “However, dietary cholesterol has little effect on blood cholesterol. More important is the amount of saturated fat in your diet”. (National Health Service). (Notice the second sentence? They just couldn’t let the theory go).
- “But the cholesterol we get from our food has much less effect on the level of cholesterol in our blood than the amount of saturated fat we eat”. (Food Standards Agency). (This link may disappear, as the FSA is bowing out of giving nutritional advice).

What the government advice should say is: The body makes cholesterol. The cholesterol you eat has no impact on the level of cholesterol in your blood – not “little”, but “no” – (and we’ve known that all along). And they should also explain how saturated fat can determine blood cholesterol levels and then provide irrefutable evidence that it does. But it must be hard for public health bodies to even go this far. As we saw in a recent thread – the FSA also now accept that there is no limit on the number of eggs we can eat:

 

If only Keys had stopped here, but he wanted to find an explanation for heart disease and he was not about to be deterred. For some reason, which I find inexplicable, he then turned to fat (the entire literature on this topic is very vague about “fat” vs. “saturated fat” so his early writings are also very vague on the topic). Here’s a bit of Mensa logic for those who like this kind of thing:

i) Only animal foods contain cholesterol (meat, fish, eggs, dairy). NO non animal foods contain cholesterol.
ii) All animal foods contain fat – saturated and unsaturated. Some may be very low in fat (e.g. white fish), but they all contain some fat.
iii) If there is no link whatsoever between increased consumption of foods containing cholesterol and blood cholesterol levels, there can be no link whatsoever between increased consumption of animal foods and blood cholesterol levels since only animal foods can be increased in consumption to increase consumption of cholesterol!

So, Keys first did the graph that was presented at the Mount Sinai hospital (which is the one shown in the Tom Naughton video and in Dr Robert Lustig’s “Sugar: The Bitter Truth” ) and then went on to do the Seven Countries study – which I have read all twenty volumes of and take apart piece by piece in Chapter Eight of The Obesity Epidemic: What caused it? How can we stop it (on this page).
As Kendrick’s two unbiased seven country studies showed – there is not even an association between saturated fat and heart disease – let alone a causation. However, Keys published his seven countries study and the rest, as they say, is history.

3) The Robert Redford film All the Presidents’ Men that had the memorable quote “follow the money”. This is absolutely at the heart of everything in the diet industry from national dietary organisations to the food, drink and drug industries and individuals in between.

The Ancel Keys work interestingly claimed that saturated fat consumption (A) caused heart disease (C) not directly, but by raising cholesterol (B). Hence A was supposed to cause C through B. For this to even get off the starting blocks, A and C have to be related (plot one against the other and there has to be a clear relationship); A and B have to be related and B and C have to be related. None of these in fact holds. The Kendrick study shows that A and C are not related. There is no logic that A and B could be related – because of the problem of fat and cholesterol being found in the same foods and Kendrick presented many studies that showed B and C were not related. I aim in this article to put the nail in the coffin for any idea that high cholesterol is even associated with high heart disease. We will, in fact, show that the evidence confirms the opposite.

By having cholesterol as this middle-man, this has allowed an entire pharmaceutical industry (and stupid cook books) to come up with ways of lowering cholesterol. The most lucrative of these has clearly been statins – drugs designed to stop the body producing the cholesterol that it is designed to produce. It never hurts to remind people that one statin alone, Lipitor, has been worth $125 billion to Pfizer since 1997. Taubes has a deeply troubling passage in The Diet Delusion where he looked at the committee who approved a lowering of the target cholesterol levels for the USA population. From memory (it’s a big book to find a reference!), a number of people were on the committee and all but one were funded by pharma companies and one didn’t want the target cholesterol level lowered. I wonder which one! (Anyone reading this – if you can find the page number I’d be so grateful – my copy has so many scribbles on I can barely read it).

So, cholesterol will remain the mass murderer for as long as statins are as lucrative as they are or until the public are enlightened and courageous enough to say no to doctors who try to put them on this medication (like my mum was after reading Dr MK!)
 
A small technicality
On p35 of The Great Cholesterol Con, Kendrick says: “How can eating saturated fat raise LDL levels? It is not merely biologically implausible, it is biologically impossible. Boy does that statement make me a hostage to fortune!”

I arranged to meet a biochemist at a local university to try to get to the bottom of this statement. The biochemist (who has more qualifications than I’ve had dark chocolate) was sadly so brainwashed in the ‘fat is bad’ theory that he just kept saying eating fat raises cholesterol. When I asked him to talk me through the biochemical pathway from fat digestion through to how this impacts cholesterol he said he didn’t know the digestive process well enough – we would need to add a dietician into the conversation. This was alarming enough. I then said – we eat 39 grams of butter per person per week in the UK and about 1.4 kilos of flour – didn’t he think it was more likely that the flour was making us fat and sick. He said it only took a drop of arsenic to kill us. I left shortly afterwards.

Kendrick has to be right (isn’t he always?) LDL (remember this is not cholesterol – it is a low density lipoprotein) is the left over from IDL (intermediate density lipoprotein), which is the left over from VLDL (very low density lipoprotein). VLDL is one of the measures you get in your blood cholesterol test (actually they estimate it – they don’t measure it – they only measure total cholesterol and HDL leaving two other unknowns in an equation with four variables and you thought this was scientific). (They also call VLDL ‘triglyceride’, which is confusing and unhelpful). Cutting a complex story short (it is explained in my book in different passages), carbohydrates can impact VLDL levels (starter for 10: Acetyl-CoA being the start of the process by which the body makes cholesterol and part of the Kreb’s cycle whereby the body turns glucose into ATP), but I really have found no way in which the fat that we eat can do so. Because fat is not water soluble, it is packaged into a lipoprotein in the digestive system. The lipoprotein that fat goes into is the biggest one – the chylomicron – and then it travels off into the body to go and do the essential repair and maintenance jobs that fat does. Does the fat say – hang on Mr chylomicron – we need to go via the liver and see if we can mess up the body’s VLDL production in some way?! Do ask this ‘how’ question (in detail) of someone who thinks that this is possible. I am still open to someone answering this, but I’m not holding my breath.
Fructose, on the other hand, we do know goes straight to the liver to be metabolised. Could that, and other carbs, impact VLDL production? The evidence I have already seen is strong that they do.
 
The serious bit
The WHO data is split into men and women. I first did the scatter diagrams for average (mean) cholesterol levels and CVD deaths. Then I ran the Pearson correlation coefficient on these numbers. This gives us the term called “r”. “r” tells us if there is some kind of a relationship: an r score of 0 would indicate no relationship; an r score of 1 would indicate a perfect relationship. A negative r score is called an inverse relationship e.g. the price of concert tickets is likely to be inversely related to the number of concert tickets bought – fewer tickets being bought at higher prices.

The “r” score for men revealed that there was a small relationship of 0.13 – however this relationship was inverse. The diagram and correlation shows that higher cholesterol levels are associated with lower CVD deaths and lower cholesterol levels are associated with higher CVD deaths. In women, the relationship is stronger – to the point of being meaningful. The r score was 0.52 – but, again, inverse. For women, higher cholesterol levels are quite significantly associated with lower CVD deaths and lower cholesterol levels are quite significantly associated with higher CVD deaths. Please note that I have added r squared on the graphs below (excel can do this for us) and it can confirm that you’ve got your r numbers right and r squared tells us the strength of any relationship we have observed.

All you need to do is to look at the lines going down to the right and wonder how on earth we ever got away with telling people that cholesterol causes heart disease. High cholesterol is associated with lower heart disease and vice versa – for all the data available in the world. High cholesterol is not even associated with high heart disease, let alone does it cause it.


It gets worse. I then kept the cholesterol information and changed the death rates to total deaths – all deaths from any cause – cancer, heart disease, diabetes, strokes – all deaths. You can see the diagrams for men and women again below. This time there is a significant relationship for both men and women: 0.66 for men and 0.74 for women – again inverse. There is a significant association between higher cholesterol levels and lower deaths and lower cholesterol levels and higher deaths for men and an even more significant relationship for women.



This is serious. I’ve shown it to a couple of academics (Professor sort of things) with whom I’ve been having great debates, as I want to see what the view is from people who wholly believe the fat/cholesterol/heart/death hypothesis. (Kendrick talks in his book about what happened when he showed an intelligent colleague his two seven countries studies and the evidence was just dismissed instantly). It is most useful to know what the resistance arguments will be before starting to invite the resistance. The two arguments I got back were:

1) “Ah yes – but this is only an association.”
Ah yes – but a) we changed global dietary advice back in 1977-1983 on the back of an association in Seven (carefully hand picked) Countries that miraculously became a causation even when the association was far from established and b) it is an association that’s the opposite to the one that the world currently holds true and c) that’s what epidemiology is supposed to be about – establish an association and then investigate if there could be any causation or useful learnings. So – go out with a new paradox – that high cholesterol is associated with low deaths and then see what dietary advice emerges.

2) “But that’s total cholesterol – the key thing is the ratio of good to bad cholesterol.”
Oh boy! The chemical formula for cholesterol is C27H46O. There is no good version or bad version. HDL and LDL are not even cholesterol, let alone good cholesterol or bad cholesterol. They are lipoproteins – see above – and they carry cholesterol, triglyceride, phospholipids and protein. Do you think that taxis are people? Or do you think that they are carriers of people (and luggage, and pets and fresh air and other things).

Back to – this is serious. Why are we lowering cholesterol when lower cholesterol is associated with more deaths from heart disease and all causes for men and women?
The doctors’ Hippocratic oath is “First do no harm”.

This also says to me – even though saturated fat has nothing to do with cholesterol, it doesn’t actually matter. Even if it did – cholesterol is only associated with CVD deaths in an inverse way. If fat did raise cholesterol – as public health officials like to claim – it could save lives! Please note I am always really careful with language in this area and never jump from association or relationship to causation. Someone may be in the bath and they may be singing – if we observe this in many cases, we may claim that there is an association. We cannot say that bathing causes singing or that singing causes bathing.

Our global dietary advice was changed in 1977 in the US and 1983 in the UK as a result of a biased study of seven handpicked counties. Had the data been available for the 192 countries we can analyse now, or had Keys even considered all the data that was available to him at the time (for France etc), our conclusion may have been that we need to protect cholesterol levels in the body. We may have realised that the last thing we should be trying to do is lowering cholesterol – unless we’re trying to lower life expectancy for some reason.

Zoë Harcombe
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Why Cholesterol May Not Be the Cause Of Heart Disease - Hyman

Why Cholesterol May Not Be the Cause Of Heart Disease

by Dr Mark Hyman

WE HAVE ALL BEEN LED TO to believe that cholesterol is bad and that lowering it is good. Because of extensive pharmaceutical marketing to both doctors and patients we think that using statin drugs is proven to work to lower the risk of heart attacks and death.

But on what scientific evidence is this based, what does that evidence really show?

Roger Williams once said something that is very applicable to how we commonly view the benefits of statins. “There are liars, damn liars, and statisticians.”

We see prominent ads on television and in medical journals — things like 36% reduction in risk of having a heart attack. But we don’t look at the fine print. What does that REALLY mean and how does it affect decisions about who should really be using these drugs.

Before I explain that, here are some thought provoking findings to ponder.

• If you lower bad cholesterol (LDL) but have a low HDL (good cholesterol) there is no benefit to statins. (i)
• If you lower bad cholesterol (LDL) but don’t reduce inflammation (marked by a test called C-reactive protein), there is no benefit to statins. (ii)
• If you are a healthy woman with high cholesterol, there is no proof that taking statins reduces your risk of heart attack or death. (iii)
• If you are a man or a woman over 69 years old with high cholesterol, there is no proof that taking statins reduces your risk of heart attack or death. (iv)
• Aggressive cholesterol treatment with two medications (Zocor and Zetia) lowered cholesterol much more than one drug alone, but led to more plaque build up in the arties and no fewer heart attacks. (v)
• 75% of people who have heart attacks have normal cholesterol
• Older patients with lower cholesterol have higher risks of death than those with higher cholesterol. (vi)
• Countries with higher average cholesterol than Americans such as the Swiss or Spanish have less heart disease.
• Recent evidence shows that it is likely statins’ ability to lower inflammation it what accounts for the benefits of statins, not their ability to lower cholesterol.

So for whom do the statin drugs work for anyway? They work for people who have already had heart attacks to prevent more heart attacks or death. And they work slightly for middle-aged men who have many risk factors for heart disease like high blood pressure, obesity, or diabetes.

So why did the 2004 National Cholesterol Education Program guidelines expand the previous guidelines to recommend that more people take statins (from 13 million to 40 million) and that people who don’t have heart disease should take them to prevent heart disease. Could it have been that 8 of the 9 experts on the panel who developed these guidelines had financial ties to the drug industry? Thirty-four other non-industry affiliated experts sent a petition to protest the recommendations to the National Institutes of Health saying the evidence was weak. It was like having a fox guard the chicken coop.

People with the lowest cholesterol as they age are in fact at highest risk of death. Under certain circumstances, higher cholesterol can actually help increase life span.

It’s all in the spin. The spin of the statistics and numbers. And it’s easy to get confused. Let me try to clear things up.

When you look under the hood of the research data you find that the touted “36% reduction” means a reduction of the number of people getting heart attacks or death from 3% to 2% (or about 30-40%).
And that data also shows that treatment only really works if you have heart disease already. In those who DON’T have documented heart disease, there is no benefit.

In those at high risk for heart disease about 50 people would need to be treated for 5 years to reduce one cardiovascular event. Just to put that in perspective: If a drug works, it has a very low NTT (number needed to treat). For example, if you have a urine infection and take an antibiotic, you will get near a 100% benefit. The number needed to treat is “1″. So if you have an NTT of 50 like statins do for preventing heart disease in 75% of the people who take them, it is basically a crap shoot.

Yet at a cost of over $28 billion a year, 75% of all statin prescriptions are for exactly this type of unproven primary prevention. Simply applying the science over 10 years would save over $200 billion. This is just one example of reimbursed but unproven care. We need not only prevent disease but also prevent the wrong type of care.

If these medications were without side effects, then you may be able to justify the risk – but they cause muscle damage, sexual dysfunction, liver and nerve damage and other problems in 10-15% of patients who take them. Certainly not a free ride.

So if lowering cholesterol is not the great panacea that we thought, how do we treat heart disease, and how do we get the right kind of cholesterol – high HDL, low LDL and low triglycerides and have cholesterol particles that are large, light and fluffy rather than small, dense and hard, which is the type that actually causes heart disease and plaque build up.

We know what causes the damaging small cholesterol particles. And it isn’t fat in the diet. It is sugar. Sugar in any form or refined carbohydrates (white food) drives the good cholesterol down, cause triglycerides to go up, creates small damaging cholesterol particles, and causes metabolic syndrome or pre-diabetes. That is the true cause of most heart attacks, NOT LDL cholesterol.

One of the reasons we don’t hear about this is because there is no good drug to raise HDL. Statin drugs lower LDL — and billions are spent advertising them, even though they are the wrong treatment.

If you’re like most of the patients I see in my practice, you’re convinced that cholesterol is the evil that causes heart disease. You may hope that if you monitor your cholesterol levels and avoid the foods that are purported to raise cholesterol, you’ll be safe from America’s number-one killer.

We are all terrified of cholesterol because for years well-meaning doctors, echoed by the media, have emphasized what they long believed is the intimate link between cholesterol and death by heart disease. If only it were so simple!

The truth is much more complex.

Cholesterol is only one factor of many — and not even the most important — that contribute to your risk of getting heart disease.

First of all, let’s take a look at what cholesterol actually is. It’s a fatty substance produced by the liver that is used to help perform thousands of bodily functions. The body uses it to help build your cell membranes, the covering of your nerve sheaths, and much of your brain. It’s a key building block for our hormone production, and without it you would not be able to maintain adequate levels of testosterone, estrogen, progesterone and cortisol.

So if you think cholesterol is the enemy, think again. Without cholesterol, you would die.

In fact, people with the lowest cholesterol as they age are at highest risk of death. Under certain circumstances, higher cholesterol can actually help to increase life span.

In reality, the biggest source of abnormal cholesterol is not fat at all — it’s sugar. The sugar you consume converts to fat in your body. And the worst culprit of all is high fructose corn syrup.

To help clear the confusion, I will review many of the cholesterol myths our culture labors under and explain what the real factors are that lead to cardiovascular disease.

Cholesterol Myths
One of the biggest cholesterol myths out there has to do with dietary fat. Although most of us have been taught that a high-fat diet causes cholesterol problems, this isn’t entirely true. Here’s why: The type of fat that you eat is more important than the amount of fat. Trans fats or hydrogenated fats and saturated fats promote abnormal cholesterol, whereas omega-3 fats and monounsaturated fats actually improve the type and quantity of the cholesterol your body produces.

In reality, the biggest source of abnormal cholesterol is not fat at all — it’s sugar. The sugar you consume converts to fat in your body. And the worst culprit of all is high fructose corn syrup.
Consumption of high fructose corn syrup, which is present in sodas, many juices, and most processed foods, is the primary nutritional cause of most of the cholesterol issues we doctors see in our patients.
So the real concern isn’t the amount of cholesterol you have, but the type of fats and sugar and refined carbohydrates in your diet that lead to abnormal cholesterol production.

Of course, many health-conscious people today know that total cholesterol is not as critical as the following:

• Your levels of HDL “good” cholesterol vs. LDL “bad” cholesterol
• Your triglyceride levels
• Your ratio of triglycerides to HDL
• Your ratio of total cholesterol to HDL

Many are also aware that there are different sizes of cholesterol particles. There are small and large particles of LDL, HDL, and triglycerides. The most dangerous are the small, dense particles that act like BB pellets, easily penetrating your arteries. Large, fluffy cholesterol particles are practically harmless–even if your total cholesterol is high. They function like beach balls and bounce off the arteries, causing no harm.

Another concern is whether or not your cholesterol is rancid. If so, the risk of arterial plaque is real.
Rancid or oxidized cholesterol results from oxidative stress and free radicals, which trigger a vicious cycle of inflammation and fat or plaque deposition under the artery walls. That is the real danger: When small dense LDL particles are oxidized they become dangerous and start the build up of plaque or cholesterol deposits in your arteries.

Now that we’ve explored when and how cholesterol becomes more problematic, let’s take a look at other factors that play a more significant role in cardiovascular disease.

Prime Contributors to Cardiovascular Disease
First of all, cardiovascular illness results when key bodily functions go awry, causing inflammation, (vii) imbalances in blood sugar and insulin and oxidative stress.

To control these key biological functions and keep them in balance, you need to look at your overall health as well as your genetic predispositions, as these underlie the types of diseases you’re most likely to develop. It is the interaction of your genes, lifestyle, and environment that ultimately determines your risks — and the outcome of your life.

This is the science of nutrigenomics, or how food acts as information to stall or totally prevent some predisposed disease risks by turning on the right gene messages with our diet and lifestyle choices. That means some of the factors that unbalance bodily health are under your control, or could be.
These include diet, nutritional status, stress levels, and activity levels. Key tests can reveal problems with a person’s blood sugar and insulin, inflammation level, level of folic acid, clotting factors, hormones, and other bodily systems that affect your risk of cardiovascular disease.

Particularly important are the causes if inflammation, which are many, and need to be assessed. Inflammation can arise from poor diet (too much sugar and trans and saturated fats), a sedentary lifestyle, stress, autoimmune disease, food allergies, hidden infections such as gum disease, and even toxins such as mercury. All of these causal factors need to be considered anytime there is inflammation.

Combined together, all of these factors determine your risk of heart disease. And I recommend that people undergo a comprehensive medical evaluation to see what their risk really is.

Zeroing in on Key Factors for Heart Disease
There’s no doubt about it, inflammation is key contributor to heart disease. A major study done at Harvard found that people with high levels of a marker called C-reactive protein (CRP) had higher risks of heart disease than people with high cholesterol. Normal cholesterol levels were NOT protective to those with high CRP. The risks were greatest for those with high levels of both CRP and cholesterol.

Another predisposing factor to heart disease is insulin resistance or metabolic syndrome, which leads to an imbalance in the blood sugar and high levels of insulin. This may affect as many as half of Americans over age 65. Many younger people also have this condition, which is sometimes called pre-diabetes.

Although modern medicine sometimes loses sight of the interconnectedness of all our bodily systems, blood sugar imbalances like these impact your cholesterol levels too. If you have any of these conditions, they will cause your good cholesterol to go down, while your triglycerides rise, which further increases inflammation and oxidative stress. All of these fluctuations contribute to blood thickening, clotting, and other malfunctions — leading to cardiovascular disease.

What’s more, elevated levels of a substance called homocysteine (which is related to your body’s levels of folic acid and vitamins B6 and B12) appears to correlate to cardiovascular illness. Although this is still somewhat controversial, I often see this inter-relationship in my practice. While genes may play a part, tests done as part of a comprehensive evaluation of cardiac risk can easily ascertain this factor. Where problematic levels occur, they can be easily addressed by adequate folic acid intake, along with vitamins B6 and B12.

Testing for Cardiovascular Risk Factors
Heart disease is not only about cholesterol. It is important to look at many factors that contribute to your overall risk. And it seems that insulin and blood sugar imbalances, and inflammation are proving to be more of a risk that cholesterol.

If you want to test your overall risk, you can consider asking your doctor to perform the following tests:

1. Total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. Your total cholesterol should be under 200. Your triglycerides should be under 100. Your HDL should be over 60. Your LDL should be ideally under 80. Your ratio of total cholesterol to HDL should be less than 3.0. Your ratio of triglycerides to HDL should be no greater than 4, which can indicate insulin resistance if elevated.
2. NMR Lipid Profile. This looks at your cholesterol under an MRI scan to assess the size of the particles, which can determine your cardiovascular risk. This is a very important test that can further differentiate the risk of your cholesterol and can be an important factor to track as your system improves and your cholesterol transforms from being small dense and dangerous to light and fluffy and innocuous. It is done by a company called Liposcience and is also available through LabCorp.
3. Glucose Insulin Tolerance Test. Measurements of fasting and 1 and 2 hour levels of glucose AND insulin helps identify pre-diabetes and excessively high levels of insulin, and even diabetes. Most doctors just check blood sugar and NOT insulin, which is the first thing to go up. By the time your blood sugar goes up, the train has left the station.
4. Hemaglobin A1c. This measures your average blood sugar level over the last 6 weeks. Anything over 5.5 is high.
5. Cardio C-reactive protein. This is a marker of inflammation in the body that is essential to understand in the context of overall risk. Your C-reactive protein level should be less than 1.
6. Homocysteine. Your homocysteine measures your folate status and should be between 6 and 8.
7. Lipid peroxides or TBARS test, which looks at the amount of oxidized or rancid fat. This should be within normal limits of the test and indicates whether or not you have oxidized cholesterol.
8. Fibrinogen, which is another test looking at clotting in the blood. It should be less than 300.
9. Lipoprotein (a), which is another factor that can promote the risk of heart disease, often in men. It should be less than 30.
10. Genes or SNPs may also be useful in terms of assessing your situation. A number of key genes regulate cholesterol and metabolism, including Apo E genes and the cholesterol ester transfer protein gene. The MTHFR gene, which regulates homocysteine is also important and may be part of an overall workup.
11. Get a high-speed CT or (EBT) scan of the heart if you are concerned that you have cardiovascular disease. This may be helpful to assess overall plaque burden and calcium score. A score higher than 100 is a concern, and a score higher than 400 indicates severe risk of cardiovascular disease.

Next I will review how to lower your risk of heart disease and fix your cholesterol. We’ll do this not by lowering the LDL, but by getting more light and fluffy LDL particles, which are protective and more HDL cholesterol, which is THE most important cholesterol.

References
(i) Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007 Sep 27;357(13):1301-10.
(ii) Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207.
(iii) Abramson J, Wright JM. Are lipid-lowering guidelines evidence-based? Lancet. 2007 Jan 20;369(9557):168-9
(iv) IBID
(v) Brown BG, Taylor AJ Does ENHANCE Diminish Confidence in Lowering LDL or in Ezetimibe? Engl J Med 358:1504, April 3, 2008 Editorial
(vi) Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet. 2001 Aug 4;358(9279):351-5.
(vii) Hansson GK Inflammation, Atherosclerosis, and Coronary Artery Disease N Engl J Med 352:1685, April 21, 2005
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Do statins really reduce the risk of cancer? - Briffa

Do statins really reduce the risk of cancer?

Nov, Fri 9th, 2012 By : Dr John Briffa

 

Yesterday saw the on-line publication of a study in the New England Journal of Medicine (NEJM) that concerns statins and is getting more than its fair share of media attention. The study, conducted in Denmark, analysed the rates of death from cancer in individuals taking statins, and compared them to those in individuals not taking these drugs. Those taking statins were found to be at a statistically significant reduced risk of dying from cancer. Some seem keen to claim that statins may not only be an answer to heart disease, but our cancer woes too. Take this headline for example which you can find here: ‘Statins cut mortality in cancer patients’. The wording of this title on a website dedicated to the education of doctors strongly suggests that statins actually reduce the risk of death from cancer.

But, not so fast. The NEJM study is what is known as ‘epidemiological’ or ‘observational’ study. The study tells us that statin use is associated with a reduced risk of death from cancer, but it can’t tell us whether or not statins actually cut cancer risk.

One fundamental problem with studies of this nature is that they are subject to what is known as the ‘healthy user effect’. Basically, what this means is that healthier, often more health-conscious individuals are more likely to end up on statins than less healthy, not so health-conscious individuals. Because of this, it’s possible that the apparent benefits of statins with regard to cancer (or anything else) are not to do with the drugs themselves, but the health characteristics of those more likely to take statins.

If we really want to know if statins reduce the risk of cancer death then we need to look to what are known as ‘intervention studies’ in which, usually, roughly equivalent groups of individuals are given statins or placebo. These studies, the gold standard of which are ‘randomised controlled trials’ do have the potential of discerning the true effects of drugs and other treatments.

Single studies such as these can provide useful data, but sometimes it makes sense to amass data from several studies to get a decent overview of the impact of a drug or class of drugs. Such grouping of studies together are referred to as ‘meta-analyses’.

One meta-analysis published in 2009 found that statin use was not associated with a reduced risk of cancer [2]. A more recent meta-analysis published this year found the same thing [3]. Meta-analyses of intervention studies are not perfect, but they are much better than (crappy) single epidemiological studies like the one currently doing the rounds. And it’s perhaps worth bearing in mind that there as been at least some concern about the impact statins might have on cancer risk in the elderly. In one study, statin use (compared to placebo) increased the risk of cancer by 25 per cent (statistically significant) [4].

Put in this context, the frothing enthusiasm exhibited by some regarding this latest study seems inappropriate. And for a website dedicated to the education of doctors to proclaim that ‘Statins cut mortality in cancer patients’ is downright negligent.

References:
1. Nielsen SF, et al. Statin Use and Reduced Cancer-Related Mortality. NEJM published online 8 October 2012
2. Brugts JJ, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009;338:b2376.
3. Cholesterol treatment trialists’ collaboraton. 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. PLoS One 2012;7(1):e29849. Epub 2012 Jan 19.
4. Shepherd J, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360(9346):1623-30
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Alzheimer’s: another reason to be sceptical about statins - Burne

Alzheimer’s: another reason to be sceptical about statins

November 5, 2012 By Jerome Burne

 

The front page of the Daily Express on Friday led with a new warning about statins – combining them with certain blood pressure pills could raise your risk of muscle pains, lung disorders and kidney damage. Hmm yes well.

Even as a cholesterol/statin sceptic I thought that was remarkably over-hyped – statin side effects are massively underplayed and finding they go up a bit when mixed with another drug is more of a clinical technicality than front page news.

However there is a statin risk which should be a serious cause for concern – lowering cholesterol may well raise your chances of developing Alzheimer’s. I’ll come to that in a moment.
First there is one aspect of the Express story that raises a wider issue – the way the buck is subtly passed when any new risk factor is identified. The standard official response is is to say: “If you are worried discuss it with your doctor.” It seems sensible but the implications aren’t reassuring. It’s a line that’s been trotted out rather a lot recently.

Need for serious sanctions

Earlier this week it was used in response to the report that found that more women are harmed by unnecessary treatment following a mammograms than benefit from detecting a cancer. The week before, when a brilliant BMJ investigation exposed the appalling corruption involved in official EU licensing of hip implants, you were also invited to discuss how it might affect you. In both cases serious sanctions would seem appropriate.

In the case of mammograms because convincing research showing that the dangers of over-diagnosis from breast screening dates back over a decade. A clear statement of risks and benefits has taken so long because of the readiness of the mammogram establishment to ignore or denigrate evidence of harm, as I described recently in the Mail. The fact that the European Medicines Agency allows licensing bodies to behave in a way that openly favours business interests rather than the patient, should also trigger an investigation.

Shifting responsibility

There’s nothing wrong with discussing safety with your doctor, but when that’s all that happens it is a brilliant way of shifting the responsibility for producing safe products from the authorities onto you. If in the future you suffer as a result of mammograms or hip implants or indeed statins then the fact you were told about the risk, discussed it and went ahead becomes just one of those things. For a book that discusses this see here.

To appreciate how odd the response to medical dangers is, look at what happens with when something dangerous about a car is picked up. In 2010 it was found that the throttle on some Toyotas could stick in the open position. But rather than saying: “If you are worried about the “dangerous acceleration” issue, discuss it with your dealer and decide if Toyota is right for you”, the company recalled nine million cars.

The truth is that medicine is far more dangerous than the motoring. An estimated 15 people died from driving 10 million cars at risk from the acceleration issue in the USA. If all drugs and other conventional treatments had to be withdrawn at that level of mortality, medicine would become impossible.

Drugs carry serious risks because of the way they work. A single molecule, such as cholesterol that is part of a complex interlocking system, is blocked or boosted with a drug – statins. Inevitably they do things you don’t want as well as the ones you do. And the more important the system you are blocking the more likely the harm. That’s why statins could cause the sort of brain damage that shows up in Alzheimer’s.

Last week I wrote about the growing evidence for links between the raised insulin and insulin resistance that diabetics suffer from and an increased risk of Alzheimer’s. What I didn’t appreciate then was that lowering cholesterol might be equally damaging.

You may be familiar with the idea that cholesterol is involved in brain function but maybe not just how important its role is. A review article in the European Journal of Internal Medicine last year makes it clear.

Cholesterol’s vital role

“The brain represents only 2% of the body’s total mass, but contains 25% of the total cholesterol,” reads an introductory paragraph. “Cholesterol is required everywhere in the brain as an antioxidant, an electrical insulator (in order to prevent ion leakage), as a structural scaffold for the neural network, and a functional component of all membranes. Cholesterol is also utilized in the wrapping and synaptic delivery of the neurotransmitters. It also plays an important role in the formation and functioning of synapses in the brain.”

Personally I’d want to know my odds of benefiting from blocking something that vital were better than the 100 -200:1 that is on offer from stains for primary prevention. The article goes on to describe a number of specific ways cholesterol is used in the brain.

It’s directly involved in the action of a gene known as ApoE. A harmful variation – ApoE4 – is well known to raised your risk of both heart disease and Alzheimer’s . So what does ApoE do? “It has an essential role in the delivery of fat, cholesterol, and antioxidants from the liver to all the cells of the body,” writes the author Stephanie Seneff, a Senior Research Scientist in the Computer Science and Artficial Intelligence Laboratory at MIT who has recently been turning her attention to biochemistry and medicine.

The ApoE4 variation causes brain problems because it doesn’t work so well and lowers the amount of cholesterol available to the hippocampus – the brain region crucial for memory.

More evidence for the harm from having too little cholesterol comes from research showing that Alzheimer’s patients have low levels of cholesterol in their spinal fluid, along with not enough lipoproteins, triglycerides, and free fatty acids. Parkinson’s patients, who also suffer brain damage, have low levels of cholesterol in their blood.

There’s still a lot more to be done to prove definitively that too too little cholesterol damages the brain along with too much insulin and glucose.But avoiding these two highly plausible risk factors is remarkably simple and doesn’t involve adding new risks the way drugs do. It’s what we advocate in our book. Make sure you have enough good fats and eat foods that don’t push up blood sugar.

It’s what Dr Seneff’s recommends too. “Simple dietary modification, towards fewer highly-processed carbohydrates and relatively more fats and cholesterol, is likely a protective measure against Alzheimer’s disease.”
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Statin Anti-Cholesterol Drugs Revisited - DACH

Statin Anti-Cholesterol Drugs Revisited By Jeffrey Dach (about the author)     (Page 1 of 7 pages) Life Arts 11/4/2012

This article takes a critical look at statin anti-cholesterol drugs, and asks the hard questions. Do statin drugs work? Who do they work for? Who do they harm? Who should be taking them, and who should not be taking them? Examples of Statin Drugs are Lipitor, Zocor, Simvastatin, Pravachol, Crestor, Mevacor, etc. These drugs reduce the production of cholesterol by the liver by inhibiting an enzyme called HMG-CoA. Due to a belief that cholesterol causes coronary artery disease, statin drug reduction of cholesterol is a mainstream medical treatment intended to prevent heart disease. Do statin drugs prevent coronary artery disease, heart attacks and mortality from heart disease? This article will answer that question.

Anti-Inflammatory Effect

After many decades of study and clinical trials, it has become clear that the benefit of statin drugs (if there is any) is probably not due to reduction in cholesterol, rather it is due to an anti-inflammatory effect of the drug.(link)

Reducing CoQ-10

Coincidentally, statin drugs inhibit the production of an important mitochondrial cofactor called Co-Q10, accounting for adverse effects as mitochondrial toxins. In addition, a low serum cholesterol level is a health risk for many reasons. Cholesterol is an important molecule in the body, and reducing cholesterol to low levels is associated with increased mortality and adverse effects on health. (27)

Asking A Few Questions

In this article we will revisit anti-cholesterol statin drugs while asking the following questions:

1) What is the efficacy for statin drugs in primary prevention of heart disease (in normal healthy people)?

2) What is the efficacy of statin drugs in secondary prevention (patients with known underlying heart disease)?

3) Which subgroups benefit from statin drugs, and which subgroups of the population are harmed by statin drugs?

The Elderly - Low Serum Cholesterol Predicts Increased Mortality

First, let's take a look at the medical practice of prescribing statin anti-cholesterol drugs for the elderly. Contrary to current dogma, higher cholesterol levels in the elderly are not a heath risk. Studies show that higher cholesterol in the elderly is associated with increased survival, while lower total serum cholesterol values in the elderly are a robust predictor of increased mortality. (1, 4,5)

The Prosper Study - Statins for the Elderly

When statin drugs are given to the elderly to reduce cholesterol values as was done in the PROSPER study, there was no mortality benefit for either primary or secondary prevention of heart disease. (1,6,7) True, there was a reduction in cardiac mortality of about 20% in the secondary prevention group in the Prosper study, however, this was counterbalanced by an increase in cancer mortality, yielding no over-all mortality benefit in the final analysis.

Women- No Mortality Benefit from Statins

Perhaps the best summary of the results of three decades of statin drug studies in women can be found in the Judith Walsh MD report in JAMA May 2004. (8) Again, Dr Walsh found that statin drug treatment to reduce cholesterol in women provided no mortality benefit in both primary and secondary prevention of heart disease. As we found in the PROSPER study for the elderly, statin drug use in women (with known heart disease) resulted in a reduction in mortality from heart disease, and a reduction in heart attacks in this secondary prevention group, however, this was offset by additional deaths from cancer and other mortality which yielded no over-all mortality benefit in the final analysis. (8)

MEN and Women- Primary Prevention- Dr Ray Archives of Internal Medicine

1 | 2 | 3 | 4 | 5 | 6 | 7

Jeffrey Dach MD is a physician and author of two books, Natural Medicine 101, and Bioidentical Hormones 101, both available on Amazon, or as a free e-book on his web sites. Dr. Dach is founder and chief medical officer of TrueMedMD, a clinic in (more...)

 

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New cholesterol-lowering drug is licensed despite no evidence of benefits for health - Briffa

 Another new cholesterol-lowering drug is licensed despite no evidence of benefits for health

I was reading here that there’s a new cholesterol-lowering drug in the pipeline. The Food and Drugs Administration in the US has approved the injectable agent mipomersen for the treatment of ‘homozygous familial hypercholesterolaemia – a genetic cause of raised cholesterol levels associated with cardiovascular disease developing early in life. Mipomersen has been shown to reduce low density lipoprotein (LDL) levels by about a quarter. The hope is that this will help reduce the risk of individuals suffering premature death from, most likely, heart attack.

I’ve used the word ‘hope’ in the preceding sentence but, in reality, the FDA panel that has ratified mipomersen has no idea whether it has health benefits or not. That’s because the studies used to assess this drug were not large enough in scope to detect change in ‘clinical endpoints’ such as risk of heart attack or death. In other words, the licensing of this drug has been on the basis of its impact on ‘surrogate endpoints’ (in this case, cholesterol levels), rather than clinical endpoints (the thing that really matters).

And I’m not splitting hairs either, as we already have examples in the not-too distant past of drugs that promised a lot in terms of their impact on cholesterol, but failed to deliver in terms of actual health. For example, the drug ezetimibe is a proven cholesterol-lowerer, yet not one single study to dates demonstrates it has benefits in terms of clinical endpoints. Also, the drug torcetrapib looked at one time to be a new hero of cholesterol management, until appropriately designed studies found it was killing people (it’s since been dropped).

But the principle that something that benefits cholesterol does not necessarily benefit health does seem to have been somewhat lost on the FDA. And worse still, it seems the panel may have put their faith in cholesterol modification above some quite troubling data. Here you can read how the FDA’s own review of mipomersen revealed a number of concerns about this drug. Here’s an excerpt from the article:

Serious adverse events of cardiac disorders occurred in 3.8% (10/261) of patients in the mipomersen group compared with 3.1% (4/129) in the placebo group. The reviewers concluded that “the possibility that mipomersen therapy increases the risk for cardiovascular events cannot be excluded.”

Other concerns were raised by the finding that mipomersen increased the levels of ‘liver enzymes’ and increased the amount of fat in the liver (both signs of damage to the liver). Here’s another except:

The FDA reviewers said they did not know whether long-term use of mipomersen could cause irreversible liver damage, but warned that patients could be at risk for cirrhosis and liver-related death if the observed liver changes progressed.

And perhaps worse still, there’s even concern that mipomersen might have cancer-inducing potential:

According to the review, during clinical testing neoplasms, both benign and malignant, were detected in 3.1% (23/749) of patients who received mipomersen compared with 0.9% (2/221) of patients who received placebo. However, the FDA clinical reviewer noted that there was a diversity of malignant neoplasms and that two out of nine mipomersen patients who developed a malignancy had been on mipomersen for less than a month, “making it highly unlikely that mipomersen played a role.” The review concluded that ”there are several confounding factors that make it difficult to conclude that mipomersen is playing a dominant role in this cancer imbalance.”

Forgive me, but personally I detect a hint of ‘sweeping the issue under the carpet’ here. The same thing, by the way, happened with ezetimibe, which has been shown to increase the risk of death from cancer, an effect which researchers put down to chance (even though the effect was statistically significant and therefore highly unlikely to be due to chance). See here for more about this.

The FDA panel’s vote on mipomersen was relatively close (9 v 6), so at least some members of the panel had their doubts. It is said that the severe nature of homozygous familial hypercholesterolaemia was a major determining factor in swaying the vote. That’s laudable, perhaps, but I don’t think it excuses the fact that this drug has been licensed despite an absence of data that it benefits health, as well as the presence of data which points very much in the opposite direction.
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