May 30, 2012

Cholesterol

The straight dope on cholesterol – Part VI

In this post we’ll address the following concept: Why is it necessary to measure LDL-P, instead of just LDL-C?

Read Time 13 minutes

Previously, in Part I, Part II, Part III, Part IV and Part V of this series, we addressed these 7 concepts:

     #1What is cholesterol?

     #2What is the relationship between the cholesterol we eat and the cholesterol in our body?

     #3Is cholesterol bad?

     #4 How does cholesterol move around our body?

     #5 How do we measure cholesterol?

     #6How does cholesterol actually cause problems?

     #7Does the size of an LDL particle matter?

 

(Not so) quick refresher on take-away points from previous posts, should you need it:

  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 formsunesterified 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.
  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. 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.

 

Concept #8 – Why is it necessary to measure LDL-P, instead of just LDL-C?

In the growing list of reasons why I used to refer to myself as “chick-repellant” in college, I have a confession to make: I find the topic of statistical concordance and discordance to be so exciting, I sometimes have a hard time containing myself. This may explain the paucity of girlfriends in college. Let me use an example to illustrate the distinction between these terms.  Let’s say you want to predict the change in home prices in the following year (I used to model this for a living).   There are at least a dozen parameters linked to this, including: GDP growth, unemployment, interest rates (both short term and long term, though to different degrees), housing inventory (i.e., how many houses are on the market), housing absorption (i.e., how quickly houses go from being on the market to being sold), major stock indices, and consumer confidence.  Historically, from the mid-1990’s until about the fourth quarter of 2006, this worked like clockwork.  While each of these variables had differing strengths of predicting changes in home prices, they all moved together.  For example, when GDP growth was robust, unemployment was low, interest rates were modest, housing inventories were about 60 to 90 days, etcetera.  All of these variables pointed to a predictable change in home values.

Around Q42006 (i.e., last 3 months of 2006), one of these variables began to deviate from the others.   The details aren’t important, but the point is one variable began to suggest home prices would fall while the others all pointed to a continued rise.   Prior to Q42006 these parameters were said to be concordant – they all predicted the same thing – either up or down.  By 2007, they became discordant – one variable said the sky was falling while others said everything was fine.

This was true on the “micro” level, too. [What I described above is called “macro” level.]  As a lender, it should be very important to know the risk of each and every loan you make (clearly this was part of the root problem in the age of mass securitization).  Will this person pay the loan back or will they default?

Same game here, but now a new set of even greater variables.  As a lender, if I want to know if YOU will default, I will want to know a lot of things about you, such as your agency credit risk scores, your bank account activity, payroll activity, how much you’re borrowing relative to the value of your house, where your house is located, and about 50 other things (literally).

Not surprisingly, the same thing that happened on the macro side happened on the micro side.  It became difficult to predict who would default and would not default because there were so many variables to consider and lenders didn’t know which ones were still predictive.  The models that predict default are very sensitive to the balance of these inputs.  When all of the variables are concordant, their accuracy is prophetic, as was the case from the mid-1990s until late 2006.  When some variables become discordant with each other, especially variables that were historically concordant with each other, really bad stuff happens, as became evident to me, personally, one Thursday afternoon in November 2007.  It became clear the sky was about to fall.  And, of course, it did.

 

What does real estate have to do with atherosclerosis?

Fortunately, predicting heart disease is a little easier than predicting changes in home prices.  It’s not perfect, of course, but it’s pretty good.  Why is it not perfect? For one thing, we can’t do the “perfect” experiment.  The “perfect” experiment would look something like this:

Take 100,000 people and randomize them into four matched groups, A, B, C, and D.  Wave a magic wand (you can see why this experiment hasn’t been and won’t be done) and give the folks in Group A an LDL particle concentration of, say, 700 nmol/L; those in Group B you give 1,200 nmol/L; those in Group C you give 1,600 nmol/L; and those in Group D get 2,000 nmol/L.

In our dream world, due to the randomization process, these four groups would be statistically identical in every way except one – they would, thanks to our magic wand, have a different number of LDL particles.  We would follow them without further intervention for 10 years and then compare their rates of heart disease, stroke, and death.

There are some areas in medicine where we can do such experiments.  But, we can’t do this experiment for this question.  Even when we do the next best thing — give people a drug that lowers their LDL-P and measure the impact of this intervention — there is always a chance we’ve done something in addition to “just” lowering LDL-P.   If you’ve been reading this series, you no doubt know my thoughts on this: while other factors are likely to be involved the pathogenesis of atherosclerosis (e.g., endothelial “health”, normal versus abnormal inflammatory response) the primary driver of atherosclerosis is the number of apoB trafficking lipoproteins in circulation, of which LDL particles are the vast majority.

The data below should further clarify this association.

 

What do concordant LDL-C and LDL-P values look like?

Among the two largest studies tracking the association between cholesterol and atherosclerotic mortality are the Framingham study and the MESA trial (the two largest trials were AMORIS and INTERHEART).  The figure below, which I’ve graciously borrowed from Jim Otvos, shows the risk stratification of LDL-C (top) and LDL-P (bottom) from the Framingham study and MESA trial, respectively. As you can see, conveniently, LDL-C values in mg/dL are about 10x off from LDL-P values in nmol/L.   In other words, in the Framingham population, the 20th percentile value of LDL-C was 100 mg/dL, while the MESA trial found the 20th percentile of the population to have an LDL-P concentration of 1,000 nmol/L.  As you will see by the end of this post, this “rule of the thumb” should never be used to infer LDL-P from LDL-C.

 

Cut-off points for LDL-C and LDL-P
Image credit: Jim Otvos

If this were always the case – that is, if LDL-C and LDL-P were always concordant – we could conclude that LDL-C and LDL-P would be of equal value in predicting heart disease.  Obviously this is not the case, or I wouldn’t be making such a fuss over the distinction.  But how bad is it?

 

What do discordant LDL-C and LDL-P values look like?

The figure below, from the Journal of Clinical Lipidology, shows the cumulative incidence of cardiovascular events (e.g., myocardial infarction, death) over time in three sub-populations:

  1. Those with concordant LDL-P and LDL-C (black line);
  2. Those with discordant LDL-P and LDL-C (LDL-P>LDL-C, shown by the red line);
  3. Those with discordant LDL-P and LDL-C (LDL-P<LDL-C, shown by the blue line).

This analysis was done using a Cox proportional hazard model and was adjusted for age, sex, and race.  The steeper the line the more people in that sub-population died or experienced adverse cardiac events relative to other sub-populations.  In other words, the folks in the red group had the worst outcomes, followed by the folks in the black group, followed by the folks in the blue group.

 

MESA LDL-P vs LDL-C

What can we infer from these data?

First, we confirm what I alluded to above.  Namely, that a non-zero percent of the population do not have LDL-C and LDL-P values that predict the same level of risk.  However, and perhaps more importantly, we get another look at an important theme of this series: LDL-P is driving atherosclerotic risk, not LDL-C.   If LDL-P and LDL-C were equally “bad” – even when discordant – you would expect the blue line to be as steep as the red line (and both to be steeper than the black line). But this is not the case.

Let’s look at these data parsed out another way.  Below we see the four possible subgroups, from the top:

  1. Not low LDL-P, low LDL-C (red line);
  2. Not low LDL-P, not low LDL-C (yellow line);
  3. Low LDL-P, low LDL-C (black line); and
  4. Low LDL-P, not low LDL-C (blue line).

Note that “low” is defined below the 30th percentile and “not low” is defined as greater than 30th percentile for each variable.   This figure is even more revealing than the one above.  Again, it demonstrates the frequency of discordance (about 20% in this population with these cut-off points), and it shows the importance of LDL-P’s predictive power, relative to that of LDL-C.

In fact, though not statistically significant, the highest risk group has high LDL-P and actually has low LDL-C (I’ll give you a hint of why, below) while the lowest risk group has low LDL-P and not-low LDL-C.  *This is not a typo.

 

MESA LDLp vs LDLc 4 groups

The highest risk and lowest risk groups are those with discordant LDL-C and LDL-P.  The high risk group has high LDL-P and low LDL-C, while the lowest risk group has high LDL-C with low LDL-P. Only a minority of physicians would know that there is a segment of the population with elevated LDL-C who are at low risk! The same conclusion will be drawn from the next study.

Let’s look at an even longer-term follow up study, below.  This study followed a Framingham offspring cohort of about 2,500 patients over a median time period of almost 15 years in each of the four possible groups (i.e., high-high, high-low, low-high, and low-low) and tracked event-free survival.  In this analysis the cut-off points for LDL-P and LDL-C were the median population values of 1,414 nmol/L and131 mg/dL, respectively. So “high” implies above these values; “low” implies below these values.  Kaplan-Meier survival curves are displayed over a 16 year period – the steeper the slope of the line the worse the outcome (survival).

 

Survival curve
Image credit: Cromwell et al., 2007

The same patterns are observed:

  1. LDL-P is the best predictor of adverse cardiac events.
  2. 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.

Amazingly the persons with the worst survival had low (below median) LDL-C but high LDL-P.  The patients most likely to have high LDL-P with unremarkable or low LDL-C are those with either small LDL particles, or TG-rich / cholesterol poor LDL particles, or both (e.g., insulin resistant patients, metabolic syndrome patients, T2DM patients).   This explains why small LDL particles, while no more atherogenic on a per particle basis than large particles, are a marker for something sinister.

 

Populations where LDL-P and LDL-C discordance are even more prevalent

As I described above, the discordance between LDL-P and LDL-C is exacerbated in patients with metabolic syndrome. The figure below, MESA data, again borrowed from Jim Otvos, presents this difference in an elegant way.  The horizontal axes show LDL-P concentration in the usual units, nmol/L.

 

Otvos ADA
Image credit: Jim Otvos

Patients with LDL-C between 100 and 118 mg/dL (i.e., second quartile of risk: 25th to 50th percentile) are shown without metabolic syndrome (top) and with metabolic syndrome (bottom).  In the patients without metabolic syndrome, LDL-C under-predicts cardiac risk 22% of the time, consistent with the population data I have shown you earlier.  However, when you look at the patients with metabolic syndrome, you can see that 63% of the time their risk of cardiac disease is under-predicted.  Again, not a typo.

There are so many subsets and cut-off points that I could devote ten more posts to showing you every one of these analyses.  Let me finish this point with the most recent, hot-off-the-press (actually, still in press in the American Journal of Cardiology, though you can get a preprint here) analysis of which Tom Dayspring is one of the authors.

 

Evaluation of Low-Density Lipoprotein Particle Number Distribution
Image credit: Malave et al., 2012

These data were collected from nearly 2,000 patients with diabetes who presented with “perfect” standard cholesterol numbers: LDL-C < 70 mg/dL; HDL-C > 40 mg/dL; TG <150 mg/dL.  However, only in 22% of cases were their LDL-P concordant with LDL-C.  That is, in only 22% of cases did these patients have an LDL-P level below 700 nmol/L.

Remember, LDL-C < 70 mg/dL is considered VERY low risk – the 5th percentile.  Yet, by LDL-P, the real marker of risk, 35% of these patients had more than 1,000 nmol/L and 7% were high risk.  When you do this analysis with the same group of patients stratified by less stringent LDL-C criteria (e.g., <100 mg/dL) the number of patients in the high risk group is even higher.

The real world tragedy: 90-95% of physicians, including cardiologists, would bet their own lives that persons with an LDL-C < 70 mg/dL have no atherosclerotic risk. 

Tim Russert, shortly before his death, had his LDL-C level checked.  It was less than 70 mg/dL.  Sadly, his doctors didn’t realize they should also have been checking his LDL-P or apoB.  The figure below, which is from one of Tom Dayspring’s presentations, shows data from this study of nearly 137,000 patients hospitalized for coronary artery disease between 2000 and 2006.  As you can see, LDL-C fails to even reasonably predict cardiovascular disease in a patient population sick enough to show up in the hospital with chest pain or outright myocardial infarction.

 

Insulin Resistance Lipids & Lipoproteins

Why are LDL-C and LDL-P so often discordant?

Think back to what you learned in a previous post in this series.  LDL particles traffic not only cholesterol ester but also triglycerides.  Each and every LDL particle has a variable number of cholesterol molecules which, because of constant particle remodeling, is constantly changing.  In other words, of the several quadrillion LDL particles floating in your plasma, no two are carrying the exact same number of cholesterol molecules. It takes many more cholesterol-depleted LDL particles than cholesterol-rich LDL particles to traffic a given cholesterol mass (i.e., number of cholesterol molecules) per volume of plasma (i.e., per dL).  Core cholesterol mass is related to both LDL particle size (the volume of a sphere is a third power of the radius — it can take 40-70% more small particles than large LDL particles to traffic a given cholesterol mass) and the number of TG molecules per LDL particle.

TG molecules are larger than cholesterol ester molecules, so as the number of TG molecules per particle increases, the number of cholesterol molecules will be less – in a very non-linear manner. Regardless of size it takes many more TG-rich LDL particles (which are necessarily cholesterol-depleted) to traffic a given cholesterol mass than TG-poor LDL particles.  The persons with the highest LDL particles typically (though not always) have small LDL particles that are TG-rich.  These are incredibly cholesterol-depleted LDL particles.

 

Summary

Take a look at this figure below from the 2011 Otvos et al. paper I referenced above.  It’s a scatterplot of each data point (i.e., patient) in the study. The solid red line shows perfect concordance between LDL-P and LDL-C.  The dashed red lines show a +/- 12% margin on each side.  Look at how many dots (remember: each dot represents a person) lie OUTSIDE of the dashed red lines. Now look again.

 

MESA LDLp vs LDLc J Clin Lip2011

When people argue with me about why it’s unnecessary to check LDL-P or apoB because it’s much easier and cheaper to check LDL-C, I like to remind them of what Clint Eastwood would probably say in such a situation:  You’ve got to ask yourself one question: Do I feel lucky? Well, do ya, punk?”

 

  1. 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.
  2. LDL-P (or apoB) is the best predictor of adverse cardiac events, which has been documented repeatedly in every major cardiovascular risk study.
  3. 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.
  4. There is no way of determining which individual patient may have discordant LDL-C and LDL-P without measuring both markers.
  5. 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.
  6. This raises the question: if indeed LDL-P is always as good and in most cases better than LDL-C at predicting cardiovascular risk, why do we continue to measure (or calculate) LDL-C at all?

Photo by Aldric RIVAT on Unsplash

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320 Comments

  1. Please people, lets try to remember that this is epidemiology and correlation is NEVER cause. Any association between LDL-P and CVD is confounded by insulin resistance which results in elevated triglycerides and therefore increased small LDL-P (essentially the cause of elevated LDL-P as small particles displace larger ones.) As the Framingham data <a href="http://www.theheart.org/documents/sitestructure/en/content/programs/1162245/images/10.jpg&quot; clearly shows, "discordance" begins at TG levels greater than 150. That is why a study <a href="http://www.theheart.org/article/767865.do&quot; discussed above found both that controlling for TG's and HDL abolished the predictive power of LDL-P. That study also found that when subjects with MetSyn were stratified by small LDL-P levels, there was no association with CVD suggesting that something else was causing arteriosclerosis (inflammation?, glycation?). "Discordance", then, would seem to be a marker for insulin resistance and MetSyn rather than LDL-P being a cause of anything. Many of the people discussed in these comments with higher range LDL-P are unlikely to be suffering from MetSyn, so before we start medicating otherwise healthy people on the basis of LDL-P, please produce the randomly controlled trials showing that treating to that value results in meaningful reductions in general as opposed to relative risk (NNT- numbers needed to treat). The record of statins in that regard is dismal. First it was TC, then HDL/LDL, then small v. large particles. Now we have LDL-P being pushed by "advanced lipodologists." Anybody see a pattern here?

  2. Peter, thank you for taking the time to make this information available. I found your blog just last week from one of your reader’s who linked to it and I’m glad I did.

    Based on the amount I’ve been able to read on your cholesterol posts, I’ve scheduled an NMR test for next week.

    I’m a little stressed because last week my internist told me he wanted me on Lipitor based on a standard lipid profile(total 272, LDL 163, HDL 98, trig 53). I told him “no thanks” for now and am trying to get a better understanding of things before I agree to go on a statin. I’m trying to read as much of your posts as I can along with other information I can find.

    I follow a “lowish” carb Primal diet and have for a little over two years. Work out regularly, and have no weight issues (wouldn’t mind putting on a few pounds actually).

    I have a couple questions:
    • Can the exercise a person does the day before having blood drawn impact the lipid profile? I did a hard sprint session the day before as I had forgot about my appointment.
    • What would be a good resource to help me analyze the results of the NMR test? I have not found a “scale” yet to tell me what would be considered a high LDL-P count. My test is kind of worthless until I can learn what the numbers mean.

    Thanks again

    • William, SO FUNNY that you ask about the impact of hard workouts on lipid profile. I’m just getting ready to kick off one of my most outrageous self-experiments looking at this based on some preliminary data. I would say the following, for now have your NMR done in the “usual” way — overnight fast, no workout that morning.
      As far as NMR goes, an LDL-P of 1,000 nmol/L is considered the 20th percentile of risk; 50th percentile is around 1,250-1,300. 2,000 is about 90-95th percentile.

    • William,

      You don’t need an NMR. You only need to do one simple thing- ask your internist to quantify for you, hopefully based on randomly controlled trials, the “Number Needed to Treat”, for a person in your risk category. In other words, out of every hundred people in that category, how many need to take Lipitor to effect a change in a hard, clinical endpoint (i.e. death, serious event, etc)? Another way to ask the question is to ask for the change in general risk as opposed to relative risk. In other words, if for a person in your risk category the chance of death or a serious event is 5 in 100, how much does it go down with statin treatment? Take these numbers and bearing in mind the side effects, acknowledged and unacknowledged, make up your own mind. If your internist cannot or will not produce these numbers, change doctors. If you do obtain the numbers, I believe you will be shocked how small they are even in terms of the most optimistic studies.

      You may also wish to review my comment above given your lipid profile. Assuming your BP and blood glucose levels are ok, it is highly unlikely that you are insulin resistant. I am certainly not giving medical advice here but it is my opinion that there is no conceivable reason for an otherwise healthy person to take a statin drug full stop.

      • I disagree entirely with this comment, Hasan, but I agree everyone should have their say.
        It’s important for readers to know that I don’t agree with many comments posted on the blog, but I don’t censor them, either. Obviously, I can’t take the time to respond to all of them.
        William, the choice is yours. In the next few weeks I’ll start go over some “real life” examples of the how advanced lipid and metabolic testing can uncover completely treatable conditions that are missed by only looking at the simple stuff. I’ll cover the number needed to treat issues in a future post, as it’s a fair question posed by Hassan.

  3. Peter,

    Its no surprise that you completely disagree with me since I also disagree with the very premise of this series which appears to be pushing yet another “screening” to the U.S. medical system. It distresses me greatly that in the discussion, persons such as William are not being asked a single question either about their actual health nor about any other standard parameters used to assess risk. In William’s case, I made some assumptions (age 45, BP 120/80, non-smoker, no BP meds) and came up with a 10-year Framingham risk score of 3%. Even a 2011 Expert Panel of Lipid Specialists:

    http://www.lipid.org/uploads/300/Expert%20Panel%20Paper.pdf

    with whom I would no doubt disagree on statins, does not recommend LDL-P testing for low-risk patients such as this. On what basis does he need an NMR then? I think you hint at the answer when you say that an NMR can “uncover completely treatable conditions that are missed by only looking at the simple stuff.” This is more screening madness pure and simple and haven’t we gone far enough down the road of turning healthy people into patients (PSA tests and mammograms come to mind not to mention “full-body CT scans” and other insanity)? There is simply no evidence that William is ill in any way and from his comment, I suspect that he is rather healthy. No doubt that if submits to enough testing of various kinds, some kind of “treatable condition” will be uncovered with medication or other treatments to follow. As I said…..madness. (As I wrote above, there isn’t even any evidence that LDL-P testing can improve risk assessment over the standard lipid panel when TG and HDL are taken into account.) Although William did not provide his lipid panels prior to his dietary change, there have been enough reports of increases in LDL-C on such diets to wonder how it might be that so many people have suddenly developed “treatable conditions.” Far more likely is that for reasons yet unknown, these diets simply result in an increased level of LDL (as measured by both LDL-C and LDL-P). As already discussed, whether this is good or bad has yet to be determined. If William is not comfortable with his lipid panel, the easiest thing for him to do is go back to his old way of eating and the issue will likely go away. So, it appears he has three choices- an NMR and the path with statins likely at the end, returning to his old way of life, or choosing to live his life based on something other than a lipd panel. I hope he lets us know which he chooses and how well it works out for him.

    As far as “real life” examples from NMR testing, sorry but irrelevant. Every kind of screening can produce testimonials as to how illnesses were discovered and lives were saved (see the recent controversy over the Preventive Services recommendation on PSA testing). What is always missing is the other side of the coin– all those people who were subject to unecessary medication and/or medical procedures as a result of the test. No doubt that if NMR testing became routine, yet another large sub-group of people would find themselves on statins or other medication. The only relevant consideration is Numbers Needed To Treat and I anxiously await your response in this regard. In the meantime, I suggest that medicine return to its traditional role of treating illness.

    • Hasan, I agree with the spirit of what I think you are saying (make an informed decision on a case-by-case basis), but you’re missing a few points. (For the sake of time, not interest, this will be my last comment on this thread. You only need to respond to me. I need to respond to a 100 others…)

      1. Framingham risk scores, which you reference in your last comment, are driven almost entirely by age. This is not a bad thing, as Allan Sniderman the “father” of understanding apoB as a risk factor has recently written, because exposure to apoB increase with age. However, there are other risk factors that are not well captured by Framingham. It’s important to keep this in mind before suggesting to William that he’s probably fine. Keep everything the same in William’s “case” but increase his age to 65, and watch the risk go up. Why? As Sniderman and others far more knowledgeable on this topic than you-and-I-put-together-squared will argue, it’s because of intimal exposure to apoB. It’s all about the AUC of apoB particles and intima.

      2. I don’t know if you’re a doctor or not, or if you’ve seen the healthcare system on the inside or not, but let me share my thoughts. Both in my time in clinical medicine taking care of patients every day and while at McKinsey doing healthcare consulting for the largest hospital systems in the U.S. and beyond, I gained insights I could not have otherwise appreciated from reading about the problem. You suggest “medicine return to its traditional role of treating illness.” Are you being facetious? Hasan, what the heck do you think we’re doing in medicine? We spend 18% of our GDP on healthcare more than any other country in both absolute AND relative terms. This is the essence of medicine and healthcare in the U.S. — we spend huge dollars treating illness! I don’t recall the exact number, and I’m sure it’s changed since I was last walking the halls of Hopkins, but we looked at clinical data and found that we spent over 80% of a person’s entire healthcare dollars in the last 30 days of their life. If there is one thing medicine is good at it’s dumping the most heroic interventions on at the last moment, often for little good. I could write a book chapter on this topic, but haven’t the time. If you think it’s more economical to treat someone with an LVAD or IABP or even “just” a CAB or PTCA once they’ve had an MI, you’re quite mistaken. Medicine talk about prevention, but actually does a lousy job. Don’t assume because that because the Western medical system is lousy at implementing prevention, that prevention is bad. You’re throwing the baby out with the bath water.

      3. While I know you’re not trying to “play doctor” I’d ask you to reconsider “assuming” William is fine. It’s not your role or mine to do this. You’re free to do and say you like, as is William free to regard or disregard what you or I say, but the internet is funny place. Try to show a bit of restraint when giving advice directly to someone you’ve never laid hands on. If I can’t look someone in the eye and answer every question they have, I don’t give medical advice.

      4. For a NNT analysis look at the following study, Circulation 2000;101:477-484. This study, one of the few to look not only at LDL-C, but also apoB, provides the data you want to do the analysis (i.e., NNT = 1/abs_risk_reduction_rate x 100). As you will see, apoB is better than LDL-C at predicting outcomes and reducing apoB saves lives. Figure 3 addresses your question for one particular statin (lovastatin). This is not the same as saying a reduction of apoB from X to Y with a lifestyle change results in Z abs risk reduction, but unfortunately those data do not exist, so we use the best data we have.

      Finally, I’m not telling anyone to take a drug, to stop eating sugar, or to do more jumping jacks. My personal belief is that dietary intervention (i.e., “proper” lifestyle change) should be first line for most lipid abnormalities. We can have a discussion about the role and risks of statins another time, but I worry you’re guilty of the same thing you’ve accused me of. When I talk about examples of where NMR offers insight standard testing does not, I’m not talking about one-off “testimonials,” which I agree are of little value. I’m talking about 30% of the people I look at. Since I can’t post hundreds of lab results, I will (assuming people are interested in seeing it – I realize you’re not) post select cases where a teaching point can me made. I would argue that your concern of over-use of statins is less robust. If you have patient data showing that 30% of patients on statins develop rhabdo, I’d like to see it.

      It’s always possible to find an example of someone who had an adverse reaction on a statin or an antibiotic, for that matter. In fact, on per dose basis there are more adverse reactions to antibiotics than any other class of drug. Should we abandon antibiotics altogether? When your child has Strep throat are you going to treat it with the appropriate antibiotic (knowing there is a non-zero chance of a horrible reaction) or will you take a chance? What about vaccination? You’re on a slippery slope. I won’t pretend to know all of the answers, and I certainly don’t know the answer for anyone else beyond myself. The reason I’m responding at length is because I think there’s a bit too much arm-chair medicine going on out there. It’s great (and important) to do NNT analyses and machinate about every little possible side-effect of drug X or drug Y, but at some point you have a make a personal decision with imperfect and incomplete information. Do you feel lucky? Sounds like you do. Does William? It’s his call. Not mine and not yours.

    • Peter (and Hasan),
      I can’t tell you how much I appreciate the dialogue and well thought out comments.
      I received my results from the NMR Lipoprofile today and have to admit I feel like I had a heart attack (exaggerating a little) when I saw my LDL-P number of 1611 nmol/L. LDL-C was 181, trig 41, HDL-P 40.8
      I’m trying to remain calm. I realize there’s not a lot I can do right this moment, but now my concern turns to what I can do. I believe in the “primal” type diet. To address some of Hasan’s comments: I’m a 41 y/o male, lean, 6’2″ tall, weigh about 190 lbs. Desk jockey, work out 4 or 5 times weekly. I feel like I have good energy levels and sleep fairly well. I have a 3.5 year old daughter who I have no problem keeping up with.
      I thought I was doing things right.
      It is starting to appear I am doing something wrong, however. I’m still not to the point of wanting to take statins, but wonder what I should do from here. Are there other tests that might help me pinpoint a problem area or should I adjust my diet (still Primal) to try to get the LDL-P down?
      I realize Peter, that you can’t give advice here, but any resources you could point me to would be hugely appreciated.
      Thanks again for all the information you provide and for your consideration and time for this blog. Good luck with your Eating Academy Project.

  4. 1. ” However, there are other risk factors that are not well captured by Framingham. ”

    Ok, like what? As I read it, the only risk factor you have advanced here is LDL-P and, according to the study I referenced, LDL-P lost its predictive power when TG’s and HDL were controlled for.

    2. “Keep everything the same in William’s “case” but increase his age to 65, and watch the risk go up”

    Yes, but why is the 64k question and it is far from being settled, Sniderman and others to the contrary but this is not the place to take that up. Whatever the age, I see no evidence that reducing LDL-P though medication has any significant impact in otherwise healthy people.

    3. “You suggest “medicine return to its traditional role of treating illness.” Hasan, what the heck do you think we’re doing in medicine? This is the essence of medicine and healthcare in the U.S.

    I would suggest that the essence of medicine and healthcare in the U.S. is making money…also beyond this discussion.

    4. “Don’t assume because that because the Western medical system is lousy at implementing prevention, that prevention is bad. You’re throwing the baby out with the bath water.

    Au Contraire! Nobody, myself included, would argue against prevention…thats like arguing against motherhood and apple pie. That said, we are talking here about screening and that is a HUGE difference. Screening only becomes prevention when more good is done than harm and that isn’t event remotely established with LDL-P which is I suspect why the Expert Panel does not recommend it for low risk patients. As noted earlier, the track record on screening is not good (PSA, mammograms, etc, etc) and runs the very real risk of turning healthy people into patients. For more on this I recommend the works of David Newman M.D., H. Gilbert Welch M.D., and writer Sharon Brownleee.

    5. ” I’d ask you to reconsider “assuming” William is fine”

    I believe I said in the absence of anything to the contrary, he seemed fine. I was the one who raised the point of actually assessing a person’s health before concluding that testing is required. Nobody else seems considered about anything but cholesterol.

    6 “If I can’t look someone in the eye and answer every question they have, I don’t give medical advice.”

    Don’t you think that suggesting an NMR for everybody who comes here to be “medical advice.”

    7. “For a NNT analysis look at the following study, Circulation 2000;101:477-484. This study, one of the few to look not only at LDL-C, but also apoB, provides the data you want to do the analysis (i.e., NNT = 1/abs_risk_reduction_rate x 100).”

    Ok, I’m game. If you go to this table from that study:

    http://circ.ahajournals.org/content/101/5/477/F3.expansion.html

    you will see that the largest risk reduction is in the fourth group (40 events in the treatment group v. 75 in the placebo.) My calculations therefore show a NNT of 99.3 for three years and that is taking the study on face value without any analyis. This is the study you want to cite as advancing your cause? I, the words of Nortin M. Hadler, professor of medicine at the University of North Carolina at Chapel Hill “Anything over an NNT of 50 is worse than a lottery ticket; there may be no winners.”

    8. “I’m not telling anyone to take a drug, to stop eating sugar, or to do more jumping jacks. My personal belief is that dietary intervention (i.e., “proper” lifestyle change) should be first line for most lipid abnormalities”

    Thats pretty ironic since the low carb/high fat diets you appear to be suggesting are the ones that are spiking the LDL numbers in the first place. I am not saying thats good or bad but to recommend such a diet and then tell people whose LDL is elevated as a result that they need testing and treatment is incomprehensible to me. Perhaps you would advise in these cases some further dietary modification (I will wait for the end of the series to see) but people who go to Dr. Dayspring with these kind of numbers are going to leave with a statin prescription in hand and it is to him and other “advanced lipidologists” you are referring people seeking treatment.

    9. “on per dose basis there are more adverse reactions to antibiotics than any other class of drug. Should we abandon antibiotics altogether? ”

    Please see point #4 above. Its always a question of doing good v. harm which is why I asked for the NNT. With appropriate use of antibiotics, the NNT approaches 1 which is so far away from statins that they shouldn’t be mentioned in the same breath. That said, as we all know, antibiotics are routinely used to treat such things as the common cold for which the NNT is infinite.

    9. ” It’s great (and important) to do NNT analyses and machinate about every little possible side-effect of drug X or drug Y, but at some point you have a make a personal decision with imperfect and incomplete information.”

    Indeed which is why I am taking the time here to try and provide more complete information. As I said, almost everybody who walks into the office of an “advanced lipidologist” with LDL numbers typical of those being reported here is going to end up on a statin. They deserve to get a more complete picture than the on being presented here and, BTW, I wouldn’t so cavalierly dismiss the concern about statin side effects as machinations about “every little possible side-effects.” Do I need to elaborate?

    • Hasan, you have disregarded the single most important line in my previous response: “For the sake of time, not interest, this will be my last comment on this thread. You only need to respond to me. I need to respond to a 100 others.”
      You’re really tempting me to respond, though. But I will refrain. I have to. I have more to get done today and tomorrow and the day after that than you can probably imagine. I don’t expect you to understand or appreciate what I’m doing or trying to do, but don’t interpret my lack of a rebuttal for anything other than a lack of time. I do like your passion, though. Perhaps you should also consider a blog of your own. It seems like you’d have something very valuable to contribute, as I think you are doing here.

    • Hasan,

      Thanks for pointing to new data. One of the reasons that I enjoy Peter’s site so much is that Atkins and other LCHF diet proponents never provided enough scientific justification for their diets and the sheer amount of data here is phenomenal. That being said, I think that may be some flaws in your reasoning.

      Given William’s numbers (total 272, LDL 163, HDL 98, trig 53), I could see three scenarios playing out in doctor’s offices, depending (mostly) on their adoption of the LDL-P hypothesis.

      1. Traditional – Total>200, straight to statins. (May also justifiably be the first course of any doctor in this litigious society, but I digress.)
      2. Curious – Total>200, BUT TC/HDL-C= 2.8, TG/HDL-C=0.54, very interesting, let’s find out more.
      3. LDL-P Aware – Discordant data, not enough information without the LDL-P results.

      When you say that LDL-P testing is unnecessary in these cases, one assumption that you make is that doing the test will lead to more statin prescriptions when the data does not show that. True, if discordant low TC/high LDL-P patients are prescribed statins (as one possible outcome), statin use would go up, but that may also significantly reduce their CVD risk, which they would not have known about without LDL-P. On the other hand, if William’s LDL-P comes back <1000, an LDL-P aware doc may not put him on statins based on just his TC level. Per the Elviser chart on this site and on pg.355 in your link: http://www.lipid.org/uploads/300/Expert%20Panel%20Paper.pdf
      The distribution of the discordancy seems fairly even.

      Which is why it doesn’t make sense to me that the expert panel in that paper recognizes that new data shows LDL-P to be important, recommends it for medium and high risk discordant situations, but then does not recommend it in low risk situations. Without the additional data of LDL-P, I don’t know how they can make that judgment, especially since NMR is not that expensive (IMHO). Their reasoning seems, for lack of a better word, discordant.

      Also, in your cited paper: http://circ.ahajournals.org/content/101/5/477.full.pdf+html
      You need to be careful as William does not fit into the cohort studied. His HDL-C is twice as high as the range allowed, something that may apply to many LCHF panels.

      And again, since data trumps assumptions, Dayspring’s algorithms are here: http://www.lipidcenter.com/pdf/Lipid_Treatment_Algorithm.pdf

      So, in the interest of time (for all of us), I think that Peter is in agreement with your desire to see more double-blind, placebo controlled LDL-P studies being done, which is one of his stated goals for NuSI.

      In answer to your question: “First it was TC, then HDL/LDL, then small v. large particles. Now we have LDL-P being pushed by "advanced lipodologists." Anybody see a pattern here?” – I would say yes, there is a pattern, it is called progress.

  5. As you wish…..we can certainly end it here. I would only add that it is a bit presumptive to assume that you have so more to do than I nor that I am incapable of understanding your purpose here. In fact, I almost never have the time to respond to blogs as I did here but I couldn’t sit back in silence any longer as I read through this series precisely because I believe I do understand your purpose.

    I reserve the right to comment on future postings if so moved.

    • Of course you can and should continue to comment on anything you see fit here! I’m sorry if I suggested I have more to do than you. That may or may not be true. I would like to continue this discussion, but let’s do it in person. Much more efficient. If you ever get to San Diego, please let me know.

  6. The discussion between Hassan and Peter describes the tense and frustrating debate over the past 10 years between my doctor and me following a high calcium score on a Heart CT scan when I turned 50. After two or three years of pressure, I started on 10mg Lipitor (never overweight, non-smoker, low to medium lipid numbers, low BP), then after increases in the CAC on two subsequent scans, was pushed to 20mg. After 18 months Paleo, standard lipid scores are up and my Doctor wants me on more Lipitor. My hope, from the information provided by Peter here, is that an NMR test might show an LDL-P low enough to make the decision to drop statins easier.

    In any case, the insight provided here by Dr. Attia is a godsend and is greatly appreciated. Decisions about what tests to demand and whether NNT analyses justifies a drug therapy or any particular test are still difficult, but at least can be made from a more informed position.

  7. JW,

    It appears that I was not clear enough above which may have resulted in some confusion about what I was actually saying. To whit:

    “When you say that LDL-P testing is unnecessary in these cases, one assumption that you make is that doing the test will lead to more statin prescriptions when the data does not show that.”

    When I referred to “these cases”, I had in the mind the sub-set of people on various diets described usually as either low carb or paleo. It is my impression that most of these are reporting LDL-C levels in excess of 150 with many if not most higher than 200 (somebody called this Paleo Lipid Syndrome, not sure where). Dayspring himself has said:

    “You certainly cannot rely on the LDL-C level as a lipid surrogate of LDL-P unless the LDL-C is very high (> 140 mg/dL).”

    http://www.lipidcenter.com/pdf/Advanced_Lipoprotein_Testing.pdf

    I am not sure exactly what he means by “surrogate” here but it suggests a reference to this scatterplot:

    http://ars.els-cdn.com/content/image/1-s2.0-S1933287411000274-gr1.jpg

    Visual inspection suggests that at LDL-C levels of 150+, it is unlikely if not impossible to have an LDL-P under the designated high risk level of 1000. Therefore in the cases I am talking about, people with LDL-C mostly in far excess of 150, an NMR is NOT going to get them “off the hook”, so to say. Other hypothetical scenarios aside, real-world evidence suggests that most, if not almost all. of these people are going to end up on statins.

    “True, if discordant low TC/high LDL-P patients are prescribed statins (as one possible outcome), statin use would go up, but that may also significantly reduce their CVD risk, which they would not have known about without LDL-P.

    In the case of “Paleo Lipid Syndrome”, it makes little sense to talk about discordance as per the above. Anybody with an LDL-C of 150+ (and therefore with an LDL-P > 1000) is going to be considered high-risk under the assumptions of this post but this begs the question of whether or not LDL-P, in the absence of other risk markers, is as definitive as is being claimed. I will accept for purposes of this discussion that LDL-P is superior as a risk marker for CVD over LDL-C but what about other markers such as TC/HDL or similarly LDL/HDL? We have already seen in the above reference that when Triglycerides and HDL were controlled for, LDL-P lost its predictive power which likely explains why LDL-P was superior to LDL-C in the first place- it contains information about TG’s and HDL that is not captured by LDL-C but is captured by ratios such as TC/HDL or simply looking at the standard lipid panel. As I have written, I believe all of this comes down to insulin resistance and MetSyn and if LDL-P is capturing additional risk, its because the LDL-P curve is shifted far to the right in people with MetSyn:

    http://eatingacademy.com/nutrition/the-straight-dope-on-cholesterol-part-vi/attachment/microsoft-powerpoint-ada-otvos-ldl-size-talk_modified-ppt-com-5

    ” if William’s LDL-P comes back <1000, an LDL-P aware doc may not put him on statins based on just his TC level. "

    This brings us to William's specific case. As already noted, with an LDL-P of over 163,
    William's LDL-P is overwhelmingly likely to be over the designated threshold of 1000. Whether or not that means he is destined for statins, and as you know I believe he is, the real question is whether or not he is, in fact, at high-risk for CVD in the absence of a single other risk parameter or health issue. For those who believe he is on the basis that all people should have an NMR, I have labeled this as an example of screening and for advocates of such NMR screening, they need to produce hard evidence that such screening actually does more good than harm. I won't repeat what I have already written above on this topic. Absent this evidence and given that LDL-P has not been demonstrated to have predictive power when TG's and HDL are controlled for, exactly what is the evidence-based criteria for an NMR? His TC/HDL ratio is more than fine, and that has been shown to be a superior risk marker over the single standard lipid parameters, and nobody here seems even remotely interested in his BP or blood glucose levels despite how important those parameters really are. Finally, my impression only, is that he is in good health and able to do strenuous sprinting sessions which denotes an individual who is taking care of himself. I think it is an example of the madness of the U.S. health care system that a seemingly healthy individual is pushed onto a medication solely on the basis of lab values such as these, whether LDL-C or LDL-P, and when the medication itself has such a small impact on an already small risk. (see discussion above)

    "Also, in your cited paper: http://circ.ahajournals.org/content/101/5/477.full.pdf+html You need to be careful as William does not fit into the cohort studied. His HDL-C is twice as high as the range allowed, something that may apply to many LCHF panels."

    I am not sure what you mean by "your cited paper" since it was Peter who cited this paper in support of statins. If anything, it speaks against his argument since the NNT was so small even with a cohort with such unfavorable lipid parameters.

    "it doesn’t make sense to me that the expert panel in that paper recognizes that new data shows LDL-P to be important, recommends it for medium and high risk discordant situations, but then does not recommend it in low risk situations. Without the additional data of LDL-P, I don’t know how they can make that judgment,"

    It makes perfect sense to me given everything I have written. Why submit people to further testing (and likely treatment) who are already at low risk when the marker does not appear to suggest higher risk in the absence of any other information to the contrary?

    "In answer to your question: “First it was TC, then HDL/LDL, then small v. large particles. Now we have LDL-P being pushed by "advanced lipodologists." Anybody see a pattern here?” – I would say yes, there is a pattern, it is called progress."

    You are of course entitled to your interpretation, but I clearly that this progression suggests a long-standing and on-going attempt to confine the totality of CVD to lipid parameters. As for why this might be, I suggest we look to the vast profit and/or profit potential in lipid testing. I don't feel like shelling out $4500 for the full report but this site reports:

    "The global market for Cholesterol and Other Cardiovascular Testing is forecast to cross 2.3 billion units by the year 2015."

    Using a rough figure of $100 per test, the math is easy.

    (P.S. Kudos to Peter for allowing this free debate)

  8. A correction is needed here for the record. When I said above:

    “That study also found that when subjects with MetSyn were stratified by small LDL-P levels, there was no association with CVD suggesting that something else was causing arteriosclerosis (inflammation?, glycation?). ”

    It should have read:

    Another study:

    http://circ.ahajournals.org/content/113/1/20.full.pdf

    found that when researchers stratified subjects with MetSyn by small LDL-P (remember that increased small LDL-P is the reason behind increased LDL-P), they found no association with CVD suggesting that other mechanisms part of MetSyn are the culprits (inflammation, glycation, ???).

    Sorry but I am writing these posts too quickly and four minutes is not enough time for proper editing.

  9. First the gratitude: Peter I LOVE this blog series…
    Now the Questions:
    Peter wrote: “The question we don’t know the answer to is if an LDL-P of 2,000 in someone who eats no carbs is the same as an LDL-P of 2,000 in someone who does. I had breakfast with Eric Westman today and we discussed this topic. Eric makes a pretty compelling case that these 2 states are not, in fact, the same thing. I think we can safely say we don’t know the answer. At least I don’t. I’ll keep looking for clues, though.” (May 31 2012)

    My Q: In other words, if 2000 LDL-P is too high for person A it does not necessarily follow that 2000 LDL-P is too high for person B? And if this is true then what happens to the previous statement: “Directly measure the number of LDL particles in your plasma using NMR technology. If this number is high, you are at risk of atherosclerosis.” – What number then should we consider to be “high”?

    Statement: It would be nice to get some LDL-P values from aboriginal peoples who have had a lifelong “palio” type diet – to try to get some kind of base line number.

    And Now I just read: “Furthermore, is it possible that once the body stops relying on glycogen and turns over to metabolic pathways of ketosis that the “numbers” we target as “normal” are irrelevant?” And if that’s true, how can we know what the “new” normal numbers are for an individual who is ketogenic? Then if that is true do the “too many” LDLs still mean high risk of atherosclerosis?

    Thank you for sharing your time! You are appreciated!
    Diana

    • I think this is correct. I’m not sure I can say that in the absence of carbs/glucose we can disregard LDL-P (or apoB or pick your favorite risk marker). We don’t have the data to know this. It’s a good hypothesis, but still untested. There are many areas where this crops up, such as the “need” for certain vitamins and minerals (e.g., less vitamin C needed; more sodium needed when carbs removed).

  10. I’m a reasonably intelligent person, but frankly need a translator. I believe, based on what I’ve gleaned from you and Gary Taubes, that conventional wisdom on cholesterol is just wrong. But I simply don’t have the time and intellectual energy to a)fully understand the technicalities of this discussion, or to b)fight my doctor over conventional treatment regimens (statins). I need a new age Cholesterol for Dummies.

    • Tim, I love your comment. You’re right about the complexity. I teeter on the edge of understand and having no clue. I also keep thinking that there’s no way my doctor is going to take MY advice on how to treat patients. Has anyone had this luck? I love Peter’s series, love Taubes, Masterjohn, et al. but I can’t imagine bringing Taubes’ Good Calories Bad Calories, a very heavy read btw, to my doctor and giving him the “assignment” to read it and rethink his entire approach to medicine. He’s a nice enough guy, but I think many if not most doctors would take offense to an assertion that I know more than he does.

  11. Quick sketch: I’m 45 y.o. guy without major medical issues, eating a low carb diet for 6 months (mostly meat, fish, butter, eggs, coconut oil, cream, dark chocolate, etc. no grain, no sugar, some veggies and fruit occasionally, but very little carbs overall< 50 grams/day.

    Here's the good I've seen so far: weight down from 185ish to 165ish, body composition much improved, mental health much better, sleep is better.

    My labs show: TGs 58, HDL 55, HS-CRP 2.2 and my cortisol, magnesium, CBC, CMP, TSH, free t4, t3 are all normal, Vitamin D 39, HBa1c 5.6 (not great but should continue to come down).

    Over a six month period my total LDLp increased from 1587 to 3076, small LDLp increased 534 to 869, total cholesterol went up from 224 to 343, and LDL went from 153 to 276. This change is from 6 months ago.

    I've been very strict on my diet because I really wanted to see what it could do for me, and for the most part I'm totally happy about my progress, but I'm a bit nervous about my LDL, TC and LDL particles now.

    In poking around various forums, there seems to be a handful of folks like me that get crazy lipids changes when going low carb.

    Would you care to speculate on what might cause this? I'm not expecting any medical advice, but just some education or ideas for "general consumption" for people that get wacky high lipids when the go low carb.

    Thank you in advance.

    P.S. Your blog is great!

    • Yes, Dan, you are not alone in this and I wish I knew why! There are many folks who have generated hypotheses that in the metabolic state you describe, an elevated LDL-P is “different” than if you were consuming a standard American diet (i.e., not predictive of disease risk). But this presents a dilemma. Until we know this is true, how should people like you be advised? If I knew this, I would be the first to say so, but I just don’t at this time. As Thomas Henry Huxley once said, “The great tragedy of science is the slaying of a beautiful hypothesis by an ugly fact.” The hypotheses of why an elevated LDL-P in a carb-restricted person is ok are still hypotheses.

  12. Simply excellent, Peter. I’m really enjoying these posts!
    One small question: Have you got information about hoe many people (percent) could be in each group? (High-Low, High-High, Low-Low and Low-High)

  13. OK, thanks. Any suggestion about information sources about this subject? I would like to read about it, because I don´t know if we are talking about 95%, 50% or 10% of the population when we talk about discordances.

  14. Back in May/June the thread was inconclusive whether a high LDL-P made a difference on this WOE. Since just a few months ago the thought was large and fluffly LDL was good and now it’s all about the number of particles, I was hoping there was some emerging evidence one way or the other about the meaning of high LDL-P when eating LCHF. (If you are looking for guinea pigs for a study, I volunteer as long as I don’t have to eat carbs or swallow pills.)

  15. You said: The persons with the highest LDL particles typically (though not always) have small LDL particles that are TG-rich.

    If your trigs are super low and your LDL-p is high-that would mean that you are still less likely to have atherosclerosis?

    • Most evidence available to day would say, “probably,” but in reality, we don’t have enough data to really answer this question. This poses a dilemma for the patient with low TG, high HDL-C, and high LDL-P. I hope we can resolve this question.

  16. Hi Peter,

    I’m in the discordant group and I’m curious about how I should interpret, at an initial level, my NMR results. The test results showed my LDL-C at 105 (20ish percentile) and my LDL-P at 1333 (approximately the 50th percentile). Small LDL-P was <90. Last years VAP test showed apoB100 at 95. The LP-IR was zero.

    I don't smoke and my BMI is 25, age 57. My BP is 120-75, so normal. I eat lowish carbs and I'm gluten free. I'm inclined to think my results are mostly unremarkable, but there is heart disease in my family (father, maternal grandfather – both had heart attacks in their 50's). I've read your thoughts on calcium scores, but I'm curious what actions you might take if the above facts were your scores?

    Many thanks for a great series that has helped my understanding immensely.

    Nick

  17. Thanks, Peter for your reply. My doctor didn’t know what the VAP or NMR test was. If you or any of your readers know how one can source a well-informed doctor in SF or the North Bay, I would appreciate referrals.

    Btw, I also appreciated your post on back pain.
    Nick

    • I had lunch with Robb Wolf and Chris Kresser to discuss this exact issue today… We need a better directory of doctors who understand these tests (which many do — we just need to be able to connect patients with them). Check Chris’ website and Jimmy Moore’s, also.

  18. Peter:

    I am confused. Above you state “To be clear, VAP is NOT a good test to get, despite the fact that I used to track my progress until last year. It estimates apoB. Your best bet is NMR (many companies can send out to LipoScience, the only company able to do this with FDA approval), or go with one of the companies can can actually measure apoB directly.” LipoScience does not direct measure or calculate apoB that I can see on my recent NMR.

    Dr. Michael Cobble, Chief Medical Director of Atherotech, the VAP people, states: “VAP directly measures NHDLc (VLDLc, IDLc, LDLc and finally Lp(a)-c), and as such, directly measures the amount of apoB100 linked to the protein apo(a). ” http://www.cobblescorner.com/2012/08/lipoproteina-cholesterol-and-the-science-of-prevention/ .

    Can you please clarify your point about direct measuring or calculated apoB as I seem to be missing something? Thanks for sharing your wealth of information.

    • VAP does not actually measure apoB. It uses an algorithm of other measurements to estimate it. It may well be accurate, but it has never been validated externally. Until that time, it’s probably best to use a lab that truly measures apoB.

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