June 13, 2012


The straight dope on cholesterol – Part VII

by Peter Attia

Read Time 15 minutes

In this post we’ll address the following concept: Does “HDL” matter after all?

Previously, in Part I, Part II, Part III, Part IV, Part V ,and Part VI of this series, we addressed these 8 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?

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

(No 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. 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.


Concept #9 – Does “HDL” matter after all?  

Last week was the largest annual meeting of the National Lipid Association (NLA) in Phoenix, AZ.  The timing of the meeting could not have been better, given the huge buzz going around on the topic of “HDL.”  (If you’re wondering why I’m putting HDL in quotes, I’ll address it shortly.)

What buzz, you ask? Many folks, including our beloved health columnists at The New York Times, are talking about the death of the HDL hypothesis – namely, the notion that HDL is the “good cholesterol.”

Technically, this “buzz” started about 6 years ago when Pfizer made headlines with a drug in their pipeline called torcetrapib.  Torcetrapib was one of the most eagerly anticipated drugs ever, certainly in my lifetime, as it had been shown to significantly raise plasma levels of HDL-C.   You’ll recall from part II of this series, HDL particles play an important role in carrying cholesterol from the subendothelial space back to the liver via a process called reverse cholesterol transport (RCT).  Furthermore, many studies and epidemiologic analyses have shown that people with high plasma levels of HDL-C have a lower incidence of coronary artery disease.

In the case of torcetrapib, there was an even more compelling reason to be optimistic.  Torcetrapib blocked the protein cholesterylester transfer protein, or CETP, which facilitates the collection and one-to-one exchange of triglycerides and cholesterol esters between lipoproteins.  Most (but not all) people with a mutation or dysfunction of this protein were known to have high levels of HDL-C and lower risk of heart disease. Optimism was very high that a drug like torcetrapib, which could mimic this effect and create a state of more HDL-C and less LDL-C, would be the biggest blockbuster drug ever.

The past month or so has seen this discussion intensify, which I’ll quickly try to cover below.


The data


After several smaller clinical trials showed that patients taking torcetrapib experienced both an increase in HDL-C and a reduction in LDL-C, a large clinical trial pitting atorvastatin (Lipitor) against atorvastatin + torcetrapib was underway.  This trial was to be the jewel in the crown of Pfizer.  It was already known that Lipitor reduced coronary artery disease (and reduced LDL-C, though this may have been a bystander effect and real reduction in mortality may be better attributed to the reduction in LDL-P).

I still remember exactly where I was standing, on the corner of Kerney St. and California St. in the heart of San Francisco’s financial district, on that December day back in 2006 when it was announced the trial had been halted because of increased mortality in the group receiving torcetrapib.  In other words, adding torcetrapib actually made things worse.  I was shocked.

Many reasons were offered for this, including the notion that torcetrapib was, indeed, helpful, but because of unanticipated side-effects, (raising blood pressure in some patients and altering electrolyte balance in others), the net impact was harmful.  Some even suggested that the drug could be useful in the “right” patients (e.g., those with low HDL-C, but normal blood pressure). Furthermore, in two subsequent studies looking at carotid IMT (thickening of the carotid arteries) and intravascular ultrasound, there was no reduction in atherosclerosis.

This was a big strike against the HDL hypothesis and work on torcetrapib was immediately halted.


Niacin has long been known to raise HDL-C and has actually been used therapeutically for this reason for many years.  The AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides – you can’t have trials in medicine without catchy names!) sought to test this.  The trial randomly assigned over 3,000 patients with known and persistent, but stable and well treated cardiovascular risk, to one of two treatments:

  1. Simvastatin (40-80 mg/day), +/- ezetimibe (10 mg/day) as necessary to maintain LDL-C below 70 mg/dL + placebo (a tiny dose of crystalline niacin to cause flushing);
  2. As above, but instead of a placebo, patients were given 1,500 to 2,000 mg/day of extended-release niacin.

Both arms of the study had their LDL-C < 70 mg/dL, non-HDL-C < 100 md/dL and apoB < 80 mg/dL, but despite the statin or statin + ezetimibe treatment still had low HDL-C.  So, if niacin raised HDL-C and reduced events, the HDL raising hypothesis would be proven.

Simvastatin, as its name suggests, is a statin which primarily works by blocking HMG-CoA reductuse, an enzyme necessary to synthesize endogenous cholesterol.  Ezetimibe works on the other end of problem, by blocking the NPC1L1 transporter on gut enterocytes and hepatocytes at the hepatobiliary junction (for a quick refresher, go back to part I of this series and look at the second figure – ezetimibe blocks the “ticket taker” in the bar).

After two years the niacin group, as expected, had experienced a significant increase in plasma HDL-C (along with some other benefits like a greater reduction in plasma triglycerides).  However, there was no improvement in patient survival.  The trial was futile and the data and safety board halted the trial.  In other words, for patients with cardiac risk and LDL-C levels at goal with medication niacin, despite raising HDL-C and lowering TG, did nothing to improve survival. This was another strike against the HDL hypothesis.


By 2008, as the AIM-HIGH trial was well under way, another pharma giant, Roche, was well into clinical trials with another drug that blocked CETP.  This drug, a cousin of torcetrapib called dalcetrapib, albeit a weaker CETP-inhibitor, appeared to do all the “right” stuff (i.e., it increased HDL-C) without the “wrong” stuff (i.e., it did not appear to adversely affect blood pressure). It did nothing to LDL-C or apoB.

This study, called dal-OUTCOMES, was similar to the other trials in that patients were randomized to either standard of care plus placebo or standard of care plus escalating doses of dalcetrapib.   A report of smaller safety studies (called dal-Vessel and Dal-Plaque) was published a few months ago in the American Heart Journal, and shortly after Roche halted the phase 3 clinical trial.  Once again, patients on the treatment arm did experience a significant increase in HDL-C, but failed to appreciate any clinical benefit.  Another futile trial.

Currently, two additional CETP inhibitors, evacetrapib (manufactured by Lilly) and anacetrapib (manufactured by Merck) are being evaluated. They are much more potent CETP inhibitors and, unlike dalcetrapib, also reduce apoB and LDL-C and Lp(a). Both Lilly and Merck are very optimistic that their variants will be successful where Pfizer’s and Roche’s were not, for a number of reasons including greater anti-CETP potency.

Nevertheless, this was yet another strike against the HDL hypothesis because the drug only raised HDL-C and did nothing to apoB. If simply raising HDL-C without attacking apoB is a viable therapeutic strategy, the trial should have worked. We have been told for years (by erroneous extrapolation from epidemiologic data) that a 1% rise in HDL-C would translate into a 3% reduction in coronary artery disease.  These trials would suggest otherwise.

Mendelian randomization

On May 17 of this year a large group in Europe (hence the spelling of randomization) published a paper in The Lancet, titled, “Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.”  Mendelian randomization, as its name sort of suggests, is a method of using known genetic differences in large populations to try to “sort out” large pools of epidemiologic data.

In the case of this study, pooled data from tens of studies where patients were known to have myocardial infarction (heart attacks) were mapped against known genetic alterations called SNPs (single nucleotide polymorphisms, pronounced “snips”).  I’m not going to go into detail about the methodology because it would take 3 more blog posts., But, the reason for doing this analysis was to ferret out if having a high HDL-C was (only) correlated with better cardiovascular outcome, which has been the classic teaching, or if there was any causal relationship.  In other words, does having a high HDL-C cause you to have a lower risk of heart disease or is it a marker for something else?

This study found, consistent with the trials I’ve discussed above, that any genetic polymorphism that seems to raise HDL-C does not seem to protect from heart disease.  That is, patients with higher HDL-C due to a known genetic alteration did not seem to have protection from heart disease as a result of that gene. This suggests that people with high or low HDL-C who get coronary artery disease may well have something else at play.

Oh boy.  This seems like the last nail in the casket of the entire “HDL” hypothesis, as evidenced by all of the front page stories worldwide.


The rub: the difference between HDL-C and HDL-P

The reason I’ve been referring to high density lipoprotein as “HDL,” unless specifically referring to HDL-C, is that HDL-P and HDL-C are not the same thing.  Just as you are now intimately familiar with the notion that LDL-C and LDL-P are not the same thing, the same is true for “HDL” which simply stands for high density lipoprotein, and like LDL is not a lab assay. In fact, unpublished data from the MESA trial found that the correlation between HDL-C and HDL-P was only 0.73, which is far from “good enough” to say HDL-C is a perfect proxy for HDL-P.

HDL-C, measured in mg/dL (or mmol/L outside of the U.S.), is the mass of cholesterol carried by HDL particles in a specified volume (typically measured as X mg of cholesterol per dL of plasma). HDL-P is something entirely different.  It’s the number of HDL particles (minus unlipidated apoA-I and prebeta-HDLs: at most 5% of HDL particles) contained in a specified volume (typically measured as Y micromole of particles per liter).

As you can see in the figure below (courtesy of Jim Otvos’ presentation at the NLA meeting 2 weeks ago), the larger an HDL particle, the more cholesterol it carries. So, an equal number of large versus small HDL particles (equal HDL-P) can carry very different amounts of cholesterol (different HDL-C).  Of course, it’s never this simple because HDL particles, like their LDL counterparts, don’t just carry cholesterol.  They carry triglycerides, too. Keep in mind, HDL core CE/TG ratio is about 10:1 or greater – if the large HDL carries TG, it will not be carrying very much cholesterol.

HDL sizes


So, the important point is that HDL-C is not the same as HDL-P (which is also not the same as apoAI, as HDL particles can carry more than one apoAI).


But there’s something else going on here.  If you look at the figure below, from the Framingham cohort, you’ll note something interesting.  As HDL-C rises, it does so not in a uniform or “across the board” fashion.  A rise in HDL-C seems to disproportionately result from an increase in large HDL particles.  In other words, as HDL-C rises, it doesn’t necessarily mean HDL-P is rising at all, and certainly not as much.


HDL-C changes with HDL-P

As you can see, for increases in HDL-C at low levels (i.e., below 40 mg/dL) the increase in small particles seems to account for much of the increase in total HDL-P, While for increases over 40 mg/dL, the increase in large particles seems to account for the increase in HDL-C. Also note that as HDL-C rises above 45 mg/dL, there is almost no further increase in total HDL-P – the rise in HDL-C is driven by enlargement of the HDL particle – more cholesterol per particle – not the drop in small HDL-P.  This reveals to us that the small HDL particles are being lipidated.


Is there a reason to favor small HDL particles over large ones?

In the 2011 article, “Biological activities of HDL subpopulations and their relevance to cardiovascular disease,” published in Trends in Molecular Medicine, the authors describe in great detail some of protective mechanisms imparted by HDL particles.

Large HDL particles may be less protective and even dysfunctional in certain pathological states, whereas small to medium-sized HDL particles seem to confer greater protection through the following mechanisms:

  • Greater antioxidant activity
  • Greater anti-inflammatory activity
  • Greater cholesterol efflux capacity
  • Greater anti-thrombotic properties

In other words, particle for particle, it seems a small HDL particle may be better at transporting cholesterol from the subendothelial space (technically, they acquire cholesterol from cholesterol-laden macrophages or foam cells in the subedothelial space) elsewhere, better at reducing inflammation, better at preventing clotting, and better at mitigating the problems caused by oxidative free radicals.

Of course, reality is complicated.  If there was no maturation from small to large HDL particles (i.e., the dynamic remodeling of HDL), the system would be faulty. So, the truth is that all HDL sizes are required and that HDL particles are in a constant dynamic state (or “flux”) of lipidating and delipidating, and the real truth is no particular HDL size can be said to be the best. If the little HDLs do not enlarge, the ApoA-I mediated lipid trafficking system is broken.


The truth about the old (and overly simplistic) term called reverse cholesterol transport (RCT)

HDL particles traffic cholesterol and proteins and last in plasma on average for 5 days. They are in a constant state of acquiring cholesterol (lipidation) and delivering cholesterol (delipidation). There are membrane receptors on cells that can export cholesterol to HDL particles (sterol efflux transporters) or extract cholesterol or cholesterol ester from HDL particles (sterol influx transporters).

The vast majority of lipidation occurs (in order): 1) at the liver, 2) the small intestine, 3) adipocytes and 4) peripheral cells, including plaque if present. The liver and intestine account for 95% of this process. The amount of cholesterol pulled out of arteries (called macrophage reverse cholesterol transport) is critical to disease prevention but is so small it has no effect on serum HDL levels. Even in patients with extensive plaque, the cholesterol in that plaque is about 0.5% of total body cholesterol. HDL particles circulate for several days as a ready reserve of cholesterol: almost no cell in humans require a delivery of cholesterol as cells synthesize all they need.  However, steroidogenic hormone producing tissues (e.g., adrenal cortex and gonads) do require cholesterol and the HDL particle is the primary delivery truck.

If, as is the case in a medical emergency, the adrenal gland must rapidly make a lot of cortisone, the HDL particles are there with the needed cholesterol.  This explains the low HDL-C typically seen in patients with severe infections (e.g., sepsis) and severe inflammatory conditions (e.g., Rheumatoid Arthritis).

Sooner or later HDL particles must be delipidated, and this takes place at: 1) the adrenal cortex or gonads 2) the liver, 3) adipocytes, 4) the small intestine (TICE or transintestinal cholesterol efflux) or give its cholesterol to an apoB particle (90% of which are LDLs) to return to the liver.  A HDL particle delivering cholesterol to the liver or intestine is called direct reverse cholesterol transport (RCT), whereas a HDL particle transferring its cholesterol to an apoB particle which returns it to the liver is indirect RCT. Hence, total RCT = direct RCT + indirect RCT.

The punch line: a serum HDL-C level has no known relationship to this complex process of RCT. The last thing a HDL does is lose its cholesterol.  The old concept that a drug or lifestyle that raises HDL-C is improving the RCT process is wrong; it may or may not be affecting that dynamic process. Instead of calling this RCT, it would be more appropriately called apoA-I trafficking of cholesterol.


Why do drugs that specifically raise HDL-C seem to be of little value?

As I’ve argued before, while statins are efficacious at preventing heart disease, it’s sort of by “luck” as far as most prescribing physicians are concerned. Most doctors use cholesterol lowing medication to lower LDL-C, not LDL-P.  Since there is an overlap (i.e., since the levels of LDL-P and LDL-C are concordant) in many patients, this misplaced use of statins seems to work “ok.”  I, and many others far more knowledgeable, would argue that if statins and other drugs were used to lower LDL-P (and apoB), instead of LDL-C, their efficacy would be even greater.  The same is true for dietary intervention.

Interestingly, (and I would have never known this had Jim Otvos not graciously spent a hour on the phone with me two weeks ago giving me a nuanced HDL tutorial), a study that went completely unnoticed by the press in 2010, published in Circulation, actually did a similar analysis to the Lancet paper, except that the authors looked at HDL-P instead of HDL-C as the biomarker and looked at the impact of phospholipid transfer protein (PLTP) on HDL metabolism.  In this study, though not the explicit goal, the authors found that an increase in the number of HDL particles and smaller HDL particles decreased the risk of cardiovascular disease.   The key point, of course, is that the total number of HDL particles rose, and it was driven by increased small HDL-P. The exact same thing was seen in the VA-HIT trial: the cardiovascular benefit of the treatment (fibrate) was related to the rise in total HDL-P which was driven by the fibrates’ ability to raise small HDL-P.

It seems the problem with the “HDL hypothesis” is that it’s using the wrong marker of HDL.  By looking at HDL-C instead of HDL-P, these investigators may have missed the point.  Just like LDL, it’s all about the particles.



  1. HDL-C and HDL-P are not measuring the same thing, just as LDL-C and LDL-P are not.
  2. Secondary to the total HDL-P, all things equal it seems smaller HDL particles are more protective than large ones.
  3. As HDL-C levels rise, most often it is driven by a disproportionate rise in HDL size, not HDL-P.
  4. 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.
  5. 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.


Two apolipoprotein A1 chains (magenta ribbons) complexed with cholesterol (orange balls) and phospholipids, after PDB 3K2S by Ayacop [Public domain], via Wikimedia Commons

Disclaimer: This blog is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this blog or materials linked from this blog is at the user's own risk. The content of this blog is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions.


Read Our Comment Policy
  • Pingback: The straight dope on cholesterol – Part VI | The Eating Academy | Peter Attia, M.D.()

  • Thank you again for another cholesterol post Dr. Attia! I’ve been referring my friends and peers to your site because of it.

    I also made a short cholesterol comic based on some of your ideas and Dr. Dayspring’s lectures to try and pull people into these newer ideas who may be intimidated by the details. If interested, you can see it here: http://thefatnurse.wordpress.com/2012/06/06/cholesterol-for-all-ages/

    Once again, thank you for this series. You and your blog are doing a great service!

    • Yes, I did see your fantastic cartoons. I’m honored to be a small part of your journey into the world of lipidology. I hope folks take a moment to check out your link. I really enjoyed it.

    • Joshua

      Fun comic! I like the idea of a low carb diet encouraging cholesterol to carpool (for some people).

      Sounds like the optimal situation would be most LDL cholesterol bits packed into big buses, and most HDL cholesterol bits riding in low occupancy sports cars.

    • Michele

      This blog just keeps on giving!

      The comics are GREAT! Thanks FatNurse and thanks Peter!

    • lorraine

      Really great comic. Hope it’s ok that I shared it on Facebook.

      And Peter, who does your art (like that nifty graphic of the HDL mop)?

    • PaulaT

      Great “Comic”! There’s a typo on page 12 in the 4th frame: “lead” should be “led.”

    • Thanks for the kind words! I’ve always wondered how Dr. Attia has so much time and energy to read and write all his insightful posts while starting his other side projects….but now I know: its powered by pure passion.

      This whole area of study is so fascinating that I find myself reading literature and reaching out to people in the field in my spare time for…fun lol. I only hope that my cartoons can pique the interest of others who have been too influenced by the low fat dogma to bother looking at anything else.

      And yes lorraine feel free to share my comic on face book. I’ll be adding more “…for all ages” comics in the future as well.

  • Joshua

    Thank you for the post Peter. I doubt the lay press will have the wherewithal to understand/communicate any of this effectively, so I fear they will throw the HDL-P out with the HDL-C bathwater. Then again now that I think about it, I’m not all that sanguine about the ability of the scientific journals to get the updated hypotheses out either.

    One of the things this series has done for me is help me understand a little better just how complicated biological processes are. I don’t doubt that the alternate hypothesis will get refined over time, but it blows my mind that much of the health services community is stuck on “fatties eat too much. duh!” with no thought to the concept that (some of) our bodies might respond in fundamentally different ways to different macronutrients.

    • Yes, that is my concern, also, which is partly why I’m writing this post (not the lay press would read anything I write).

  • David Nelsen

    Peter, you and others have said the best heart disease indicator on a standard lipid panel is Trig/HDL. Would Trig/HDL-P be a better indicator? You showed that Niacin raises HDL-C but in a way that offers no added heart health protection. Does Niacin affect LDL-P? Does Metformin raise HDL-C/P or lower LDL-P? Thanks, Dave

    • It might be (I don’t know if it’s been validated) and the units don’t really make sense. The TG/HDL-C ratio “works” because both are units of mg/dL. The advantage of this ratio is “everyone” can get it. It’s cheap and easily accessible. Niacin does have some impact on LDL-P, but not much, and it depends on the dose and the underlying reason for elevated LDL-P.

    • Thomas Dayspring aka “Dr Lipid”

      You can not use lipid concentrations and lipoprotein concentration ratios in the same ratio – no relationship. Niacin significantly lowers apoB and LDL-P and that is it’s major benefit. It raises HDL-C by making HDL particles larger but does not raise total HDL-P. Thus it is not an effective HDL drug. Metformin can lower LDL-P.

  • Thomas Dayspring

    Your cartoon story is fantastic
    Dr Lipid

  • Obee

    Not specifically about this post, but you have emphasized that LDL-P is the only significant number regarding cholesterol. My question is (maybe I’ve missed this), in the absence of inflammation, will the particles be able to penetrate the arterial wall? In other words, does LDL-P even matter if there’s no systemic inflammation? Or perhaps it depends on the degree of inflammation?

    • Typically inflammation is the result of the following sequence: LDL particle crosses endothelium, gets retained in S-E space while proteoglycans “hold” it in place, inflammatory cells arrive and begin immune response to modulate “invader.”

    • lorraine

      I must admit that I view this scenario as including two different phases of inflammation; the one that is caused by the retention of the particle in the S-E space, and the one that is systemic and attracts the particle to the endothelium in the first place. Apologies, but my physiologist’s gut still does not allow me to accept the concentration gradient causing “crash” idea. Of the various species in circulation at any given time, why is it only the LDL particle that crashes? It seems to me that what distinguishes LDL-p from everything else is ApoB, and in my scenario, ApoB is being signalled into the endothelium. My money says that ApoB has an immune function which is being signalled by an existing inflammatory process in the vessels and system wide, caused by autoimmunity and/or infection. There’s no crash at all in this scenario, but rather signalling. This idea has some consistency with observations of changes in cholesterol concentration with sepsis and I believe there was some work done on another Apo molecule on HDL as a potential mediator of this. I got 50 bucks on this if anyone wants to take the bet. Potential candidates as cause are autoimmunity/infection from intestinal permeability or injury from blood pressure.

      • You might be right, Lorraine. Let’s assume there is a specific immune trigger uniquely or at least “affectionately” directed towards apoB. What is a better treatment? Knock down the immune system? Or reduce apoB? In my former life, both in medical school and my fellowship, I worked specifically on immunology. The former problem is MUCH more difficult than the latter. In fact, we have many solutions to the latter, and very few to the former. The solutions we do have to the former come with side-effects that make anti-apoB treatments look like drinking water. Even if (like I said, this is a valid argument) we could put people of FK506 to reduce their inflammatory response to the apoB particles, what other mess have we created?

    • lorraine

      Ah, perhaps we should say that there are few if any agreeable *pharmaceutical* solutions to “knocking down the immmune system”. I wouldn’t suggest that approach at all. How about reducing the potential antigen load altogether by healing the permeable intestine? This is the basis of Robb Wolf’s entire perspective, as well as that of the Weston Price folks. And in the end, the solution comes back to what you’re doing, a diet that is as much anti-inflammatory as it is anything else. Many of the foods that we eliminate in carb restriction are the very suspects in autoimmunity.

      I’m also not suggesting that we shouldn’t treat the known agents in atherosclerosis. My point of view is merely that the cascade of events described once the LDL particle retains is possibly secondary to a previous inflammatory event that causes that cascade.

      • Ah, I see your point. Yes, agree with you.

    • Obee

      It just seemed to me that if there’s no event like inflammation to force the particles into the arterial wall that what you’re saying, in essence, is that we’re all doomed, some just faster than others, because this is a natural process that happens to everyone.

      • Yes, some would argue this. Since age is the single greatest risk factor for CVD it suggests that eventually everyone will succumb to this process, even if every other disease could be mitigated. A 10 year old with and LDL-P of 3,000 has a lower 5 year risk than a 70 year old with an LDL-P of 1,000. Why? Probably because the 70-year old’s arteries have had much longer aggregate exposure to apoB particles.

    • Lorraine, my money’s on you! 🙂 I put down 50 EUR sayin’ that the ApoB particles only (excessively!) find their way into the subendothelial space if they are signaled-in by pathogenic factors. TNF-alpha, anyone? 🙂

      Peter, age is obviously a factor, but you can’t rule out exposure history to pathogens as the driving factor, over the exposure to a body-produced particle that is a critical part of metabolism. Is there any data toward this (pathogens vs. age)? I doubt it, it’s bound to be virtually impossible to measure.

    • Hi Peter.
      You know, I’m re-reading GCBC, and the whole chapter about insulin and cardiovascular disease makes wonder how you could name your blog (initially) as “The War on Insulin” and then forget about insulin in this series of articles about cholesterol.
      In fact, according to Taubes, the smoking gun of arterial wall disruption is most probably in the hands of insulin.
      To me, it looks like it is the combination of active disruption (by insulin and blood sugars) AND the available by-standing ammunition (Apo-B containing lipoprotein particles) that is responsible for atherosclerosis.
      Which begs the question (which I take it is being observed in people like me), that perhaps a high Apo-B particle count (high LDL-P) is NOT more atherosclerotic than a low LDL-P while in the absence of high insulin?…

      • This is a very good point, Vasco, and it is the heart of the argument/thesis put forth by folks like Gary Taubes, Eric Westman, and several others, as to why the standards of predictive cut-offs may not apply to the population you describe. However, until we do a properly designed clinical trial to test this hypothesis, it remains a hypothesis. It makes sense, I agree, but we only have bits of the story worked out. Remember the words of Thomas Henry Huxley (Darwin’s “bulldog”): “The great tragedy of science is the slaying of a beautiful hypothesis by an ugly fact.”

  • Pingback: Peter Attia: Does “HDL” Cholesterol matter after all? « NIKHILHOGAN.COM()

  • Bruce Blakely

    Peter – any comments on the famous HDL ratios that we are all supposed to be paying so much attention to? Would you say that it doesn’t matter at all, or only to a point? I would guess that given the limited correlation between LDL-P and LDL-C in “most” people, a “bad” ratio usually is bad but a “good” ratio may not mean much at all?

    • I certainly wouldn’t say they don’t matter. I like to think of the TG/HDL-C as a “poor man’s test” for IR. When someone has a ratio less than 1.0 (i.e., they have more HDL-C than TG), odds are they are doing well. That said, if I had a dollar for every time I saw a normal ratio there, but a stronger marker of IR elsewhere (e.g., HOMA-IR, LP-IR), I’d have a lot of dollars. There is no one number that is “perfect” and there is no test, even LDL-P, that should be taking in complete isolation.

    • Hasan Hanachi

      The correlation between LDL-P and LDL-C is not at all “limited”….its just not perfect. (I will try to find time to dig out some correlation coefficients on this). Their high degree of correlation is why LDL-P has not been found to add predictive power to LDL-C.

      As for ratios, in all the studies I looked at TC/HDL was superior to LDL-P as a predictor so hardly a “poor man’s” substitute there.

      • It’s about 0.7; very similar to that of HDL-P and HDL-C.

    • Hasan Hanachi

      Well, .7 is considered “high.”

      Also, I should have said “TC/HDL was EQUAL TO to LDL-P”, not necessarily superior.

  • Dear Peter,
    I have an off topic question. I have been reading your blog nearly since it started. My 22 yr old son is home for the summer and so he has automatically gone on a low carb diet. He signed up with a gym and the trainer there told him to get off of low carb for weight training.

    I have ordered Jeff Volek’s book Art and Science of Low Carb Performance. But, it seems like you addressed this issue but can’t find the post without rereading reams of material.

    • Check out the posts about the interplay of exercise and ketosis (2 parts). Of course, your son does not need to be in ketosis. Simply removing sugar and highly refined grains will do wonders for him.

    • greensleeves

      Hi Pam:

      Ok, so I got Volek’s book as soon as it came out, and got a blood ketone meter 1 week later.

      As a woman, I was at 50 g total carbs a day, eating 65% fat, 25% protein, and 10% carbs for 1750 calories. I lift Superslow and at the time my max leg press was 305.

      My husband was at 65g total carbs a day, eating 60% fat, 25% protein and 15% carbs for 2100 calories a day. He swims at Stanford 3x a week and played a game of water polo.

      We started out at 1.4 and .4 on the ketone meter. After 1 week of implementing Volek’s suggestions, I switched to eating 75% fat, 18% protein, and the rest carbs, going down to 30 total g a day. My calories remained the same.

      My husband made similar changes. His ketones shot up to 2.4 and his stroke rate improved (he swam the pool lengths with fewer strokes). He also dropped to 8.5% body fat, down from 10. He lost an inch off his waist and his chest muscles suddenly appeared to balloon.

      The effect for him was really dramatic. My leg press weight, instead of going up 1/2 or 1 pound a week, went up 3 pounds to 308!

      As time has gone on, we have continued to improve. My leg press after about 5-6 weeks of Volek’s advice is now 320. My husband’s swimming continues to improve – he swims more tirelessly and has greater mental focus in the moment, allowing him to really concentrate on improving the details of his Total Immersion technique.

      He believed his balance in the water is much better and that he has more power in what is called “hip drive.”

      Volek himself pushes 1/2-ton boulders and was a weight-lifting champion. He personally lives at 1.5-2.0 on the ketone meter. I can attest there are many athletic and mental benefits to this level of ketones.

    • @ Pam F

      High-carb pre-workout, low-carb the rest of the time; high-protein post-workout (recovery’s where you make your gains), low pro the rest of the time. So, he will be high-fat, low-carb, low-pro outside the pre- and post-lifting windows.

      The carbs will power the weight-lifting, making the session maximally productive/efficient; the lifting session will burn off those carbs.

      (“High-carb doesn’t mean go hog wild, nor is it an excuse to eat junk food.)


  • solid information

  • James

    Great stuff once again. The shift in thinking about HDL-c is one of the more difficult things for people (including myself) to wrap their heads around. In trying to share this information with people, it’s difficult to get past their incredulity at the fact that just because their HDL-c is high doesn’t mean their arteries are teflon coated works of art that are impervious to insult. Hopefully there are a lot of clinicians reading what you and some of the other people on the forefront of this topic are writing.

  • jw

    Interestingly, in the (admittedly different) context of their LP-IR score, Liposcience’s green-red line puts small HDL size on the negative side.

    • Good point. Suggests how confusing this whole area is…

    • Thomas Dayspring aka “Dr Lipid”

      The only LipoSciene LP-IR score predicts is insulin resistance – not CV risk!!! It is also only valid in drug naive patients, since drugs (artificially) interfere with size and the score hasn’t been validated under these conditions.

      DR Lipid

    • Maryann

      Is someone considered “drug-naive” if they are taking red yeast rice (CAM alternative to a statin)? And should RYR be avoided without monitoring sterol absorption and synthesis, since statin momotherapy is contraindicated in some people? Thanks, maryann

      • Hmmm. That’s a good question. I don’t know the answer. It depends on how much it impacts particle size and number.

    • jw

      Understood. But then small HDL size may be bad for IR but may be good for CV. Just saying that it will be interesting to see how this plays out.

      • Completely agree. The journey is as much fun as the destination.

    • Peter, I’m seeing that the NMR or test for IR may be inaccurate when one is taking cholesterol lowering meds. I’m in that boat & having my tests this week. Will I get anything beneficial from these tests under the circumstances? I’ve been 7 weeks Keto adapted but still not losing on scale.

      • Correct, the LP-IR has only been validated in patients not taking cholesterol-lowering drugs.

  • Susan

    “you can’t have trials in medicine without catchy names!”

    SO true! And it seems like the more they have to cleverly torture the language to come up with the “appropriate” acronym, the better they like it.

  • Harry35

    Peter, take a look at this paper by Dr. Asztalos, et al. entitled “High-Density Lipoprotein Subpopulation Profile and Coronary Heart Disease Prevalence in Male Participants of the Framingham Offspring Study.” It’s at http://atvb.ahajournals.org/content/24/11/2181.full.pdf+html
    In this study, Dr. Aztalos used 2-dimensional Gradient Gel Electrophoresis to subdivide HDL into several different particle sizes and charges, from the smallest, pre-beta HDL particles to the largest particles, alpha-1. In this study he shows that the parameter that best correlates with with no CHD is a high concentration of alpha-1 particles, which are quite large as HDL particles go(>11nm). In the study reported in this reference, the prevalence of CHD was almost linear (and inverse) with alpha-1 HDL. Note that there were about 106 Framingham Offspring out of a total of 1446 with alpha-1 of 30 or greater, and not one of them had CHD. All of the 169 people with CHD had alpha-1 less than 30, and most had alpha-1 less than 20. Neither of the other two common measures of HDL, HDL-C or ApoA-1, are as clearly definitive about CHD risk as alpha-1, which has an almost monotonic curve of alpha-1 vs risk, as may be seen from Figure 2 of the paper. In short, the more alpha-1 the better. Which suggests that the more large HDL a person has, the less likely to develop CHD. This study prevents me from concluding that small HDL is more protective than large HDL.

    • Harry, this study has some limitations. HDL-P via NMR was not measured (they Boston heart lab uses 2 dimensional gel electrophoresis with apoA-I staining) and confirms that people at risk lack large HDL particles — although not measured in this study, the risk is likely due to high LDL-P and low total HDL-P due to catabolism of TG-rich large HDLs and delayed maturation of prebeta HDL (not captured by NMR).

  • Good stuff, but it made my brain work extra hard. Thanks for putting this info out, I need to re read this so I make sure I’m understanding everything. I’ve started writing some posts on cholesterol for my non-sciencey friends and family. I just hope I’m not totally botching it up as I try to simplify the concepts…because they really aren’t simple. I have learned so much from this series, anxiously awaiting the next one!

    • Last night wife, while reading this post, suggested I take a break from it for a while. She’s worried the blog is getting too “technical” and that I’m going to turn many folks off. I see her point. The cholesterol series isn’t exactly lunchroom discussion. I’m glad you find it interesting enough to turn it into family/friend discussions.

    • Alex Carvalho

      Dr. Attia, your wife may indeed have a point. As much as I have enjoyed reading the seven parts (and I was initially expecting a total of 3 parts, maybe) so far posted on this series and learning enough to make my endocrinologist look completely puzzled with the extent of my knowledge, I’m really searching for the answer to one question: what should I do to improve my odds of living a longer, healthier life? Honestly, I think we’re taking too long to get to it. I’m sure the answers, if at all known, will come with several qualifications about the precarious state of our knowledge. That’s fine. But, please, get to it soon…

      • I may start alternating “lighter” posts with cholesterol posts. I think there are still around 3 or 4 more cholesterol posts waiting to be written.

    • Alex Carvalho

      Oh,no! If you start alternating posts it will take further two months for us to get to the effects of diet, statins, exercise, etc. over CVD…

    • Jacob

      I like the “alternating” idea — especially since there are so many great topics on the wish list! I’d also consider some videos on the cholesterol content — that’d make the material more accessible for folks who prefer to learn that way.

      Big picture though, this blog is fantastic. Thank you!

    • jw

      I vote for continuing the deep dive into cholesterol. As with others, I can’t wait for the payoff.
      That being said, I did not mind the timely Bloomberg digression as it is getting even more nuts out there since, they are now proposing banning buttered popcorn and milkshakes. (It’s a short, slippery road to red meat and butter…).

  • David

    Like JW, I’m confused here. I have always read that Large HDL-P is more protective than Small HDL particles. Are you saying that the new wisdom on HDL particles is itself mistaken?

    • It might be. I don’t think we can say definitively. The REAL challenge is understanding for certain the cause vs. the bystander. For example, we know people with small LDL particle tend to have more. But what is cause of their greater disease risk? Size or number or both? Jim Otvos’ amazing analysis which I reviewed previously, suggests size is NOT an independent predictor of risk, so it’s all particle number. We have less data on the HDL size question, and functionality of the particles plays a very important role. As I said, we can’t “measure” this, so we’re stuck a bit.

    • Thomas Dayspring aka “Dr Lipid”

      HDL size per se has no clinically important meaning and the NLA discourages its measurement. HDL particles undergo a dynamic remodeling process (lipidation followed by delipidation) No tests are available to measure this. If you had to pick a size, most experts would say the small HDL is the most crucial.

  • Laura

    Hope my questions r.e. men vs women aren’t getting tiresome- but I was wondering if the graph of the Framingham data showing that small HDL particles increase up to about 40 then go down is from men only, or pooled men and women. (I assume it isn’t from women only.) I ask this because my understanding is that the good/optimal levels of HDL-C are defined as higher for women than men. I was wondering if this correlates with a higher level of total HDL-C at which the increase in small HDL particles stops in women as compared to men.


    • Laura, how could I find a question tiresome that impacts 50% of the population? If you were asking questions about redheads, who were born on the eve of the summer solstice on leap years, who are between 6-foot-10.5 and 6-foot-11, who had purple eyes, I might find it tiresome.
      Those data are from men and women.

  • Mike A.

    Peter- I am completely engrossed in this series. Thanks for you efforts. Perhaps you will address this in a future post (if so, I can patiently wait), but I’ve heard conflicting statements regarding whether there have been any studies that definitively show that cholesterol lowering medications reduce mortality in patients who have not yet had a cardiac event. I have had one physician tell me that obviously drug companies would love nothing more to be able to demonstrate this, yet they have not been able to do so. I am curious as to which studies, if any, show that lowering cholesterol through medication lowers cardiovascular risk or mortality rates in patients that haven’t had a cardiac event.

    Thanks again,


    • Mike, this is a very important topic, and one that warrants an entire post — which it will receive. What you’re asking about is called “primary prevention,” and there is a lot to discuss.

    • David Nelsen

      I read the book “The great cholesterol con” and one of the authors principal conclusions was that Statins didn’t help women at all, and only helped men who had already had a heart incident. After reading Peter’s and others work, I think there might be a more nuanced answer here but in general there is not a lot of data supporting statins for patients without a previous heart incident. Once you factor in LDL-P in to the equation I think statins can play a role, but that data wasn’t available for the author of that book. I believe in general that statins are over prescribed and that their use needs to be to treat the correct symptom (i.e. non LDL-C).

      • I agree completely (despite my back and forth with one particularly erudite reader) — statins are almost certainly over-prescribed. But the binary view (“Everyone should be on statins” versus “Statins are horrible and should be abolished”) is utterly baseless and naive. Statins are a tool. Simple and plain. Use the tool for the RIGHT job at the RIGHT time, and it helps. If you don’t, it doesn’t, and it might cause harm.

    • Thomas Dayspring aka “Dr Lipid”

      Low risk people do not die and thus mortality cannot be tested unless you study 50000 folks for 30 years. No one will pay for such a study, of course.

    • David Nelsen

      I was going to comment on last weeks ping pong match with said erudite reader but decided that the thread had run its course. I think in general he felt that any preventative testing would be followed up by drugs to treat. In some larger sense he has a point that there are a lot of diagnostic tests out there and if you test long and hard enough you’ll probably find something. In the pragmatic world we live in I think there is some filtering by physicians as to the tests they think their patients need based on gender, age, race etc. I don’t think my 8 year old daughter needs an NMR lipid panel (even though she lives on ice cream and waffles). I on the other hand got this and a few other selective tests done. It’s all probability & statistics and common sense.

      On another point, it would appear that the drug manufacturers have thrown a lot of money at the raise HDL-C hypotheis and have not had anything stick. You can imagine the profit potential for those companies if they found a drug that actually improved CVD without side effects. I would imagine that they are revising their hypothesis about HDL-C about now. It would seem that forcing the body to make more HLD-C upsets the balance of the system and that there is a different mechanism in play when drugs are in play versus someone who has naturally occuring high HDL-C. Nature does not give up its secrets easily it would seem. Keep up the great work.

      • Yes, I think you’re taking the right approach, David.

    • Barkeater

      Regarding statins and all-cause mortality.: As Dr. Dayspring points out, it’s a very long-term and expensive project to do a mortality study on low risk (primary prevention) folks. Of course, heart disease risk correlates best with age, so to get a higher risk test group you need to test old people. One key thing that is almost completely overlooked is that, in people over age 60 or 65, higher cholesterol is associated with reduced mortality rate (lots of studies show this). Lower may well not be better for older folks, at least at some cut point (I would argue that guidelines-sanctioned levels may be relatively dangerous for the elderly). Just to be clear, I am throwing this out as hypothesis and not established fact.

      We may not know whether statins provide their benefit (reduced heart attacks, but more reduction of the non-fatal variety and with 65% to 85% residual risk) by reducing LDL-P or through anti-inflammatory effects or something else, but they certainly do reduce cholesterol, and lower cholesterol in the elderly may be disadvantageous for longevity. This may not be the case for a middle-aged man with familial hypercholesterolemia and a family history of early heart disease. It may not be the case for other people at high enough risk. So, results may be mixed for different groups. At the moment, the received wisdom on prescribing statins makes little distinction regarding age or gender, and the presumption is that, once started, one should take statins for life.

      I don’t take Dr. Dayspring‘s comment to mean that, if only it were practical to do a very long-term mortality study on statins in low-risk folks, we would certainly see a mortality rate benefit. Maybe we would or maybe we would see the opposite. Statins are very powerful drugs and are blunt instruments, interfering with a very significant biological process at an upstream point in order to lower blood lipid levels. Long-term bad effects might start to show up if there were seriously long-term trials (I quit Lipitor after 11 years due to side effects). Of course, long-term testing means that the cohort gets older, too, which (I hypothesize) makes it less likely that there would be a mortality rate benefit for statins.

  • George Henderson

    In Uffe Ravnskoff’s book “The Cholesterol Myths” there’s an interesting sidelight on this (or a similar) niacin trial; there was no benefit while it lasted, but five years after it stopped there was a significant drop in CVD mortality in the niacin arm…

    From memory I believe rodents lack CEPT and this is one of many differences in their lipid transport systems that make rats poor surrogates for humans in diet trials.

    • Hmmm. The niacin trial only stopped 2 years ago. I wonder if this is a different trial.

  • Eric

    I have a question about concordance/discordance as it relates to LDL-P and LDL-C which you may or may not be able to answer. If LDL-P and LDL-C are concordant while eating a ketogenic diet, will they typically or necessarly be in concordance while eating a traditional diet? A follow up question would be if they are also concordant while taking cholesterol lowering medication. In other words, is LDL-P and LDL-C concordance/discordance (not actual values but rather the correlation) influenced by exogenous factors? This may not be within the scope of your research and I agree with what you have stated before that there is further research that needed regarding how a ketogenic diet influences atherosclerosis beyond the known mechanicms – increased LDL-P, insulin resistance, infalmmatory markers, etc. Thanks for your time.

    • Great questions, Eric. I do not know the answer this, beyond some anecdotal observations (e.g., in myself – I went from being discordant to concordant). Obviously no conclusions can be drawn, as this has not been studied to my knowledge.

  • Glenda Glass

    Another great installment to a fascinating series! I teach a class on chronic illness prevention through diet and lifestyle, and am hoping to incorporate your information before my next lecture. Please please please don’t stop until you cover the factors that influence particle number and size, and how to fix it when things go wrong.

    • Will do.

    • KevinF

      Yes seriously Dr. Attia, next Tuesday I’ll be the exact age my father was when he dropped dead of a heart attack. So, kind of a sense of urgency. If I suddenly quit leaving comments, you’ll know what happened…

    • lorraine

      Kevin, LOL! But Peter, I’m in the camp that deeply appreciates all the advanced learning that you are offering in this series and hope that you will proceed until your heart is content that you’ve delivered what you set out to accomplish with this information. You do a great job of explaining difficult and complex topics in a manner which is accessible to common sense, even if it takes a couple of reads for folks to get the lingo. And it has been amply demonstrated in the comments that a lot of your readers have real skin in the game in understanding this topic for their own well-being. Creating a sophisticated medical consumer is something I’m sure is a primary goal of NuSI.

  • Dorian


    I am one of your readers who looks forward to the weekly post, and I sure hope you continue. However, if you and your wife do decide to take a break from the Cholesterol series, please don’t leave us with a cliff hanger until next season for some key questions — please at least give us a preview to some questions, such as:

    (1) Once we get our LDL-P from Health Diagnostics Labs (HDL=cute), can we work towards modifying it through diet? And which foods, macronutrients, or nutrients lower the number — and which raise the number?

    (2) You’ve said statins are wonderful tools, but not the best tool (like a hammer) for all situations (like cleaning windows). For which situations are statins in fact wonderful tools?

    Many thanks!

    • Have no fear, Dorian. We aren’t done yet and certainly won’t be until I address these very important issues.

  • PhilM

    Hi Peter,

    This series has been one of the most informative series and I really appreciate your effort. As my knowledge and awareness of cholesterol has increased many fold, I am finding it harder to make sense of my cardiologist who still talks to me in terms of good/bad cholesterol. I have thoughts of printing this series and presenting it to him for his bedtime reading but that would essentially end our relationship. My FP is worse. He is so afraid of eating saturated fat that he won’t allow me to eat eggs and he is still wondering how I managed to raise my HDL-C from a measly 23 to 55 (thanks to 4-6 eggs I eat everyday)

    I guess I was happier when eating “healthy” vegetarian lifestyle and everybody telling me how good I was! I just have to find a doctor who is not afraid to have an open mind and up to date on all this research you and others write about.

    Thanks again for this wonderful series.

    • Phil, I hate to suggest this, as it’s not my place, but have you considered looking for new doctors?

  • I’ve never bought into the reverse cholesterol transport theory. I’m much more interested in the role of HDL-associated proteins such as paraoxonase, which is known to metabolize oxidized lipids (which we know can become trapped in the endothelial space). If you have small dense LDL with lots of omega-6 fats, these fats will easily oxidize, and the oxidized lipids act as potent inflammation triggers, leading to atherosclerosis. The paraoxonase (from the HDL) can help deal with this problem. Just measuring the cholesterol levels tells you nothing useful.

  • Hasan Hanachi

    “the binary view (“Everyone should be on statins” versus “Statins are horrible and should be abolished”) is utterly baseless and naive. Statins are a tool. Simple and plain. Use the tool for the RIGHT job at the RIGHT time, and it helps. If you don’t, it doesn’t, and it might cause harm.”

    I assume you are referring to our discussion here. I want to go on record as disassociating myself with what I would call a parody of my view on statins. Its hard to argue with maxims like “right tool for the right job” but I would counter with another old standby “when the only tool you have is a hammer, then every problem looks like a nail.” Enough said.

    “There is no one number that is “perfect” and there is no test, even LDL-P, that should be taking in complete isolation.”

    Glad to hear you say that. Even if we disagree on when, whether, or if an NMR is warranted, we seem to agree on integrating a larger set of information. That was far from clear from our earlier discussion.

    Some additional thoughts:

    1) Has anybody ever considered evaluating LDL-P/HDL-P as a risk marker.? Not sure we need yet another one of those but it would solve the units of measurement issue.

    2) Kudos to lorraine for raising the issue of inflammation……’

    3) I am doing some interesting reading on insulin resistance and HDL-P. I have some thoughts but they are not yet ready for prime time.

    • Hasan, I was not referring to you when I made that statement. It’s a very broad statement reflecting a view held by many. Also, I agree that when you only have a hammer, everything looks like a nail. Fortunately, we have an entire tool kit.

  • Hasan Hanachi

    ” It would seem that forcing the body to make more HLD-C upsets the balance of the system and that there is a different mechanism in play when drugs are in play versus someone who has naturally occuring high HDL-C”

    The recent Mendelian randomization study:


    has also cast some doubt on the idea that “naturally occurring” HDL is protective. While this is not the end of the story, it may be once again that HDL is only a risk marker that covaries with insulin resistance and that natural variations in HDL levels have no inherent meaning. It does seem that wherever I look, insulin resistance rears its ugly head!

    • Hasan Hanachi

      ” it may be once again that HDL is only a risk marker ”

      Commenting on own comment, I want to head off any misunderstanding I may have created by bad phrasing. I don’t mean to suggest that HDL has no other function other than as a risk marker only that all lipid markers have to be looked in a larger context rather than as meaningful in and of themselves. I hope that makes sense.

  • steve

    I am wondering if the effort of drug companies to start to focus on HDL effecting drugs is a result of the fact that there are still way to many heart incidents for many who are already on statins? Of course, the reason for this is focus by to many physicians(and maybe drug co’s)on LDL-C and not LDL-P. Not to say that raising HDL-P won’t be helpful, particularly in combination with lowering LDL-P, and for those who already have some CAD,but it appears that overwhelmingly the emphasis should be on lowering LDL-P.
    Tim Russert was a prime example of this: low LDL-C of under 70, but no idea where his particles were. Am betting above 1,000.
    Since NMR measures LDL-P particles in the bloodstream not taken up by the liver( I think?) then something has to happen to these particles regardless of the number of them. It would be my guess that they degrade and regardless of amount, as they get smaller, particularly in a person in an inflammatory state, not only penetrate the endothelial layer, but are of the oxidized variety setting off the whole process of CAD. Any thoughts about this?
    From my point of view, the posts are not to technical. I would find it hard to understand if you did not go in to the science.
    I do think there are certain things not yet answered: cholesterol may not matter, but can the same be said for sat fat and its impact on LDL-P?
    Thanks for all your hard work. You are providing us with an amazing education to allow us to go about how we want to address the risk of heart disease which remains the number one killer of far to many, way to soon.

    • Tim Russert’s LDL-C, as you note, was under 70 mg/dL. His TG was about 380 mg/dL, if I recall. If I were a betting man, I would have guessed his LDL-P was over 3,000 nmol/L. His LDL particles carried virtually all TG and very little CE. Of course, his doctors didn’t need an NMR to measure his risk. His TG alone was an elephant in the room. But most doctors aren’t thinking through these issues. LDL-C, and even non-HDL-C, are really, really primitive. TG/HDL-C is probably better. apoB to apoAI is excellent, and recent data would suggest LDL-P to HDL-P is especially good [ratio of LDL-P to HDL-P less than 30 is ideal].

  • PhilM


    I have been looking around for doctors who are following up new research and aren’t afraid to challenge conventional wisdom. My hospital publishes many of its doctor’s philosophy and answers to questions. As I poured through those, it was clear to me that there is either no useful information about what they actually believe in and then there are those who stress the same old ideas.

    One of the questions was about coconut oil. The Doctor’s answer revolved around the nature of coconut fat, lack of conclusive studies and advice to avoid eating it. The last thing he stated was the (supposedly) high incidence of CHD in some parts of South India where a lot of coconut oil is used in cooking. And he was one of the few that I thought worth checking out! He also considers rice to be as bad as fat (some consolation there!).

    My frustration is that my doctors don’t seem to have time for anything but routine tests and medication. My doctor continues to do the standard lipid profile and talks to me about good and bad cholesterol every six months! He looks at me as if I am nuts when ask him about cholesterol density and particles. I can almost visualize the rolling of eyes 🙂

    Thanks for your advise. I will continue my search for a good doctor and hope it ends up well.

    • So sorry to hear that. NuSI has a lot of work to do.

    • Patrick

      I’m currently pondering the same issue raised here, as elsewhere in the comments to this latest post.

      How do I find a doctor who will accept a patient eating high fat, moderate protein, and very low carb?

      How do we find our own Dr Westman, or Dr Phinney?


      • If I knew I’d tell you. I think it just takes a lot of time and diligence. It’s no different than buying a house or a car. Nobody does something like that without REALLY shopping around, right? Yet how many folks just “show up” in their doctor’s office? I was very lucky. 1) My doctor was naturally very open to my “crazy” idea for how I was going to cure my metabolic syndrome 2) As a doctor, it probably but me more slack in pushing the envelope.

        You may not have factor #2 in your favor, but you can shop around until you find factor #1 in your favor.

    • Mugs

      Yeah, can you get on the NuSI thing? 😉 There is a decided lack of forward-thinking doctors here on the East coast. I think we have 2 in Maryland on Jimmy Moore’s site. 🙁

    • Alexandra M

      I’m very lucky in that my doctor is a believer – sort of. He saw what I did, he read Gary Taubes, gave the book to his other patients, etc. BUT, when I run up against a block, he really doesn’t know what to do. Last time he suggested bariatric surgery! (I said absolutely not.)

    • KevinF

      Folks, Jimmy Moore maintains a “low-carb doctor” blog list. You can check it for a doctor in your area who may be accepting of a lo carb diet. See:

    • Patrick

      Thanks for your response, Peter.

      I’m keen to find a doctor primarily because I would like a prescription for a ketone meter and strips. My insurance company will apparently cover a free Precision xtra meter, and reduce the cost of the ketone and glucose test strips, but the catch is that I must have a prescription. So either I try to persuade my doctor to provide one, which I anticipate will be a sisyphean labor, or I find a doctor already “concordant” with the idea of ketogenic eating.

      I am not diabetic, not suffering from metabolic syndrome (or anything else). Lucky me. But I would like to know about the ketone levels I’m producing, as I tweak the fat and protein in my daily eating.

      I mention this because other readers here, especially those with a doctor already well informed, can perhaps take advantage of the reduced costs of a meter and test strips via a prescription.


  • Bob West

    Hi Peter,
    Thanks for another rewarding post.

    I have one request: please don’t start spacing out these “hard” posts with “lighter” ones. Yes, the subject is difficult and the discussion is exhaustive (I didn’t say “exhausting”) — but the subject is crucially important, and you are laying to rest some important mistakes that we have been taught for years.

    I certainly would like to get to the conclusion, so I can say, “Well, I understand all that better,” but if you spend time on lighter subjects in between, it will just take longer to finish this one.

    Notice that you are not getting a lot of comments like, “Gee, this is too hard, stop boring us….” 🙂

    • Fair point. The other thing I have to balance is the time it takes to write “hard” posts versus “soft” ones. Each of these cholesterol posts takes me a minimum of 12 hours to write, all of which I have to do on weekends. Cuts into family time and training time…It’s a balance for me, too.

  • D

    I just listened to live radio show this morning with Dr Michael Richman, who I think may be associated somehow with Dr Dayspring through lipidcenter.com(apologies if this isn’t correct). It was interesting. He seemed very much up to date on the importance of measuring LDL-P (also sounded like a very bright guy), but boy was he certain that eating fat, particularly saturated fat, would give you heart disease. Is this the view of most lipidologists?

    • Actually it is. One of the reasons Tom Dayspring, Tara Dall, and others have become such good friends is that they are really open minded about learning out “my” world, just as I’m interested in learning about “theirs.” It’s a slow process to undo 40 years of bad science and nutritional “wisdom.”

  • To answer my own question about the LDL-p/HDL-p ratio as well as to address the assertion above that this ratio is the best risk marker for CVD. From:


    “In our large study cohort, a predictive model for future coronary events incorporating the best-available novel lipid parameter (LDL-p/HDL-p ratio) was comparable with the same model that incorporated conventional lipid ratios such as the TC/HDL-c ratio . The use of LDL-p/HDL-p ratio did not appear to offer incremental value over more traditional risk prediction models.”

    So, similar to LDL-P, LDL-p/HDL-p does in fact not to seem to offer any value over the standard risk markers.

    • Not sure I agree, Hasan. An “ideal” ratio of LDL-P to HDL-P is probably less than 30 or 35 (when reported in the typical units – nmol/L and umol/L, respectively; if both actually in the same units, ideal ratio is less than 0.03). This ratio is actually better than TC to HDL-C or even apoB to apoA-I when used to predict CV risk. This was validated in the Women’s Health Study and VA-HIT Trial. However, ratios are never meant to be used as goals of therapy as they have not been validated for that purpose and the numerator carries far more weight than the denominator. In drug naïve patients, low risk (bottom quartile) is LDL-P to HDL-P < 35, while a ratio greater than 70 is considered high risk (top quartile). The figure that shows this can be found in Circulation 2006;113:1556-63.

    • ” In drug naïve patients, low risk (bottom quartile) is LDL-P to HDL-P < 35, while a ratio greater than 70 is considered high risk (top quartile)….The figure that shows this can be found in Circulation 2006;113:1556-63."

      Hmm…going to Circulation 2006;113:1556-63 brings us to this study:


      which clearly CANNOT be used to evaluate LDL-P/HDL-P as a risk marker in the general population since the study was designed to test Gemfibrozil in a cohort that already had an established diagnosis of CHD. Additionally, there were the following "lipid eligibility criteria" for the participants:

      "Lipid eligibility criteria were HDL-C ?40 mg/dL, LDL-C ?140 mg/dL, and triglycerides ?300 mg/dL."

      In contrast, the study I cited above, this is hardly the appropriate cohort to test anything as a risk marker for the general population.

      The only other study I found of LDL-P/HDL-P as a risk marker was cited by Dayspring here:


      who claimed that it was one of "Several epidemiologic studies that enrolled both genders found the best predictors of risk to be: elevated levels of apoB or LDL-P and reduced levels of apoA-I or HDL-P [OR} a high apoB/apoA-I ratio or LDL-P/HDL-P ratio. 6,13,14"

      However, only reference 14:


      discussed LDL-P/HDL-P and it neither concerned both genders nor did it find LDL-P/HDL-P to be the best predictor of risk. In fact, it concluded:

      "In this prospective study of healthy women, cardiovascular disease risk prediction associated with lipoprotein profiles evaluated by NMR was comparable but not superior to that of standard lipids or apolipoproteins."

      Interestingly, and germane to this conversation, it also found no additional value for LDL-P itself:

      "Essentially no reclassification improvement was found with the addition of the LDLNMR particle concentration or apolipoprotein B100 to a model that already included the total/HDL cholesterol ratio and nonlipid risk factors (net reclassification index 0% and 1.9%, respectively), nor did the addition of either variable result in a statistically significant improvement in the c-index."

      To add to this growing body of evidence against the routine use of LDL-P is this brand new study:


      that concluded:

      "In a population at 2% average coronary event risk per year, cholesterol, apolipoprotein, and particle measures of LDL were strongly correlated and had similar predictive value for incident major occlusive vascular events."

      I think it should be very clear by this point why the a 2011 Expert Panel of Lipid Specialists:


      does not recommend LDL-P testing for low-risk patients as as it does not appear to add any value, either alone or in a ratio, to the standard risk markers.

      While it may have some value in the subset of those with insulin resistance/Met Syn, I continue to be disturbed by the assertion that LDL-P (and NMR testing) is an advance on standard risk predictors for the general population. I won't recapitulate all of my arguments against LDL-P screening which can be found above or in Part VI of this series but I will leave you with this from "Advanced Lipoprotein Testing and Subfractionation Are Not (Yet) Ready for Routine Clinical Use":


      'In summary, a lipoprotein measure obtained from an advanced test is clinically useful if the following criteria are met: It adds to clinical knowledge; it provides risk information that is independent of established predictors; it is easy to measure and interpret in a clinical setting; it is accurate, reproducible, and internationally standardized; and it has a favorable cost-benefit ratio.55 Importantly, the lipoprotein measures should improve patient management, particularly through more accurate risk classification and guiding choice of therapy.55,56 "

      I submit that LDL-P, in the general population and alone or in a ratio with HDL-P, is not independent of established predictors, has an unknown cost-benefit ratio, and does not result in more accurate risk classification for that population. I am always willing to hear any evidence to the contrary but in the absence of that evidence, I would conclude that there is no reason at the current time for a healthy person to measure his LDL-P, via NMR or by any other means.

      • Yes, I misspoke about this trial being in drug naive patients and was thinking of something else. For an easier view of the paper, you can get the pdf here: http://circ.ahajournals.org/content/113/12/1556.full.pdf+html. Table 5 has a nice summary.

        Before we pick on this study too much, however, we need to keep an important principle in mind. When powering a study you have a choice — A) make it as broad as possible (e.g., include young, old, sick, healthy, men, women, cats, dogs), or B) make it as narrow as possible.

        Most elaborate studies do the latter for the obvious reason that an 80% power can be achieved, as in the case of this study, with 1200 patients or so. If the former, it would have required 2 million patients. That, obviously, will not happen. We trade power for applicability every single time we do these studies. When we don’t, the results often get lost in the noise.

        So these are some of the natural limitations of clinical trials. What you are pointing out is true in the sense that you (I’m assuming) and I don’t fit the demographic of this study. But your conclusion, namely that it is necessarily the case that the results don’t apply, is not. It just has not been validated yet. Of course, the same is true of many things in medicine. Right or wrong, medicine often has to use interventions or diagnostic tests on a population (A) that was not appropriately represented by the studies validating it on a different population (B).

        Is this ideal? No. Is there a chance of error? Of course. But we do the best we can and we continue to try to make forward progress. Almost nothing in medicine would have progressed without this challenge of conventional wisdom. If you have not already done so, the chapter on radical mastectomy in The Emperor of all Maladies (the biography of cancer) is a bold example.

        In 1957 Ancel Keys and his wife Margaret would have told us, definitively, that measuring total cholesterol was enough to predict heart disease.
        Today we know that is silly.

        In 1984 the NIH consensus panel told us LDL-C was the best way to measure risk for CHD. Same story.

        Almost certainly in 30 years we will have enough information to say marker X or ratio Y is the best predictor of disease, but today we’re at a transition point. Most of the studies (i.e., the bulk of the patient interventions) have involved “typical” markers. A select few, usually on smaller cohorts, have begun to test other markers, but as you point out, the populations may not be representative of the average “healthy” person.

        Of course, the term “healthy” is misleading. How do we really define it? For any metric of healthy out there (e.g., normal glucose, insulin, TG, HDL-C), I have personally seen a dozen with hidden pathology. I know you reject this type of “individualization” of the discussion, but this is where you and I really differ.

        Medicine is an art that tries to relay on science whenever possible. I take care of some people with an LDL-P of 1,400 who I suggest do nothing but continue their course. I take care of others with an LDL-P of 1,100 that I would like to see on 2 drugs. Why? It would take me an hour of typing, which I’m not going to do, to explain the differences between these patients and why the first requires only a lifestyle interaction and why the second does not.

        I’m going to leave it at that and hope you can respect the fact that I can’t spend an additional hour each day defending this point. I know you disagree. Everyone else knows you disagree. We’ve reached a point of diminishing returns on this topic. Perhaps there are other topics on this blog worthy of your scrutiny. There is obviously a big discussion going around about the role of inflammation as the primary driver of CHD. This might be something to weigh in on.

    • I am sorry Peter but it is just not appropriate to end this discussion without me having the opportunity to respond. You are going to have a lot of people here unnecessarily running off to get NMR’s based on what appears to be wrong information. You cited two studies above to prove your point about LDL-P:

      “This was validated in the Women’s Health Study and VA-HIT Trial.”

      Neither one says what you claimed it did. As already discussed the VA-HIT Trial was not appropriate given the cohort and now you are arguing that it is too difficult to construct a proper study in a healthy population. Well, I am sorry to say that the Women’s Health Study, which did manage to construct a proper study of a healthy cohort (cmon, its not that hard) also does not support your claim:


      It says:

      “To the best of our knowledge, this study is the first large, prospective comparison of associations of NMR-measured lipoproteins with both standard lipids and immunoassay measured apolipoproteins for predicting incident CVD. We found that NMR-measured total LDLNMR particle concentration was similar in CVD risk prediction to apolipoprotein B100 , and both measurements performed better than LDL cholesterol; however, the differences compared with triglycerides, non-HDL cholesterol, and the total/HDL cholesterol ratio were small and do not support the routine measurement of NMR lipoproteins or immunoassay apolipoproteins when a standard lipid panel is available. The data from the present study, along with our prior findings 14,29 and recent data from the Framingham Study, 30 provide evidence-based confirmation for guidelines that are based on the use of standard lipid measurements, particularly the total/HDL cholesterol ratio.”

      To be fair, they do go on to qualify by suggesting that NMR results may have a role in certain situations, something I am not arguing with.

      I am not sure why you are continuing to argue this point when even Dr. Dayspring has said that in healthy populations, such as those in the WHS above, these lipid measures are all highly correlated:


      I will agree to move off this topic and on to inflammation if you will just explain why you are continuing to assert your position even in light of the fact that the studies you are citing do not, in any way, uphold it. It would only reflect well on you to acknowledge that perhaps you overestimated the evidence on this one subject. I think people always respect an analyst who is willing to change his mind on the basis of new evidence.

      I know you are busy and I respect the fact that you continue to publish my remarks. I look forward to moving on to a new topic.

      • Hasan, I’m not suggesting everyone get an NMR. When folks send lab results that look bad (e.g., high LDL-C, high TG, low HDL-C) I suggest an NMR because I still believe LDL-P is the best target of therapy (i.e., diet or medication).

    • ” I’m not suggesting everyone get an NMR.”

      Fair enough then but that hasn’t been the tone of the thread until now.

      As for the rest, if there is evidence that treating to LDL-P could make a real difference in the health of an individual, then of course I am all for it. That said, I maintain that the real issue here is insulin resistance/ MetSyn and absent that or some other heath issue/risk marker, I am opposed to medication based on LDL-P or LDL-C alone. “Lifestyle changes” are another matter I await your thoughts on this.

      Thank you again for being open enough to allow me to say my piece. I look forward to the rest of the series.

    • jw

      I think we are bumping up against the NC medical advice controversy again. This site has convinced me to make a personal decision about managing my health. I got the NMR (insurance happened to pay for it, but if it didn’t, no problem, $129), got a carotid ultrasound (covered), got a CAC score (not covered, $350), all with my doc saying that it was unnecessary.

      For a few hundred dollars I now have more data about my health than I knew was possible a few months ago and in my individual case, more data is always better. Considering the importance of the information received, and the possible concordance issues raised here, this financial risk/information reward ratio was easily economically justifiable for me even though nothing changed, treatment wise. So my doc made the correct assumption, but she didn’t KNOW.

      I know a little about risk and modeling and studies in the financial community, and know that there are a lot of prestigious, expensive and flawed theories out there. I was not shocked to find Peter pointing out a few in medical research as well.

      And if you think medical professionals have theoretically strongly grounded (but different) opinions on your health, you really don’t want to know what the issues are with the theory professionals use to manage your money…

    • David Nelsen

      Hasan, I understand you are playing devil’s advocate here and your posts are reasoned and not inflammatory. I’m not sure that you’ve picked the best argument to advance however. Pragmatically I think the NMR test costs about $30 more than a standard Lipid profile. So what do we get for our extra money? LDL-P and other markers that could predict if you are pre diabetic.

      You contend that the studies you have cited show that LDL-P provides no predictive benefit. I’ve read all of Peter’s posts and never came away with the idea that he supports NMR lipid testing for everyone. If a 20 year old male had normal Lipid profile no one would suggest he get an NNR test. If he had an abnormal lipid panel, he might benefit from an NMR test. Move our test subject to his 40’s – an age range where many males suffer heart attacks. I might convince you he could benefit from the test if he showed signs of Insulin Resistance (belly fat, elevated BP, etc). But what if he exercised and had a good height/weight ratio and no other risk factors? Can I convince you that he should get the test?

      Jim Fixx the marathon runner and author died of a heart attack while running. He may be a 1 off case, but in shapetrim guys have heart attacks all the time. Could these heart attacks be prevented with an NMR test? I would think that anyone who has an actual heart attack will likely have some predictive markers that if detected could lead to treatment prior to suffering irreparable damage. There is a subset of individuals male & female that will ultimately suffer a heart attack or stroke.

      Is NMR lipid testing the best and cheapest way to weed them out? Maybe, maybe not – the data Peter has provided is compelling. As he pointed out however, the signal to noise ratio of NMR lipid testing where you have a lot of patients with low risk factors is likely to show a null result. That doesn’t mean that there isn’t a signal present, only that you need a test group with greater risk factors to accentuate it.

      Now if we take a step back and view things from the 40000 ft level – in the old days information transfer was pretty limited. You went to your doctor and trusted what you were told. It would take a lot of work to find relevant research and most people didn’t do it. We now have the internet age where everyone can search for most anything and find it. If you think salt and fat are bad for you – you can find lots of information to confirm your feelings. If you feel salt and fat are good for you – it may be a bit harder but you can confirm this information as well. You can do this same exercise with almost any subject.

      I take everything I read on the net with a grain of salt – even what Peter writes. I do feel that he goes the extra mile to ensure what he writes is accurate and looks for contrary data that might oppose his own views. In 20 years there will almost certainly be some new test out there that is much better than NMR. But we don’t have the benefit of future findings and must do the best we can with what we have. Do doctors prescribe unwarranted tests? Of course, there is a tendency to cover their backsides and also give in to patient requests. Peter has provided the data he feels supports his arguments and it appears compelling.

      There are no absolutes or guarantees in life. Steve Jobs might be alive today if he’d taken a different treatment for his cancer. He might also be just as dead, but he made a choice based on the data he had and it wasn’t the one with the best probability for the condition he had. We all have decisions to make concerning our health. If you’re rich you can have the best doctors and run every possible test. If you’re poor you generally have no money for preventative medical care. If you’re in between you make choices based on your own personal data. Since we live in a free country so if you don’t want an NMR or any other test you don’t have to get one. You may think everyone on this site is a hypochondriac or overly concerned with their health. I don’t know, but it seems to me you’re barking up the wrong tree on this one.

    • Hasan Hanachi


      “Pragmatically I think the NMR test costs about $30 more than a standard Lipid profile. So what do we get for our extra money”

      You question is based on one very wrong assumption- that the cost of diagnostic testing is only represented only by the cost of the test itself and the same question could be asked about a myriad of other lab tests and diagnostic procedures. What is the cost of a PSA test after all and by that measure, there should be no controversy whatsoever about the cost of that testing.(Please see the latest Preventive Task Force recommendation on this) However, the real cost lies in the so-called “false-positives” which frequently lead to unnecessary further testing and treatment not to mention the attendant anxiety involved. In the matter discussed here, the likely further treatment is statin therapy. If routine NMR testing leads to statins, with the NNT’s I have already discussed, then the cost will be far above the $30.00 of the test. As I have tried to explain already, any screening procedure has to meet the cost/benefit criteria (using the expanded definition of cost already defined.). I see no such data for an NMR.

      “There are no absolutes or guarantees in life. Steve Jobs might be alive today if he’d taken a different treatment for his cancer…….Jim Fixx the marathon runner and author died of a heart attack while running. He may be a 1 off case, but in shapetrim guys have heart attacks all the time. Could these heart attacks be prevented with an NMR test? ”

      This is the argument by anecdote always used to justify screening. It may seem heartless, but there will always be people who would have been saved by a test or procedure but that simply does not justify that same test or procedure as routine screening. Otherwise we could say that every person should have every conceivable one of them. You are simply not taking into account the issue of false positives.

      “Since we live in a free country so if you don’t want an NMR or any other test you don’t have to get one. You may think everyone on this site is a hypochondriac or overly concerned with their health”

      I don’t think that but clearly there are a subset of people who are going to be panicked with the thought that they have undiagnosed “discordance.” There was already one person in this thread who contrary to the advice of his physician went out and obtained $500 worth of further diagnostic testing, some of which was paid by insurance and some out of pocket. The result was money wasted, some paid by the individual and some by the rest of us. (Aren’t medical costs a high enough percentage of the U.S. GDP?) To save time, before responding with the question “what if it had saved his life”, read the above again.

      “So what do we get for our extra money? LDL-P and other markers that could predict if you are pre diabetic.”

      We already have criteria for “pre-diabetes” and even here, an argument could be made that like “pre-hypertension”, the notion itself is just pushing more screening onto the U.S. population. However, assuming that “pre-diabetes” is a worthwhile concept, I would like to see the evidence that an NMR has demonstrable reclassification utility. In other words, does adding an NMR to the existing criteria for pre-diabetes make a significant impact on reassigning people to high or low risk groups. This is just a standard question in evaluating new testing.

      “the signal to noise ratio of NMR lipid testing where you have a lot of patients with low risk factors is likely to show a null result. That doesn’t mean that there isn’t a signal present, only that you need a test group with greater risk factors to accentuate it………
      Move our test subject to his 40’s – an age range where many males suffer heart attacks. I might convince you he could benefit from the test if he showed signs of Insulin Resistance (belly fat, elevated BP, etc). But what if he exercised and had a good height/weight ratio and no other risk factors? Can I convince you that he should get the test?”

      If your hypothetical patient had “belly fat, elevated BP” and by “etc” you meant the additional criteria for Metabolic Syndrome, I have already said several times that this is already a situation which requires treatment or change of some kind. Before convincing me that an NMR is additionally warranted, I need to see the evidence (the kind of evidence I have already requested) that the NMR will demonstrably assist in risk classification and/or lead to a different treatment with a reasonable NNT.

      You may think that I am being unnecessary quarrelsome here as you have said that you find the case for NMR and LDL-P testing “compelling.” Well, medicine is littered with compelling arguments that led nowhere or, worse, down roads we came to later regret. That is why actual evidence is the only way we have to settle arguments such as these. For those who want a more comprehensive and technical overview of the issues involved, see:


      We do seem to me making progress in this discussion since we already agree that not everybody needs an NMR (no routine testing). The subject now to be resolved is that in people with additional risk factors, does NMR testing add further value? I do not yet see the case for that in terms of actual evidence as opposed to theory.

      • I think you mean to be responding to someone else.

    • Hasan Hanachi

      BTW, even a first year statics student learns that if you want improve a regression equation, look for variables that are not inter-correlated, so if you want to add a lab test for purposes of risk classification, I would suggest hs-CRP. Unlike LDL-P, CRP has been validated as adding predictive power to the set of Framingham variables:

      http://circ.ahajournals.org/content/118/22/2243 (note that the author invented the test but do we want to go there???)

      and conceptually makes sense since inflammation is inextricably tied up with CVD.

      If you want to play around with CRP as a risk factor, there is a neat calculator here:


      which lets you compare a whole bunch of different risk assessment algorithms. (A word of caution, make sure you read the notes in order to have some understanding of each of the different algorithms before drawing any conclusions. Otherwise you might get odd results such as 0% risk.)

      All that said, I don’t support using hs-CRP as another screening test (lets not talk about the JUPITER trail please!) and as a gateway to stain therapy. Rather, as noted, it has utility in improving risk classifications, reinforcing the need for lifestyle interventions, and possibly as a tool to bolster the case that higher LDL on various diets may not raising risk as much as thought (or not at all?), although this is a subject for another time.

      (One additional note on CRP- since so many things can raise it, multiple measurements over time might be necessary before concluding that it is elevated. )

    • Hasan Hanachi

      “I think you mean to be responding to someone else.”

      Yes sorry, that was my response to David.

  • steve

    Had never heard Russert Trgs were so high! Hard to believe his doc did not have him on some meds to lower that! Anyone with a family history of heart disease in my view should ignore ratio’s, and caution should be exhibited in their use in any event. MY Trg to HDL ratio has always be no greater that 1:1 and yet when an NMR was done it showed very very high levels of LDL-C almost all small. Docs always said perfect numbers and no worry with family history: you exercise lots, normal weight, good BP, diet, etc.

  • steve

    Dr attia: you might find this interesting commentary by Dr Ron Krauss:

    favors a low carb, hi fat diet, but says not only are polyunsaturated sources better than saturated fat, but goes on to say that in his studies, hi red meat intake causes all LDL particle sizes to increase, and he believes small LDL is much worse than large LDL-P and to him it sounds like size matters which is different than your and Dr.Dayspring’s viewpoint. Interesting.

    • Yes, interesting indeed. Ron Krauss does does really excellent work, so this is certainly worthy of further investigation.

    • KevinF

      Steve, Kraus did not say red meat causes all LDL particle SIZES to increase, he said it causes all types of LDL particle NUMBERS to increase; hence he is suggesting fat is OK as long as you limit intake of red meat. (Unfortunately that sentence was written unclearly, but that’s what he’s saying.)

    • steve

      I understood what Krauss said,but may not have related correctly.
      Most interesting is his preference for polyunsaturates, and his statement that small LDL-P is worse than large LDL-P. Dr. Dayspring thinks otherwise, and Dr Attia has posted his view which is in line with Dr. Dayspring. With such expertise expressing an opinion, it might not be that clear, and particle size may matter. Dr Bill Davis of heartscan blog thinks small LDL-P matters more and advocates a level of carb restriction(and fat addition) to virtually eliminate them.
      Would be nice to know which is it: does size of LDL-P matter or not?

    • In his red meat study, both exp groups ate the same lean red meat, it was only the saturated fat that changed between them and that saturated fat was made up with saturated dairy fat. With that in mind, I don’t think it’s necessarily that red meat is bad, but that red meat for breakfast lunch and dinner coupled with a high saturated fat lifestyle could be potentially atherogenic.

  • catherine

    Palmitoleic acid: is an omega-7 monounsaturated fatty acid that is a common constituent of the glycerides of human adipose tissue It is biosynthesized from palmitic acid by the action of the enzyme delta-9 desaturase. A beneficial fatty acid, it has been shown to increase insulin sensitivity by suppressing inflammation, as well as inhibit the destruction of insulin-secreting pancreatic beta cells.[1]

  • catherine
    • The thing you always need to be careful of in animal studies is that they are animal studies. What works in animals doesn’t always work in humans, as we’ve got different evolutionary trajectories.
      For example, hypoxia: bad for mice (or pythons); bad for humans. Cats: bad for mice; not bad for humans.

  • catherine
  • Chris

    Hello Peter,

    Thank you for all the time invested in providing such important information. Do you plan to relate all this info to some dietary specifics? It would very helpful if you were able to translate this information into an action plan of sorts regarding dietary as well as exercise suggestions.

    Thank you!

  • Harry35

    Peter, in the study by Asztalos referenced above, it wasn’t necessary to measure large HDL-P, because the two largest HDL’s in his scheme (alpha-1 and alpha-2) nicely blanket the size of the large HDL-P from NMR, and are therefore likely to be equivalent. So when alpha-1 and alpha-2 go up, so does large HDL-P. And I don’t think we can assume without evidence that LDL goes up when HDL goes down in these cases, although it may. That appears to an unjustified assumption from these studies, although the data should be out there somewhere, since both of these 2 studies were done on well know patient populations. Also, take a look at this study of VA-HIT patients, where Astalos uses 2D-GGE to evaluate the risk of CHD vs eight of his variables.
    Table 5 of that study shows that recurring CVD risk increases with increasing values of pre-beta-1 and alpha-3, and decreases with increasing values of the other alphas, pre-alphas, and pre-beta-2. This suggests to me that large alpha particles are strongly atheroprotective, except for alpha-3.

  • Joanna

    Please, please finish this series and if possible make some dietary recommendations – I find this subject fascinating but at times overwhelming – I need to reread segments until I understand it better. But am very personally interested, and realize that everything I keep hearing from doctors, including highly paid cardiologists, is mostly simplistic and possibly dead wrong! Thank you for making this information more available.

  • Dr. Attia

    Thank you for this wonderful overview of key concepts in lipidology and the role of different different subtypes of cholesterol and other lipoproteins for the risk of cardiovascular disease.

    I am a practicing cardiologist myself and I am always trying to improve my knowledge on the effects of diet and lifestyle interventions on the risk of cardiovascular disease. As a profesional I rely on clinical guidelines during my daily practice. But, as you are aware of, there is so much evidence suggesting that we have been on the wrong track for many years concerning diet, obesity, sugar, carbohydrate, fats and cardiovascular risk.

    As a clinician I tend to go for the big questions. For example, we know that statins improve prognosis in patients with documented coronary artery disease. However, we still don´t really know whether that is due to their LDL-lowering effect or due to something else, possibly their antiinflammatory effect.

    Although we know that there is a relationship between cholesterol levels, LDL-C, LDL-P and cardiovascular risk, we still don´t really know the mechanisms, or whether there is a causative relationship. Is cholesterol really a causative factor or just a surrogate. Is lowering cholesterol really as important as previously thought. We know that there are no studies showing that lowering cholesterol reduces the risk of heart disease, apart from the statin studies.

    Again. Thanks for your wonderful blog. I really look forward to seeing you adress the big clinical questions;
    Does lowering cholesterol by diet reduce the risk of heart disease?
    What is the best way to lower cholesterol by diet?
    Most clinical guidelines on the prevention of cardiovascular disease recommend staying away from saturated fat. Do you think this is an evidence based conclusion?
    What is your opinion on statin therapy in primary prevention?

    I have been dreaming about blogging about those big questions myself. Maybe you will get there in # 45.

    • Axel, there really aren’t good data on primary prevention due the time issue. Funding such studies would be very costly due to power (size) and intervention (drug).
      The problem with the statin studies, of course, is that they are typically done for non-primary prevention, and they are only funded by drug companies.
      What we really need is a properly done, appropriately controlled (the key) study on primary prevention.

    • greensleeves

      Hi Axel:

      Here is my current understanding to all your queries. If I am wrong, hopefully other commenters will correct:
      Q. Does lowering cholesterol by diet reduce the risk of heart disease?
      A. Current evidence appears mixed at best, depending on what cholesterol measures you use. Reducing particle count appears beneficial.
      Q. What is the best way to lower cholesterol by diet?
      A. A low-carb diet, such as Dr. Eric Westman’s No Sugar No Starch or Dr. Dean Ornish’s (which Peter argues is actually a low-carb diet in disguise).
      Q. Most clinical guidelines on the prevention of cardiovascular disease recommend staying away from saturated fat. Do you think this is an evidence based conclusion?
      A. A few months ago, I would have cited the Siri-Torino/Hu/Krauss meta-analysis from 2010 to say no, sat fat has been exonerated. However in the past few months, that paper has seemingly died an ugly death and the authors apparently no longer bother to defend it. Currently, I am not sure we have strong evidence either way. I think at this time we have to say we don’t really know.
      Q. What is your opinion on statin therapy in primary prevention?
      A. Currently it appears that if you are what Peter calls “discordant,” they may be useful. Likewise, if you are a man or woman who has already suffered a cardiac-type incident. If you are a woman who still has a period, there may be doubt they do much for you. As Peter says, the evidence is poor and seems mixed, maybe biased.

      Welcome to the murk of uncertainty. 🙂

  • Margaretrc

    Another excellent post. This has been fascinating, so far. I look forward to more.

    I don’t live in SD, but I live close enough I think I can get to your talk at UCSD and am planning on trying. Looking forward to hearing your speech! Along with your friend Gary Taubes, you are one of my heroes.

  • Barry

    Not asking for any advice, just thought I’d share an anecdote of possibly some interest. Pre-LCHF, LDL-C was 166 (tested 5 years ago). 4 months into LCHF, LDL-C just came back at 401, TC 499. Still waiting on ApoB results before I totally freak out. One positive (yay!) is that my Trigs/HDL ratio has improved from 2.44 to 1.266.

    NMR not available where I live. I’ve read that this sometimes happens to people – don’t know why other than possible ApoE problems. I’ll wait for the ApoB and ApoE and go from there. Not sure of the likelihood of it coming back particularly good. Fingers crossed it isn’t terrible.

    • vernon

      Barry, I don’t understand why NMR is not available in your area. My understanding is only one lab in the country does the test, and your blood sample has to be sent there. You can order this test from several online services.

    • Barry

      Hello Vernon. I do not live in your country.

  • Mark

    Sorry, still dont get it. You are what you eat! If you enjoy a bit deep fried meal your plasma colesterol jumps up as does the lipid content in general come to that? I’d love to see the data proving the contrary, Thanks

    • Overly simplistic view of a much more complex process. Go back to part I of this series if you want to understand the interaction between ingested cholesterol and serum cholesterol.

  • Robin

    I don’t have access to an NMR test so I am looking at ApoB to estimate particle number. How can I translate from ApoB to LDL-P? The ApoB result is measured in mg/dL.

    The graph of LDL-P distribution showing percentiles (like the one from the MESA trial) is useful so my end goal is to approximate where an ApoB result would sit on this graph.

    Thanks. I’ve really enjoyed this series of posts.

  • Hi Peter,

    I haven’t seen any commentary by you about the role homocysteine plays in all this. Dr. Kilmer McCully’s pioneering work in 1968 on homocysteine was prior to the growing domination of the cholesterol theory. As the cholesterol theory gained momentum, he was demonized, stripped of tenure and ultimately fired and black-listed. In the 1990s, international studies confirmed his earlier work and he began to be given credibility again.

    Essentially, as I understand it, his work indicates that elevated homocysteine levels cause the inflammation that is necessary for atherosclerosis to develop by enabling cholesterol to enter the arterial walls.

    His “cure” for atherosclerosis is to avoid the all too common dietary deficiency of B6, B12 and folic acid by dietary means if possible and supplement them if not possible due to veganism or some other reason that limits access to animal products.



    P. S. Some of his papers over the years:

    1. McCully K S, “Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis”, Am. J. Pathol. (1969), 56: pp. 111–128.
    2. McCully K S, “Chemical pathology of homocysteine”, I. Atherogenesis Ann. Clin. Lab. Sci. (1993), 23: pp. 477–493.
    3. McCully K S, “Homocysteine and vascular disease”, Nature Med. (1996), 2: pp. 386–389.
    4. McCully K S, “Homocysteine, folate, vitamin B6 and cardiovascular disease”, J.Am. Med.Assoc. (1998), 279: pp. 392–393.
    5. McCully K S,“Atherosclerosis, serum cholesterol and the homocysteine theory: a study of 194 consecutive autopsies”, J.Am. Med. Sci. (1990), 299: pp. 217–221.
    6. McCully K S,“Keeping the Young-Elderly Healthy. Homocysteine, vitamins, and vascular disease prevention”, Am. J. Clin. Nutr. Nov. 2007 Vol. 86, No. 5, 1563S-8S http://www.ajcn.org/cgi/content/full/86/5/1563S.

    • Thanks, Edward. I have not written about this topic (yet), but hope to at some point.

  • I’m still 100% convinced its all about avoiding inflammation. Your Cholesterol just doesn’t get under the “cracks” unless the cracks show-up first – you need a reason the cholesterol shows up and gets “stuck”. Avoid the “cracks” and avoid the problems. How’s that for a simple conclusion 🙂

    Once you have inflammation – your cholesterol numbers and size doesn’t matter – you may postpone the inevitable, but by how much? What if inflammation triggers “bad cholesterol” to be produced in the first place?

    • If this were true, how would it explain the association between apoB and CHD? If it were only about inflammation, as you hypothesize, any association with apoB would vanish or be so significantly diluted that we could never see it. Yet we see it loud and clear?

    • Hasan Hanachi

      This debate between inflammation v. cholesterol as a cause of heart disease is a prevalent theme in the health blogosphere. The “cholesterol deniers” champion the inflammation hypothesis while most of the medical/pharmaceutical community goes with cholesterol. Unfortunately, nobody seems to be pointing out that there is a much more sophisticated history of competing theories in the medical research literature- the “Response to Retention” v. the “Response to Injury” hypotheses which pretty much parallel the blogosphere debate. It is just not possible to review the extensive literature here but we can say, albeit grossly oversimplified, that the Retention hypothesis corresponds pretty much to the “LDL particles get stuck in the arterial walls” idea while the Injury hypothesis mirrors the “inflammation damages the arterial wall” concept. As often the case, there may not be a stark dichotomy between the two explanations but the most important observation I can make is in reference to Peter’s “Take Away Points” 19-20:

      “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….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.”

      This clearly comes down hard on the side of the “Response to Retention” hypothesis and neatly, perhaps too neatly, meshes with LDL-P as the critical variable. My objection is that this is presented as if it was settled fact instead of the subject of ongoing debate and research. The “association between apoB and CHD” is NOT conclusive evidence on the side of Retention. Since LDL cholesterol has immune functions, immune signaling is a possible explanation for the association, as noted by Lorraine in the above comments, and could also support the Injury hypothesis (Some interesting research in this area was done in Russia in the 1990’s showing that cholesterol in circulating immune complexes was a much more reliable marker of coronary atherosclerosis than standard measures).

      Also ignored in the series is the role of serum oxidized cholesterol which has also been shown to be a superior marker for atherosclerosis over standard measures as well as having the ability to move back and forth between vessel wall and the circulation.

      All of this cries out for far more discussion and debate than has been given here.

  • steve

    Eating cholesterol has very little impact on the cholesterol levels in your body.
    Yes, but can the same be said about saturated fat. Dr. Krauss appears to think otherwise and suggests caution with regard to red meat. I hope you discuss this as it appears that diet via sat fat may affect cholesterol levels and number of particles. Thanks

    • Hope you can attend my talk at UCSD tomorrow. I’ll be addressing this question.

    • jw

      Somebody PLEASE sit in the front row with a good, HD cellphone camera…

  • steve

    Were I near by I would absolutely attend! Living in New York City makes the logistics a little tough! Come out this way and I will be there for sure! Hope you address the question in a subsequent cholesterol post. Am guessing it is on the minds of many who have cut carbs( low or vlc) only to find sky rocketing LDL-C and LDL-P

    • Hopefully I can find someone to record it.

  • Donna Oman

    ? Peter–So, is this work simply wrong from heart.org??

    June 20, 2012
    View the most recent content at: http://www.theheart.org
    Most recent news
    Measuring apolipoproteins does not help risk prediction

    • From Dayspring, Dall, and others:

      All of these analyses are flawed with respect to examining the atherogenic lipoprotein variables in patients in which cholesterol measurements and lipoprotein concentration measurements are not also examined in the patients where the variables are discordant. These measures (cholesterol concentrations and apolipoprotein B) correlate highly – yet as we all know and these studies never address it, is in the many patients where the measures are discordant, apoB and LDL-P are the proven better variables to measure both risk prediction and therapeutic goals. It is also unfortunate that this study provided no LDL-P analysis. Thus these analyses might be of some interest to epidemiologists who look at entire populations and have virtually no value to practicing clinicians who treat people one at a time.

      It is difficult to make the case for apoA-I by itself in routine screening as it is not the most accurate way of quantifying total HDL-P. Thus I have little use for that measure by itself other than the investigation of patients with significant hypoalpha or hperalphalipoproteinemia. However both AMORIS (which this analysis conveniently left out) and INTERHEART (two gigantic trials) revealed that the best risk predictor was the apoB/apoA-I ratio. So in drug naive patients the ratio (which requires apoA-I measurement) is validated. No ratio is likely valid in patients on lipid modulating meds as drugs do not effect apoB and apoA-I equally nor do apoB and apoA-I have equal predictive abilities.

      With respect to inflammation markers: their appropriate use (as discussed in the recent NLA biomarker statement) is to be used not in place of lipid or lipoprotein concentrations but afterwards to better fine tune risk which several studies have shown they do. Their elevation, based on current knowledge, should lead the clinician to get more aggressive in attaining lipid and lipoprotein goals of therapy not per se any (now nonexistent) inflammatory goals of therapy. However current studies do suggest but further studies will be needed to show if it is important to also normalize at least some inflammatory markers.

      The paper actual states: “The addition of the combination apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipaseA2to risk scores containing total cholesterol and HDL-C provided slight improvement in CVD prediction.” When you apply that slight improvement to 350 million Americans you are talking about millions of persons who would indeed benefit

      Interestingly, last year the NLA reviewed all of this data and more and came to the conclusion that apoB, LDL-P, Lp-PLA2 and Lp(a) were indeed useful in almost all folks who have greater than a 5% ten year Framingham Risk score (virtually every adult > 30-40 years old).

    • Hasan Hanachi


      You indicate this response is from “Dayspring, Dall, and others” so I don’t know who I am actually responding to. I will continue nevertheless.

      I see two parts to this rebuttal to the JAMA article:


      first, that it failed to take “discordance” into account and second, that other studies show that apoB/apoA-I ratio is “the best risk predictor.” I will deal with the risk predictor argument first as stated here:

      “both AMORIS (which this analysis conveniently left out) and INTERHEART (two gigantic trials) revealed that the best risk predictor was the apoB/apoA-I ratio. ”

      In fact, neither study says that at all. INTERHEART:


      looked ONLY at apoB/apoA-I and for reasons of practicality as they wrote:

      “Because apolipoprotein concentrations are not affected by the fasting status of the individual (unlike calculated LDL), we used the ApoB/ApoA1 ratio as an index of abnormal lipids in the current analysis. 10”

      The study did not look at or compare any other predictors nor was the study designed to do that.

      As for AMORIS:

      “High apolipoprotein B, low apolipoprotein AI, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study” (only abstract available online”

      Lets first deal with the rather underhanded swipe at the JAMA article authors, suggesting that there was something sinister in the omission of AMORIS. However, as they clearly state:

      “Data from the Apolipoprotein Related Mortality Risk Study (AMORIS) could not be incorporated into these current analyses because it did not measure baseline levels of HDL-C, blood pressure, smoking status, body mass index, or diabetes (eTable 5).17”

      Hardly “mysterious.” In any case AMORIS only looked at ApoB/ApoA1 compared to TC, TG, and LDL leaving out TC/HDL or Non-HDL cholesterol so it was hardly a comprehensive analysis.

      So, it does not seem that these two studies in any way speak to the superiority of ApoB/ApoA1 over the traditional markers. (As for the lament that LDL-P was not included in the JAMA study, I have spoken my piece on that already earlier.)

      You seem to want to salvage something for your case by arguing that claiming:

      “The paper actual states: “The addition of the combination apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipaseA2to risk scores containing total cholesterol and HDL-C provided slight improvement in CVD prediction.” When you apply that slight improvement to 350 million Americans you are talking about millions of persons who would indeed benefit.”

      Aside from the silliness of applying the numbers to every, single American (what happened to your statement that not everybody needs an NMR???), unfortunately you didn’t include their analysis here:

      …we showed that each of the lipid-related markers studied herein slightly increased CVD prediction when using measures (eg, the C index and D measure) that are independent of clinical risk categories. Second, we found that none of these markers significantly improved reclassification of participants across the clinical risk cutoff levels that are currently used to inform treatment decisions. Third, we modeled a scenario assuming targeted lipid-related marker assessment in people judged as being at intermediate risk (10%- <20% 10-year predicted CVD risk) after initial screening by conventional risk factors alone. If such targeted measurement were to be coupled with allocation of statins per US Adult Treatment Panel III guidelines,24 then our data suggest that it could help prevent 1 extra CVD outcome over 10 years for approximately every 4500 people additionally screened with a combination of apolipoprotein B and A-I, …..

      Even if you accept the statin numbers, screening 4500 people to prevent one outcome, and on the basis of epidemiological evidence, is……well……madness. Thats why we have reclassification analysis, to bring some sanity to medical screening.

      Lets turn to the second argument" which is this assertion about discordance:

      "…in the many patients where the measures are discordant, apoB and LDL-P are the proven better variables to measure both risk prediction and therapeutic goals.

      I have no doubt that such measures are superior risk predictors to LDL-C but that begs the more important question. Since we already know, as I have commented in an earlier post, that discordance is closely associated with Metabolic Syndrome/Insulin Resistance, the real question is whether or not "discordance" is a better risk predictor than the usual set of markers used to diagnose MetSyn. Another way to ask that that question would be whether or not "discordance, in the absence of MetSyn/IR, adds any useful predictive information. I see no evidence for that here.

      Similarly, for those already with MetSyn/IR, we also need to ask if there is any evidence that the "therapeutic goal" (I suspect meaning medication) of reducing discordance has any value over any other treatment for the condition. I will wait for the treatment part of the series for an answer on this but, in the mean time, I am seeing a disturbing pattern here of studies not actually saying what they are purported to say. I will extend to you the benefit of the doubt since as you say, this posts taking a great deal of time to write and you are doing it in your spare time.

      • It’s a fair point you make, Hasan, about the filter of MetSyn/IR to predict discordance, and ultimately, the need for NMR. Something to consider is the following: Is there a harm in knowing someone’s LDL-P (whether concordant or discordant)? Assume, of course, that in the MetSyn/IR patients there will be much greater discordance, but as we saw in MESA, even in non-MetSyn/IR discordance can be present, albeit to a lesser degree. What I’m asking is, do we lose anything by having this information? Furthermore, when coupled with other clinical information (e.g., calcium score, Lp-PLA2, hs-CRP, LP-IR score), can a good clinician make a better decision with better targets of therapy?

    • Hasan Hanachi

      ” Is there a harm in knowing someone’s LDL-P (whether concordant or discordant)? ”

      If you mean that knowledge in the hands of a physician the harm, aside from cost, will depend on any ensuing treatment either based on that number or because that number was added to the mix. If you mean that knowledge in the hands of blog readers, well, thats another story and you have to measure the advantage of having more informed patients v. the reality that such knowledge can end up in added expense, anxiety, and possibly treatment if the patient is insistent enough. That takes us back full circle.

      “Furthermore, when coupled with other clinical information (e.g., calcium score, Lp-PLA2, hs-CRP, LP-IR score), can a good clinician make a better decision with better targets of therapy?”

      If the targets really are better which has yet to be established but if the truth be known I kind of hate the notion of “targets.” I would rather talk about the health of people.

      ” …as we saw in MESA, even in non-MetSyn/IR discordance can be present, albeit to a lesser degree.”

      You have yet to convince me that discordance in the absence of MetSyn/IR or other risk indictors is a risk marker.

      Don’t get me wrong, I am NOT trying to minimize the significance of MetSyn/IR. In fact, I consider it to be the hallmark of our time. If this series is heading towards “lifestyle change” as an approach to this problem, I am with you. If its headed toward adding even more people to the statin pool who have yet to participate because their LDL was not high enough, I am against you. I will anticipate the response that these two approaches are not mutually exclusive but, in reality, I believe they are for all intents and purposes but thats a discussion for another day.

    • Bill

      “Is there a harm in knowing someone’s LDL-P (whether concordant or discordant)?”

      Yes, there could be substantial harm, and this is one of the main reasons I think Hasan is raising questions here.

      I suspect that Hasan has been influenced by some of the same people I have, such as Dr. Gilbert Welch of Dartmouth and Dr. Nortin Hadler of UNC. They have written extensively about the harms that can come looking too hard for signs of illness in apparently well people (i.e., screening).

      When even seemingly no-brainer tests to detect cancer early (e.g., PSA test, colonoscopy, mammography) are subjected to large, long-term clinical trials, it becomes clear that the harms are very real and may very well outweigh any benefits. In these cases, the physical harms are such very serious things as incontinence, impotence, loss of breasts, radiation-induced cancer, bowel perforation, or death, from the tests themselves or the further invasive tests and interventions that inevitably follow in large numbers. On top of this are the often excruciating psychological harms of health scares, endless testing, and becoming permanently labeled as, and feeling like, a sick person instead of a well one.

      The sought-after benefits, such as preventing or successfully treating cancers that otherwise would have killed, have turned out to be so elusive that even massive, long-term trials have had great difficulty detecting them. If they exist, which does not even seem entirely clear, they have to be extremely small.

      As Dr. Welch says, even if the chance of being seriously injured by agreeing to screening is very small, so is the chance of being helped, so it is far from clear that we should all be good boys and girls and agree to the standard of care in these matters. It is a personal choice, and also a social one given the enormous costs. Welch and Hadler write extensively about how to think about these choices. I myself have declined all such tests after looking into them. I am quite happy to forgo the minute possibility that I will be saved in return for avoiding the far more likely possibility of getting sucked into the medical mill unnecessarily, with perhaps dire consequences. I have seen it happen.

      How do we know the same won’t turn out to be the case for LDL-P screening? Statin drugs, for example, are certainly not benign, and their long-term risks are not even fully understood yet. I would guess that LDL-P will ultimately fare no better than PSA, colonoscopy, standard lipid screening, and all the rest, when applied to healthy populations. There are fundamental underlying reasons for this rooted in Bayesian statistics, the natural history of most illness, and the limitations of medical interventions. Testing and treating the truly sick is one thing, often able to produce benefit in excess of harm. Testing, and then inevitably treating, the well, e.g. in search for “risk factors,” is another matter entirely.

      Peter says, “When you apply that slight improvement to 350 million Americans you are talking about millions of persons who would indeed benefit.” But what of any slight, or maybe not so slight, *harms* of the testing and treatment, when also multiplied over 350 million people?

      Maybe if applied to a small subset of clearly sick people, LDL-P could be useful, just as all those other tests can be in some circumstances. But to assume away the harms of generalized population testing could be to repeat enormous mistakes of the past that will take many years to unwind. Notice the tantrums and hysteria that result when even when staid mainstream bodies such as the U.S. Preventive Task Force recommend the slightest relaxing of heavily-promoted prostate or breast cancer screening protocols.

      • All fair points, Bill, but keep a few things in mind. The overzealous interventions that have caused so much harm with unnecessary colonoscopy, PSA, and mammography are VERY different from what I think you’re suggesting (i.e., unnecessary prescription of a drug to reduce apoB/LDL-P/LDL-C/pick-your-target). This is a night and day difference. If folks were suggesting that elevated LDL-P means a trip to the cath lab, I’d be in 100% agreement with you. That’s crazy. It’s like doing a biopsy on every man with an elevated PSA, or like doing a full colonoscopy on everyone over the age of 30. But it doesn’t. It means (in the hands of a good doctor) more screening tests to determine how great your risk is and at the very least careful monitoring for progression of this, or other markers.
        I realize you, and others, may reject the idea that a cluster of biomarkers is of value (e.g., elevated apoB, elevated LpPLA2, elevated MPO), but at some point we have to pay attention even if a person in clinically asymptomatic.

        Do you know what the most common presentation of myocardial infarction is in the U.S.? Not chest pain. Not shortness of breath. It’s sudden death. So the single most common presentation of heart disease (this was true 10 years and may not be true today) was death. If you had looked at the person the day before they died, what would you have seen? Would it have been bad enough to justify treating? What about a year before? What about 5 years before? What would have been enough to treat? How high should the calcium score get before a treatment was suggested? When is and LDL particle screaming loud enough to justify treatment?

        These are not easy questions. If they were I’m sure we wouldn’t be doing this back and forth and back and forth and back and forth and back and forth … that I’m enjoying so much.

        But keep in mind the difference between the mindless algorithmic application of “standards” and a thoughtful, individual approach to patient care. I’m not here to tell anyone to take drug X or get test Y, but I refuse to accept that information is power. With this power comes responsibility. If someone can’t handle that, fine. Perhaps the information is not right.

        We shop around like crazy to find the best car mechanic or hair dresser (well, I don’t, but I’m sure some people do). Why are we not applying this same standard to our doctors? Maybe if people had better doctors who understood the nuances of this, fewer patients would have unnecessary colonoscopies, breast biopsies, prostate biopsies, and be prescribed fewer drugs.

    • Donna Oman


      Apologies–above is the correct site–Title: Measuring apolipoproteins does not help risk prediction, date June 19, 2012.. Cambridge, UK. I think it is exactly contrary to what you are saying. D.Oman

    • Donna Oman

      I wanted you to see the website–but here is the complete article to save your time.

      heartwire home
      Measuring apolipoproteins does not help risk prediction
      June 19, 2012 Sue Hughes

      Cambridge, UK – Measuring newer lipid biomarkers with the aim of honing risk prediction for heart disease doesn’t actually appear to help very much in this regard, according to a the largest study yet to look at this issue [1].

      The study, published in the June 20, 2012 issue of the Journal of the American Medical Association, found that measuring a combination of apolipoprotein B (apoB) and apoA1, lipoprotein (a) (Lp[a]), or lipoprotein-associated phospholipase A2 (Lp-PLA2) gave worse predictions of risk than current lipid measures—total and HDL cholesterol. In addition, the study showed that measuring these alternative biomarkers added little information when added to conventional risk factors.

      Coauthor of the current study, Dr Emanuele Di Angelantonio (University of Cambridge, UK), commented to heartwire: “These are the best data yet on these apolipoprotein biomarkers, and our conclusion is that it is probably not worth measuring them routinely for screening purposes.”

      Di Angelantonio explained that there have been previous studies on these apolipoproteins in smaller data sets, but this is the first study to look at all these markers on top of conventional risk factors in a large primary-prevention population.

      The researchers combined data on 165 000 individuals from 37 cohort studies where these apolipoproteins were measured at baseline and the patients followed for an average of 10 years. They conducted two analyses—one on the use of the new biomarkers instead of total and HDL cholesterol, and the other on using the alternative biomarkers in addition to total and HDL cholesterol.

      “We found that use of any of the apolipoproteins instead of current markers gave a worse prediction. And use of any of them on top of current markers improved risk prediction but only very slightly. It is probably too small an effect to be worth doing.”

      The study measured improvement in risk prediction by looking at changes in the C statistic. These were improved by very small amounts with the different apolipoproteins.
      Improvement in C statistic with apolipoproteins on top of conventional factors

      Improvement in C statistic

      The researchers also estimated how many individuals would be reclassified as high risk with these new measures. They calculated that for 100 000 adults aged 40 years or older, 15 436 would be initially classified at intermediate risk using conventional risk factors alone and that additional testing with a combination of apoB and apoA1 would reclassify 1.1% of people to high risk and, therefore, eligible for statin treatment under current guidelines. Corresponding numbers for Lp(a) and Lp-PLA2 were 4.1% and 2.7%, respectively.

      They further estimate that this would lead to the prevention of one extra cardiovascular outcome over 10 years for approximately every 4500 people additionally screened for a combination of apoB and apoA1, about 800 people screened for Lp(a), or about 1000 people screened for Lp-PLA2.

      “Not completely closing the door on Lp(a)”

      Di Angelantonio commented to heartwire: “Of the three markers, Lp(a) came out best, but even here the benefits were still very small.” However, he added that they did not include data on genotype or isoform size, which may be important for Lp(a), “so we are not completely closing the door on Lp(a) assessment for the future.”

      Noting that measurement of Lp(a) to augment risk prediction in intermediate-risk individuals was recommended in the most recent European Atherosclerosis Society guidelines, Di Angelantonio suggested that these may need to be “carefully revised.”

      Grundy in agreement

      In an accompanying editorial [2], Dr Scott Grundy (University of Texas Southwestern Medical Center, Dallas) agrees that these apolipoproteins “do not add much to risk prediction over routine lipid measures.” He suggests that the main reason for this is that cardiovascular disease is multifactorial and that apolipoproteins are only one set of factors among many.

      He writes: “A common mistake in clinical practice is to overly emphasize one or another risk factor as a predictive factor. This is particularly problematic when risk factors are colinearly linked, as occurs between lipid and apolipoprotein risk factors.”

      He also points out that the predictive power of various biomarkers does not necessarily equate to the benefit achieved by reducing them. So epidemiological studies cannot be taken as the final word, and drug therapy that targets the risk factor might still prove more efficacious than would be predicted from epidemiological studies.

      Grundy adds that recommendations for statin use in primary prevention may need to be revisited now anyway, highlighted by the recent meta-analysis from the Oxford group that showed benefits of statins in much lower-risk individuals than those for whom treatment is currently advised. And he suggests that risk assessment may in the future move away from measuring many biomarkers and instead focus on subclinical atherosclerosis with imaging methods or simple risk projection based on age, sex, LDL levels, and perhaps another major risk factor.


      « Previous heartwire article
      Alarming increase in hypertension in US children
      Jun 19, 2012 13:30 EDT Next heartwire article »
      Which drug, when? New anticoagulants force new decisions in AF treatment
      Jun 20, 2012 10:30 EDT

      The Emerging Risk Factors Collaboration. Lipid-related markers and cardiovascular disease prediction. JAMA 2012; 307:2499-2506.
      Grundy S M. Use of emerging lipoprotein risk factors in assessment of cardiovascular risk. JAMA 2012; 307:2540-2542.

      Related links

      Statins benefit those at much lower CV risk
      [Lipid/Metabolic > Lipid/Metabolic; May 16, 2012]
      ApoA size independently associated with MI
      [heartwire > Medscape Medical News; Apr 24, 2012]
      Lp(a) does predict risk in blacks, new ARIC data show
      [Lipid/Metabolic > Lipid/Metabolic; Dec 01, 2011]
      European Atherosclerosis Society recommends screening for Lp(a)
      [Prevention > Prevention; Jun 23, 2010]
      High Lp(a) levels and small ApoA size predict CV risk in dialysis patients
      [Lipid/Metabolic > Lipid/Metabolic; May 03, 2005]

    • jw

      Hasan, comments inline:

      “If you mean that knowledge in the hands of blog readers, well, thats another story and you have to measure the advantage of having more informed patients v. the reality that such knowledge can end up in added expense, anxiety, and possibly treatment if the patient is insistent enough. That takes us back full circle.”

      >> The genie is out of the bottle. It is all out there now. I think that the highly detailed, fundamental foundation approach that Peter is taking here is the perfect compromise between a simplistic and standardized site (like the Mayo site, which is a great place for patients who don’t want to go into this level of detail) and the medical journals, which are far too numerous and full of jargon (the actual concepts aren’t that bad until you get into the organic chemistry, but the studies and stats are no big deal once you develop a decoder ring).

      >> In any case, the uninformed patient is thankfully a thing of the past. If you look at the bright side, this kind of in depth analysis helps to counter the four page statin ads you see everywhere.

      “Don’t get me wrong, I am NOT trying to minimize the significance of MetSyn/IR. In fact, I consider it to be the hallmark of our time. If this series is heading towards “lifestyle change” as an approach to this problem, I am with you. If its headed toward adding even more people to the statin pool who have yet to participate because their LDL was not high enough, I am against you. ”

      >> Besides the fact that this cholesterol series is just the latest topic of hopefully many, many more topics in nutrition, I think the new title of “Eating Academy” and NuSI, the “Nutrition Science Institute”, should provide some clues as to where this is (frustratingly slowly) headed…

    • Hasan Hanachi


      I suspect that Hasan has been influenced by some of the same people I have, such as Dr. Gilbert Welch of Dartmouth and Dr. Nortin Hadler of UNC.” They have written extensively about the harms that can come looking too hard for signs of illness in apparently well people (i.e., screening).”

      Indeed and I would add to that list Dr. David H. Newman. As for the rest, beautifully written (much better than I) and I concur 100%!


      “The overzealous interventions that have caused so much harm with unnecessary colonoscopy, PSA, and mammography are VERY different from what I think you’re suggesting (i.e., unnecessary prescription of a drug to reduce apoB/LDL-P/LDL-C/pick-your-target). This is a night and day difference.”

      There is a difference but not “night and day.” Unecessary testing/treatment of any kind, statin medication included, incurs a variety of costs- monetary, psychological, and time as well as the side effects. These are not trivial by any means as Bill has noted. (This idea that more information is necessarily better is part of the reason why the U.S. is spending 16% of its GDP on medical care as opposed to 8% in Europe).

      “Do you know what the most common presentation of myocardial infarction is in the U.S.? Not chest pain. Not shortness of breath. It’s sudden death. So the single most common presentation of heart disease (this was true 10 years and may not be true today) was death. If you had looked at the person the day before they died, what would you have seen? Would it have been bad enough to justify treating? What about a year before? What about 5 years before? What would have been enough to treat? How high should the calcium score get before a treatment was suggested? When is and LDL particle screaming loud enough to justify treatment? These are not easy questions.

      Indeed they are not easy questions but they won’t be answered without proper research and evaluation which is what I have been asking for here.. Dramatizing the issue doesn’t negate the need for such evidence. I haven’t seen it yet.

      “We shop around like crazy to find the best car mechanic or hair dresser (well, I don’t, but I’m sure some people do). Why are we not applying this same standard to our doctors? Maybe if people had better doctors who understood the nuances of this, fewer patients would have unnecessary colonoscopies, breast biopsies, prostate biopsies, and be prescribed fewer drugs.”

      I am sorrry but this is always the fallback position when evidence doesn’t support a procedure or treatment. To whit, well maybe the research doesn’t support it but in the hands of the annointed who now how to use it, it is miraculously transformed into something wonderful. Ok, if the argument is now that the testing under discussion should be left to the hands of such trusted practioners, have them produce the evidence that what they are doing is working. Otherwise, all we have are testimonials. On that basis I can argue that reading tea leaves or animal entrails are valid in the hands of those who know what they are doing.

      • Hasan, it seems we agree on much more than we disagree on, but you continue to belabor this point. I want to make a few points for clarification (others, not yours).

        You accuse me of “dramatizing the issue,” which perhaps I have, but you close by suggesting that an exceptional doctor with exceptional judgment versus a mediocre doctor with mediocre judgement is akin to someone who is really good at “reading tea leaves of animal entrails” versus someone who is not. Really?

        I say the following not be derogatory, though I realize it will come across as condescending, but if you haven’t done so I suggest spending more time with physicians in training and trying to gain an understanding of why residency — the training period POST 8 years of college and medical school — is anywhere from 3 to 12 years. In residency, and beyond, physicians are not learning new facts. If that were the case, an internist could be replaced by Google or a computer algorithm. Instead they learn judgment. There are great generals and poor generals. There are great surgeons and poor surgeons. There are are great internists and poor internists. The difference isn’t knowledge of military history, “gifted” hands, or encyclopedic knowledge. The difference is judgment. It’s knowing how to incorporate all of the evidence that is knowable and applying it to a situation where the limits of that evidence may be exceeded. I understand your disdain for this. That’s fine. It’s your right to hold everything to that highest standard. Just be mindful of what you’re dong.

        There are no randomized controlled trials showing that cigarette smoking increases the risk of lung cancer. There are no randomized controlled trials showing that jumping out of airplane with a parachute is safer than without a parachute. There are no randomized controlled trials showing that seatbelts save lives. There are no randomized controlled trials demonstrating the off-label efficacy of certain drugs we commonly use. But we use our judgement when we decide whether or not to employ these “treatments.”

        Few people enjoy a discussion of the poor quality of science out there running amok more than I do, but be mindful that you don’t confuse this issues. Some things can never be tested. Some thing haven’t been tested, but can be. It’s good to know the difference. I can think of a hundred “dramatizations” to make this point, but I have a feeling more examples will only serve to ensure I never write another blog post and instead continue in this back-and-forth discussion with you.

        Hasan, you’ve made your point. Anyone who fails to understand it by now is probably unworthy of hearing it. I’d really like to keep working on other blog posts, but I can’t do both (blog and go back-and-forth with you). I’m happy to respectfully disagree with you on this issue and I trust we’ve given the readers more than enough substrate to make up their own minds.

        Lastly, the U.S. is currently spending 17.6% of GDP on healthcare based on the most recent CMS figures and annual healthcare report from McKinsey & Co. I would argue, having studied this problem for 6 years, that it has much less to do with ordering too many screening tests or generating too much information, and much more to do with 3 other factors:

        1) Physician behavior in response to a litigious climate — doctors order head CT scans for an obvious case of caffeine withdrawal to ensure they are never sued, for example;
        2) Americans are culturally very different from Europeans and even Canadians (I’m highly qualified to make this statement since I’ve lived half my life in each Country) — in the U.S. we will nearly always make the choice to operate on 90 year-old-patient with a ruptured AAA, though the probability of that person returning to “normal” is infinitesimally small. Other nations are far more strict about explicitly (e.g., UK) or implicitly (e.g., Canada) applying QALY (Quality-adjusted life years) standards to these decisions. We are not;
        3) When a significant percentage of the population is uninsured, as is the case here, the relationship between payers and providers becomes an elaborate game of cross-subsidization. The heavy subsidization, which varies by payer type, insurance type, and even venue of service, is an embarrassing charade that is actually at the heart of our healthcare spending epidemic.

        Of course, my preferred solution to reducing healthcare spending to less than 10% of GDP by 2025 is just to have less people be sick. But that’s another story called NuSI for another day. Be well, Hasan, and know that I, and surely others, have appreciated your insights and devotion to this discussion.

    • Bill

      Peter, I appreciate your points that 1) statin drugs are not the same as cutting off breasts, irradiating prostates, etc., 2) waiting for CVD to present itself symptomatically can mean you are dead before any chance of treatment, and 3) tests in the hands of a thoughtful, skilled clinician are not the same as tests in the context of a pre-defined standard of care that automatically triggers a cascade of further tests and intervention upon positive findings.

      On the first point, perhaps it’s true that statin drugs are more benign than the interventions that follow other screening tests. But in both cases, if you are screening healthy populations, due to basic Bayesian statistics your test must virtually 100% specific to avoid “treating” dozens, hundreds, or thousands of people unnecessarily to perhaps help one who really needed it. And so far at least screening tests, and medical tests in general, just aren’t anywhere near that specific.

      So unless the follow-on tests and treatments are 100% benign—also certainly not the case for any screening test I’m aware of—inevitably healthy people are unnecessarily harmed by the sequelae of screening. Then we can ask, say, if I’d rather lose my erections or my memory. I enjoy both, so it’s a difficult choice for me. I need to know the risks relative to the benefits. And the track record of screening when big enough studies are done to find out is so poor that I’m skeptical about subjecting myself, or anyone else, to new ones. Would the benefit-risk ratio be better with LDL-P (or other alternative) CVD screening and follow-on statin therapy, etc? Maybe. Maybe not. History is not encouraging, and the Bayesian challenge is enormous, but I must concede it’s possible and I hope it’s true.

      On the second point, this is really the same argument used to justify the other screening tests, e.g. my own primary care doc warns me that if I wait until colon cancer shows itself clinically, the outcome can be extremely grim. But true though this is, it’s not enough information to justify screening me now for the potential illness. I also need to know how effective the screening is at saving the people who are really destined to get sick vs. how harmful it is for the vastly larger pool of people who can’t benefit because they’re not going to get colon cancer anyway—or if they do, at an advanced age when something else was going to get them anyway (Nortin Hadler in particular emphasizes this critical last point: no medical intervention can actually “save a life,” contrary to screening propaganda, since death inevitably comes one per customer; the real issue is how much the quantity and quality of life might be extended). And now we are back to the very poor record of screening in this regard and the need for big, long-term trials to test seemingly common sense ideas like finding and treating catastrophic illnesses early.

      On the third point, I could not agree with you more. I allow my very smart, flexible, holistically-oriented doc, whom I see for a full hour at a time, to perform tests on me that I would certainly refuse in a more conventional medical context. I know that he and I will carefully discuss results and mutually decide further steps, even if outside the standard of care. It’s a big difference.

      However, even here I feel the need to be very careful. For example, when I had hand problems that *could* have been signs of serious early autoimmune illness, I refused rheumatological screening tests from both the conventional doc who insisted I needed them and from my holistic doc, who offered them if I wanted. The “information” I might have gotten seemed more likely to harm me than help me. Here again, the tests have low specificity, so I would risk becoming inappropriately labelled with an awful diagnosis, or the possibility of one, and I would not, at that point, agree to the treatments that a rheumatologist might suggest anyway (e.g., immune suppressing drugs) due to their substantial toxicity and risks. Much better ways to diagnose and treat these illnesses would have to exist, or I would have to be much sicker, for those rheumatological screening tests to make sense to me, even in the hands of my wonderful holistic doc. (Unlike the conventional orthopedist, who refused to even see me again unless I did the rheumatological screening, he found my position reasonable—and it was a good call, as it turned out, since the hand problem now seems to be non-inflammatory, which was the likelihood all along.)

      So I can easily appreciate how the alternative lipid tests might be useful in, say, your hands, even if not as part of yet another mass screening program pushed on the entire population long before evidence to justify it exists. But still we need such evidence to know if those tests will really advantage us, to use Hadler’s formulation. I greatly look forward to seeing your posts on what is known about that when you get to treatment. These are decisions I myself will have to make soon, since I am one of the LCHF people with (calculated) LDL-C high enough to make my primary care doc quite stern.

      And as others have said, many thanks for your herculean efforts here.

      • All very well said, Bill. Thanks for taking the time to comment on this issue. I trust your comments and those of others are as valuable, if not more valuable, than my actual posts.

    • Bill

      Peter and Hasan, thanks for your kind words, and I can say them back to you both with much more validity!

      Peter has made clear—very reasonably—that it’s now time to move on, so all I will say is that to me a lot of the differences in point of view here come down to the question of how to think and what to do about important matters under conditions of uncertainty. This is a very large and to me a very interesting topic, which goes far beyond medicine (climate change is an all too obvious example) and in fact touches every moment of life for all conscious beings. Perhaps there will be opportunities to explore this critical topic along the way.

    • jw

      So, a question that may have been answered previously (this place is going to need a wiki soon, please get on it in your spare time…): The standard statin guidelines are based on studies. Do these studies track weight gain or loss during the study? If one assumes a constant or increasing weight with elevated TC for a guideline, maybe the guidelines make sense in those cases (leaving LCHF out of it for a moment). But wouldn’t elevated TC during weight loss be expected as more lipids are transferred from fat cells to the liver, especially on a LCHF diet? If that makes sense, have these studies been done?

      • Good question, but I don’t know the specific answer off hand.

  • Back to primary prevention of CVD.

    So far LDL-C has been our main target for statin therapy. Do you know of any studies showing that LDL-P or Apo B may be better targets for choosing who to treat? Is TG/HDL-C ratio helpful in this respect? Or should we just look at total risk, and not so much at lipids, when deciding who to treat with statin drugs?


    • Not for primary prevention, Axel. Of all the ratios, in patients with known CVD, it appears LDL-P/HDL-P > TG/HDL-C > TC/HDL-C. But as you know, a ratio is never used as a target of therapy, rather as a marker of risk.

    • LeonRover

      Hi Peter,

      I hope you cover studies which elicit what to do when LDL-P/HDL-P is discordant with TG/HDL-C.


      • I already have. LDL-P/HDL-P is probably better than apoB/apoAI, which is better than TG/HDL-C in most people.

  • Jeff

    Diet and Response of Triglycerides:

    4 cups cooked/eaten cold beans and wheat,barley,lentils.rice,millet mixture
    1 can tuna
    1 cup water fried potatoes
    1 large lettuce salad with vinegar
    1 slice whole wheat bread

    A 1500 calorie – very low fat diet that lasted six months – 70 pound weight loss – male subject(me) 35-6′ 3″ – 270 pounds starting

    A very low fat diet – my Grandma always tried to sneak some oil in when she fried the potatoes I usually kept an eye on her –

    Blood lipid Test near end of this six month diet:

    TC 150
    LDL can’t remember – this was in 1985
    HDL can’t remember

    Triglycerides 30

    The low Triglyceride number is what my Doctor mentioned as perhaps being too Low –

    The point of this post is that a high carb/very low fat diet can produce a very low triglyceride number

    Since the triglycerides where so low – I would assume a low LDL -P (particle number) and HDL -P( particle number)

    The 4 cups of cooked beans/mixture – eaten cold – and the low fat diet is what produced it

    The draw-backs of this diet where: I could smell the bean nitrogen coming out thru the pores of my skin and the cooking of the food produced indigestible food into the lower colon – which produced leg, thigh and buttock acne –

    This was in 1985 – now I have to eat a Raw Vegetable Diet (producing perfectly clear skin) without ant Yeast Contaminated Bread – I eat Low Carb now for other reasons – but at least a Teaspoon of DRY Beans/Mixture And One Teaspoon Fermented Bean/Mixture is i in my everyday Diet –

    The Dry Beans are for Carb Control and the Fermented Beans are used to fix my back issues(which works 100% by the way)-(via possible Vitamin K3 production)

    I also believe Theoretically – that the Bean/Mixtures – lower LDL and HDL Particle Numbers

  • John Dawson

    Listening to the interview with Dr. Dayspring on the June 20, 2012 podcast of The Livin’ La Vida Low-Carb Show with Jimmy Moore. Dr. Dayspring generally recommended a low carb diet to improve LDL(P) throughout the podcast, but at the end, briefly said that a low fat diet may help some people, those who are not insulin resistant, but that is not most people. It seems it would be very important to know whether you are insulin resistant, and if you are not, then low carb may not be the right diet for you? First time I’ve heard this, and would like to learn more.

    • It remains to be seen. I think the point is this, if you have dyslipidemia and you are IR, the likelihood that fixing your IR (via diet) will also correct your dyslipidemia is higher.

  • George G


    Is #7 the final post in this cholesterol series?

    Thank you for your generosity with the information you’re packing into this web site. Quite a boon!

    Kind regards,

  • Pingback: HDL for all ages! | The Fat Nurse()

  • Hi Peter,

    Thanks for a thought-provoking series.

    I’m curious if you plan to cover the role of ox-LDL as a risk factor. I’ve read multiple studies suggesting that it’s an independent predictor of CVD with equal or superior predictive value to any other single marker. However, I havent been able to find a study comparing ox-LDL to LDL-P or apoB:apoA (or either marker individually), or a study investigating ox-LDL that controlled for LDL-P or apoB. Are you (or is anyone else following this thread) aware of such a study?

    Up until very recently, this would have been a moot point because it has been impossible to test for ox-LDL outside of research settings. But there are now at least two labs (Shiel and Doctor’s Data) that are offering this test, and I’m sure more will follow (if there aren’t already more).


    • Chris, see response to your next question.

  • Just found this study:

    Suggests that after adjusting for traditional risk factors and apoB, ox-LDL has no additional predictive value.

    • Ah, the joy of WordPress…I had just typed up a 30 minute response to this very important question and, voila, lost it! I won’t be able to repeat it, but here’s a shorter version of my thoughts.

      First off, great to have you involved in this discussion, Chris. I really love your work and the nuance you bring to it. It’s an honor to use your question as a broader response to a very important theme. Whether we’re discussing ox-LDL or another sophisticated marker, the problem we face is one of population homogeneity (or lack thereof). [For those not interested in ox-LDL (oxidized LDL particles), please read this response, as it addresses an important theme.]

      Most studies try to minimize the degree of heterogeneity somewhat — men vs. women, diabetic vs. non-diabetic, previous MI vs. not, etc. — but ultimately, even within such populations, vast differences (e.g., polymorphisms, apoE genetics) exist. Until we can do a better job of this, I opt for a more “personalized” approach of triangulation. Let me use IR as an example.

      Besides using a euglycemic clamp, which is too impractical outside of a research setting, what is the best way to assess someone’s IR? HOMA-IR? TG/HDL-L? OGTT? LP-IR? I propose there is no one “best” tool. There probably are best tools, if we knew which were most predictive in which sub-population, but a priori we don’t know.

      Instead, through constant clinical interaction, we start to see patterns. For example, LP-IR seems, in most, to precede elevation of HOMA-IR and TG/HDL-C, and elevation of HOMA-IR seems to precede TG/HDL-C.

      Guidelines, both for risk and treatment targets, are often helpful, but they need to be interpreted in the context of the patient. Someone with and LDL-P of 1,500 and normal Lp-PLA2 is probably at lower risk than an age-matched person at 1,200 with an elevated Lp-PLA2, as an example.

  • Thanks for your reply, Peter.

    My current approach *with low risk individuals* (no IR, normal weight, physically active, Paleo/Primal diet) is to begin with TC:HDL, since many studies suggest that is roughly analogous in predictive value to apoB:apoA or LDL-P (especially if triglycerides are in the normal range), and also because these markers are cheap and readily available. If >3.5, I’ll re-test in a couple of weeks because I’m aware that the TC:HDL ratio can vary by as much as 0.8 per measurement without any dietary/lifestyle changes or therapeutic intervention.

    If again elevated, I’ll order the NMR to check LDL-P and apoB:apoA. I also run a few other markers like an iron panel + ferritin (iron overload is correlated with higher ox-LDL levels, and ferritin is an acute-phase reactant that can signal both iron overload and inflammation), CRP and homocysteine (more as a marker for methylation status). If LDL-P and apoB:apoA and the inflammatory markers are normal, that’s where I stop.

    If any of those markers are elevated, my next step is to investigate possible causes of poor LDL receptor function (leptin resistance, thyroid hypofunction, infection/inflammation, genetics), and treat those if present. I will also suggest additional dietary tweaks and some nutritional/botanical supplements to address the inflammation.

    What I’ve been wondering is whether ox-LDL adds anything to step 2 in that process. For example, if a patient has elevated LDL-P, but low ox-LDL, is their risk lower than someone with elevated LDL-P and ox-LDL? Probably, but hard to know how much lower. Likewise, if a patient has normal LDL-P but elevated ox-LDL, what does that say about their risk?

    The study I linked to indicates that ox-LDL is as good at predicting risk as apoB:apoA, but doesn’t add anything to the mix when particle number is controlled for. But that only speaks to risk at the population level, which speaks to your point. ox-LDL may still be a useful marker in the “individual triangulation” process you mentioned.

    Again, great series Peter. I look forward to the remaining articles.

  • Hi Peter,
    I’m not sure if this point got covered and I missed it or maybe it needs to be made more obvious, but, if dietary cholesterol (CE) does NOT have a significant impact on the cholesterol (UC) in our plasma lipids, why then do we see a significant jump in the LDL-Ps or any other lipid markers for that matter in people who go on a LCHF diet? I hope this question makes sense. Thanks, Diana

    • We don’t see this in all folks, but we do see it in some folks. This week’s post will touch on this. Stay tuned.

    • John Dawson

      Hi Diana

      I don’t see that your question has really been addressed yet. Dr. Attia has done a great job of personally validating a dietary approach that works for him, with a highly positive effect on his lipids and other markers. And it apparently works for many others. But some of us don’t see the same effects, in fact, the LCHF diet seems to worsen lipids. Dr. Dayspring referred to this in passing, in one of his commentaries on this site, something to the effect that low carb helps many, but not all people.

      Do you have any theories, conjectures on this?

  • Peter,

    Are you (or is anyone else) aware of a study indicating that apoB/LDL-P adds predictive value when adjusted for *both* trigs and HDL?

    I found one study suggesting apoB:apoA-1 still had value after adjustment for TC:HDL, but although they did measure trigs, as far as I can tell they didn’t adjust for them. http://www.ncbi.nlm.nih.gov/pubmed/18676970

    In the one study I could find that did adjust for both trigs & HDL, apoB & LDL-P didn’t have additional predictive value. http://www.ncbi.nlm.nih.gov/pubmed/17276177


    • I do not believe this study has been done yet. Allan Sniderman, who in my estimation understands this as well as anyone, wrote a wonderful paper on this exact point in 2008. I have it, but it does not appear to be available for free: http://www.ingentaconnect.com/content/fm/flp/2008/00000003/00000003/art00006
      AMORIS and INTERHEART come close, but don’t adjust for both. There is little doubt that *on average* adjusting for HDL-C, non-HDL-C, and TG sufficient. Furthermore, in patients with MS, the rate of discordance is high enough to justify the look at apoB/LDL-P. The question that remains unanswered is what to do with the patient with, say, 0-2 of the 5 MS criteria (who, *on average*, should be fine with just the other test)? Clearly *some* will be discordant, even after adjustment. But how many? What to do about it?

  • Thanks, Peter. Actually the study I linked to did control for both TC:HDL and triglycerides, and found that apoB:apoA-1 lost its additional predictive value.

    It seems to me that, as you pointed out, apoB:apoA is helpful when LDL-C and LDL-P are discordant. According to the Framingham data, that begins to happen as trigs >125.

    So one possible approach in clinical practice would be starting with a basic lipid panel, and then proceeding to NMR if TC:HDL >4 and trigs >125.

    Another possibility would be going ahead with the NMR regardless of trigs, but giving it more weight when trigs >125.

    Thanks for the link to the paper. I have full-text access to many journals, so I may be able to get the PDF. Looking forward to reading it.

    • All great points, Chris. This is tricky stuff.

  • Anne

    I really enjoyed reading your blog Dr Attia BUT I live in the UK where it is impossible to measure the particle sizes of LDL, never mind HDL ! I once asked a doctor, a “lipid specialist” no less, if I could have an LDL particle size test done privately – I was willing to pay for it – and he said no ! So what do people who can’t get particle sizes tested do ? I don’t know one person in the UK who has had this test done !

    • Don’t worry about NMR if it’s not available. ApoB testing is almost as good under most circumstances. That should be readily available.

  • Anne

    Hi Peter – ApoB testing is not available either in the UK…well I just looked at a private laboratory and yes they do the test BUT they require a doctor to request it and that’s what bugs me that I can’t get a doctor to request it for me even though I’m willing to pay.

    Btw, I like your website, been looking through your blogs. I’ve been very low carbing for nearly six years now à la Paleo though I do add some milk to tea and coffee, but that’s the only dairy, I have no grains at all and the only fruit, like you, is berries. I’ve never been overweight but I turned to this way of eating after reading about the general health benefits of Paleo and low carb (I do have atypical Type 2 diabetes but I’m skinnny and not insulin resistant !). I eat tons – lots of meat, fish, eggs and nuts – I notice you don’t eat many veggies, I eat a lot of leafy green ones which I sauté in coconut oil to give me extra fats. My cholesterol profile is pretty good I think…although your post on HDL made me think twice ! My HDL is 3 which is 116 in American, and my triglycerides are only 0.5 or 44 in American – not that my doctor is impressed with my total cholesterol but he knows nothing !

  • James Fox

    Anne NMR testing is available in the UK through: http://www.gdx.net/uk/product/123 This company was recommended by Liposcience:
    Name: Genova Diagnostics UK
    Address: 356 West Barnes Lane
    City: New Maiden Surrey State: UK Zip Code: KT36NB
    Office Phone: (800)522-4762

    • Anne

      Hi James – I know and I know that the Doctors Laboratory in London can now do it BUT those labs all require that a doctor write the request form, a patient cannot self refer. I’ve asked a lipid specialist for a request for these tests, I’ve offered to pay for them knowing that the NHS would not pay for it and he said “no”.

  • anthony

    Dr. Attia:

    I’m new to this incredibly sophisticated yet relatively easy to understand explication of the myriad issues involved. I have a couple questions: first off – have there been studies looking at TG/HDL-C studies and known mortality as a function of the presence of worst case scenario LDL-P/LDL-C concordance/discordance. Perhaps better said: is TG/HDL-C <1 a protective variable irrespective of concordance/discordance in LDL-P/LDL-C values?

    Second, where does one access a lab to have the Health Diagnostic Lab NMR evaluation carried out? There website is notably obscure with respect to that?

    Excellent work to you and all the commenters here, what a pleasure to read this blog 🙂


    • This point is not entirely clear. I think what you’re asking is this: Is elevated TG/HDL-C an independent predictor of risk, even in the presence of elevated LDL-P or apoB. Current data would probably say no, but the patients in which these evaluations are made are on a standard American diet. Hence, it may or may not be true in people on other diets. Only a physician can order the panel of labs through HDL labs. Check with your doctor.

  • Raymund Edwards

    Peter would you comment on this http://www.lipidcenter.com/pdf/Niacin_MOA.pdf a good overview of Niacin.

    esp this

    “With respect to macrophage RCT, it is preferable to have it performed by smaller, unlipidated
    apoA-I or prebeta HDLs. Unlike fibrates niacin does not increase production of apoA-I but rather
    by delaying the catabolism of the large HDL, increases the number of larger, mature alpha HDLs
    (explaining the rise in HDL-C so characteristic of niacin use).

    Arterial wall foam cells are complex
    cells capable of synthesizing multiple proteins involved with HDL remodeling, such as lipoprotein,
    endothelial and hepatic lipase and phospholipid transfer protein. As the niacin-induced large
    mature HDLs (each usually carrying 3-4 apoA-I molecules approach the foam cells they are
    subject to lipolysis and as they reduce in size, apoA-I disassociate. The now unlipidated apoA-I is
    in a perfect position to induce efficient macrophage RCT. Although macrophage RCT would not
    change HDL-C it would increase plaque delipidation ”

    Now Thomas Dayspring suggests–>

    “Only recently was the niacin receptor called HM74A, identified. By the way, no has discovered the natural ligand for HM74A.

    Now here is the main point I find a few papers that suggest the natural ligand is in fact beta-hydroxybutyrate .

    Would this suggest a ketogenic diet would produce the effects on HDL and RCT that Thomas Dayspring is relating to Niacin ( but perhaps only better as it is the natural ligand and in a ketogenic diet associated with other natural factors that go along with higher ketone levels . Glucose /insulin etc )

    “The human ortholog HM74a is also a nicotinic acid receptor and likely has a similar role in anti-lipolysis. Endogenous levels of nicotinic acid are too low to significantly impact receptor activity, hence the natural ligands(s) of HM74a/PUMA-G remain to be elucidated. Here we show that the fatty acid-derived ketone body (D)-beta-hydroxybutyrate ((D)-beta-OHB) specifically activates PUMA-G/HM74a at concentrations observed in serum during fasting. Like nicotinic acid,(D)-beta-OHB inhibits mouse adipocyte lipolysis in a PUMA-G-dependent manner and is thus the first endogenous ligand described for this orphan receptor. These findings suggests a homeostatic mechanism for surviving starvation in which (D)-beta-OHB negatively regulates its own production, thereby preventing ketoacidosis and promoting efficient use of fat stores.

    • Need a specific question, if I’m going to have any hope to addressing.

  • Johnboy_65

    Thank you very much for this blog. I have been mulling over blood test results for years and like many other non-medical/scientific folk have been perplexed and baffled. At last I feel I have some understanding of the subject, and how to manage me cholesterol levels in a way that will be actually beneficial to my health.

    Intuitively it seems to me that people who crash/yo yo diet might be doing great harm to their health, as they might be triggering their liver to up its’ production of cholesterol (during low carb/fat intake), whilst continuing to maintain a poor diet (when/if they relapse). Is this possible?

  • Read Curry

    I read through this material in one (long) sitting and I feel like I finally understand cholesterol. I probably get most of the science as you explain complicated processes and concepts very well. I wish doctors would read this and think about the subject before advising patients. I think most doctors regurgitate the accepted mythology without knowing what they are talking about. I had a family doctor tell me one time to eat a lot of carbs because they were easy on my liver. I now know how wrong he was in giving me and many others that advice.

    Anyway, thank you for the massive effort this took. The subject is fascinating. You should consider writing a textbook.

    • Well, depending on the type of carb and the relative comparison, he may have been right. Rice is easier on the liver than Jack Daniels!

  • Pauleis

    Hi Peter & everyone else:

    If you haven’t done so already, check out this interview of Dr. Dayspring by Jimmy Moore. This discussion is the best I have seen on the “Paleo Lipid” problem (Low carb diet with High TC, LDL-P & LDL-C; but all other CHD & Diabetes risk factors are low)

  • Pauleis
  • Pingback: Il colesterolo, questo sconosciuto — Codice Paleo()

  • Andrew Cobb

    You are amazing and I thank you for your extensive studies and research. I know you have said many times you cannot practice medicine over the internet, and of course it is understandable. I’m sure it is not only me who comes to you with an “emergency” question…but, I have one (or I think I do) a big problem and I feel very, very scared. Very quick and prayimg God you will just in a sentence direct me towards the solution. I have been on a ketogenic diet for a year and a half. I lost 120 pounds. I’m moderately active ( work out 2-3 times a week) I do not drink, smoke or do any drugs. I do not have cheat meals or carb up days. ( Did it for around 5 months and hated it, never did it again) My “numbers” in the lipid panel a year ago ( 3 months into keto ) were “apparently bad”. Cholesterol was 250, HDL 31, Triglycerides 150, LDL 250. I dont have a lipid panel prior to this one in order to compare. my “number” was 5.0 according to the test. Now my numbers are higer than before, and all that it comes to mind it is you saying that we must lower our LDL to avoid arteriosclerosis. My now numbers. Cholesterol 331, HDL 32, Triglycerides 185, LDL 262. My number is 10.3. i was doing during that month a really high fat-extreme low carb diet. For a month I fixed my macros to 75% fat, which worked beautifully against a plateau I had. I am back to regular Keto macros 65 % fat, 30 % protein 5% carbs which is mostly greens and fiber. I wonder whats happening? Am I at risk of anything? Everything else the doctor is impressed with, my health is amazing. I am 21 years old, 220 pounds in a 6’2 frame. Doctor told me that my body fat was lower than 18 %. I track me blood ketones and i am always between 1.8 and 2.5. Not only me, but my fiancee. We ate the same ( just different calorie intake) I consume 2200 calories a day. I am scared even for her, even tho she has not blood test at hand, she will have one in 2 months as we are super scared with my numbers. I increased my intake of nuts and decreased the consuption of nitrate foods. Other than that I feel lost. I take all my supplements as well. I hope in God you can answer a simple “Do this” or “read here” to help me out. I will never take statins, never. I am reading about this topic as much as i can, and i keep seeing the same advice “lower ldl” but it doesnt come from food, so…what can i do? It is not genetic in my family and i am not a diabetic. Well, I think this is it, whatever else I say is redundant. I do thank you beforehand even if you tell me you cannot answer me. Thank you. Andrew Cobb

  • Andrew Cobb

    ****Correction**** I am 31 years old. Also, when I had my last lipid panel done, i was at the end of my high fat month trial ( 75%fat ). Thank you, again. Andrew Cobb

  • PNW

    This looks like an inspiring article and group but . . . for a newbie, there’s much too much to read. Can anyone summarize for me just what I should and shouldn’t eat? . . . or is that way too simplified? If so, any summary would help.
    Thank you ~

    • RoseAnne Mussar

      I recently also discovered this blog and have been going through the whole thing from the beginning for the past few days. My head is buzzing and my eyes are burning. Please allow me to offer up the following observation/advice. Knowledge is power, but acquiring knowledge is never easy. Thinking it is easy is what gets people in trouble. The obvious bumper-sticker answer (to use Dr. Attia’s terminology) is “don’t eat carbs”. But of course that too is too easy. It all depends on what your goals are in terms of health, fitness, weight management, lifestyle etc. Many of these questions only you can answer. But some guidance is nice – I would recommend starting with the “most popular” posts that are listed on the right-hand side of the browser page. I also recommend Gary Taubes’ books, especially “Why We Get Fat”. Also just FYI, I started my low-carb journey one year ago. When I stepped on the scale that cold January day and saw the needle go up to 200, I realized that something had to be done. So I educated myself. I took an admittedly half-assed approach to the whole low carb thing, but lost a painless 15 lbs in one year. I plan on sticking with it, maybe gearing up to three-quarter-assed in 2014. Have faith in yourself, read all you can, and just jump in and do it.

  • Dr Attia;

    As a layman I am trying to grasp the value of the LMR test. I ordered it on my own and I need assistance. I already did the test ratio of TG/HDL 78/55 = 1.3 Sounds good right? Here is LMR report:
    NMR report shows;
    LDL-P = 2108 High
    LDL-C = 171 High
    HDL -C = 55
    TG = 72
    Small LDL-P = 588 High
    TC = 240
    HDL-P Total = 29.2 Low
    LDL size = 21.1
    HDL size = 8.6 Low
    LP – IR Score = 37 Ref less than 45

    So I am confused. Sounds like a horrible LMR. I am below 50Carbs daily and only carb back load for events the next day like Ice hockey game. What are your thoughts?


  • BB

    Hi there,

    I am new to all this and would like to understand more.
    From what I can gather…

    1. Based on your analogy LDL-C = passengers/cargo where as LDL- P= number of ships (to transport the passengers/cargo).
    2. So, based on your discussion, it is the LDL-P that is bad and not necessarily the LDL-C. Thus, the more ships you have, the more “traffic” you have, the higher the likely hood of an accident/crash into an artery wall (irrespective of the amount of passengers/cargo)
    3. But surely the more cargo/passengers (i.e. cholesterol) you have the more need for more ships ie LDL-P? isnt there a correlation then that the more cholesterol content LDL-C translate to the need for more LDL-P? ie the problem?
    4. Also, I fail to understand how HDL reduces LDL?
    5. How else can we/ the body reduce the LDL-P in our bodies?

    • 1. Right
      2. Right
      3. Right, they are correlated but not perfectly. TG need to be carried, too.
      4. It doesn’t
      5. Longer discussion.

    • Maryann

      Hi Peter,

      Jimmy’s book Cholesterol Clarity cites many studies and experts who are militant about the danger of low cholesterol and how it harms our body and causes premature death. Dr. Perlmutter cites the need for abundant cholesterol in the brain to avoid dementia and perform optimally. Some of these studies indicated that people with the highest cholesterol live the longest, healthiest lives; and low cholesterol is especially dangerous in women. Is the goal to have high cholesterol and low particle count? Is that possible?

      Thank you very much,

      • I don’t know. The data suggesting people with the highest cholesterol live longest are misleading. The distribution is closer to bell-shaped — very high and very low both do less well (but for different reasons).

  • Kevin

    Hello Dr. Attia,

    Your presentation -The Straight Dope on Cholesterol- in the Ancestral Health Symposium was outstanding and I can’t thank you enough for your efforts in educating individuals with your nutritional knowledge. In addition, your performance at TED is astounding; we need qualified professionals like you with minds oriented towards critical thinking and that’s what I was shown. I have two questions.

    You claimed in your video it’s not debatable the gonad and the adrenal cortex can’t produce sufficient cholesterol on their own. This means people require some exogenous cholesterol daily. Besides the presentation, is there a way for me to confirm this is true?

    Also, in 2009, the American Dietetic Association makes the position of vegan and vegetarian diets being safe for all age groups and athletes. http://www.ncbi.nlm.nih.gov/m/pubmed/19562864/ A friend and I are attempting to have a better understanding of the organization’s position. What are the implications of meat’s role in the human diet as a result of the organization’s position? Is it a necessity?

    It’ll bring me warm comfort to receive your guidance. Thank you.


    • Your conclusion is not correct. That the adrenal cortex and gonad can’t make endogenous cholesterol does not imply exogenous cholesterol is necessary, it only implies other tissues capable of endogenous production must “subsidize” these tissues. This is a primary role of HDL — to transport cholesterol from one tissue to another. Not sure I understand your second question.

    • Kevin

      Hello Dr. Attia,

      It’s fine if you don’t understand nor answer my second question. I needed at least my first question answered and I think I’m starting to understand the concept a lot better.

      Thank you so much.


  • Linda Iles Martin

    Thank-you very much for all the info in your article, although much of it is over my head, I did read it all with the hope of learning more about cholesterol as I was just advised by my new doctor to start taking Lipitor. I do not want to take a drug and I feel that the simple test given to me must have deeper and more complicated results than the lab investigated. Since I am a healthy, active average-weight women with no other problems, I refuse to believe that my arteries are unhealthy. So I think I will pursue a more investigative test as you suggest, that will measure the LDL-P…if I got it right!

  • OldTech

    I just came across the 2012 paper “The emerging role of HDL in glucose metabolism” published in Nature. It seems to suggests that that HDL is a key element in controlling glucose! It seems to me that if HDL has a significant role in glucose management then it would also have a significant role in treatment. Especially since we know that a low carb diet generally improves HDL levels.

    Have you seen this paper and do you have any comment on it?

    The paper is at http://www.nature.com/nrendo/journal/v8/n4/full/nrendo.2011.235.html.

  • Pingback: Colesterol | No vuelvo a engordar()

  • Pingback: Diet, Cholesterol and Lipoproteins Explained in Human Terms()

  • Pingback: HDL particle size HDL-P | Surviving a heart attack and the NHS()

  • Pingback: Diet, Cholesterol and Lipoproteins Explained in Human Terms | Slim 2B Healthy...()

  • Dániel Fülöp

    Great post, explains a lot about cholesterol. I’m going to have my ApoB checked. Is g/L a good measure for that? What is the optimal range according to your view? There is no lab doing LDL-P over here though…

    I have another question if you could help me out with that. Last time I checked my LDL-C, uric acid and carbamide was quite high (my doc freaked out). I’m in ketosis for 3 months now, ate paleo before, but no insulin or overweight problems. I can’t find out why my uric acid is so high, since I eat practically zero fructose. Since my carbamide is high as well, I was thinking my kidneys are not doing something right. What do you think? Could you direct me towards the right direction? Maybe some relevant studies you heard about? (ketosis / hyperuricemia) thanks a lot

  • Pingback: Why Cholesterol Is Not Bad()

  • geraldine

    I have just come across this very informative blog, and have spent the last three hours reading.
    Thankyou Peter.
    Obviously I have only just touched on all this information, but you have answered one question for me.
    It is not numbers but particle size that we should be concerned with.
    Now you do explain how to evaluate particle size, but maybe i’ve missed something, but is there a particular drug that deals with this issue.
    Do statins do it by default while reducing/increasing numbers?
    Is there a better drug?
    Are patients wise to try the ‘more natural’ red yeast products which seem to have fewer side effects?
    So from what i read we need to have an NMR lipoprofile test and if particle size is not acceptable we then need to take drugs/ diet that rectify this.
    BUT can we do this?
    Is there a definite solution?
    Thanks again
    Much appreciated

    • The benefit of statins are most likely through their ability to reduce apoB/LDL-P in patients by reducing the amount of cholesterol carried by the particles. They do, however, disproportionately lower LDL-C (vs. LDL-P), so the doctor needs to be sure to treat LDL-P, not -C when statins are indicated.

  • jes

    The information is very helpful. I have been struggling with bordeline to high cholesterol numbers. My doctor finally ordered a lipid breakdown. I’ll have plenty of questions to ask my doctor regarding the results but at least I have a greater understanding of the information just reading through the blog. Thank you for sharing your knowledge. I’m going to keep an eye on this blog.

  • Pingback: Why Cholesterol Isn’t Bad – KevMD()

  • Brian Tkatch

    Great series. Thank you!

    Two typos:
    “I’m not going to go into detail about the methodology because it would take 3 more blog posts.,”

    I believe “methodology” should be “method,” unless you meant to explain the study of the methods used.

    There is a comma after the period.

  • Brian

    Dr. Peter Attila, I just found your site and find it incredibly informative. I am 48 and have known about my genetic cholesterol disorder since I was 8 years old. I am the poster child for this disorder in that I appear to be fit and trim and no issues with diabetes or high blood pressure yet I still had a heart attack. I stumbled across this site because I am recovering from quad bypass surgery and have been trying to use my time productively to keep my bypass veins and artery clean and healthy so I don’t find myself in the same situation a few years from now. I have been taking statins for as long as there have been statins, as well I try to watch my diet. Through the years the sponsored heart healthy diet has changed a lot and regretfully I think the heart healthy diet I subscribed to for most of my life did more harm than good. I am trying desperately to find some medication or natural remedies to keep my risks down and appreciate all you are doing to research and provide truth to the mystery of heart disease and atherosclerosis. Please keep up the research – I have been reading about my condition most of my life and it seems the medical community is finally making some progress in defining the “real” cause of atherosclerosis. Your research is especially beneficial and easier than most for someone without a medical degree to benefit from. I continue to take the highest dose Crestor statin and have adopted a mostly whole food, lean meat, low carbohydrate, low sugar, high in antioxidant diet sourced from mostly berries, and I am hoping to see some positive results at my first CTA test post surgery. It has been suggested to me to try some of the injectable cholesterol lowering drugs and wondered if you are familiar with any of them and their effectiveness? Thanks again for your contribution.

  • CuriousBurke

    Dr. Attila, your cholesterol posts have been fascinating and informative. I only wish this information were more common knowledge. Your description of the three parameters (*DL-C, *DL-P, and size) that describe the amount of cholesterol sheds so much light on how poor the standard cholesterol measurement is.

    In part 7, I was wondering: is there a drug that specifically focuses on reducing HDL particle size?


Send this to friend

Facebook icon Twitter icon Instagram icon Pinterest icon Google+ icon YouTube icon LinkedIn icon Contact icon